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<table width="100%" styleCode="Noautorules"><col width="60%" align="left" valign="top"/><col width="40%" align="right" valign="top"/><tbody><tr><td>Contraindications ( <linkHtml href="#S4">4</linkHtml>) </td><td>3/2026</td></tr><tr><td>Warnings and Precautions ( <linkHtml href="#S5.12">5.12</linkHtml>, <linkHtml href="#S5.14">5.14</linkHtml>) </td><td>3/2026</td></tr></tbody></table>

1 INDICATIONS AND USAGE TROKENDI XR is indicated for: Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older ( 1.1 ); adjunctive therapy for the treatment of partial-onset, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome (LGS) in patients 6 years of age and older ( 1.2 ) Preventive treatment of migraine in patients 12 years of age and older ( 1.3 ) 1.1 Monotherapy Epilepsy TROKENDI XR is indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older [see Clinical Studies (14.2) ] . 1.2 Adjunctive Therapy Epilepsy TROKENDI XR is indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older [see Clinical Studies (14.3) ] . 1.3 Migraine TROKENDI XR is indicated for the preventive treatment of migraine in patients 12 years of age and older [see Clinical Studies (14.4) ] .

2 DOSAGE AND ADMINISTRATION TROKENDI XR initial dose, titration, and recommended maintenance dose varies by indication and age group. See Full Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush ( 2.7 ) 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures The recommended dose for TROKENDI XR monotherapy in adults and in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate TROKENDI XR according to the following schedule: Week 1: 50 mg once daily Week 2: 100 mg once daily Week 3: 150 mg once daily Week 4: 200 mg once daily Week 5: 300 mg once daily Week 6: 400 mg once daily Pediatric Patients Ages 6 to 9 Years of Age Dosing in patients 6 to 9 years of age is based on weight. During the titration period, the initial dose of TROKENDI XR is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day in the second week. Dosage can be increased by 25 mg to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5-7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 mg to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (see Table 1 ). Table 1: Monotherapy Target Total Daily Maintenance Dosing for Patients 6 to 9 Years of Age Weight (kg) Total Daily Dose (mg/day) Minimum Maintenance Dose Total Daily Dose (mg/day) Maximum Maintenance Dose Up to 11 150 250 12 - 22 200 300 23 - 31 200 350 32 - 38 250 350 Greater than 38 250 400 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Older) The recommended total daily dose of TROKENDI XR as adjunctive therapy in adults with partial-onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily and with primary generalized tonic-clonic seizures is 400 mg orally once daily. Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures. Pediatric Patients 6 to 16 Years of Age The recommended total daily dose of TROKENDI XR as adjunctive therapy for patients 6 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day.

n a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day. 2.3 Dosing for the Preventive Treatment of Migraine The recommended total daily dose of TROKENDI XR as treatment for the preventive treatment of migraine in patients 12 years of age and older is 100 mg once daily. Titrate TROKENDI XR for the preventive treatment of migraine according to the following schedule: Week 1: 25 mg once daily Week 2: 50 mg once daily Week 3: 75 mg once daily Week 4: 100 mg once daily Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used. 2.4 Administration With Alcohol Alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR administration [see Warnings and Precautions (5.5) ] . 2.5 Dose Modifications in Patients With Renal Impairment In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose of TROKENDI XR is recommended [see Use in Specific Populations (8.5 , 8.6) , Clinical Pharmacology (12.3) ] . 2.6 Dosage Modifications in Patients Undergoing Hemodialysis To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of TROKENDI XR may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . 2.7 Administration Instructions TROKENDI XR can be taken without regard to meals. Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush.

3 DOSAGE FORMS AND STRENGTHS TROKENDI XR extended-release capsules are available in the following strengths and colors: 25 mg: Size 2 capsules, light green opaque body/yellow opaque cap (printed "SPN" on the cap, "25" on the body) 50 mg: Size 0 capsules, light green opaque body/orange opaque cap (printed "SPN" on the cap, "50" on the body) 100 mg: Size 00 capsules, green opaque body/blue opaque cap (printed "SPN" on the cap, "100" on the body) 200 mg: Size 00 capsules, pink opaque body/blue opaque cap (printed "SPN" on the cap, "200" on the body) Extended-release capsules: 25 mg, 50 mg, 100 mg, and 200 mg ( 3 )

4 CONTRAINDICATIONS TROKENDI XR is contraindicated in patients with: recent alcohol use (i.e., within 6 hours prior to and 6 hours after TROKENDI XR use) [see Warnings and Precautions (5.5) ]. a history of hypersensitivity reaction to topiramate, TROKENDI XR, or any of the inactive ingredients of TROKENDI XR. Anaphylaxis and angioedema have occurred [see Warnings and Precautions (5.14) ]. With recent alcohol use, i.e., within 6 hours prior to and 6 hours after TROKENDI XR use ( 4 , 5.5 ) History of hypersensitivity reaction to topiramate. TROKENDI XR, or any of the inactive ingredients of TROKENDI XR ( 4 , 5.14 )

5 WARNINGS AND PRECAUTIONS Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue TROKENDI XR as soon as possible ( 5.1 ) Visual field defects: consider discontinuation of TROKENDI XR ( 5.2 ) Oligohydrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients ( 5.3 ) Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of TROKENDI XR if clinically appropriate ( 5.4 ) Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.6 ) Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur ( 5.7 ) Fetal toxicity: use during pregnancy can cause major congenital malformations, including but not limited to cleft lip and/or palate, and being small for gestational age ( 5.8 ) Withdrawal of AEDs: withdraw TROKENDI XR gradually ( 5.9 ) Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients ( 5.10 ) Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy ( 5.11 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity, serious skin reactions, anaphylaxis, and angioedema: Discontinue TROKENDI XR if an alternative etiology cannot be established ( 5.12 , 5.13 , 5.14 ) Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur ( 5.15 ) Kidney stones: avoid use with other carbonic anhydrase inhibitors, other drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.16 ) Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use ( 5.17 ) 5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of TROKENDI XR as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TROKENDI XR, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate.

ated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with TROKENDI XR, consideration should be given to discontinuing the drug. 5.3 Oligohydrosis and Hyperthermia Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures. The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated with TROKENDI XR should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when TROKENDI XR is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity . 5.4 Metabolic Acidosis TROKENDI XR can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by TROKENDI XR. TROKENDI XR-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of TROKENDI XR. Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was as high as 67% for immediate-release topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and ≥5 mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤2% for placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions (5.10 , 5.16) ] .

g cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions (5.10 , 5.16) ] . A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that immediate-release topiramate decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions (5.10) , Use in Specific Populations (8.4) ]. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 months old pediatrics. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4) ] . TROKENDI XR treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1) ] . Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing TROKENDI XR (using dose tapering). If the decision is made to continue patients on TROKENDI XR in the face of persistent acidosis, alkali treatment should be considered. 5.5 Interaction With Alcohol In vitro data show that, in the presence of alcohol, the pattern of topiramate release from TROKENDI XR capsules is significantly altered. As a result, plasma levels of topiramate with TROKENDI XR may be markedly higher soon after dosing and subtherapeutic later in the day. Therefore, alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR administration . 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including TROKENDI XR for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts, or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing TROKENDI XR or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.7 Cognitive/Neuropsychiatric Adverse Reactions Immediate-release topiramate can cause, and therefore expected to be caused by TROKENDI XR, cognitive/neuropsychiatric adverse reactions. The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue. Adult Patients Cognitive-Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction. In adult adjunctive epilepsy controlled trials, which used rapid titration (100-200 mg/day weekly increments), and target immediate-release topiramate doses of 200 mg-1000 mg/day, 56% of patients in the 800 mg/day and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200-400 mg/day groups and 14% for placebo.

sed rapid titration (100-200 mg/day weekly increments), and target immediate-release topiramate doses of 200 mg-1000 mg/day, 56% of patients in the 800 mg/day and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200-400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase. In the monotherapy epilepsy controlled trial conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day. In the 6-month controlled trials for the preventive treatment of migraine with immediate release topiramate using a slower titration regimen (25 mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day, 22% for 100 mg per day (the recommended dose), 28% for 200 mg per day and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations treated with topiramate [see Warnings and Precautions (5.6) ]. Somnolence/Fatigue Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue was dose-related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both somnolence and fatigue were dose-related and more common in the titration phase. Pediatric Patients In pediatric epilepsy trials (adjunctive and monotherapy) conducted with topiramate, the incidence of cognitive/neuropsychiatric adverse reactions in pediatric patients was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in immediate-release topiramate-treated patients compared to placebo. The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline at the end of the Study 3 [see Clinical Studies (14.4) ].

ometimes persisted for various durations after completion of titration. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline at the end of the Study 3 [see Clinical Studies (14.4) ]. Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency. 5.8 Fetal Toxicity TROKENDI XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations (8.1) ] . Consider the benefits and risks of TROKENDI XR when administering the drug in women of childbearing potential, particularly when TROKENDI XR is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.1) ] . TROKENDI XR should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus [see Use in Specific Populations (8.1) ] . 5.9 Withdrawal of Antiepileptic Drugs In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including TROKENDI XR, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14) ] . In situations where rapid withdrawal of TROKENDI XR is medically required, appropriate monitoring is recommended. 5.10 Decrease in Bone Mineral Density Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations (8.4) ]. Twenty-one percent of immediate-release topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of -0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions (5.4) ]. Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in immediate-release topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium. 5.11 Negative Effects on Growth (Height and Weight) Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on growth (i.e., height and weight) [see Use in Specific Populations (8.4) ].

n increased excretion of urinary calcium. 5.11 Negative Effects on Growth (Height and Weight) Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on growth (i.e., height and weight) [see Use in Specific Populations (8.4) ]. Although continued growth was observed in both treatment groups, the immediate-release topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all immediate-release topiramate age subgroups. Growth (height and weight) of children receiving prolonged TROKENDI XR therapy should be carefully monitored. 5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking topiramate. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. TROKENDI XR should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.13 Serious Skin Reactions Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. TROKENDI XR should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed, and alternative therapy should be considered. Inform patients about the signs of serious skin reactions. 5.14 Anaphylaxis and Angioedema Hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with topiramate in the postmarketing setting. If a hypersensitivity reaction occurs, discontinue TROKENDI XR and initiate appropriate therapy [see Contraindications (4) ] . 5.15 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions (6.2) ] . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions (7.2) ] . Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment.

iously tolerated either drug alone [see Drug Interactions (7.2) ] . Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose. Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial onset epilepsy, and this was not due to a pharmacokinetic interaction. In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate or TROKENDI XR treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. 5.16 Kidney Stones Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1-24 months old with epilepsy, 7% developed kidney or bladder stones. TROKENDI XR would be expected to have the same effect as immediate-release topiramate on the formation of kidney stones. TROKENDI XR is not approved for treatment of epilepsy in pediatric patients less than 6 years old [see Use in Specific Populations (8.4) ] . Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions (5.4) ] . The concomitant use of TROKENDI XR with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in immediate-release topiramate-treated pediatric patients in a one-year active-controlled study [see Use in Specific Populations (8.4) ]. This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. 5.17 Hypothermia With Concomitant Valproic Acid Use Hypothermia, defined as a drop in body core temperature to <35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid (VPA) both in conjunction with and in the absence of hyperammonemia.

of kidney stones and/or nephrocalcinosis. 5.17 Hypothermia With Concomitant Valproic Acid Use Hypothermia, defined as a drop in body core temperature to <35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid (VPA) both in conjunction with and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.2) ] . Consideration should be given to stopping TROKENDI XR or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

<table width="75%" ID="table2"><caption>Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</caption><col width="20%" align="left" valign="top"/><col width="20%" align="left" valign="top"/><col width="20%" align="left" valign="top"/><col width="20%" align="left" valign="top"/><col width="20%" align="left" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Indication</th><th styleCode="Rrule">Placebo Patients with Events per 1,000 Patients</th><th styleCode="Rrule">Drug Patients with Events per 1,000 Patients</th><th styleCode="Rrule">Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients</th><th styleCode="Rrule">Risk Difference: Additional Drug Patients with Events per 1,000 Patients</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epilepsy</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">3.4</td><td styleCode="Rrule">3.5</td><td styleCode="Rrule">2.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Psychiatric</td><td styleCode="Rrule">5.7</td><td styleCode="Rrule">8.5</td><td styleCode="Rrule">1.5</td><td styleCode="Rrule">2.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Other</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">0.9</td></tr><tr><td styleCode="Lrule Rrule">Total</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">4.3</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">1.9</td></tr></tbody></table>

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1) ] Visual Field Defects [see Warnings and Precautions 5.2 ] Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.3) ] Metabolic Acidosis [see Warnings and Precautions (5.4) ] Interaction With Alcohol [see Warnings and Precautions (5.5) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6) ] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.7) ] Fetal Toxicity [see Warnings and Precautions (5.8) ] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.9) ] Decrease of Bone Mineral Density [see Warnings and Precautions (5.10) ] Negative Effects on Growth (Height and Weight) [see Warnings and Precautions (5.11) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions (5.12) ] Serious Skin Reactions [see Warnings and Precautions (5.13) ] Anaphylaxis and Angioedema [see Warnings and Precautions (5.14) ] Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) [see Warnings and Precautions (5.15) ] Kidney Stones [see Warnings and Precautions (5.16) ] Hypothermia With Concomitant Valproic Acid Use [see Warnings and Precautions (5.17) ] The data described in the following sections were obtained using immediate-release topiramate tablets. TROKENDI XR has not been studied in a randomized, placebo-controlled Phase III clinical study; however, it is expected that TROKENDI XR would produce a similar adverse reaction profile as immediate-release topiramate. Epilepsy: Most common (≥10% more frequent than placebo or low-dose topiramate) adverse reactions in adult and pediatric patients were paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever ( 6.1 ). Migraine: Most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain, and upper respiratory tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Supernus Pharmaceuticals, Inc. at 1-866-398-0833 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Monotherapy Epilepsy Adults 16 Years of Age and Older The most common adverse reactions in the controlled trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher (≥10%) than in the 50 mg per day group were: paresthesia, weight loss, and anorexia (see Table 3 ). Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia. Pediatric Patients 6 Years to 15 Years of Age The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (≥10%) than in the 50 mg/day group were fever and weight loss (see Table 3 ). Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (≥2% more frequent than in the 50 mg/day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion. Table 3 represents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day immediate-release topiramate and occurring with greater incidence than 50 mg/day topiramate. Table 3: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trial in Adult and Pediatric Patients Age Group Pediatric (6 to 15 Years) Adult (Age ≥16 Years) Immediate-release Topiramate Daily Dosage Group (mg/day) 50 400 50 400 Body System/ Adverse Reaction (N=74) % (N=77) % (N=160) % (N=159) % Body as a Whole-General Disorders Asthenia 0 3 4 6 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Paresthesia 3 12 21 40 Dizziness 13 14 Ataxia 3 4 Hypoesthesia 4 5 Hypertonia 0 3 Involuntary Muscle contraction 0 3 Vertigo 0 3 Gastro-intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Dry mouth 1 3 Liver and Biliary System Disorders Increase in gamma-GT 1 3 Metabolic and Nutritional Disorders Weight loss 7 17 6 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Anorexia 4 14 Anxiety 4 6 Cognitive problems 1 6 1 4 Confusion 0 3 Depression 0 3 7 9 Difficulty with concentration or attention 7 10 7 8 Difficulty with memory 1 3 6 11 Insomnia 8 9 Decrease in libido 0 3 Mood problems 1 8 2 5 Personality disorder (behavior problems) 0 3 Psychomotor slowing 3 5 Somnolence 10 15 Red Blood Cell Disorders Anemia 1 3 Reproductive Disorders, Female Intermenstrual bleeding 0 3 Vaginal hemorrhage 0 3 Resistance Mechanism Disorders Infection 3 8 2 3 Viral infection 3 6 6 8 Respiratory System Disorders Bronchitis 1 5 3 4 Upper respiratory tract infection 16 18 Rhinitis 5 6 2 4 Sinusitis 1 4 Skin and Appendages Disorders Alopecia 1 4 3 4 Pruritus 1 4 Rash 3 4 1 4 Acne 2 3 Special Senses Other, Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Micturition frequency 0 3 0 2 Renal calculus 0 3 Urinary incontinence 1 3 Vascular (Extracardiac) Disorders Flushing 0 5 Adjunctive Therapy Epilepsy Adults 16 Years of Age and Older In pooled controlled clinical trials in adults with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with immediate-release topiramate at dosages of 200 to 400 mg/day (recommended dosage range), and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to immediate-release topiramate or placebo.

staut syndrome, 183 patients received adjunctive therapy with immediate-release topiramate at dosages of 200 to 400 mg/day (recommended dosage range), and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to immediate-release topiramate or placebo. The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200-400 mg/day topiramate group with an incidence higher (≥10%) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (see Table 4 ) [see Clinical Studies (14.3) ] . Table 4 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day topiramate and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended topiramate dosing (i.e., 600 to 1000 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (200 to 400 mg/day) range. Table 4: Most Common Adverse Reactions in Pooled Placebo- Controlled, Adjunctive Epilepsy Trials in Adults Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. , Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. Body System/ Placebo Topiramate Dosage (mg/day) 200-400 Adverse Reaction (N=291) % (N=183) % Body as a Whole-General Disorders Fatigue 13 15 Asthenia 1 6 Back pain 4 5 Chest pain 3 4 Influenza-like symptoms 2 3 Central & Peripheral Nervous System Disorders Dizziness 15 25 Ataxia 7 16 Speech disorders/Related speech problems 2 13 Paresthesia 4 11 Nystagmus 7 10 Tremor 6 9 Language problems 1 6 Coordination abnormal 2 4 Gait abnormal 1 3 Gastro-Intestinal System Disorders Nausea 8 10 Dyspepsia 6 7 Abdominal pain 4 6 Constipation 2 4 Metabolic and Nutritional Disorders Weight loss 3 9 Psychiatric Disorders Somnolence 12 29 Nervousness 6 16 Psychomotor slowing 2 13 Difficulty with memory 3 12 Confusion 5 11 Anorexia 4 10 Difficulty with concentration/attention 2 6 Mood problems 2 4 Agitation 2 3 Aggressive reaction 2 3 Emotional liability 1 3 Cognitive problems 1 3 Reproductive Disorders, Female Breast pain 2 4 Respiratory System Disorders Rhinitis 6 7 Pharyngitis 2 6 Sinusitis 4 5 Vision Disorders Vision abnormal 2 13 Diplopia 5 10 In controlled clinical trials in adults, 11% of patients receiving immediate-release topiramate 200 to 400 mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg per day. Adverse reactions associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia. Pediatric Patients 2 to 15 Years of Age In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with immediate-release topiramate at dosages of 5 mg to 9 mg/kg/day (recommended dosage range) and 101 patients received placebo.

rials in pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with immediate-release topiramate at dosages of 5 mg to 9 mg/kg/day (recommended dosage range) and 101 patients received placebo. The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg to 9 mg/kg/day immediate-release topiramate group with an incidence higher (≥10%) than in the placebo group were: fatigue and somnolence (see Table 5 ). Table 5 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg to 9 mg/kg/day (recommended dosage range) of immediate-release topiramate and was greater than placebo incidence. Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients 2 to 15 Years of Age Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo , Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category Body System/ Adverse Reaction Placebo (N=101) % Topiramate (N=98) % Body as a Whole-General Disorders Fatigue 5 16 Injury 13 14 Central & Peripheral Nervous System Disorders Gait abnormal 5 8 Ataxia 2 6 Hyperkinesia 4 5 Dizziness 2 4 Speech disorders/Related speech problems 2 4 Gastro-Intestinal System Disorders Nausea 5 6 Saliva increased 4 6 Constipation 4 5 Gastroenteritis 2 3 Metabolic and Nutritional Disorders Weight loss 1 9 Platelet, Bleeding & Clotting Disorders Purpura 4 8 Epistaxis 1 4 Psychiatric Disorders Somnolence 16 26 Anorexia 15 24 Nervousness 7 14 Personality disorder (Behavior problems) 9 11 Difficulty with concentration/attention 2 10 Aggressive reaction 4 9 Insomnia 7 8 Difficulty with memory 0 5 Confusion 3 4 Psychomotor slowing 2 3 Resistance Mechanism Disorders Infection viral 3 7 Respiratory System Disorders Pneumonia 1 5 Skin and Appendages Disorders Skin disorder 2 3 Urinary System Disorders Urinary incontinence 2 4 None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Migraine Adults In the four multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine (which included 35 pediatric patients 12 to 15 years of age), most adverse reactions occurred more frequently during the titration period than during the maintenance period. The most common adverse reactions with immediate-release topiramate 100 mg in the clinical trials for the preventive treatment of migraine of predominantly adults that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 6 ). Table 6 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any immediate-release topiramate group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (100 mg/day).

incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (100 mg/day). Table 6: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults Includes 35 adolescent patients age 12 to 15 years , Values represent the percentage of patients reporting a given reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. , Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for more than 50% of reactions coded as vision abnormal, a preferred term. Topiramate Dosage (mg/day) Body System/ Adverse Reaction Placebo (N=445) % 50 (N=235) % 100 (N=386) % Body as a Whole-General Disorders Fatigue 11 14 15 Injury 7 9 6 Central & Peripheral Nervous System Disorders Paresthesia 6 35 51 Dizziness 10 8 9 Hypoaesthesia 2 6 7 Language problems 2 7 6 Gastro-Intestinal System Disorders Nausea 8 9 13 Diarrhea 4 9 11 Abdominal pain 5 6 6 Dyspepsia 3 4 5 Dry mouth 2 2 3 Gastroenteritis 1 3 3 Metabolic and Nutritional Disorders Weight loss 1 6 9 Musculoskeletal System Disorders Arthralgia 2 7 3 Psychiatric Disorders Anorexia 6 9 15 Somnolence 5 8 7 Difficulty with memory 2 7 7 Insomnia 5 6 7 Difficulty with concentration/attention 2 3 6 Mood problems 2 3 6 Anxiety 3 4 5 Depression 4 3 4 Nervousness 2 4 4 Confusion 2 2 3 Psychomotor slowing 1 3 2 Reproductive Disorders, Female Menstrual disorder 2 3 2 Reproductive Disorders, Male Ejaculation premature 0 3 0 Resistance Mechanism Disorders Viral infection 3 4 4 Respiratory System Disorders Upper respiratory tract infection 12 13 14 Sinusitis 6 10 6 Pharyngitis 4 5 6 Coughing 2 2 4 Bronchitis 2 3 3 Dyspnea 2 1 3 Skin and Appendages Disorders Pruritus 2 4 2 Special Sense Other, Disorders Taste perversion 1 15 8 Urinary System Disorders Urinary tract infection 2 4 2 Vision Disorders Blurred vision 2 4 2 Of the 1135 patients exposed to immediate-release topiramate in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in the immediate-release topiramate-treated patients in these studies included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%). Patients treated in these studies experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, immediate-release topiramate 50 mg, 100 mg, and 200 mg groups, respectively. Pediatric Patients 12 to 17 Years of Age In five randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine, most of the adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period. In four, fixed-dose, double-blind clinical trials for the preventive treatment of migraine in pediatric patients 12 to 17 years of age, the most common adverse reactions with immediate-release topiramate 100 mg that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 7 ).

reventive treatment of migraine in pediatric patients 12 to 17 years of age, the most common adverse reactions with immediate-release topiramate 100 mg that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 7 ). Table 7 shows adverse reactions from the pediatric trial (Study 13 [see Clinical Studies (14.4) ] ) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of immediate-release topiramate, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years of age) were treated with placebo or 50 mg, 100 mg, or 200 mg of immediate-release topiramate [see Clinical Studies (14.4) ]. Table 7 also shows adverse reactions in pediatric patients in controlled migraine trials when the incidence in an immediate-release topiramate dose group was at least 5% or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 7 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose-related and greater at higher than recommended immediate-release topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). Table 7: Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults. Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. Immediate-Release Topiramate Dosage Body System/ Adverse Reaction Placebo (N=45) % 50 mg/day (N=46) % 100 mg/day (N=48) % Body as a Whole – General Disorders Fatigue 7 7 8 Fever 2 4 6 Central & Peripheral Nervous System Disorders Paresthesia 7 20 19 Dizziness 4 4 6 Gastrointestinal System Disorders Abdominal pain 9 7 15 Nausea 4 4 8 Metabolic and Nutritional Disorders Weight loss 2 7 4 Psychiatric Disorders Anorexia 4 9 10 Somnolence 2 2 6 Insomnia 2 9 2 Resistance Mechanism Disorders Infection viral 4 4 8 Respiratory System Disorders Upper respiratory tract infection 11 26 23 Rhinitis 2 7 6 Sinusitis 2 9 4 Coughing 0 7 2 Special Senses Other, Disorders Taste perversion 2 2 6 Vision Disorders Conjunctivitis 4 7 4 In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of immediate-release topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one immediate-release topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%). Increased Risk for Bleeding Topiramate is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse reaction for topiramate than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages.

analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants). Other Adverse Reactions Observed During Clinical Trials Other adverse reactions seen during clinical trials were abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect. Laboratory Test Abnormalities Adult Patients In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride, and ammonia, immediate-release topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions (5.4 , 5.15) ] . Controlled trials of adjunctive topiramate treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate versus 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate versus 1% placebo), and decreased serum potassium (0.4% topiramate versus 0.1% placebo). Pediatric Patients In pediatric patients (1-24 months) receiving adjunctive topiramate for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs. placebo) for the following clinical laboratory analytes: creatinine, blood urea nitrogen (BUN), alkaline phosphatase, and total protein. The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis) and potassium with immediate-release topiramate (vs. placebo) [see Use in Specific Populations (8.4) ] . TROKENDI XR is not indicated for partial-onset seizures in pediatric patients less than 6 years of age. In pediatric patients (ranging from 6-17 years of age) receiving immediate-release topiramate for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs. placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils. The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations (8.4) ]. TROKENDI XR is not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Postmarketing Experience The following adverse reactions have been identified during post-approval use of topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole-General Disorders : immediate hypersensitivity reactions (including anaphylaxis and angioedema [see Warnings and Precautions (5.14) ] ), delayed hypersensitivity reactions (including facial swelling, lip swelling, periorbital swelling, tongue swelling), oligohydrosis and hyperthermia [see Warnings and Precautions (5.3) ] , hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions (5.15) ] , hypothermia with concomitant valproic acid [see Warnings and Precautions 5.17) ] . Gastrointestinal System Disorders : hepatic failure (including fatalities), hepatitis, pancreatitis Skin and Appendage Disorders : bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions (5.13) ] , pemphigus, urticaria Urinary System Disorders : kidney stones, nephrocalcinosis [see Warnings and Precautions (5.16) ] Vision Disorders : acute myopia, secondary angle closure glaucoma [see Warnings and Precautions (5.1) ], maculopathy Hematological Disorders : decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.

<table width="75%" ID="table3"><caption>Table 3: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trial in Adult and Pediatric Patients</caption><col width="44%" align="left" valign="bottom"/><col width="14%" align="center" valign="bottom"/><col width="14%" align="center" valign="bottom"/><col width="14%" align="center" valign="bottom"/><col width="14%" align="center" valign="bottom"/><thead><tr><th/><th colspan="4">Age Group</th></tr><tr><th/><th colspan="2" styleCode="Botrule">Pediatric (6 to 15 Years) </th><th colspan="2" styleCode="Botrule">Adult (Age &#x2265;16 Years) </th></tr><tr><th/><th colspan="4">Immediate-release Topiramate Daily Dosage Group (mg/day)</th></tr><tr><th/><th styleCode="Botrule">50</th><th styleCode="Botrule">400</th><th styleCode="Botrule">50</th><th styleCode="Botrule">400</th></tr><tr><th>Body System/ Adverse Reaction </th><th>(N=74) % </th><th>(N=77) % </th><th>(N=160) % </th><th>(N=159) % </th></tr></thead><tbody><tr><td colspan="5"><content styleCode="bold">Body as a Whole-General Disorders</content></td></tr><tr><td> Asthenia</td><td>0</td><td>3</td><td>4</td><td>6</td></tr><tr><td> Fever</td><td>1</td><td>12</td><td/><td/></tr><tr><td> Leg pain</td><td/><td/><td>2</td><td>3</td></tr><tr><td colspan="5"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></td></tr><tr><td> Paresthesia</td><td>3</td><td>12</td><td>21</td><td>40</td></tr><tr><td> Dizziness</td><td/><td/><td>13</td><td>14</td></tr><tr><td> Ataxia</td><td/><td/><td>3</td><td>4</td></tr><tr><td> Hypoesthesia</td><td/><td/><td>4</td><td>5</td></tr><tr><td> Hypertonia</td><td/><td/><td>0</td><td>3</td></tr><tr><td> Involuntary Muscle contraction</td><td>0</td><td>3</td><td/><td/></tr><tr><td> Vertigo</td><td>0</td><td>3</td><td/><td/></tr><tr><td colspan="5"><content styleCode="bold">Gastro-intestinal System Disorders</content></td></tr><tr><td> Constipation</td><td/><td/><td>1</td><td>4</td></tr><tr><td> Diarrhea</td><td>8</td><td>9</td><td/><td/></tr><tr><td> Gastritis</td><td/><td/><td>0</td><td>3</td></tr><tr><td> Dry mouth</td><td/><td/><td>1</td><td>3</td></tr><tr><td colspan="5"><content styleCode="bold">Liver and Biliary System Disorders</content></td></tr><tr><td> Increase in gamma-GT</td><td/><td/><td>1</td><td>3</td></tr><tr><td colspan="5"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td></tr><tr><td> Weight loss</td><td>7</td><td>17</td><td>6</td><td>17</td></tr><tr><td colspan="5"><content styleCode="bold">Platelet, Bleeding &amp; Clotting Disorders</content></td></tr><tr><td> Epistaxis</td><td>0</td><td>4</td><td/><td/></tr><tr><td colspan="5"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr><td> Anorexia</td><td/><td/><td>4</td><td>14</td></tr><tr><td> Anxiety</td><td/><td/><td>4</td><td>6</td></tr><tr><td> Cognitive problems</td><td>1</td><td>6</td><td>1</td><td>4</td></tr><tr><td> Confusion</td><td>0</td><td>3</td><td/><td/></tr><tr><td> Depression</td><td>0</td><td>3</td><td>7</td><td>9</td></tr><tr><td> Difficulty with concentration or attention</td><td valign="top">7</td><td valign="top">10</td><td valign="top">7</td><td valign="top">8</td></tr><tr><td> Difficulty with memory</td><td>1</td><td>3</td><td>6</td><td>11</td></tr><tr><td> Insomnia</td><td/><td/><td>8</td><td>9</td></tr><tr><td> Decrease in libido</td><td/><td/><td>0</td><td>3</td></tr><tr><td> Mood problems</td><td>1</td><td>8</td>

gn="top">10</td><td valign="top">7</td><td valign="top">8</td></tr><tr><td> Difficulty with memory</td><td>1</td><td>3</td><td>6</td><td>11</td></tr><tr><td> Insomnia</td><td/><td/><td>8</td><td>9</td></tr><tr><td> Decrease in libido</td><td/><td/><td>0</td><td>3</td></tr><tr><td> Mood problems</td><td>1</td><td>8</td> <td>2</td><td>5</td></tr><tr><td> Personality disorder (behavior problems)</td><td valign="top">0</td><td valign="top">3</td><td/><td/></tr><tr><td> Psychomotor slowing</td><td/><td/><td>3</td><td>5</td></tr><tr><td> Somnolence</td><td/><td/><td>10</td><td>15</td></tr><tr><td colspan="5"><content styleCode="bold">Red Blood Cell Disorders</content></td></tr><tr><td> Anemia</td><td>1</td><td>3</td><td/><td/></tr><tr><td colspan="5"><content styleCode="bold">Reproductive Disorders, Female</content></td></tr><tr><td> Intermenstrual bleeding</td><td>0</td><td>3</td><td/><td/></tr><tr><td> Vaginal hemorrhage</td><td/><td/><td>0</td><td>3</td></tr><tr><td colspan="5"><content styleCode="bold">Resistance Mechanism Disorders</content></td></tr><tr><td> Infection</td><td>3</td><td>8</td><td>2</td><td>3</td></tr><tr><td> Viral infection</td><td>3</td><td>6</td><td>6</td><td>8</td></tr><tr><td colspan="5"><content styleCode="bold">Respiratory System Disorders</content></td></tr><tr><td> Bronchitis</td><td>1</td><td>5</td><td>3</td><td>4</td></tr><tr><td> Upper respiratory tract infection</td><td>16</td><td>18</td><td/><td/></tr><tr><td> Rhinitis</td><td>5</td><td>6</td><td>2</td><td>4</td></tr><tr><td> Sinusitis</td><td>1</td><td>4</td><td/><td/></tr><tr><td colspan="5"><content styleCode="bold">Skin and Appendages Disorders</content></td></tr><tr><td> Alopecia</td><td>1</td><td>4</td><td>3</td><td>4</td></tr><tr><td> Pruritus</td><td/><td/><td>1</td><td>4</td></tr><tr><td> Rash</td><td>3</td><td>4</td><td>1</td><td>4</td></tr><tr><td> Acne</td><td/><td/><td>2</td><td>3</td></tr><tr><td colspan="5"><content styleCode="bold">Special Senses Other, Disorders</content></td></tr><tr><td> Taste perversion</td><td/><td/><td>3</td><td>5</td></tr><tr><td colspan="5"><content styleCode="bold">Urinary System Disorders</content></td></tr><tr><td> Cystitis</td><td/><td/><td>1</td><td>3</td></tr><tr><td> Micturition frequency</td><td>0</td><td>3</td><td>0</td><td>2</td></tr><tr><td> Renal calculus</td><td/><td/><td>0</td><td>3</td></tr><tr><td> Urinary incontinence</td><td>1</td><td>3</td><td/><td/></tr><tr><td colspan="5"><content styleCode="bold">Vascular (Extracardiac) Disorders</content></td></tr><tr><td> Flushing</td><td>0</td><td>5</td><td/><td/></tr></tbody></table>

><td>2</td></tr><tr><td> Renal calculus</td><td/><td/><td>0</td><td>3</td></tr><tr><td> Urinary incontinence</td><td>1</td><td>3</td><td/><td/></tr><tr><td colspan="5"><content styleCode="bold">Vascular (Extracardiac) Disorders</content></td></tr><tr><td> Flushing</td><td>0</td><td>5</td><td/><td/></tr></tbody></table> <table width="65%" ID="table4"><caption>Table 4: Most Common Adverse Reactions in Pooled Placebo- Controlled, Adjunctive Epilepsy Trials in Adults <footnote ID="K5204">Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.</footnote>^,<footnote ID="K5208">Values represent the percentage of patients reporting a given reaction.

lacebo- Controlled, Adjunctive Epilepsy Trials in Adults <footnote ID="K5204">Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.</footnote>^,<footnote ID="K5208">Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.</footnote></caption><col width="60%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule" valign="top">Body System/</th><th valign="top">Placebo</th><th styleCode="Rrule" valign="top">Topiramate Dosage (mg/day) 200-400 </th></tr><tr><th styleCode="Lrule" valign="top">Adverse Reaction</th><th valign="top">(N=291) % </th><th styleCode="Rrule" valign="top">(N=183) % </th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Body as a Whole-General Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Fatigue</td><td>13</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Asthenia</td><td>1</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Back pain</td><td>4</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Chest pain</td><td>3</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Influenza-like symptoms</td><td>2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Dizziness</td><td>15</td><td styleCode="Rrule">25</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Ataxia</td><td>7</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Speech disorders/Related speech problems</td><td valign="top">2</td><td styleCode="Rrule" valign="top">13</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Paresthesia</td><td>4</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Nystagmus</td><td>7</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Tremor</td><td>6</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Language problems</td><td>1</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Coordination abnormal</td><td>2</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Gait abnormal</td><td>1</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Gastro-Intestinal System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Nausea</td><td>8</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Dyspepsia</td><td>6</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Abdominal pain</td><td>4</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Constipation</td><td>2</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Weight loss</td><td>3</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Somnolence</td><td>12</td><td sty

</tr><tr styleCode="Botrule"><td styleCode="Lrule">Weight loss</td><td>3</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Somnolence</td><td>12</td><td sty leCode="Rrule">29</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Nervousness</td><td>6</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Psychomotor slowing</td><td>2</td><td styleCode="Rrule">13</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Difficulty with memory</td><td>3</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Confusion</td><td>5</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Anorexia</td><td>4</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Difficulty with concentration/attention</td><td valign="top">2</td><td styleCode="Rrule" valign="top">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Mood problems</td><td>2</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Agitation</td><td>2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Aggressive reaction</td><td>2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Emotional liability</td><td>1</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Cognitive problems</td><td>1</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Reproductive Disorders, Female</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Breast pain</td><td>2</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Rhinitis</td><td>6</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Pharyngitis</td><td>2</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Sinusitis</td><td>4</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Vision Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Vision abnormal</td><td>2</td><td styleCode="Rrule">13</td></tr><tr><td styleCode="Lrule">Diplopia</td><td>5</td><td styleCode="Rrule">10</td></tr></tbody></table>

Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Vision Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Vision abnormal</td><td>2</td><td styleCode="Rrule">13</td></tr><tr><td styleCode="Lrule">Diplopia</td><td>5</td><td styleCode="Rrule">10</td></tr></tbody></table> <table width="65%" ID="table5"><caption>Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients 2 to 15 Years of Age <footnote ID="K5723">Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo</footnote>^,<footnote ID="K5727">Values represent the percentage of patients reporting a given adverse reaction.

Trial in Pediatric Patients 2 to 15 Years of Age <footnote ID="K5723">Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo</footnote>^,<footnote ID="K5727">Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category</footnote></caption><col width="60%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule" valign="top">Body System/ Adverse Reaction </th><th valign="top">Placebo (N=101) % </th><th styleCode="Rrule" valign="top">Topiramate (N=98) % </th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Body as a Whole-General Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Fatigue</td><td>5</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Injury</td><td>13</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Gait abnormal</td><td>5</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Ataxia</td><td>2</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Hyperkinesia</td><td>4</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Dizziness</td><td>2</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Speech disorders/Related speech problems</td><td>2</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Gastro-Intestinal System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Nausea</td><td>5</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Saliva increased</td><td>4</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Constipation</td><td>4</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Gastroenteritis</td><td>2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Weight loss</td><td>1</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Platelet, Bleeding &amp; Clotting Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Purpura</td><td>4</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Epistaxis</td><td>1</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Somnolence</td><td>16</td><td styleCode="Rrule">26</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Anorexia</td><td>15</td><td styleCode="Rrule">24</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Nervousness</td><td>7</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Personality disorder (Behavior problems)</td><td>9</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Difficulty with concentration/attention</td><td>2</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Ag

tr><tr styleCode="Botrule"><td styleCode="Lrule">Personality disorder (Behavior problems)</td><td>9</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Difficulty with concentration/attention</td><td>2</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Ag gressive reaction</td><td>4</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Insomnia</td><td>7</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Difficulty with memory</td><td>0</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Confusion</td><td>3</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Psychomotor slowing</td><td>2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Resistance Mechanism Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Infection viral</td><td>3</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Pneumonia</td><td>1</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Skin and Appendages Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Skin disorder</td><td>2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Urinary System Disorders</content></td></tr><tr><td styleCode="Lrule">Urinary incontinence</td><td>2</td><td styleCode="Rrule">4</td></tr></tbody></table> <table width="75%" ID="table6"><caption>Table 6: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults <footnote ID="K6171">Includes 35 adolescent patients age 12 to 15 years</footnote>^,<footnote ID="K6175">Values represent the percentage of patients reporting a given reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.</footnote>^,<footnote ID="K6179">Blurred vision was the most common term considered as vision abnormal.

es represent the percentage of patients reporting a given reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.</footnote>^,<footnote ID="K6179">Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for more than 50% of reactions coded as vision abnormal, a preferred term.</footnote></caption><col width="55%" align="left" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule"/><th/><th colspan="2" styleCode="Rrule" valign="top">Topiramate Dosage (mg/day) </th></tr><tr><th styleCode="Lrule" valign="top">Body System/ Adverse Reaction </th><th valign="top">Placebo (N=445) % </th><th valign="top">50 (N=235) % </th><th styleCode="Rrule" valign="top">100 (N=386) % </th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Body as a Whole-General Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Fatigue</td><td>11</td><td>14</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Injury</td><td>7</td><td>9</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Paresthesia</td><td>6</td><td>35</td><td styleCode="Rrule">51</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Dizziness</td><td>10</td><td>8</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Hypoaesthesia</td><td>2</td><td>6</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Language problems</td><td>2</td><td>7</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Gastro-Intestinal System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Nausea</td><td>8</td><td>9</td><td styleCode="Rrule">13</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Diarrhea</td><td>4</td><td>9</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Abdominal pain</td><td>5</td><td>6</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Dyspepsia</td><td>3</td><td>4</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Dry mouth</td><td>2</td><td>2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Gastroenteritis</td><td>1</td><td>3</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Weight loss</td><td>1</td><td>6</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Arthralgia</td><td>2</td><td>7</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Anorexia</td><td>6</td><td>9</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Somnolence</td><td>5</td><td>8</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Difficulty with memory</td><td>2</td><td>7</td><

tr styleCode="Botrule"><td styleCode="Lrule">Anorexia</td><td>6</td><td>9</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Somnolence</td><td>5</td><td>8</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Difficulty with memory</td><td>2</td><td>7</td>< td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Insomnia</td><td>5</td><td>6</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Difficulty with concentration/attention</td><td>2</td><td>3</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Mood problems</td><td>2</td><td>3</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Anxiety</td><td>3</td><td>4</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Depression</td><td>4</td><td>3</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Nervousness</td><td>2</td><td>4</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Confusion</td><td>2</td><td>2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Psychomotor slowing</td><td>1</td><td>3</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Reproductive Disorders, Female</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Menstrual disorder</td><td>2</td><td>3</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Reproductive Disorders, Male</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Ejaculation premature</td><td>0</td><td>3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Resistance Mechanism Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Viral infection</td><td>3</td><td>4</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Upper respiratory tract infection</td><td>12</td><td>13</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Sinusitis</td><td>6</td><td>10</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Pharyngitis</td><td>4</td><td>5</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Coughing</td><td>2</td><td>2</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Bronchitis</td><td>2</td><td>3</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Dyspnea</td><td>2</td><td>1</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Skin and Appendages Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Pruritus</td><td>2</td><td>4</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Special Sense Other, Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Taste perversion</td><td>1</td><td>15</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Urinary System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Urinary tract infection</td><td>2</td><td>4</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Vision Disorders</content></t

le"><content styleCode="bold">Urinary System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Urinary tract infection</td><td>2</td><td>4</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Vision Disorders</content></t d></tr><tr><td styleCode="Lrule">Blurred vision</td><td>2</td><td>4</td><td styleCode="Rrule">2</td></tr></tbody></table>

le"><content styleCode="bold">Urinary System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Urinary tract infection</td><td>2</td><td>4</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Vision Disorders</content></t d></tr><tr><td styleCode="Lrule">Blurred vision</td><td>2</td><td>4</td><td styleCode="Rrule">2</td></tr></tbody></table> <table width="75%" ID="table7"><caption>Table 7: Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age <footnote ID="K6855">35 adolescent patients aged 12 to &lt;16 years were also included in adverse reaction assessment for adults.</footnote><footnote ID="K6857">Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events.</footnote></caption><col width="25%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th/><th colspan="2" styleCode="Rrule">Immediate-Release Topiramate Dosage</th></tr><tr><th styleCode="Lrule Rrule" valign="top">Body System/ Adverse Reaction </th><th styleCode="Rrule">Placebo (N=45) % </th><th styleCode="Rrule">50 mg/day (N=46) % </th><th styleCode="Rrule">100 mg/day (N=48) % </th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Body as a Whole &#x2013; General Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">7</td><td styleCode="Rrule">7</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fever</td><td styleCode="Rrule">2</td><td styleCode="Rrule">4</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Paresthesia</td><td styleCode="Rrule">7</td><td styleCode="Rrule">20</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">4</td><td styleCode="Rrule">4</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain</td><td styleCode="Rrule">9</td><td styleCode="Rrule">7</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">4</td><td styleCode="Rrule">4</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Weight loss</td><td styleCode="Rrule">2</td><td styleCode="Rrule">7</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anorexia</td><td styleCode="Rrule">4</td><td styleCode="Rrule">9</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Somnolence</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">2</td><td styleCode="Rrule">9</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Resistance Mechanism Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rru

"><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">2</td><td styleCode="Rrule">9</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Resistance Mechanism Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rru le">Infection viral</td><td styleCode="Rrule">4</td><td styleCode="Rrule">4</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule" valign="top">11</td><td styleCode="Rrule" valign="top">26</td><td styleCode="Rrule" valign="top">23</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rhinitis</td><td styleCode="Rrule">2</td><td styleCode="Rrule">7</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Sinusitis</td><td styleCode="Rrule">2</td><td styleCode="Rrule">9</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Coughing</td><td styleCode="Rrule">0</td><td styleCode="Rrule">7</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Special Senses Other, Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Taste perversion</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Vision Disorders</content></td></tr><tr><td styleCode="Lrule Rrule">Conjunctivitis</td><td styleCode="Rrule">4</td><td styleCode="Rrule">7</td><td styleCode="Rrule">4</td></tr></tbody></table>

7 DRUG INTERACTIONS Contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day ( 7.5 ) Monitor lithium levels if lithium is used with high-dose TROKENDI XR ( 7.8 ) 7.1 Alcohol Alcohol use is contraindicated within 6 hours prior to and 6 hours after TROKENDI XR administration [see Contraindications (4) and Warnings and Precautions (5.5) ]. 7.2 Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed [see Dosage and Administration (2.1) , Clinical Pharmacology (12.3) ]. Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.15 , 5.17) and Clinical Pharmacology (12.3) ] . 7.3 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when TROKENDI XR is given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology (12.3) ]. 7.4 CNS Depressants Concomitant administration of topiramate with other CNS depressant drugs or alcohol has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, TROKENDI XR should be used with extreme caution if used in combination with alcohol and other CNS depressants [see Contraindications (4) and Warnings and Precautions (5.7) ]. 7.5 Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with TROKENDI XR. Patients taking estrogen-containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology (12.3) ] . 7.6 Hydrochlorothiazide (HCTZ) Topiramate C max and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to TROKENDI XR may require a decrease in the TROKENDI XR dose [see Clinical Pharmacology (12.3) ] . 7.7 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when TROKENDI XR is added to pioglitazone therapy or pioglitazone is added to TROKENDI XR therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology (12.3) ] . 7.8 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose TROKENDI XR [see Clinical Pharmacology (12.3) ].

adequate control of their diabetic disease state [see Clinical Pharmacology (12.3) ] . 7.8 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose TROKENDI XR [see Clinical Pharmacology (12.3) ]. 7.9 Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of TROKENDI XR and any adjustments in amitriptyline dose should be made according to the patients' clinical response and not on the basis of plasma levels [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as TROKENDI XR, during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/. Risk Summary TROKENDI XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data ] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data ] . All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor. TROKENDI XR treatment can cause metabolic acidosis [see Warnings and Precautions (5.4) ] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor.

ee Warnings and Precautions (5.4) ] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4) ] . Newborns of mothers treated with TROKENDI XR should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery. Data Human Data Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to reference AEDs (0.3%), or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval=[CI] 5.9-26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED, and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data When topiramate (0, 20, 100, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis.

A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre-and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. 8.2 Lactation Risk Summary Topiramate is excreted in human milk [see Data ]. The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TROKENDI XR and any potential adverse effects on the breastfed infant from TROKENDI XR or from the underlying maternal condition. Data Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma. 8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions (7.5) and Use in Specific Populations (8.1) ] .

Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions (7.5) and Use in Specific Populations (8.1) ] . 8.4 Pediatric Use Seizures in Pediatric Patients 6 Years of Age and Older The safety and effectiveness of TROKENDI XR for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Adverse Reactions (6.1) , Clinical Studies (14.2 , 14.3) ] . The adverse reactions in pediatric patients treated for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome are similar to those seen in adults [see Warnings and Precautions (5) and Adverse Reactions (6) ] . These include, but are not limited to: oligohydrosis and hyperthermia [see Warnings and Precautions (5.3) ] dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.4) ] dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.15) ] Not Recommended for Pediatric Patients Younger than 6 Years of Age The safety and effectiveness of TROKENDI XR for treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients younger than 6 years of age have not been established. Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, TROKENDI XR is recommended only for children age 6 or older. The following pediatric use information for adjunctive treatment for partial onset epilepsy in infants and toddlers (1 to 24 months) is based on studies conducted with immediate-release topiramate, which failed to demonstrate efficacy. Safety and effectiveness of immediate-release topiramate in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%).

severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions (6.1) ]. Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Adverse Reactions (6.1) ] . The significance of these findings is uncertain. Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Adverse Reactions (6.1) ] . There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain. Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.15) ] . Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions (5.4) and Adverse Reactions (6) ] . In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions (5.7) ] . In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known. Other Pediatric Studies Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study [see Adverse Reactions (6.1) ] .

t known. Other Pediatric Studies Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study [see Adverse Reactions (6.1) ] . A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28, 6-15 years of age) versus levetiracetam (N=35, 4-15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 8 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect an immediate-release topiramate-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight). Table 8: Summary of Immediate-release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval) Annual Change in BMD Lumbar Spine (g/cm 2 ) -0.036 (-0.058, -0.014) Annual Change in BMD TBLH TBLH=total body less head (g/cm 2 ) -0.026 (-0.039, -0.012) Annual Change in Height (cm) (4-9 years, Primary Analysis Population for Height) Whereas no patients were randomized to 2-5 year age subgroup for immediate-release topiramate, 5 patients (4-5 years) were randomized to the active control group. -0.84 (-2.67, 0.99) Annual Change in Height (cm) (4-15 years) -0.75 (-2.21, 0.71) Annual Change in Height (cm) (10-15 years) -1.01 (-3.64, 1.61) Height Velocity (cm/year) (4-9 years) -1.00 (-2.76, 0.76) Height Velocity (cm/year) (4-15 years) -0.98 (-2.33, 0.37) Height Velocity (cm/year) (10-15 years) -0.96 (-3.24, 1.32) Annual Change in Weight (kg) -2.05 (-3.66, -0.45) Metabolic acidosis (serum bicarbonate <20 mEq/L) was observed in all immediate-release topiramate-treated patients at some time in the study [see Warnings and Precautions (5.4) ]. Over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate <20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and ≥5mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients.

uggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 mg/day to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies (14.4) ], a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 3 [see Clinical Studies (14.4)] . Efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients 12 to 16 years of age) for 20 weeks. In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release topiramate that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions (6.1) ] . The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions (5.7) ] . Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions (5.4) ] . In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs. placebo treatment for phosphorus and bicarbonate [see Adverse Reactions (6.1) ] . Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse that were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology (12.2) ] . Preventive Treatment of Migraine in Pediatric Patients 6 to 11 Years of Age Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age.

tablished for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. The risk for cognitive adverse reactions was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.7) ] . Juvenile Animal Studies When topiramate (30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5-8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis. 8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2 . Estimate GFR should be measured prior to dosing [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m 2 ) and severe (creatinine clearance less than 30 mL/min/1.73m 2 ) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . 8.7 Patients Undergoing Hemodialysis Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ] .

<table width="75%" ID="table8"><caption>Table 8: Summary of Immediate-release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes</caption><col width="50%" align="left" valign="top"/><col width="15%" align="left" valign="top"/><col width="10%" align="left" valign="top"/><col width="25%" align="left" valign="top"/><thead><tr><th align="center" styleCode="Lrule Rrule">Safety Parameter</th><th colspan="3" align="center" styleCode="Rrule">Treatment Difference in Least Square Means (95 % Confidence Interval)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Annual Change in BMD Lumbar Spine (g/cm ²) </content></td><td/><td><content styleCode="bold">-0.036</content></td><td styleCode="Rrule"><content styleCode="bold">(-0.058, -0.014)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Annual Change in BMD TBLH <footnote ID="K8351">TBLH=total body less head</footnote>(g/cm ²) </content></td><td/><td><content styleCode="bold">-0.026</content></td><td styleCode="Rrule"><content styleCode="bold">(-0.039, -0.012)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Annual Change in Height (cm) (4-9 years, Primary Analysis Population for Height) <footnote ID="K8374">Whereas no patients were randomized to 2-5 year age subgroup for immediate-release topiramate, 5 patients (4-5 years) were randomized to the active control group.</footnote></content></td><td/><td><content styleCode="bold">-0.84</content></td><td styleCode="Rrule"><content styleCode="bold">(-2.67, 0.99)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Annual Change in Height (cm) (4-15 years)</content></td><td/><td><content styleCode="bold">-0.75</content></td><td styleCode="Rrule"><content styleCode="bold">(-2.21, 0.71)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Annual Change in Height (cm) (10-15 years)</content></td><td/><td><content styleCode="bold">-1.01</content></td><td styleCode="Rrule"><content styleCode="bold">(-3.64, 1.61)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Height Velocity (cm/year) (4-9 years)</content></td><td/><td><content styleCode="bold">-1.00</content></td><td styleCode="Rrule"><content styleCode="bold">(-2.76, 0.76)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Height Velocity (cm/year) (4-15 years)</content></td><td/><td><content styleCode="bold">-0.98</content></td><td styleCode="Rrule"><content styleCode="bold">(-2.33, 0.37)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Height Velocity (cm/year) (10-15 years)</content></td><td/><td><content styleCode="bold">-0.96</content></td><td styleCode="Rrule"><content styleCode="bold">(-3.24, 1.32)</content></td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Annual Change in Weight (kg)</content></td><td/><td><content styleCode="bold">-2.05</content></td><td styleCode="Rrule"><content styleCode="bold">(-3.66, -0.45)</content></td></tr></tbody></table>

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as TROKENDI XR, during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/. Risk Summary TROKENDI XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data ] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data ] . All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor. TROKENDI XR treatment can cause metabolic acidosis [see Warnings and Precautions (5.4) ] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4) ] .

ic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4) ] . Newborns of mothers treated with TROKENDI XR should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery. Data Human Data Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to reference AEDs (0.3%), or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval=[CI] 5.9-26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED, and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data When topiramate (0, 20, 100, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day.

on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre-and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD for epilepsy or migraine on a mg/m 2 basis.

8.4 Pediatric Use Seizures in Pediatric Patients 6 Years of Age and Older The safety and effectiveness of TROKENDI XR for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Adverse Reactions (6.1) , Clinical Studies (14.2 , 14.3) ] . The adverse reactions in pediatric patients treated for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome are similar to those seen in adults [see Warnings and Precautions (5) and Adverse Reactions (6) ] . These include, but are not limited to: oligohydrosis and hyperthermia [see Warnings and Precautions (5.3) ] dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.4) ] dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.15) ] Not Recommended for Pediatric Patients Younger than 6 Years of Age The safety and effectiveness of TROKENDI XR for treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients younger than 6 years of age have not been established. Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, TROKENDI XR is recommended only for children age 6 or older. The following pediatric use information for adjunctive treatment for partial onset epilepsy in infants and toddlers (1 to 24 months) is based on studies conducted with immediate-release topiramate, which failed to demonstrate efficacy. Safety and effectiveness of immediate-release topiramate in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%).

tablished for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. The risk for cognitive adverse reactions was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.7) ] . Juvenile Animal Studies When topiramate (30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5-8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis.

8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2 . Estimate GFR should be measured prior to dosing [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] .

10 OVERDOSAGE Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate. Topiramate overdose has resulted in severe metabolic acidosis [see Warnings and Precautions (5.4) ] . A patient who ingested a dose of immediate-release topiramate between 96 g and 110 g was admitted to a hospital with a coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days. Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of TROKENDI XR. In the event of overdose, TROKENDI XR should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.

11 DESCRIPTION Topiramate, USP, is a sulfamate-substituted monosaccharide. TROKENDI XR (topiramate) extended-release capsules are available as 25 mg, 50 mg, 100 mg, and 200 mg capsules for oral administration. Topiramate is a white to off-white powder. Topiramate is freely soluble in polar organic solvents such as acetonitrile and acetone; and very slightly soluble to practically insoluble in non-polar organic solvents such as hexanes. Topiramate has the molecular formula C 12 H 21 NO 8 S and a molecular weight of 339.4. Topiramate is designated chemically as 2,3:4,5-Di- O -isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula: TROKENDI XR (topiramate) is an extended-release capsule. TROKENDI XR capsules contain the following inactive ingredients: Sugar Spheres, NF Hypromellose (Type 2910), USP Mannitol, USP Docusate Sodium, USP Sodium Benzoate, NF Ethylcellulose, NF Oleic Acid, NF Medium Chain Triglycerides, NF Polyethylene Glycol, NF Polyvinyl Alcohol, USP Titanium Dioxide, USP Talc, USP Lecithin, NF Xanthan Gum, NF Glycerin, USP-NF The capsule shells contain gelatin, USP; Titanium Dioxide, USP; and Colorants. The colorants are: FD&C Blue #1 (all strength capsules) Yellow Iron Oxide, USP (25 mg and 50 mg capsules) FD&C Red #3 (50 mg, 100 mg and 200 mg capsules) FD&C Yellow #6 (50 mg, 100 mg and 200 mg capsules) Riboflavin, USP (25 mg capsules) All capsule shells are imprinted with black print that contains shellac, NF, and black iron oxide, NF. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV. 12.2 Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP <90 mm Hg, DBP <50 mm Hg, SBP or DBP increases or decreases ≥20 mm Hg, and pulse increases or decreases ≥30 beats per minute. These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established. 12.3 Pharmacokinetics Absorption and Distribution Linear pharmacokinetics of topiramate from TROKENDI XR were observed following a single oral dose over the range of 50 mg to 200 mg. At 25 mg, the pharmacokinetics of TROKENDI XR is nonlinear possibly due to the binding of topiramate to carbonic anhydrase in red blood cells. The peak plasma concentrations (C max ) of topiramate occurred at approximately 24 hours following a single 200 mg oral dose of TROKENDI XR. At steady-state, the (AUC 0-24 , C max , and C min ) of topiramate from TROKENDI XR administered once-daily and the immediate-release tablet administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for TROKENDI XR administered once-daily was approximately 26% and 42% in healthy subjects and in epileptic patients, respectively, compared to approximately 40% and 51%, respectively, for immediate-release topiramate [see Clinical Pharmacology (12.6) ] . Compared to the fasted state, high-fat meal increased the C max of topiramate by 37% and shortened the T max to approximately 8 hours following a single dose of TROKENDI XR, while having no effect on the AUC. Modeling of the observed single dose fed data with simulation to steady state showed that the effect on C max is significantly reduced following repeat administrations. TROKENDI XR can be taken without regard to meals.

x to approximately 8 hours following a single dose of TROKENDI XR, while having no effect on the AUC. Modeling of the observed single dose fed data with simulation to steady state showed that the effect on C max is significantly reduced following repeat administrations. TROKENDI XR can be taken without regard to meals. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of TROKENDI XR. Specific Populations Renal Impairment The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73m 2 ) [see Dosage and Administration (2.5) ] . Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration (2.6) and Use in Specific Populations (8.7) ] . Hepatic Impairment Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Age, Gender, and Race The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration (2.4) and Use in Specific Populations (8.5) ].

amate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration (2.4) and Use in Specific Populations (8.5) ]. In a study of 13 healthy elderly subjects and 18 healthy young adults who received TROKENDI XR, 30% higher mean C max and 44% higher AUC values were observed in elderly compared to young subjects. Elderly subjects exhibited shorter median T max at 16 hours versus 24 hours in young subjects. The apparent elimination half-life was similar across age groups. As recommended for all patients, dosage adjustment is indicated in elderly patients with a creatinine clearance rate less than 70 mL/min/1.73 m 2 ) [see Dosage and Administration (2.5) and Use in Specific Populations (8.5) ] . Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of immediate-release topiramate were evaluated in patients ages 2 to <16 years of age. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients age 2 years to <16 years of age (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years of age) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Pediatric Patients with Obesity A population PK analysis of topiramate was conducted in 129 children <21 years of age with and without obesity to evaluate the potential impact of obesity on plasma topiramate exposures. Obesity was defined as BMI ≥95 percentile for age and sex based on CDC-recommended BMI-for-age growth charts for males and females. Using the currently recommended dosing regimens, children with obesity are likely to have median values of average concentration at steady-state and trough concentration at steady-state that are up to 20% lower and 19% lower, respectively, compared to children without obesity. Dosage adjustment according to obesity status is not necessary. Drug-Drug Interaction Studies In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that immediate-release topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. The same drug interactions can be expected with the use of TROKENDI XR. Antiepileptic Drugs Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. Interaction of TROKENDI XR and standard AEDs is not expected to differ from the experience with immediate-release topiramate products.

nd standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. Interaction of TROKENDI XR and standard AEDs is not expected to differ from the experience with immediate-release topiramate products. In Table 9, the second column (AED concentration) describes what happens to the concentration of the co-administered AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 9: Summary of AED Interactions with Topiramate AED Coadministered AED Concentration Topiramate Concentration NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate Phenytoin NC or 25% increase =Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide =Is not administered but is an active metabolite of carbamazepine NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400mg per day 13% decrease Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), immediate-release topiramate, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET, and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known [see Drug Interactions (7.5) ] . Digoxin In a single-dose study, serum digoxin AUC decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination [see Drug Interactions (7.6) ]. Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin T max .

ate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin T max . The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate or TROKENDI XR pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known [see Drug Interactions (7.7) ]. Glyburide A drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C max and 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced C max by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions (7.8) ]. Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of immediate-release topiramate [see Drug Interactions (7.9) ]. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses.

of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Diltiazem Co-administration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg/day) resulted in a 10% decrease in C max and 25% decrease in diltiazem AUC, 27% decrease in C max and 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate. 12.6 Relative Bioavailability of TROKENDI XR Compared to Immediate-Release Topiramate Study in Healthy Normal Volunteers TROKENDI XR taken once a day provides steady state plasma levels comparable to immediate-release topiramate taken every 12 hours, when administered at the same total 200-mg daily dose. In a crossover study, 33 healthy subjects were titrated to a 200-mg dose of either TROKENDI XR or immediate-release topiramate and were maintained at 200 mg per day for 10 days. The 90% CI for the ratios of AUC 0-24 , C max and C min , as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose) for multiple time points were within the 80 to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80 to 125% bioequivalence limits, except for the initial time points before 1.5 hours post-dose. Study in Patients with Epilepsy In a study in epilepsy patients treated with immediate-release topiramate alone or in combination with either enzyme-inducing or neutral AEDs who were switched to an equivalent daily dose of TROKENDI XR, there was a 10% decrease in AUC 0-24 , C max , and C min on the first day after the switch in all patients. At steady state, AUC 0-24 and C max were comparable to immediate-release topiramate in all patients. While patients treated with TROKENDI XR alone or in combination with neutral AEDs showed comparable C min at steady state, patients treated with enzyme-inducers showed a 10% decrease in C min . This difference is likely not clinically significant and probably due to the small number of patients on enzyme-inducers.

12.1 Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

12.2 Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP <90 mm Hg, DBP <50 mm Hg, SBP or DBP increases or decreases ≥20 mm Hg, and pulse increases or decreases ≥30 beats per minute. These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established.

12.3 Pharmacokinetics Absorption and Distribution Linear pharmacokinetics of topiramate from TROKENDI XR were observed following a single oral dose over the range of 50 mg to 200 mg. At 25 mg, the pharmacokinetics of TROKENDI XR is nonlinear possibly due to the binding of topiramate to carbonic anhydrase in red blood cells. The peak plasma concentrations (C max ) of topiramate occurred at approximately 24 hours following a single 200 mg oral dose of TROKENDI XR. At steady-state, the (AUC 0-24 , C max , and C min ) of topiramate from TROKENDI XR administered once-daily and the immediate-release tablet administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for TROKENDI XR administered once-daily was approximately 26% and 42% in healthy subjects and in epileptic patients, respectively, compared to approximately 40% and 51%, respectively, for immediate-release topiramate [see Clinical Pharmacology (12.6) ] . Compared to the fasted state, high-fat meal increased the C max of topiramate by 37% and shortened the T max to approximately 8 hours following a single dose of TROKENDI XR, while having no effect on the AUC. Modeling of the observed single dose fed data with simulation to steady state showed that the effect on C max is significantly reduced following repeat administrations. TROKENDI XR can be taken without regard to meals. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of TROKENDI XR. Specific Populations Renal Impairment The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73m 2 ) [see Dosage and Administration (2.5) ] . Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min.

ine clearance greater than 70 mL/min/1.73m 2 ) [see Dosage and Administration (2.5) ] . Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration (2.6) and Use in Specific Populations (8.7) ] . Hepatic Impairment Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Age, Gender, and Race The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration (2.4) and Use in Specific Populations (8.5) ]. In a study of 13 healthy elderly subjects and 18 healthy young adults who received TROKENDI XR, 30% higher mean C max and 44% higher AUC values were observed in elderly compared to young subjects. Elderly subjects exhibited shorter median T max at 16 hours versus 24 hours in young subjects. The apparent elimination half-life was similar across age groups. As recommended for all patients, dosage adjustment is indicated in elderly patients with a creatinine clearance rate less than 70 mL/min/1.73 m 2 ) [see Dosage and Administration (2.5) and Use in Specific Populations (8.5) ] . Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of immediate-release topiramate were evaluated in patients ages 2 to <16 years of age. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients age 2 years to <16 years of age (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years of age) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.

ion for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Pediatric Patients with Obesity A population PK analysis of topiramate was conducted in 129 children <21 years of age with and without obesity to evaluate the potential impact of obesity on plasma topiramate exposures. Obesity was defined as BMI ≥95 percentile for age and sex based on CDC-recommended BMI-for-age growth charts for males and females. Using the currently recommended dosing regimens, children with obesity are likely to have median values of average concentration at steady-state and trough concentration at steady-state that are up to 20% lower and 19% lower, respectively, compared to children without obesity. Dosage adjustment according to obesity status is not necessary. Drug-Drug Interaction Studies In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that immediate-release topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. The same drug interactions can be expected with the use of TROKENDI XR. Antiepileptic Drugs Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. Interaction of TROKENDI XR and standard AEDs is not expected to differ from the experience with immediate-release topiramate products. In Table 9, the second column (AED concentration) describes what happens to the concentration of the co-administered AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 9: Summary of AED Interactions with Topiramate AED Coadministered AED Concentration Topiramate Concentration NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate Phenytoin NC or 25% increase =Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide =Is not administered but is an active metabolite of carbamazepine NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400mg per day 13% decrease Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), immediate-release topiramate, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET, and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known [see Drug Interactions (7.5) ] .

king valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET, and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known [see Drug Interactions (7.5) ] . Digoxin In a single-dose study, serum digoxin AUC decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination [see Drug Interactions (7.6) ]. Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin T max . The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate or TROKENDI XR pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known [see Drug Interactions (7.7) ]. Glyburide A drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C max and 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced C max by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions (7.8) ]. Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females).

ure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions (7.8) ]. Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of immediate-release topiramate [see Drug Interactions (7.9) ]. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Diltiazem Co-administration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg/day) resulted in a 10% decrease in C max and 25% decrease in diltiazem AUC, 27% decrease in C max and 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.

<table width="75%" ID="table9"><caption>Table 9: Summary of AED Interactions with Topiramate</caption><col width="34%" align="left" valign="top"/><col width="33%" align="left" valign="top"/><col width="33%" align="left" valign="top"/><thead><tr><th styleCode="Lrule Rrule">AED Coadministered</th><th styleCode="Rrule">AED Concentration</th><th styleCode="Rrule">Topiramate Concentration</th></tr></thead><tfoot><tr><td align="left" colspan="3" valign="top">NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Phenytoin</td><td styleCode="Rrule">NC or 25% increase <footnote ID="K9286">=Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin</footnote></td><td styleCode="Rrule">48% decrease</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Carbamazepine (CBZ)</td><td styleCode="Rrule">NC</td><td styleCode="Rrule">40% decrease</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">CBZ epoxide <footnote ID="K9307">=Is not administered but is an active metabolite of carbamazepine</footnote></td><td styleCode="Rrule">NC</td><td styleCode="Rrule">NE</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Valproic acid</td><td styleCode="Rrule">11% decrease</td><td styleCode="Rrule">14% decrease</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Phenobarbital</td><td styleCode="Rrule">NC</td><td styleCode="Rrule">NE</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Primidone</td><td styleCode="Rrule">NC</td><td styleCode="Rrule">NE</td></tr><tr><td styleCode="Lrule Rrule">Lamotrigine</td><td styleCode="Rrule">NC at TPM doses up to 400mg per day</td><td styleCode="Rrule">13% decrease</td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis An increase in urinary bladder tumors was observed in mice given topiramate (0, 20, 75, and 300 mg/kg/day) in the diet for 21 months. An increase in the incidence of bladder tumors in males and females receiving 300 mg/kg was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy and approximately 4 times the MRHD for migraine (100 mg) on a mg/m 2 basis. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m 2 basis). Mutagenesis Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo . Impairment of Fertility No adverse effects on male or female fertility were observed in rats administered oral doses of up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2 basis) prior to and during mating and early pregnancy.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis An increase in urinary bladder tumors was observed in mice given topiramate (0, 20, 75, and 300 mg/kg/day) in the diet for 21 months. An increase in the incidence of bladder tumors in males and females receiving 300 mg/kg was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy and approximately 4 times the MRHD for migraine (100 mg) on a mg/m 2 basis. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m 2 basis). Mutagenesis Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo . Impairment of Fertility No adverse effects on male or female fertility were observed in rats administered oral doses of up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2 basis) prior to and during mating and early pregnancy.

14 CLINICAL STUDIES 14.1 Bridging Study to Demonstrate Pharmacokinetic Equivalence between Extended-Release and Immediate-Release Topiramate Formulations The basis for approval of the extended-release formulation (TROKENDI XR) included the studies described below using an immediate-release formulation and the demonstration of the pharmacokinetic equivalence of TROKENDI XR to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see Clinical Pharmacology (12.6) ]. The clinical studies described in the following sections were conducted using immediate-release topiramate. 14.2 Monotherapy Epilepsy Patients With Partial-Onset or Primary Generalized Tonic-Clonic Seizures Adults and Pediatric Patients 10 Years of Age and Older The effectiveness of topiramate as initial monotherapy in adults and pediatric patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1). Study 1 was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg per day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day of topiramate. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty-eight percent of patients achieved the maximal dose of 400 mg/day for >2 weeks, and patients who did not tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use. Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure in Study 1 Figure 1 Pediatric Patients 6 to 9 Years of Age The conclusion that topiramate is effective as initial monotherapy in pediatric patients 6 to 9 years of age with partial-onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach using data from the controlled epilepsy trials conducted with immediate-release topiramate described in labeling. The approach consisted of first showing a similar exposure response relationship between pediatric patients down to 2 years of age and adults when immediate-release topiramate was given as adjunctive therapy [see Use in Specific Populations (8.4) ] . Similarity of exposure-response was demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy.

atric patients down to 2 years of age and adults when immediate-release topiramate was given as adjunctive therapy [see Use in Specific Populations (8.4) ] . Similarity of exposure-response was demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy. Specific dosing in pediatric patients 6 to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with immediate-release topiramate initial monotherapy [see Dosage and Administration (2.1) ] . 14.3 Adjunctive Therapy Epilepsy Adult Patients With Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for adults with partial-onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures. Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a pre-specified minimum number of partial-onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 10. Pediatric Patients 6 to 16 Years of Age With Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for pediatric patients 6 to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures. Patients in Study 8 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225 or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

e was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225 or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period. Patients With Primary Generalized Tonic-Clonic Seizures The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 6 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo (see Table 11 ). Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225 or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period. Patients With Lennox-Gastaut Syndrome The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10), comparing a single dosage of topiramate with placebo (see Table 11 ). Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity. Table 10: Immediate Release Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults With Partial-Onset Seizures Dose-response studies were not conducted for other indications or pediatric partial-onset seizures Target Topiramate Dosage (mg per day) Study Stabilization Dose Placebo Placebo dosages are given as the number of tablets.

h of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults With Partial-Onset Seizures Dose-response studies were not conducted for other indications or pediatric partial-onset seizures Target Topiramate Dosage (mg per day) Study Stabilization Dose Placebo Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day) 200 400 600 800 1,000 2 N 42 42 40 41 -- -- Mean Dose 5.9 200 390 556 -- -- Median Dose 6.0 200 400 600 -- -- 3 N 44 -- -- 40 45 40 Mean Dose 9.7 -- -- 544 739 796 Median Dose 10.0 -- -- 600 800 1,000 4 N 23 -- 19 -- -- -- Mean Dose 3.8 -- 395 -- -- -- Median Dose 4.0 -- 400 -- -- -- 5 N 30 -- -- 28 -- -- Mean Dose 5.7 -- -- 522 -- -- Median Dose 6.0 -- -- 600 -- -- 6 N 28 -- -- -- 25 -- Mean Dose 8.0 -- -- -- 568 -- Median Dose 8.0 -- -- -- 600 -- 7 N 90 157 -- -- -- -- Mean Dose 8 200 -- -- -- -- Median Dose 8 200 -- -- -- -- In all adjunctive topiramate trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 11. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial. Table 11: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials Target Topiramate Dosage (mg per day) Study # # Placebo 200 400 600 800 1,000 ≈6mg/kg/day For Studies 8 and 9, specified target dosages (<9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6mg/kg per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day Comparisons with placebo: Partial Onset Seizures Studies in Adults 2 N 45 45 45 46 -- -- -- Median % Reduction 12 27 p=0.080; 48 p≤0.010; 45 p≤0.001; -- -- -- % Responders 18 24 44 p≤0.050; 46 -- -- -- 3 N 47 -- -- 48 48 47 -- Median % Reduction 2 -- -- 41 41 36 % Responders 9 -- -- 40 41 36 4 N 24 -- 23 -- -- -- -- Median % Reduction 1 -- 41 p=0.065; -- -- -- -- % Responders 8 -- 35 -- -- -- -- 5 N 30 -- -- 30 -- -- -- Median % Reduction -12 -- -- 46 p≤0.005; -- -- -- % Responders 10 -- -- 47 -- -- -- 6 N 28 -- -- -- 28 -- -- Median % Reduction -21 -- -- -- 24 -- -- % Responders 0 -- -- -- 43 -- -- 7 N 91 168 -- -- -- -- -- Median % Reduction 20 44 -- -- -- -- -- % Responders 24 45 Partial Onset Seizures Studies in Pediatric Patients Studies included pediatric patients 2 years of age and older, an age group for which TROKENDI XR is not indicated [see Indications and Usage (1.2) and Use in Specific Populations (8.4)] 8 N 45 -- -- -- -- -- 41 Median % Reduction 11 -- -- -- -- -- 33 % Responders 20 -- -- -- -- -- 39 Primary Generalized Tonic-Clonic Median % reduction and % responders are reported for PGTC seizures; , 9 N 40 -- -- -- -- -- 39 Median % Reduction 9 -- -- -- -- -- 57 % Responders 20 -- -- -- -- -- 56 Lennox-Gastaut Syndrome Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures , 10 N 49 -- -- -- -- -- 46 Median % Reduction -5 -- -- -- -- -- 15 % Responders 14 28 p=0.071; Improvement in Seizure Severity Percentage of subjects who were minimally, much, or very much improved from baseline. 28 52 Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.

8 p=0.071; Improvement in Seizure Severity Percentage of subjects who were minimally, much, or very much improved from baseline. 28 52 Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 mg per day to 100 mg per day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated. 14.4 Preventive Treatment of Migraine Adult Patients The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted in US (Study 11) or the US and Canada (Study 12) established the effectiveness of immediate-release topiramate in the preventive treatment of migraine. The design of both trials was identical, enrolling patients with a history of migraine with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventative medications before starting the baseline phase. Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, 200 mg/day (twice the recommended daily dosage for migraine prophylaxis) or placebo, and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period.). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate (according to migraines classified by IHS criteria) from the baseline phase to double-blind treatment period in each immediate-release topiramate treatment group compared to placebo in the Intent-To-Treat (ITT) population. In Study 11, a total of 469 patients (416 females, 53 males) ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of topiramate 50, 100 and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the immediate-release topiramate 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 2 ). The treatment differences between the immediate release topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p <0.001 for both comparisons). In Study 12, a total of 468 patients (406 females, 62 males) ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of immediate-release topiramate 50, 100, and 200 mg/day, respectively.

ge from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of immediate-release topiramate 50, 100, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the immediate-release topiramate 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 2 ). The differences between the immediate-release topiramate 100 and 200 mg per day groups versus placebo were similar and statistically significant (p=0.008 and p<0.001, respectively). In both studies there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race. For patients withdrawing from immediate-release topiramate, daily dosages were decreased in weekly intervals by 25 to 50 mg/day. Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents) Figure 2 Pediatric Patients 12 to 17 Years of Age The effectiveness of immediate-release topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial (Study 13). The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]). Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and ≤14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12 week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Approximately 80% or more patients in each treatment group completed the study. The median average daily dosages were 45 and 79 mg/day in the target dose groups of immediate-release topiramate 50 and 100 mg/day, respectively. Effectiveness of treatment was assessed by comparing each immediate-release topiramate treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint). The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 12. The 100 mg immediate-release topiramate dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate. The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12 of adults) was 3.0 for 100 mg immediate-release topiramate dose and 1.7 for placebo.

migraine attack rate. The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12 of adults) was 3.0 for 100 mg immediate-release topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p=0.0087). Table 12: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set) Category Placebo (N=33) Immediate-Release Topiramate 50 mg/day (N=35) Immediate-Release Topiramate 100 mg/day (N=35) Baseline Median 3.6 4.0 4.0 Last 12 Weeks of Double-Blind Phase Median 2.3 2.3 1.0 Percent Reduction (%) Median 44.4 44.6 72.2 P-value versus Placebo P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject's stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate. , P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure. 0.7975 0.0164 Indicates p-value is <0.05 (two-sided).

<table width="65%" ID="table10"><caption>Table 10: Immediate Release Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults With Partial-Onset Seizures <footnote ID="K10182">Dose-response studies were not conducted for other indications or pediatric partial-onset seizures</footnote></caption><col width="10%" align="center" valign="middle"/><col width="25%" align="left" valign="middle"/><col width="15%" align="right" valign="middle"/><col width="10%" align="right" valign="middle"/><col width="10%" align="right" valign="middle"/><col width="10%" align="right" valign="middle"/><col width="10%" align="right" valign="middle"/><col width="10%" align="right" valign="middle"/><thead><tr styleCode="Botrule"><th align="center" colspan="8" styleCode="Lrule Rrule">Target Topiramate Dosage (mg per day)</th></tr><tr><th styleCode="Lrule Rrule">Study</th><th align="center" styleCode="Rrule">Stabilization Dose</th><th align="center" styleCode="Rrule">Placebo <footnote ID="K10236">Placebo dosages are given as the number of tablets.

h align="center" colspan="8" styleCode="Lrule Rrule">Target Topiramate Dosage (mg per day)</th></tr><tr><th styleCode="Lrule Rrule">Study</th><th align="center" styleCode="Rrule">Stabilization Dose</th><th align="center" styleCode="Rrule">Placebo <footnote ID="K10236">Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day)</footnote></th><th align="center" styleCode="Rrule">200</th><th align="center" styleCode="Rrule">400</th><th align="center" styleCode="Rrule">600</th><th align="center" styleCode="Rrule">800</th><th align="center" styleCode="Rrule">1,000</th></tr></thead><tbody><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">2</td><td styleCode="Rrule">N</td><td styleCode="Rrule">42</td><td styleCode="Rrule">42</td><td styleCode="Rrule">40</td><td styleCode="Rrule">41</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Mean Dose</td><td align="right" styleCode="Rrule">5.9</td><td styleCode="Rrule">200</td><td styleCode="Rrule">390</td><td styleCode="Rrule">556</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Rrule">Median Dose</td><td align="right" styleCode="Rrule">6.0</td><td styleCode="Rrule">200</td><td styleCode="Rrule">400</td><td styleCode="Rrule">600</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">3</td><td styleCode="Rrule">N</td><td styleCode="Rrule">44</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">40</td><td styleCode="Rrule">45</td><td styleCode="Rrule">40</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Mean Dose</td><td align="right" styleCode="Rrule">9.7</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">544</td><td styleCode="Rrule">739</td><td styleCode="Rrule">796</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median Dose</td><td align="right" styleCode="Rrule">10.0</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">600</td><td styleCode="Rrule">800</td><td styleCode="Rrule">1,000</td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">4</td><td styleCode="Rrule">N</td><td align="right" styleCode="Rrule">23</td><td styleCode="Rrule">--</td><td styleCode="Rrule">19</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Mean Dose</td><td align="right" styleCode="Rrule">3.8</td><td styleCode="Rrule">--</td><td styleCode="Rrule">395</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median Dose</td><td align="right" styleCode="Rrule">4.0</td><td styleCode="Rrule">--</td><td styleCode="Rrule">400</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">5</td><td styleCode="Rrule">N</td><td align="right" styleCode="Rrule">30</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">28</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Mean Dose</td><td align="right" styleCode="Rrule">5.7</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">522</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode

r><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Mean Dose</td><td align="right" styleCode="Rrule">5.7</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">522</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode ="Rrule">Median Dose</td><td align="right" styleCode="Rrule">6.0</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">600</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">6</td><td styleCode="Rrule">N</td><td align="right" styleCode="Rrule">28</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">25</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Mean Dose</td><td align="right" styleCode="Rrule">8.0</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">568</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median Dose</td><td align="right" styleCode="Rrule">8.0</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">600</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">7</td><td styleCode="Rrule">N</td><td align="right" styleCode="Rrule">90</td><td align="right" styleCode="Rrule">157</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Mean Dose</td><td align="right" styleCode="Rrule">8</td><td align="right" styleCode="Rrule">200</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr><td align="left" styleCode="Rrule">Median Dose</td><td align="right" styleCode="Rrule">8</td><td align="right" styleCode="Rrule">200</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr></tbody></table>

>--</td><td styleCode="Rrule">--</td></tr><tr><td align="left" styleCode="Rrule">Median Dose</td><td align="right" styleCode="Rrule">8</td><td align="right" styleCode="Rrule">200</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr></tbody></table> <table width="75%" ID="table11"><caption>Table 11: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials</caption><col width="7%" align="center" valign="middle"/><col width="24%" align="left" valign="middle"/><col width="11%" align="right" valign="middle"/><col width="9%" align="right" valign="middle"/><col width="8%" align="right" valign="middle"/><col width="9%" align="right" valign="middle"/><col width="8%" align="right" valign="middle"/><col width="9%" align="right" valign="middle"/><col width="15%" align="right" valign="middle"/><thead><tr styleCode="Botrule"><th align="center" colspan="9" styleCode="Lrule Rrule">Target Topiramate Dosage (mg per day)</th></tr><tr><th styleCode="Lrule Rrule" valign="top">Study #</th><th align="center" styleCode="Rrule" valign="top">#</th><th align="center" styleCode="Rrule" valign="top">Placebo</th><th align="center" styleCode="Rrule" valign="top">200</th><th align="center" styleCode="Rrule" valign="top">400</th><th align="center" styleCode="Rrule" valign="top">600</th><th align="center" styleCode="Rrule" valign="top">800</th><th align="center" styleCode="Rrule" valign="top">1,000</th><th align="center" styleCode="Rrule" valign="top">&#x2248;6mg/kg/day <footnote ID="K10823">For Studies 8 and 9, specified target dosages (&lt;9.3 mg/kg/day) were assigned based on subject&apos;s weight to approximate a dosage of 6mg/kg per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day</footnote></th></tr></thead><tfoot><tr><td align="left" colspan="9" valign="top">Comparisons with placebo:</td></tr></tfoot><tbody><tr styleCode="Botrule"><td align="left" colspan="9" styleCode="Lrule Rrule"><content styleCode="bold">Partial Onset Seizures Studies in Adults</content></td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">2</td><td styleCode="Rrule">N</td><td styleCode="Rrule">45</td><td styleCode="Rrule">45</td><td styleCode="Rrule">45</td><td styleCode="Rrule">46</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median % Reduction</td><td align="right" styleCode="Rrule">12</td><td styleCode="Rrule">27 <footnote ID="foot2">p=0.080;</footnote></td><td styleCode="Rrule">48 <footnote ID="foot3">p&#x2264;0.010;</footnote></td><td styleCode="Rrule">45 <footnote ID="foot4">p&#x2264;0.001;</footnote></td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">% Responders</td><td align="right" styleCode="Rrule">18</td><td styleCode="Rrule">24</td><td styleCode="Rrule">44 <footnote ID="foot5">p&#x2264;0.050;</footnote></td><td styleCode="Rrule">46 <footnoteRef IDREF="foot5"/></td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">3</td><td styleCode="Rrule">N</td><td styleCode="Rrule">47</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">48</td><td styleCode="Rrule">48</td><td styleCode="Rrule">47</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median % Reduction</td><td align="right" styleCode="Rrule">2</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">41 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">41 <footnoteRef IDREF="foo

d styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median % Reduction</td><td align="right" styleCode="Rrule">2</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">41 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">41 <footnoteRef IDREF="foo t4"/></td><td styleCode="Rrule">36 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">% Responders</td><td align="right" styleCode="Rrule">9</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">40 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">41 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">36 <footnoteRef IDREF="foot5"/></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">4</td><td styleCode="Rrule">N</td><td styleCode="Rrule">24</td><td styleCode="Rrule">--</td><td styleCode="Rrule">23</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median % Reduction</td><td align="right" styleCode="Rrule">1</td><td styleCode="Rrule">--</td><td styleCode="Rrule">41 <footnote ID="foot6">p=0.065;</footnote></td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">% Responders</td><td align="right" styleCode="Rrule">8</td><td styleCode="Rrule">--</td><td styleCode="Rrule">35 <footnoteRef IDREF="foot5"/></td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">5</td><td styleCode="Rrule">N</td><td styleCode="Rrule">30</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">30</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median % Reduction</td><td align="right" styleCode="Rrule">-12</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">46 <footnote ID="foot7">p&#x2264;0.005;</footnote></td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">% Responders</td><td align="right" styleCode="Rrule">10</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">47 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">6</td><td styleCode="Rrule">N</td><td styleCode="Rrule">28</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">28</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median % Reduction</td><td align="right" styleCode="Rrule">-21</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">24 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">% Responders</td><td align="right" styleCode="Rrule">0</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">43 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">7</td><td styleCode="Rrule">N</td>

"Rrule">0</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">43 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">7</td><td styleCode="Rrule">N</td> <td styleCode="Rrule">91</td><td styleCode="Rrule">168</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median % Reduction</td><td align="right" styleCode="Rrule">20</td><td styleCode="Rrule">44 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">% Responders</td><td align="right" styleCode="Rrule">24</td><td styleCode="Rrule">45 <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td align="left" colspan="9" styleCode="Lrule Rrule"><content styleCode="bold">Partial Onset Seizures Studies in Pediatric Patients</content><footnote ID="foot8">Studies included pediatric patients 2 years of age and older, an age group for which TROKENDI XR is not indicated [see Indications and Usage (1.2) and Use in Specific Populations (8.4)]</footnote></td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">8</td><td styleCode="Rrule">N</td><td align="right" styleCode="Rrule">45</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">41</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median % Reduction</td><td align="right" styleCode="Rrule">11</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">33 <footnoteRef IDREF="foot5"/></td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">% Responders</td><td align="right" styleCode="Rrule">20</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">39</td></tr><tr styleCode="Botrule"><td align="left" colspan="9" styleCode="Lrule Rrule"><content styleCode="bold">Primary Generalized Tonic-Clonic <footnote ID="foot9">Median % reduction and % responders are reported for PGTC seizures;</footnote>^,<footnoteRef IDREF="foot8"/></content></td></tr><tr styleCode="Botrule"><td rowspan="3" styleCode="Lrule Rrule">9</td><td styleCode="Rrule">N</td><td styleCode="Rrule">40</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">39</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median % Reduction</td><td align="right" styleCode="Rrule">9</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">57 <footnoteRef IDREF="foot5"/></td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">% Responders</td><td align="right" styleCode="Rrule">20</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">56 <footnoteRef IDREF="foot4"/></td></tr><tr styleCode="Botrule"><td align="left" colspan="9" style

onders</td><td align="right" styleCode="Rrule">20</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">56 <footnoteRef IDREF="foot4"/></td></tr><tr styleCode="Botrule"><td align="left" colspan="9" style Code="Lrule Rrule"><content styleCode="bold">Lennox-Gastaut Syndrome <footnote ID="foot10">Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures</footnote>^,<footnoteRef IDREF="foot8"/></content></td></tr><tr styleCode="Botrule"><td rowspan="4" styleCode="Lrule Rrule">10</td><td styleCode="Rrule">N</td><td styleCode="Rrule">49</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">46</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">Median % Reduction</td><td align="right" styleCode="Rrule">-5</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">--</td><td styleCode="Rrule">15 <footnoteRef IDREF="foot5"/></td></tr><tr styleCode="Botrule"><td align="left" styleCode="Rrule">% Responders</td><td align="right" styleCode="Rrule">14</td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule">28 <footnote ID="foot11">p=0.071;</footnote></td></tr><tr><td align="left" styleCode="Rrule" valign="top">Improvement in Seizure Severity <footnote ID="foot12">Percentage of subjects who were minimally, much, or very much improved from baseline.</footnote></td><td align="right" styleCode="Rrule" valign="top">28</td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule" valign="top">52 <footnoteRef IDREF="foot5"/></td></tr></tbody></table> <table width="100%" ID="fig2" styleCode="Noautorules"><col width="100%" align="center" valign="top"/><tbody><tr><td><content styleCode="bold">Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents)</content></td></tr><tr><td><renderMultiMedia referencedObject="MM3"/></td></tr></tbody></table>

="fig2" styleCode="Noautorules"><col width="100%" align="center" valign="top"/><tbody><tr><td><content styleCode="bold">Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents)</content></td></tr><tr><td><renderMultiMedia referencedObject="MM3"/></td></tr></tbody></table> <table width="75%" ID="table12"><caption>Table 12: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set)</caption><col width="25%" align="left" valign="top"/><col width="25%" align="left" valign="top"/><col width="25%" align="left" valign="top"/><col width="25%" align="left" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Category</th><th styleCode="Rrule">Placebo (N=33) </th><th styleCode="Rrule">Immediate-Release Topiramate 50 mg/day (N=35) </th><th styleCode="Rrule">Immediate-Release Topiramate 100 mg/day (N=35) </th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Baseline</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Median</td><td styleCode="Rrule">3.6</td><td styleCode="Rrule">4.0</td><td styleCode="Rrule">4.0</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Last 12 Weeks of Double-Blind Phase</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Median</td><td styleCode="Rrule">2.3</td><td styleCode="Rrule">2.3</td><td styleCode="Rrule">1.0</td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Percent Reduction (%)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Median</td><td styleCode="Rrule">44.4</td><td styleCode="Rrule">44.6</td><td styleCode="Rrule">72.2</td></tr><tr><td styleCode="Lrule Rrule">P-value versus Placebo <footnote ID="K11966">P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject&apos;s stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate.</footnote>^,<footnote ID="K11970">P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure.</footnote></td><td styleCode="Rrule"/><td styleCode="Rrule">0.7975</td><td styleCode="Rrule">0.0164 <footnote ID="K11980">Indicates p-value is &lt;0.05 (two-sided).</footnote></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied TROKENDI XR (topiramate) extended-release capsules are available in the following strengths and colors: 25 mg (light green opaque body/yellow opaque cap with black print "SPN" and "25"): bottles of 7-count (NDC-17772-101-70), 30-count (NDC-17772-101-30) and 100-count (NDC-17772-101-01) blister packages of 30-count (NDC-17772-101-15) 50 mg (light green opaque body/orange opaque cap with black print "SPN" and "50"): bottles of 7-count (NDC-17772-102-70), 30-count (NDC-17772-102-30) and 100-count (NDC-17772-102-01) blister packages of 30-count (NDC-17772-102-15) 100 mg (green opaque body/blue opaque cap with black print "SPN" and "100"): bottles of 7-count (NDC-17772-103-70), 30-count (NDC-17772-103-30) and 100-count (NDC-17772-103-01) blister packages of 30-count (NDC-17772-103-15) 200 mg (pink opaque body/blue opaque cap with black print "SPN" and "200"): bottles of 7-count (NDC-17772-104-70), 30-count (NDC-17772-104-30) and 100-count (NDC-17772-104-01) blister packages of 30-count (NDC-17772-104-15) 16.2 Storage and Handling TROKENDI XR (topiramate) extended-release capsules should be stored in well closed containers at controlled room temperature [25°C (77°F); excursions 15°C-30°C (59°F-86°F)]. Protect from moisture and light.

16.2 Storage and Handling TROKENDI XR (topiramate) extended-release capsules should be stored in well closed containers at controlled room temperature [25°C (77°F); excursions 15°C-30°C (59°F-86°F)]. Protect from moisture and light.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration Instructions Counsel patients to swallow TROKENDI XR capsules whole and intact. TROKENDI XR should not be sprinkled on food, chewed, or crushed [see Dosage and Administration (2.7)] . Consumption of Alcohol Advise patients to completely avoid consumption of alcohol at least 6 hours prior to and 6 hours after taking TROKENDI XR [see Warnings and Precautions (5.5) ] . Eye Disorders Advise patients taking TROKENDI XR to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain [see Warnings and Precautions (5.1 , 5.2) ] . Oligohydrosis and Hyperthermia Counsel patients that TROKENDI XR, especially pediatric patients, can cause decreased sweating and increased body temperature, especially in hot weather, and they should seek medical attention if this is noticed [see Warnings and Precautions (5.3) ] . Metabolic Acidosis Inform patients about the potentially significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus [see Warnings and Precautions (5.4) ] . Suicidal Behavior and Ideation Counsel patients, their caregivers, and families that AEDs, including TROKENDI XR, may increase the risk of suicidal thoughts and behavior and they should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers [see Warnings and Precautions (5.6) ]. Interference With Cognitive and Motor Performance Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects and advise them not to drive or operate machinery until they have gained sufficient experience on TROKENDI XR to gauge whether it adversely affects their mental performance, motor performance, and/or vision [see Warnings and Precautions (5.7) ] . Advise patients that even when taking TROKENDI XR or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, counsel all patients taking TROKENDI XR for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Physicians should discuss the appropriate level of caution with their patients, before patients with epilepsy engage in such activities. Fetal Toxicity Counsel pregnant women and women of childbearing potential that use of TROKENDI XR during pregnancy can cause fetal harm. TROKENDI increases the risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be SGA [see Use in Specific Populations (8.1) ] .

he risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be SGA [see Use in Specific Populations (8.1) ] . There may also be risks to the fetus from chronic metabolic acidosis with use of TROKENDI XR during pregnancy [see Warnings and Precautions (5.4 , 5.8) ]. When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing or progestin-only contraceptives with topiramate [see Warnings and Precautions (5.8) and Drug Interactions (7.5) ] . Encourage pregnant women using TROKENDI XR to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1) ] . Decrease in Bone Mineral Density Inform the patient or caregiver that long-term treatment with TROKENDI XR can decrease bone formation and increase bone resorption in children [see Warnings and Precautions (5.10) ]. Negative Effects on Growth (Height and Weight) Discuss with the patient or caregiver that long-term TROKENDI XR treatment may attenuate growth as reflected by slower height increase and weight gain in pediatric patients [see Warnings and Precautions (5.11) ]. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related. Advise patients to report such reactions to a healthcare provider immediately [see Warnings and Precautions (5.12) ] . Serious Skin Reactions Inform patients about the signs of serious skin reactions. Instruct patients to immediately inform their healthcare provider at the first appearance of skin rash [see Warnings and Precautions (5.13) ] . Anaphylaxis and Angioedema Inform patients about the signs and symptoms of hypersensitivity reactions such as anaphylaxis and angioedema, which can occur with TROKENDI XR. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.14) ] . Hyperammonemia and Encephalopathy Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Patients should be instructed to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see Warnings and Precautions (5.15) ] . Kidney Stones Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation [see Warnings and Precautions (5.16) ] . Hypothermia Counsel patients that TROKENDI XR can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature.

risk of kidney stone formation [see Warnings and Precautions (5.16) ] . Hypothermia Counsel patients that TROKENDI XR can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction [see Warnings and Precautions (5.17) ] .

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 3/2026 MEDICATION GUIDE TROKENDI XR ® (tro-KEN-dee eks ahr) (topiramate) Extended-Release Capsules What is the most important information I should know about Trokendi XR? Take Trokendi XR capsules whole. Do not sprinkle Trokendi XR on food, or break, crush, dissolve, or chew Trokendi XR capsules before swallowing. If you cannot swallow Trokendi XR capsules whole, tell your healthcare provider. You may need a different medicine. Do not drink alcohol within 6 hours prior to and 6 hours after Trokendi XR administration. Trokendi XR may cause eye problems. Serious eye problems include: any sudden decrease in vision with or without eye pain and redness, a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma). These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms, including any new problems with your vision. Trokendi XR may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. If a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away. Trokendi XR can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will: feel tired not feel hungry (loss of appetite) feel changes in heartbeat have trouble thinking clearly Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with Trokendi XR. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis. Like other antiepileptic drugs, Trokendi XR may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Do not stop Trokendi XR without first talking to a healthcare provider. Stopping Trokendi XR suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Trokendi XR can harm your unborn baby.

d actions? Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Trokendi XR can harm your unborn baby. If you take Trokendi XR during pregnancy, your baby has a higher risk for birth defects including cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant. Birth defects may happen even in children born to women who are not taking any medicines and do not have other risk factors. There may be other medicines to treat your condition that have a lower chance of birth defects. All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of Trokendi XR. If the decision is made to use Trokendi XR, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your doctor about the best kind of birth control to use while you are taking Trokendi XR. Tell your healthcare provider right away if you become pregnant while taking Trokendi XR. You and your healthcare provider should decide if you will continue to take Trokendi XR while you are pregnant. If you take Trokendi XR during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. Talk to your healthcare provider if you have questions about this risk during pregnancy. Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if Trokendi XR has caused metabolic acidosis during your pregnancy. Pregnancy Registry: If you become pregnant while taking Trokendi XR, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of Trokendi XR and other antiepileptic drugs during pregnancy. Trokendi XR may decrease the density of bones when used over a long period. Trokendi XR may slow height increase and weight gain in children and adolescents when used over a long period. What is Trokendi XR? Trokendi XR is a prescription medicine used: to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic seizures) in people 6 years and older, with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 6 years and older to prevent migraine headaches in adults and adolescents 12 years of age and older. Who should not take Trokendi XR? Do not take Trokendi XR if you are allergic to topiramate, Trokendi XR, or any of the ingredients in Trokendi XR. See end of this Medication Guide for a complete list of ingredients in Trokendi XR. Before taking Trokendi XR, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems, or suicidal thoughts or behavior have kidney problems, kidney stones, or are getting kidney dialysis have a history of metabolic acidosis (too much acid in the blood) have liver problems have weak, brittle or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density) have lung or breathing problems have eye problems, especially glaucoma have diarrhea have a growth problem are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet are having surgery are pregnant or plan to become pregnant are breastfeeding. Trokendi XR passes into your breast milk.

density) have lung or breathing problems have eye problems, especially glaucoma have diarrhea have a growth problem are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet are having surgery are pregnant or plan to become pregnant are breastfeeding. Trokendi XR passes into your breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the Trokendi XR that passes into breast milk can cause other serious harm to your baby. Talk to your healthcare provider about the best way to feed your baby if you take Trokendi XR. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially, tell your healthcare provider if you take: Valproic acid (such as DEPAKOTE). any medicines that impair or decrease your thinking, concentration, or muscle coordination. birth control that contains hormones (such as pills, implants, patches, or injections). Trokendi XR may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you are using birth control and Trokendi XR. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider. How should I take Trokendi XR? Take Trokendi XR exactly as prescribed. Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider. Take Trokendi XR capsules whole. Do not sprinkle Trokendi XR on food, or break, crush, dissolve, or chew Trokendi XR capsules before swallowing. Trokendi XR can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking Trokendi XR. If you take too much Trokendi XR, call your healthcare provider right away or go to the nearest emergency room. Talk to your health care provider on what you should do if you miss a dose. Do not stop taking Trokendi XR without talking to your healthcare provider. Stopping Trokendi XR suddenly may cause serious problems. If you have epilepsy and you stop taking Trokendi XR suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking Trokendi XR slowly. Your healthcare provider may do blood tests while you take Trokendi XR. What should I avoid while taking Trokendi XR? Do not drink alcohol within 6 hours before or 6 hours after taking Trokendi XR capsules. Trokendi XR and alcohol can cause serious side effects such as severe sleepiness and dizziness and an increase in seizures. Do not drive a car or operate heavy machinery until you know how Trokendi XR affects you. Trokendi XR can slow your thinking and motor skills and may affect vision. What are the possible side effects of Trokendi XR? Trokendi XR may cause serious side effects, including: See " What is the most important information I should know about Trokendi XR? " Effects on thinking and alertness. Trokendi XR may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. Trokendi XR may cause depression or mood problems, tiredness, and sleepiness. Dizziness or loss of muscle coordination. Severe multiorgan reactions. Treatment with Trokendi XR may cause a serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death, particularly if it is not treated as early as possible.

ere multiorgan reactions. Treatment with Trokendi XR may cause a serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death, particularly if it is not treated as early as possible. Contact your healthcare provider or get medical help right away if you have: blistering and peeling of your skin or skin rash fever or swollen glands that do not go away hives swelling of your face, eyes, lips, tongue, or throat sores in your mouth trouble swallowing or breathing dark urine yellowing of the skin or whites of the eyes Serious skin reactions. Trokendi XR may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). Trokendi XR may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters. Allergic reactions. Serious allergic reactions can happen after you take Trokendi XR. Get emergency help right away if you have swelling of the face, lips, eyes, tongue, or throat, or trouble swallowing or breathing. High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when Trokendi XR is taken with a medicine called valproic acid (DEPAKOTE). Call your healthcare provider right away if you develop unexplained tiredness, vomiting, slowing of your thinking or reaction time, or changes in your mental activities. Kidney stones. Drink plenty of fluids when taking Trokendi XR to decrease your chances of getting kidney stones. Low body temperature. Taking Trokendi XR when you are also taking valproic acid can cause a drop in body temperature to less than 95°F, feeling tired, confusion, or coma. Call your healthcare provider right away if you have any of the symptoms above. The most common side effects of Trokendi XR include: tingling of the arms and legs (paresthesia) not feeling hungry nausea weight loss abnormal vision a change in the way foods taste nervousness speech problems dizziness slow reactions upper respiratory tract infection fever tiredness sleepiness/drowsiness difficulty with memory diarrhea pain in abdomen decreased feeling or sensitivity, especially on the skin Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of Trokendi XR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Supernus Pharmaceuticals, Inc. at 1-866-398-0833. How should I store Trokendi XR? Store Trokendi XR capsules at room temperature between 59°F to 86°F (15°C to 30°C). Keep Trokendi XR in a tightly closed container. Keep Trokendi XR dry and away from moisture and light. Keep Trokendi XR and all medicines out of the reach of children. General information about the safe and effective use of Trokendi XR. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Trokendi XR for a condition for which it was not prescribed. Do not give Trokendi XR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Trokendi XR that is written for health professionals. What are the ingredients in Trokendi XR?

condition for which it was not prescribed. Do not give Trokendi XR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Trokendi XR that is written for health professionals. What are the ingredients in Trokendi XR? Active ingredient: topiramate Inactive ingredients: Sugar spheres, NF; hypromellose (Type 2910), USP; mannitol, USP; docusate sodium, USP; sodium benzoate, NF; ethylcellulose, NF; oleic acid, NF; medium chain triglycerides, NF; polyethylene glycol, NF; polyvinyl alcohol, USP; titanium dioxide, USP; talc, USP; lecithin, NF; xanthan gum, NF; glycerin, USP-NF. Capsule shells: Gelatin, USP; titanium dioxide, USP; colorants. Colorants: FD&C blue #1 (all strength capsules) Yellow iron oxide, USP (25 mg and 50 mg capsules) FD&C red #3 (50 mg, 100 mg, and 200 mg capsules) FD&C yellow #6 (50 mg, 100 mg, and 200 mg capsules) Riboflavin, USP (25 mg capsules) All capsule shells are imprinted with black print that contains shellac, NF, and black iron oxide, NF. Manufactured by: Catalent Pharma Solutions, Winchester, KY USA 40391 Manufactured for: Supernus Pharmaceuticals, Inc., Rockville, MD USA 20850 TROKENDI XR is a registered trademark of Supernus Pharmaceuticals, Inc. © 2026 Supernus Pharmaceuticals, Inc. All rights reserved. RA-TRO-MGV13 For more information, go to www.trokendixr.com or call 1-866-398-0833.

<table width="100%"><col width="3%" align="left" valign="top"/><col width="30%" align="left" valign="top"/><col width="30%" align="left" valign="top"/><col width="30%" align="left" valign="top"/><col width="7%" align="right" valign="top"/><tfoot><tr><td align="left" colspan="3" valign="top">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td colspan="2" align="right" valign="top">Revised: 3/2026</td></tr></tfoot><tbody><tr styleCode="Botrule"><td align="center" colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">MEDICATION GUIDE</content> TROKENDI XR ^&#xAE;(tro-KEN-dee eks ahr) (topiramate) Extended-Release Capsules </td></tr><tr><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">What is the most important information I should know about Trokendi XR?</content> <content styleCode="bold">Take Trokendi XR capsules whole. Do not</content>sprinkle Trokendi XR on food, or break, crush, dissolve, or chew Trokendi XR capsules before swallowing. If you cannot swallow Trokendi XR capsules whole, tell your healthcare provider. You may need a different medicine. Do not drink alcohol within 6 hours prior to and 6 hours after Trokendi XR administration. <content styleCode="bold">Trokendi XR may cause eye problems.</content>Serious eye problems include: <list listType="unordered" styleCode="Disc"><item>any sudden decrease in vision with or without eye pain and redness,</item><item>a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma).</item><item>These eye problems can lead to permanent loss of vision if not treated.</item><item>You should call your healthcare provider right away if you have any new eye symptoms, including any new problems with your vision.</item></list><content styleCode="bold">Trokendi XR may cause decreased sweating and increased body temperature (fever).</content>People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. If a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away. <content styleCode="bold">Trokendi XR can increase the level of acid in your blood (metabolic acidosis).</content>If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will: <list listType="unordered" styleCode="Disc"><item>feel tired</item><item>not feel hungry (loss of appetite)</item><item>feel changes in heartbeat</item><item>have trouble thinking clearly</item></list>Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with Trokendi XR. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis. <content styleCode="bold">Like other antiepileptic drugs, Trokendi XR may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

od before and during your treatment with Trokendi XR. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis. <content styleCode="bold">Like other antiepileptic drugs, Trokendi XR may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: </content></td></tr><tr><td styleCode="Lrule"/><td><list listType="unordered" styleCode="Disc"><item>thoughts about suicide or dying</item><item>attempts to commit suicide</item><item>new or worse depression</item><item>new or worse anxiety</item><item>feeling agitated or restless</item><item>panic attacks</item></list></td><td><list listType="unordered" styleCode="Disc"><item>trouble sleeping (insomnia)</item><item>new or worse irritability</item><item>acting aggressive, being angry, or violent</item><item>acting on dangerous impulses</item><item>an extreme increase in activity and talking (mania)</item><item>other unusual changes in behavior or mood</item></list></td><td colspan="2" styleCode="Rrule"/></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Do not stop Trokendi XR without first talking to a healthcare provider.</content><list listType="unordered" styleCode="Disc"><item>Stopping Trokendi XR suddenly can cause serious problems.</item><item>Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.</item></list><content styleCode="bold">How can I watch for early symptoms of suicidal thoughts and actions?</content><list listType="unordered" styleCode="Disc"><item>Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.</item><item>Keep all follow-up visits with your healthcare provider as scheduled.</item><item>Call your healthcare provider between visits as needed, especially if you are worried about symptoms.</item></list><content styleCode="bold">Trokendi XR can harm your unborn baby.</content><list listType="unordered" styleCode="Disc"><item>If you take Trokendi XR during pregnancy, your baby has a higher risk for birth defects including cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant.</item><item>Birth defects may happen even in children born to women who are not taking any medicines and do not have other risk factors.</item><item>There may be other medicines to treat your condition that have a lower chance of birth defects.</item><item>All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of Trokendi XR. If the decision is made to use Trokendi XR, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your doctor about the best kind of birth control to use while you are taking Trokendi XR.</item><item>Tell your healthcare provider right away if you become pregnant while taking Trokendi XR. You and your healthcare provider should decide if you will continue to take Trokendi XR while you are pregnant.</item><item>If you take Trokendi XR during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. Talk to your healthcare provider if you have questions about this risk during pregnancy.</item><item>Metabolic acidosis may have harmful effects on your baby.

are pregnant.</item><item>If you take Trokendi XR during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. Talk to your healthcare provider if you have questions about this risk during pregnancy.</item><item>Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if Trokendi XR has caused metabolic acidosis during your pregnancy.</item><item>Pregnancy Registry: If you become pregnant while taking Trokendi XR, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of Trokendi XR and other antiepileptic drugs during pregnancy.</item></list><content styleCode="bold">Trokendi XR may decrease the density of bones when used over a long period. Trokendi XR may slow height increase and weight gain in children and adolescents when used over a long period. </content></td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">What is Trokendi XR?</content> Trokendi XR is a prescription medicine used: <list listType="unordered" styleCode="Disc"><item>to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic seizures) in people 6 years and older,</item><item>with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 6 years and older</item><item>to prevent migraine headaches in adults and adolescents 12 years of age and older.</item></list></td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Who should not take Trokendi XR?</content> Do not take Trokendi XR if you are allergic to topiramate, Trokendi XR, or any of the ingredients in Trokendi XR. See end of this Medication Guide for a complete list of ingredients in Trokendi XR. </td></tr><tr><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Before taking Trokendi XR, tell your healthcare provider about all of your medical conditions, including if you:</content><list listType="unordered" styleCode="Disc"><item>have or have had depression, mood problems, or suicidal thoughts or behavior</item><item>have kidney problems, kidney stones, or are getting kidney dialysis</item><item>have a history of metabolic acidosis (too much acid in the blood)</item><item>have liver problems</item><item>have weak, brittle or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density)</item><item>have lung or breathing problems</item><item>have eye problems, especially glaucoma</item><item>have diarrhea</item><item>have a growth problem</item><item>are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet</item><item>are having surgery</item><item>are pregnant or plan to become pregnant</item><item>are breastfeeding. Trokendi XR passes into your breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the Trokendi XR that passes into breast milk can cause other serious harm to your baby. Talk to your healthcare provider about the best way to feed your baby if you take Trokendi XR.</item></list></td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule">Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

ealthcare provider about the best way to feed your baby if you take Trokendi XR.</item></list></td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule">Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially, tell your healthcare provider if you take: <list listType="unordered" styleCode="Disc"><item>Valproic acid (such as DEPAKOTE).</item><item>any medicines that impair or decrease your thinking, concentration, or muscle coordination.</item><item>birth control that contains hormones (such as pills, implants, patches, or injections). Trokendi XR may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you are using birth control and Trokendi XR.</item></list>Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider. </td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">How should I take Trokendi XR?</content><list listType="unordered" styleCode="Disc"><item>Take Trokendi XR exactly as prescribed.</item><item>Your healthcare provider may change your dose. <content styleCode="bold">Do not</content>change your dose without talking to your healthcare provider. </item><item>Take Trokendi XR capsules whole. <content styleCode="bold">Do not</content>sprinkle Trokendi XR on food, or break, crush, dissolve, or chew Trokendi XR capsules before swallowing. </item><item>Trokendi XR can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking Trokendi XR.</item><item>If you take too much Trokendi XR, call your healthcare provider right away or go to the nearest emergency room.</item><item>Talk to your health care provider on what you should do if you miss a dose.</item><item>Do not stop taking Trokendi XR without talking to your healthcare provider. Stopping Trokendi XR suddenly may cause serious problems. If you have epilepsy and you stop taking Trokendi XR suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking Trokendi XR slowly.</item><item>Your healthcare provider may do blood tests while you take Trokendi XR.</item></list></td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">What should I avoid while taking Trokendi XR?</content><list listType="unordered" styleCode="Disc"><item>Do not drink alcohol within 6 hours before or 6 hours after taking Trokendi XR capsules. Trokendi XR and alcohol can cause serious side effects such as severe sleepiness and dizziness and an increase in seizures.</item><item>Do not drive a car or operate heavy machinery until you know how Trokendi XR affects you. Trokendi XR can slow your thinking and motor skills and may affect vision.</item></list></td></tr><tr><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">What are the possible side effects of Trokendi XR? Trokendi XR may cause serious side effects, including: </content> See &quot; <linkHtml href="#important">What is the most important information I should know about Trokendi XR?</linkHtml>&quot; <list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Effects on thinking and alertness.</content>Trokendi XR may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. Trokendi XR may cause depression or mood problems, tiredness, and sleepiness.

uot; <list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Effects on thinking and alertness.</content>Trokendi XR may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. Trokendi XR may cause depression or mood problems, tiredness, and sleepiness. </item><item><content styleCode="bold">Dizziness or loss of muscle coordination.</content></item><item><content styleCode="bold">Severe multiorgan reactions.</content>Treatment with Trokendi XR may cause a serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death, particularly if it is not treated as early as possible. Contact your healthcare provider or get medical help right away if you have: <list listType="unordered"><item>blistering and peeling of your skin or skin rash</item><item>fever or swollen glands that do not go away</item><item>hives</item><item>swelling of your face, eyes, lips, tongue, or throat</item><item>sores in your mouth</item><item>trouble swallowing or breathing</item><item>dark urine</item><item>yellowing of the skin or whites of the eyes</item></list></item><item><content styleCode="bold">Serious skin reactions.</content>Trokendi XR may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). Trokendi XR may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters. </item><item><content styleCode="bold">Allergic reactions.</content>Serious allergic reactions can happen after you take Trokendi XR. Get emergency help right away if you have swelling of the face, lips, eyes, tongue, or throat, or trouble swallowing or breathing. </item><item><content styleCode="bold">High blood ammonia levels.</content>High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when Trokendi XR is taken with a medicine called valproic acid (DEPAKOTE). Call your healthcare provider right away if you develop unexplained tiredness, vomiting, slowing of your thinking or reaction time, or changes in your mental activities. </item><item><content styleCode="bold">Kidney stones.</content>Drink plenty of fluids when taking Trokendi XR to decrease your chances of getting kidney stones. </item><item><content styleCode="bold">Low body temperature.</content>Taking Trokendi XR when you are also taking valproic acid can cause a drop in body temperature to less than 95&#xB0;F, feeling tired, confusion, or coma. </item></list>Call your healthcare provider right away if you have any of the symptoms above.

s. </item><item><content styleCode="bold">Low body temperature.</content>Taking Trokendi XR when you are also taking valproic acid can cause a drop in body temperature to less than 95&#xB0;F, feeling tired, confusion, or coma. </item></list>Call your healthcare provider right away if you have any of the symptoms above. <content styleCode="bold">The most common side effects of Trokendi XR include:</content></td></tr><tr><td styleCode="Lrule"/><td><list listType="unordered" styleCode="Disc"><item>tingling of the arms and legs (paresthesia)</item><item>not feeling hungry</item><item>nausea</item><item>weight loss</item><item>abnormal vision</item><item>a change in the way foods taste</item></list></td><td><list listType="unordered" styleCode="Disc"><item>nervousness</item><item>speech problems</item><item>dizziness</item><item>slow reactions</item><item>upper respiratory tract infection</item></list></td><td><list listType="unordered" styleCode="Disc"><item>fever</item><item>tiredness</item><item>sleepiness/drowsiness</item><item>difficulty with memory</item><item>diarrhea</item><item>pain in abdomen</item><item>decreased feeling or sensitivity, especially on the skin</item></list></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule">Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of Trokendi XR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Supernus Pharmaceuticals, Inc. at 1-866-398-0833. </td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">How should I store Trokendi XR?</content><list listType="unordered" styleCode="Disc"><item>Store Trokendi XR capsules at room temperature between 59&#xB0;F to 86&#xB0;F (15&#xB0;C to 30&#xB0;C).</item><item>Keep Trokendi XR in a tightly closed container.</item><item>Keep Trokendi XR dry and away from moisture and light.</item><item><content styleCode="bold">Keep Trokendi XR and all medicines out of the reach of children.</content></item></list></td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">General information about the safe and effective use of Trokendi XR.</content> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Trokendi XR for a condition for which it was not prescribed. Do not give Trokendi XR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Trokendi XR that is written for health professionals. </td></tr><tr><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">What are the ingredients in Trokendi XR?</content> <content styleCode="bold">Active ingredient:</content>topiramate <content styleCode="bold">Inactive ingredients:</content>Sugar spheres, NF; hypromellose (Type 2910), USP; mannitol, USP; docusate sodium, USP; sodium benzoate, NF; ethylcellulose, NF; oleic acid, NF; medium chain triglycerides, NF; polyethylene glycol, NF; polyvinyl alcohol, USP; titanium dioxide, USP; talc, USP; lecithin, NF; xanthan gum, NF; glycerin, USP-NF. <content styleCode="bold">Capsule shells:</content>Gelatin, USP; titanium dioxide, USP; colorants. <content styleCode="bold">Colorants:</content> FD&amp;C blue #1 (all strength capsules) Yellow iron oxide, USP (25 mg and 50 mg capsules) FD&amp;C red #3 (50 mg, 100 mg, and 200 mg capsules) FD&amp;C yellow #6 (50 mg, 100 mg, and 200 mg capsules) Riboflavin, USP (25 mg capsules) All capsule shells are imprinted with black print that contains shellac, NF, and black iron oxide, NF.

1 (all strength capsules) Yellow iron oxide, USP (25 mg and 50 mg capsules) FD&amp;C red #3 (50 mg, 100 mg, and 200 mg capsules) FD&amp;C yellow #6 (50 mg, 100 mg, and 200 mg capsules) Riboflavin, USP (25 mg capsules) All capsule shells are imprinted with black print that contains shellac, NF, and black iron oxide, NF. Manufactured by: Catalent Pharma Solutions, Winchester, KY USA 40391 Manufactured for: Supernus Pharmaceuticals, Inc., Rockville, MD USA 20850 TROKENDI XR is a registered trademark of Supernus Pharmaceuticals, Inc. &#xA9; 2026 Supernus Pharmaceuticals, Inc. All rights reserved. RA-TRO-MGV13 For more information, go to www.trokendixr.com or call 1-866-398-0833. </td></tr></tbody></table>

1 INDICATIONS AND USAGE Topiramate extended-release capsules are indicated for: Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older ( 1.1) ; adjunctive therapy for the treatment of partial-onset, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome (LGS) in patients 6 years of age and older (1.2) Preventive treatment of migraine in patients 12 years of age and older ( 1.3 ) 1.1 Monotherapy Epilepsy Topiramate extended-release capsules are indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older [see Clinical Studies (14.2) ] . 1.2 Adjunctive Therapy Epilepsy Topiramate extended-release capsules are indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older [ see Clinical Studies (14.3) ] . 1.3 Migraine Topiramate extended-release capsules are indicated for the preventive treatment of migraine in patients 12 years of age and older [see Clinical Studies (14.4) ] . 1.1 Monotherapy Epilepsy Topiramate extended-release capsules are indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older [see Clinical Studies (14.2) ] . 1.2 Adjunctive Therapy Epilepsy Topiramate extended-release capsules are indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older [ see Clinical Studies (14.3) ] . 1.3 Migraine Topiramate extended-release capsules are indicated for the preventive treatment of migraine in patients 12 years of age and older [see Clinical Studies (14.4) ] .

2 DOSAGE AND ADMINISTRATION Topiramate extended-release capsules initial dose, titration, and recommended maintenance dose varies by indication and age group. See Full Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis ( 2.1, 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush (2.7 ) 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures The recommended dose for topiramate extended-release capsules monotherapy in adults and in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate topiramate extended-release capsules according to the following schedule: Week 1: 50 mg once daily Week 2: 100 mg once daily Week 3: 150 mg once daily Week 4: 200 mg once daily Week 5: 300 mg once daily Week 6: 400 mg once daily Pediatric Patients Ages 6 to 9 Years of Age Dosing in patients 6 to 9 years of age is based on weight. During the titration period, the initial dose of topiramate extended-release capsules is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day in the second week. Dosage can be increased by 25 mg/day to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to 7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 mg/day to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (see Table 1). Table 1: Monotherapy Target Total Daily Maintenance Dosing for Patients 6 to 9 Years of Age Weight (kg) Total Daily Dose (mg/day) Minimum Maintenance Dose Total Daily Dose (mg/day) Maximum Maintenance Dose Up to 11 150 250 12 to 22 200 300 23 to 31 200 350 32 to 38 250 350 Greater than 38 250 400 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Older) The recommended total daily dose of topiramate extended-release capsules as adjunctive therapy in adults with partial-onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily and with primary generalized tonic-clonic seizures is 400 mg orally once daily. Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures. Pediatric Patients 6 to 16 Years of Age The recommended total daily dose of topiramate extended-release capsules as adjunctive therapy for patients 6 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome.

gin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day. 2.3 Dosing for the Preventive Treatment of Migraine The recommended total daily dose of topiramate extended-release capsules as treatment for the preventive treatment of migraine in patients 12 years of age and older is 100 mg once daily. Titrate topiramate extended-release capsules for the preventive treatment of migraine according to the following schedule: Week 1: 25 mg once daily Week 2: 50 mg once daily Week 3: 75 mg once daily Week 4: 100 mg once daily Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used. 2.4 Administration With Alcohol Alcohol use should be completely avoided within 6 hours prior to and 6 hours after topiramate extended-release capsules administration [see Warnings and Precautions ( 5. 5) ] . 2.5 Dose Modifications in Patients With Renal Impairment In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose of topiramate extended-release capsules are recommended [see Use in Specific Populations ( 8.5 , 8.6 ) , Clinical Pharmacology ( 12.3) ] . 2.6 Dosage Modifications in Patients Undergoing Hemodialysis To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate extended-release capsules may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3) ] . 2.7 Administration Instructions Topiramate extended-release capsules can be taken without regard to meals. Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush.

ve renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3) ] . 2.7 Administration Instructions Topiramate extended-release capsules can be taken without regard to meals. Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush. 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures The recommended dose for topiramate extended-release capsules monotherapy in adults and in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate topiramate extended-release capsules according to the following schedule: Week 1: 50 mg once daily Week 2: 100 mg once daily Week 3: 150 mg once daily Week 4: 200 mg once daily Week 5: 300 mg once daily Week 6: 400 mg once daily Pediatric Patients Ages 6 to 9 Years of Age Dosing in patients 6 to 9 years of age is based on weight. During the titration period, the initial dose of topiramate extended-release capsules is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day in the second week. Dosage can be increased by 25 mg/day to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to 7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 mg/day to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (see Table 1). Table 1: Monotherapy Target Total Daily Maintenance Dosing for Patients 6 to 9 Years of Age Weight (kg) Total Daily Dose (mg/day) Minimum Maintenance Dose Total Daily Dose (mg/day) Maximum Maintenance Dose Up to 11 150 250 12 to 22 200 300 23 to 31 200 350 32 to 38 250 350 Greater than 38 250 400

weight (see Table 1). Table 1: Monotherapy Target Total Daily Maintenance Dosing for Patients 6 to 9 Years of Age Weight (kg) Total Daily Dose (mg/day) Minimum Maintenance Dose Total Daily Dose (mg/day) Maximum Maintenance Dose Up to 11 150 250 12 to 22 200 300 23 to 31 200 350 32 to 38 250 350 Greater than 38 250 400 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Older) The recommended total daily dose of topiramate extended-release capsules as adjunctive therapy in adults with partial-onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily and with primary generalized tonic-clonic seizures is 400 mg orally once daily. Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures. Pediatric Patients 6 to 16 Years of Age The recommended total daily dose of topiramate extended-release capsules as adjunctive therapy for patients 6 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day. 2.3 Dosing for the Preventive Treatment of Migraine The recommended total daily dose of topiramate extended-release capsules as treatment for the preventive treatment of migraine in patients 12 years of age and older is 100 mg once daily. Titrate topiramate extended-release capsules for the preventive treatment of migraine according to the following schedule: Week 1: 25 mg once daily Week 2: 50 mg once daily Week 3: 75 mg once daily Week 4: 100 mg once daily Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.

se capsules for the preventive treatment of migraine according to the following schedule: Week 1: 25 mg once daily Week 2: 50 mg once daily Week 3: 75 mg once daily Week 4: 100 mg once daily Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used. 2.4 Administration With Alcohol Alcohol use should be completely avoided within 6 hours prior to and 6 hours after topiramate extended-release capsules administration [see Warnings and Precautions ( 5. 5) ] . 2.5 Dose Modifications in Patients With Renal Impairment In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose of topiramate extended-release capsules are recommended [see Use in Specific Populations ( 8.5 , 8.6 ) , Clinical Pharmacology ( 12.3) ] . 2.6 Dosage Modifications in Patients Undergoing Hemodialysis To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate extended-release capsules may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3) ] . 2.7 Administration Instructions Topiramate extended-release capsules can be taken without regard to meals. Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush.

3 DOSAGE FORMS AND STRENGTHS Topiramate extended-release capsules are available as 200 mg: Hard gelatin capsule with yellow opaque cap and white opaque body, imprinted with “par” on the cap and “C368” on the body in black ink, containing white to off-white spherical-shaped film-coated pellets. Extended-release capsules: 200 mg ( 3)

4 CONTRAINDICATIONS Topiramate extended-release capsules are contraindicated in patients: With recent alcohol use (i.e., within 6 hours prior to and 6 hours after topiramate extended-release capsules use) [see Warnings and Precautions ( 5.5 )] With recent alcohol use, i.e., within 6 hours prior to and 6 hours after topiramate extended-release capsules use ( 4 , 5.5 )

5 WARNINGS AND PRECAUTIONS Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue topiramate extended-release capsules as soon as possible ( 5.1 ) Visual field defects: consider discontinuation of topiramate extended-release capsules ( 5.2 ) Oligohydrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients ( 5.3 ) Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of topiramate extended-release capsules if clinically appropriate ( 5.4 ) Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.6 ) Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur ( 5.7 ) Fetal toxicity: use during pregnancy can cause cleft lip and/or palate and being small for gestational age (5.8) Withdrawal of AEDs: withdraw topiramate extended-release capsules gradually (5.9) Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients ( 5.10) Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy (5.11) Serious skin reactions: If SJS or TEN is suspected, discontinue topiramate extended-release capsules ( 5.12 ) Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur (5.13 ) Kidney stones: avoid use with other carbonic anhydrase inhibitors, other drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.14 ) Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use ( 5.15 ) 5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate extended-release capsules as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate extended-release capsules, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate.

ated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with topiramate extended-release capsules, consideration should be given to discontinuing the drug. 5.3 Oligohydrosis and Hyperthermia Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures. The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated with topiramate extended-release capsules should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate extended-release capsules is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. 5.4 Metabolic Acidosis Topiramate extended-release capsules can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due carbonic anhydrase inhibition by topiramate extended-release capsules. Topiramate extended-release capsules-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of topiramate extended-release capsules. Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was as high as 67% for immediate-release topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and ≥5mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤2% for placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions (5.10 , 5.14 )] .

g cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions (5.10 , 5.14 )] . A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that immediate-release topiramate decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions ( 5.10) , Use in Specific Populations ( 8.4 )]. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 month old pediatrics. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations ( 8.4 )] . Topiramate extended-release capsules treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.1 )] . Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate extended-release capsules (using dose tapering). If the decision is made to continue patients on topiramate extended-release capsules in the face of persistent acidosis, alkali treatment should be considered. 5.5 Interaction With Alcohol In vitro data show that, in the presence of alcohol, the pattern of topiramate release from topiramate extended-release capsules is significantly altered. As a result, plasma levels of topiramate with topiramate extended-release capsules may be markedly higher soon after dosing and subtherapeutic later in the day. Therefore, alcohol use should be completely avoided within 6 hours prior to and 6 hours after topiramate extended-release capsules administration. 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including topiramate extended-release capsules for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts, or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

or. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing topiramate extended-release capsules or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.7 Cognitive/Neuropsychiatric Adverse Reactions Immediate-release topiramate can cause, and therefore expected to be caused by topiramate extended-release capsules, cognitive/neuropsychiatric adverse reactions. The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue. Adult Patients Cognitive-Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction.

problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue. Adult Patients Cognitive-Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction. In adult adjunctive epilepsy controlled trials, which used rapid titration (100 mg/day to 200 mg/day weekly increments), and target immediate-release topiramate doses of 200 mg/day to 1,000 mg/day, 56% of patients in the 800 mg/day and 1,000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200 mg/day to 400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase. In the monotherapy epilepsy controlled trial conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day. In the 6-month controlled trials for the preventive treatment of migraine with immediate-release topiramate using a slower titration regimen (25 mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day, 22% for 100 mg per day (the recommended dose), 28% for 200 mg per day and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations treated with topiramate [see Warnings and Precautions ( 5.6) ] . Somnolence/Fatigue Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue was dose-related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both somnolence and fatigue were dose-related and more common in the titration phase. Pediatric Patients In pediatric epilepsy trials (adjunctive and monotherapy) conducted with topiramate, the incidence of cognitive/neuropsychiatric adverse reactions in pediatric patients was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in immediate-release topiramate-treated patients compared to placebo. The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention.

st at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline at the end of the Study 3 [see Clinical Studies ( 14.4 )] . Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency. 5.8 Fetal Toxicity Topiramate extended-release capsules can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations ( 8.1 )] . Consider the benefits and risks of topiramate extended-release capsules when administering the drug in women of childbearing potential, particularly when topiramate extended-release capsules is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations ( 8.1 )] . Topiramate extended-release capsules should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus [see Use in Specific Populations (8.1 )] . 5.9 Withdrawal of Antiepileptic Drugs In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including topiramate extended-release capsules, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies ( 14) ] . In situations where rapid withdrawal of topiramate extended-release capsules is medically required, appropriate monitoring is recommended. 5.10 Decrease in Bone Mineral Density Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations ( 8.4 )]. Twenty-one percent of immediate-release topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of -0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions ( 5.4) ].

study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions ( 5.4) ]. Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in immediate-release topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium. 5.11 Negative Effects on Growth (Height and Weight) Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on growth (i.e., height and weight) [see Use in Specific Populations ( 8.4) ] . Although continued growth was observed in both treatment groups, the immediate-release topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all immediate-release topiramate age subgroups. Growth (height and weight) of children receiving prolonged topiramate extended-release capsules therapy should be carefully monitored. 5.12 Serious Skin Reactions Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. Topiramate extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions. 5.13 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions ( 6.2)] . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions (7.2) ] . Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose. Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial onset epilepsy, and this was not due to a pharmacokinetic interaction. In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.

al onset epilepsy, and this was not due to a pharmacokinetic interaction. In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate or topiramate extended-release capsules treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. 5.14 Kidney Stones Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 to 24 months old with epilepsy, 7% developed kidney or bladder stones. Topiramate extended-release capsules would be expected to have the same effect as immediate-release topiramate on the formation of kidney stones. Topiramate extended-release capsules are not approved for treatment of epilepsy in pediatric patients less than 6 years old [see Use in Specific Populations (8.4) ] . Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions ( 5.4 )] . The concomitant use of topiramate extended-release capsules with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in immediate-release topiramate-treated pediatric patients in a one-year active-controlled study [see Use in Specific Populations ( 8.4 )]. This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. 5.15 Hypothermia With Concomitant Valproic Acid Use Hypothermia, defined as a drop in body core temperature to < 35ºC (95ºF), has been reported in association with topiramate use with concomitant valproic acid (VPA) both in conjunction with and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions ( 7.2) ] . Consideration should be given to stopping topiramate extended-release capsules or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate extended-release capsules as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate extended-release capsules, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with topiramate extended-release capsules, consideration should be given to discontinuing the drug.

al trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with topiramate extended-release capsules, consideration should be given to discontinuing the drug. 5.3 Oligohydrosis and Hyperthermia Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures. The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated with topiramate extended-release capsules should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate extended-release capsules is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

increased body temperature, especially in hot weather. Caution should be used when topiramate extended-release capsules is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. 5.4 Metabolic Acidosis Topiramate extended-release capsules can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due carbonic anhydrase inhibition by topiramate extended-release capsules. Topiramate extended-release capsules-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of topiramate extended-release capsules. Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was as high as 67% for immediate-release topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and ≥5mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤2% for placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions (5.10 , 5.14 )] . A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that immediate-release topiramate decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions ( 5.10) , Use in Specific Populations ( 8.4 )]. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 month old pediatrics. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations ( 8.4 )] .

, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 month old pediatrics. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations ( 8.4 )] . Topiramate extended-release capsules treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.1 )] . Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate extended-release capsules (using dose tapering). If the decision is made to continue patients on topiramate extended-release capsules in the face of persistent acidosis, alkali treatment should be considered. 5.5 Interaction With Alcohol In vitro data show that, in the presence of alcohol, the pattern of topiramate release from topiramate extended-release capsules is significantly altered. As a result, plasma levels of topiramate with topiramate extended-release capsules may be markedly higher soon after dosing and subtherapeutic later in the day. Therefore, alcohol use should be completely avoided within 6 hours prior to and 6 hours after topiramate extended-release capsules administration.

tly altered. As a result, plasma levels of topiramate with topiramate extended-release capsules may be markedly higher soon after dosing and subtherapeutic later in the day. Therefore, alcohol use should be completely avoided within 6 hours prior to and 6 hours after topiramate extended-release capsules administration. 5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including topiramate extended-release capsules for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts, or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing topiramate extended-release capsules or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

cribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.7 Cognitive/Neuropsychiatric Adverse Reactions Immediate-release topiramate can cause, and therefore expected to be caused by topiramate extended-release capsules, cognitive/neuropsychiatric adverse reactions. The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue. Adult Patients Cognitive-Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction. In adult adjunctive epilepsy controlled trials, which used rapid titration (100 mg/day to 200 mg/day weekly increments), and target immediate-release topiramate doses of 200 mg/day to 1,000 mg/day, 56% of patients in the 800 mg/day and 1,000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200 mg/day to 400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase. In the monotherapy epilepsy controlled trial conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day. In the 6-month controlled trials for the preventive treatment of migraine with immediate-release topiramate using a slower titration regimen (25 mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day, 22% for 100 mg per day (the recommended dose), 28% for 200 mg per day and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations treated with topiramate [see Warnings and Precautions ( 5.6) ] . Somnolence/Fatigue Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue was dose-related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both somnolence and fatigue were dose-related and more common in the titration phase. Pediatric Patients In pediatric epilepsy trials (adjunctive and monotherapy) conducted with topiramate, the incidence of cognitive/neuropsychiatric adverse reactions in pediatric patients was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue.

dults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in immediate-release topiramate-treated patients compared to placebo. The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline at the end of the Study 3 [see Clinical Studies ( 14.4 )] . Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

ed to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline at the end of the Study 3 [see Clinical Studies ( 14.4 )] . Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency. 5.8 Fetal Toxicity Topiramate extended-release capsules can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations ( 8.1 )] . Consider the benefits and risks of topiramate extended-release capsules when administering the drug in women of childbearing potential, particularly when topiramate extended-release capsules is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations ( 8.1 )] . Topiramate extended-release capsules should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus [see Use in Specific Populations (8.1 )] . 5.9 Withdrawal of Antiepileptic Drugs In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including topiramate extended-release capsules, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies ( 14) ] . In situations where rapid withdrawal of topiramate extended-release capsules is medically required, appropriate monitoring is recommended.

, including topiramate extended-release capsules, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies ( 14) ] . In situations where rapid withdrawal of topiramate extended-release capsules is medically required, appropriate monitoring is recommended. 5.10 Decrease in Bone Mineral Density Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations ( 8.4 )]. Twenty-one percent of immediate-release topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of -0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions ( 5.4) ]. Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in immediate-release topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium.

m alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in immediate-release topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium. 5.11 Negative Effects on Growth (Height and Weight) Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on growth (i.e., height and weight) [see Use in Specific Populations ( 8.4) ] . Although continued growth was observed in both treatment groups, the immediate-release topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all immediate-release topiramate age subgroups. Growth (height and weight) of children receiving prolonged topiramate extended-release capsules therapy should be carefully monitored. 5.12 Serious Skin Reactions Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. Topiramate extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions.

ate. Topiramate extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions. 5.13 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions ( 6.2)] . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions (7.2) ] . Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose. Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial onset epilepsy, and this was not due to a pharmacokinetic interaction. In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate or topiramate extended-release capsules treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. 5.14 Kidney Stones Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 to 24 months old with epilepsy, 7% developed kidney or bladder stones. Topiramate extended-release capsules would be expected to have the same effect as immediate-release topiramate on the formation of kidney stones. Topiramate extended-release capsules are not approved for treatment of epilepsy in pediatric patients less than 6 years old [see Use in Specific Populations (8.4) ] . Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions ( 5.4 )] . The concomitant use of topiramate extended-release capsules with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in immediate-release topiramate-treated pediatric patients in a one-year active-controlled study [see Use in Specific Populations ( 8.4 )]. This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis.

n urinary calcium and a marked decrease in urinary citrate was observed in immediate-release topiramate-treated pediatric patients in a one-year active-controlled study [see Use in Specific Populations ( 8.4 )]. This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. 5.15 Hypothermia With Concomitant Valproic Acid Use Hypothermia, defined as a drop in body core temperature to < 35ºC (95ºF), has been reported in association with topiramate use with concomitant valproic acid (VPA) both in conjunction with and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions ( 7.2) ] . Consideration should be given to stopping topiramate extended-release capsules or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

<table cellspacing="0" cellpadding="0" border="1"><col width="6.65in"/><col/><col/><col/><col/><tbody><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Indication</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo Patients with Events per 1,000 Patients</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Drug Patients with Events per 1,000 Patients</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risk Difference: Additional Drug Patients with Events per 1,000 Patients</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Epilepsy</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Psychiatric</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Other</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Total</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.9</paragraph></td></tr></tbody></table>

tyleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.9</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="6.65in"/><col/><col/><col/><col/><tbody><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Indication</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo Patients with Events per 1,000 Patients</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Drug Patients with Events per 1,000 Patients</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risk Difference: Additional Drug Patients with Events per 1,000 Patients</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Epilepsy</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Psychiatric</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Other</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Total</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.9</paragraph></td></tr></tbody></table>

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1 )] Visual Field Defects [see Warnings and Precautions ( 5.2 )] Oligohydrosis and Hyperthermia [see Warnings and Precautions ( 5.3 )] Metabolic Acidosis [see Warnings and Precautions ( 5.4) ] Interaction With Alcohol [see Warnings and Precautions ( 5.5) ] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.6 )] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions ( 5.7 )] Fetal Toxicity [see Warnings and Precautions ( 5.8 )] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions ( 5.9) ] Decrease of Bone Mineral Density [see Warnings and Precautions ( 5.10) ] Negative Effects on Growth (Height and Weight) [see Warnings and Precautions ( 5.11 )] Serious Skin Reactions [see Warnings and Precautions ( 5.12 )] Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) [see Warnings and Precautions ( 5.13 )] Kidney Stones [see Warnings and Precautions ( 5.14 )] Hypothermia With Concomitant Valproic Acid Use [see Warnings and Precautions ( 5.15 )] The data described in the following sections were obtained using immediate-release topiramate tablets. Topiramate extended-release capsules have not been studied in a randomized, placebo-controlled Phase III clinical study; however, it is expected that topiramate extended-release capsules would produce a similar adverse reaction profile as immediate-release topiramate. Epilepsy: Most common (≥ 10% more frequent than placebo or low-dose topiramate) adverse reactions in adult and pediatric patients were paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever ( 6.1 ). Migraine: Most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain, and upper respiratory tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Endo at 1-800-828-9393 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Monotherapy Epilepsy Adults 16 Years of Age and Older The most common adverse reactions in the controlled trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg per day group were: paresthesia, weight loss, and anorexia (see Table 3). Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

n the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia. Pediatric Patients 6 Years to 15 Years of Age The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were fever and weight loss (see Table 3). Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than in the 50 mg/day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion. Table 3 represents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day immediate-release topiramate and occurring with greater incidence than 50 mg/day topiramate. Table 3: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trial in Adult and Pediatric Patients Body System/ Adverse Reaction Age Group Pediatric (6 to 15 Years) Adult (Age ≥16 Years) Immediate-release Topiramate Daily Dosage Group (mg/day) 50 400 50 400 (N=74) % (N=77) % (N=160) % (N=159) % Body as a Whole-General Disorders Asthenia 0 3 4 6 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Paresthesia 3 12 21 40 Dizziness 13 14 Ataxia 3 4 Hypoesthesia 4 5 Hypertonia 0 3 Involuntary Muscle contraction 0 3 Vertigo 0 3 Gastro-intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Dry mouth 1 3 Liver and Biliary System Disorders Increase in Gamma-GT 1 3 Metabolic and Nutritional Disorders Weight loss 7 17 6 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Anorexia 4 14 Anxiety 4 6 Cognitive problems 1 6 1 4 Confusion 0 3 Depression 0 3 7 9 Difficulty with concentration or attention 7 10 7 8 Difficulty with memory 1 3 6 11 Insomnia 8 9 Decrease in libido 0 3 Mood problems 1 8 2 5 Personality disorder (behavior problems) 0 3 Psychomotor slowing 3 5 Somnolence 10 15 Red Blood Cell Disorders Anemia 1 3 Reproductive Disorders, Female Intermenstrual bleeding 0 3 Vaginal hemorrhage 0 3 Resistance Mechanism Disorders Infection 3 8 2 3 Viral infection 3 6 6 8 Respiratory System Disorders Bronchitis 1 5 3 4 Upper respiratory tract infection 16 18 Rhinitis 5 6 2 4 Sinusitis 1 4 Skin and Appendages Disorders Alopecia 1 4 3 4 Pruritus 1 4 Rash 3 4 1 4 Acne 2 3 Special Senses Other, Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Micturition frequency 0 3 0 2 Renal calculus 0 3 Urinary incontinence 1 3 Vascular (Extracardiac) Disorders Flushing 0 5 Adjunctive Therapy Epilepsy Adults 16 Years of Age and Older In pooled controlled clinical trials in adults with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with immediate-release topiramate at dosages of 200 mg/day to 400 mg/day (recommended dosage range), and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to immediate-release topiramate or placebo.

yndrome, 183 patients received adjunctive therapy with immediate-release topiramate at dosages of 200 mg/day to 400 mg/day (recommended dosage range), and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to immediate-release topiramate or placebo. The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200 mg/day to 400 mg/day topiramate group with an incidence higher (≥10%) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (see Table 4) [see Clinical Studies ( 14.3 )] . Table 4 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 mg/day to 400 mg/day topiramate and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended topiramate dosing (i.e., 600 mg/day to 1,000 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (200 mg/day to 400 mg/day) range. Table 4: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults *, † Placebo Topiramate Dosage (mg/day) 200 to 400 Body System/Adverse Reaction (N=291) (N=183) % % Body as a Whole-General Disorders Fatigue 13 15 Asthenia 1 6 Back pain 4 5 Chest pain 3 4 Influenza-like symptoms 2 3 Central & Peripheral Nervous System Disorders Dizziness 15 25 Ataxia 7 16 Speech disorders/Related speech problems 2 13 Paresthesia 4 11 Nystagmus 7 10 Tremor 6 9 Language problems 1 6 Coordination abnormal 2 4 Gait abnormal 1 3 Gastro-Intestinal System Disorders Nausea 8 10 Dyspepsia 6 7 Abdominal pain 4 6 Constipation 2 4 Metabolic and Nutritional Disorders Weight loss 3 9 Psychiatric Disorders Somnolence 12 29 Nervousness 6 16 Psychomotor slowing 2 13 Difficulty with memory 3 12 Confusion 5 11 Anorexia 4 10 Difficulty with concentration/attention 2 6 Mood problems 2 4 Agitation 2 3 Aggressive reaction 2 3 Emotional liability 1 3 Cognitive problems 1 3 Reproductive Disorders, Female Breast pain 2 4 Respiratory System Disorders Rhinitis 6 7 Pharyngitis 2 6 Sinusitis 4 5 Vision Disorders Vision abnormal 2 13 Diplopia 5 10 * Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. In controlled clinical trials in adults, 11% of patients receiving immediate-release topiramate 200 mg to 400 mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg per day. Adverse reactions associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia. Pediatric Patients 2 to 15 Years of Age In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with immediate-release topiramate at dosages of 5 mg/kg/day to 9 mg/kg/day (recommended dosage range) and 101 patients received placebo.

n pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with immediate-release topiramate at dosages of 5 mg/kg/day to 9 mg/kg/day (recommended dosage range) and 101 patients received placebo. The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg/kg/day to 9 mg/kg/day immediate-release topiramate group with an incidence higher (≥10%) than in the placebo group were: fatigue and somnolence (see Table 5). Table 5 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg/kg/day to 9 mg/kg/day (recommended dosage range) of immediate-release topiramate and was greater than placebo incidence. Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients 2 to 15 Years of Age *, † Placebo Topiramate Body System/ Adverse Reaction (N=101) (N=98) % % Body as a Whole-General Disorders Fatigue 5 16 Injury 13 14 Central & Peripheral Nervous System Disorders Gait abnormal 5 8 Ataxia 2 6 Hyperkinesia 4 5 Dizziness 2 4 Speech disorders/Related speech problems 2 4 Gastro-Intestinal System Disorders Nausea 5 6 Saliva increased 4 6 Constipation 4 5 Gastroenteritis 2 3 Metabolic and Nutritional Disorders Weight loss 1 9 Platelet, Bleeding & Clotting Disorders Purpura 4 8 Epistaxis 1 4 Psychiatric Disorders Somnolence 16 26 Anorexia 15 24 Nervousness 7 14 Personality disorder (Behavior Problems) 9 11 Difficulty with concentration/attention 2 10 Aggressive reaction 4 9 Insomnia 7 8 Difficulty with memory 0 5 Confusion 3 4 Psychomotor slowing 2 3 Resistance Mechanism Disorders Infection viral 3 7 Respiratory System Disorders Pneumonia 1 5 Skin and Appendages Disorders Skin Disorder 2 3 Urinary System Disorders Urinary incontinence 2 4 * Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Migraine Adults In the four multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine (which included 35 pediatric patients 12 to 15 years of age), most adverse reactions occurred more frequently during the titration period than during the maintenance period. The most common adverse reactions with immediate-release topiramate 100 mg in the clinical trials for the preventive treatment of migraine of predominantly adults that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 6). Table 6 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any immediate-release topiramate group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (100 mg/day).

incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (100 mg/day). Table 6: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults *,†,‡ Topiramate Dosage (mg/day) Placebo 50 100 Body System/ Adverse Reaction (N=445) (N=235) (N=386) % % % Body as a Whole-General Disorders Fatigue 11 14 15 Injury 7 9 6 Central & Peripheral Nervous System Disorders Paresthesia 6 35 51 Dizziness 10 8 9 Hypoaesthesia 2 6 7 Language problems 2 7 6 Gastro-Intestinal System Disorders Nausea 8 9 13 Diarrhea 4 9 11 Abdominal pain 5 6 6 Dyspepsia 3 4 5 Dry mouth 2 2 3 Gastroenteritis 1 3 3 Metabolic and Nutritional Disorders Weight loss 1 6 9 Musculoskeletal System Disorders Arthralgia 2 7 3 Psychiatric Disorders Anorexia 6 9 15 Somnolence 5 8 7 Difficulty with memory 2 7 7 Insomnia 5 6 7 Difficulty with concentration/attention 2 3 6 Mood problems 2 3 6 Anxiety 3 4 5 Depression 4 3 4 Nervousness 2 4 4 Confusion 2 2 3 Psychomotor slowing 1 3 2 Reproductive Disorders, Female Menstrual disorder 2 3 2 Reproductive Disorders, Male Ejaculation premature 0 3 0 Resistance Mechanism Disorders Viral Infection 3 4 4 Respiratory System Disorders Upper respiratory tract infection 12 13 14 Sinusitis 6 10 6 Pharyngitis 4 5 6 Coughing 2 2 4 Bronchitis 2 3 3 Dyspnea 2 1 3 Skin and Appendages Disorders Pruritis 2 4 2 Special Sense Other, Disorders Taste perversion 1 15 8 Urinary System Disorders Urinary tract infection 2 4 2 Vision Disorders Blurred vision 2 4 2 * Includes 35 adolescent patients age 12 to 15 years † Values represent the percentage of patients reporting a given reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. ‡ Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for more than 50% of reactions coded as vision abnormal, a preferred term Of the 1,135 patients exposed to immediate-release topiramate in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in the immediate-release topiramate-treated patients in these studies included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%). Patients treated in these studies experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, immediate-release topiramate 50 mg, 100 mg, and 200 mg groups, respectively. Pediatric Patients 12 to 17 Years of Age In five randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine, most of the adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period. In four, fixed-dose, double-blind clinical trials for the preventive treatment of migraine in pediatric patients 12 to 17 years of age, the most common adverse reactions with immediate-release topiramate 100 mg that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 7).

preventive treatment of migraine in pediatric patients 12 to 17 years of age, the most common adverse reactions with immediate-release topiramate 100 mg that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 7). Table 7 shows adverse reactions from the pediatric trial (Study 13 [see Clinical Studies ( 14.4)] ) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of immediate-release topiramate, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years of age) were treated with placebo or 50 mg, 100 mg, or 200 mg of immediate-release topiramate [see Clinical Studies ( 14.4 )] . Table 7 also shows adverse reactions in pediatric patients in controlled migraine trials when the incidence in an immediate-release topiramate dose group was at least 5% or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 7 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose-related and greater at higher than recommended immediate-release topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). Table 7: Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age *† Immediate-Release Topiramate Dosage Placebo 50 mg/day 100 mg/day Body System/ Adverse Reaction (N=45) (N=46) (N=48) % % % Body as a Whole - General Disorders Fatigue 7 7 8 Fever 2 4 6 Central & Peripheral Nervous System Disorders Paresthesia 7 20 19 Dizziness 4 4 6 Gastrointestinal System Disorders Abdominal pain 9 7 15 Nausea 4 4 8 Metabolic and Nutritional Disorders Weight loss 2 7 4 Psychiatric Disorders Anorexia 4 9 10 Somnolence 2 2 6 Insomnia 2 9 2 Resistance Mechanism Disorders Infection viral 4 4 8 Respiratory System Disorders Upper respiratory tract infection 11 26 23 Rhinitis 2 7 6 Sinusitis 2 9 4 Coughing 0 7 2 Special Senses Other, Disorders Taste perversion 2 2 6 Vision Disorders Conjunctivitis 4 7 4 * 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults † Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of immediate-release topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one immediate-release topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%). Increased Risk for Bleeding Topiramate is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse reaction for topiramate than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages.

analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants). Other Adverse Reactions Observed During Clinical Trials Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect. Laboratory Test Abnormalities Adult Patients In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride, and ammonia, immediate-release topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions (5.4 , 5.13 )] . Controlled trials of adjunctive topiramate treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate versus 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate versus 1% placebo), and decreased serum potassium (0.4% topiramate versus 0.1% placebo). Pediatric Patients In pediatric patients (1 to 24 months) receiving adjunctive topiramate for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, alkaline phosphatase, and total protein. The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis) and potassium with immediate-release topiramate (vs. placebo) [see Use in Specific Populations (8.4) ] . Topiramate extended-release capsules are not indicated for partial-onset seizures in pediatric patients less than 6 years of age. In pediatric patients (ranging from 6 to 17 years of age) receiving immediate-release topiramate for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils. The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations ( 8.4) ] . Topiramate extended-release capsules are not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of immediate-release topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole-General Disorders: oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3) ] , hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions ( 5.13) ] , hypothermia with concomitant valproic acid [see Warnings and Precautions 5.15) ] .

sh a causal relationship to drug exposure. Body as a Whole-General Disorders: oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3) ] , hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions ( 5.13) ] , hypothermia with concomitant valproic acid [see Warnings and Precautions 5.15) ] . Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions ( 5. 12 )] , pemphigus Urinary System Disorders: kidney stones, nephrocalcinosis [see Warnings and Precautions ( 5.14 )] Vision disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions ( 5.1 )] , maculopathy Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.

( 5.14 )] Vision disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions ( 5.1 )] , maculopathy Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Monotherapy Epilepsy Adults 16 Years of Age and Older The most common adverse reactions in the controlled trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg per day group were: paresthesia, weight loss, and anorexia (see Table 3). Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia. Pediatric Patients 6 Years to 15 Years of Age The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were fever and weight loss (see Table 3). Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than in the 50 mg/day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion. Table 3 represents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day immediate-release topiramate and occurring with greater incidence than 50 mg/day topiramate.

in this trial were difficulty with concentration/attention, fever, flushing, and confusion. Table 3 represents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day immediate-release topiramate and occurring with greater incidence than 50 mg/day topiramate. Table 3: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trial in Adult and Pediatric Patients Body System/ Adverse Reaction Age Group Pediatric (6 to 15 Years) Adult (Age ≥16 Years) Immediate-release Topiramate Daily Dosage Group (mg/day) 50 400 50 400 (N=74) % (N=77) % (N=160) % (N=159) % Body as a Whole-General Disorders Asthenia 0 3 4 6 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Paresthesia 3 12 21 40 Dizziness 13 14 Ataxia 3 4 Hypoesthesia 4 5 Hypertonia 0 3 Involuntary Muscle contraction 0 3 Vertigo 0 3 Gastro-intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Dry mouth 1 3 Liver and Biliary System Disorders Increase in Gamma-GT 1 3 Metabolic and Nutritional Disorders Weight loss 7 17 6 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Anorexia 4 14 Anxiety 4 6 Cognitive problems 1 6 1 4 Confusion 0 3 Depression 0 3 7 9 Difficulty with concentration or attention 7 10 7 8 Difficulty with memory 1 3 6 11 Insomnia 8 9 Decrease in libido 0 3 Mood problems 1 8 2 5 Personality disorder (behavior problems) 0 3 Psychomotor slowing 3 5 Somnolence 10 15 Red Blood Cell Disorders Anemia 1 3 Reproductive Disorders, Female Intermenstrual bleeding 0 3 Vaginal hemorrhage 0 3 Resistance Mechanism Disorders Infection 3 8 2 3 Viral infection 3 6 6 8 Respiratory System Disorders Bronchitis 1 5 3 4 Upper respiratory tract infection 16 18 Rhinitis 5 6 2 4 Sinusitis 1 4 Skin and Appendages Disorders Alopecia 1 4 3 4 Pruritus 1 4 Rash 3 4 1 4 Acne 2 3 Special Senses Other, Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Micturition frequency 0 3 0 2 Renal calculus 0 3 Urinary incontinence 1 3 Vascular (Extracardiac) Disorders Flushing 0 5 Adjunctive Therapy Epilepsy Adults 16 Years of Age and Older In pooled controlled clinical trials in adults with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with immediate-release topiramate at dosages of 200 mg/day to 400 mg/day (recommended dosage range), and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to immediate-release topiramate or placebo. The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200 mg/day to 400 mg/day topiramate group with an incidence higher (≥10%) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (see Table 4) [see Clinical Studies ( 14.3 )] . Table 4 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 mg/day to 400 mg/day topiramate and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended topiramate dosing (i.e., 600 mg/day to 1,000 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (200 mg/day to 400 mg/day) range.

ems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended topiramate dosing (i.e., 600 mg/day to 1,000 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (200 mg/day to 400 mg/day) range. Table 4: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults *, † Placebo Topiramate Dosage (mg/day) 200 to 400 Body System/Adverse Reaction (N=291) (N=183) % % Body as a Whole-General Disorders Fatigue 13 15 Asthenia 1 6 Back pain 4 5 Chest pain 3 4 Influenza-like symptoms 2 3 Central & Peripheral Nervous System Disorders Dizziness 15 25 Ataxia 7 16 Speech disorders/Related speech problems 2 13 Paresthesia 4 11 Nystagmus 7 10 Tremor 6 9 Language problems 1 6 Coordination abnormal 2 4 Gait abnormal 1 3 Gastro-Intestinal System Disorders Nausea 8 10 Dyspepsia 6 7 Abdominal pain 4 6 Constipation 2 4 Metabolic and Nutritional Disorders Weight loss 3 9 Psychiatric Disorders Somnolence 12 29 Nervousness 6 16 Psychomotor slowing 2 13 Difficulty with memory 3 12 Confusion 5 11 Anorexia 4 10 Difficulty with concentration/attention 2 6 Mood problems 2 4 Agitation 2 3 Aggressive reaction 2 3 Emotional liability 1 3 Cognitive problems 1 3 Reproductive Disorders, Female Breast pain 2 4 Respiratory System Disorders Rhinitis 6 7 Pharyngitis 2 6 Sinusitis 4 5 Vision Disorders Vision abnormal 2 13 Diplopia 5 10 * Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. In controlled clinical trials in adults, 11% of patients receiving immediate-release topiramate 200 mg to 400 mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg per day. Adverse reactions associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia. Pediatric Patients 2 to 15 Years of Age In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with immediate-release topiramate at dosages of 5 mg/kg/day to 9 mg/kg/day (recommended dosage range) and 101 patients received placebo. The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg/kg/day to 9 mg/kg/day immediate-release topiramate group with an incidence higher (≥10%) than in the placebo group were: fatigue and somnolence (see Table 5). Table 5 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg/kg/day to 9 mg/kg/day (recommended dosage range) of immediate-release topiramate and was greater than placebo incidence.

he placebo group were: fatigue and somnolence (see Table 5). Table 5 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg/kg/day to 9 mg/kg/day (recommended dosage range) of immediate-release topiramate and was greater than placebo incidence. Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients 2 to 15 Years of Age *, † Placebo Topiramate Body System/ Adverse Reaction (N=101) (N=98) % % Body as a Whole-General Disorders Fatigue 5 16 Injury 13 14 Central & Peripheral Nervous System Disorders Gait abnormal 5 8 Ataxia 2 6 Hyperkinesia 4 5 Dizziness 2 4 Speech disorders/Related speech problems 2 4 Gastro-Intestinal System Disorders Nausea 5 6 Saliva increased 4 6 Constipation 4 5 Gastroenteritis 2 3 Metabolic and Nutritional Disorders Weight loss 1 9 Platelet, Bleeding & Clotting Disorders Purpura 4 8 Epistaxis 1 4 Psychiatric Disorders Somnolence 16 26 Anorexia 15 24 Nervousness 7 14 Personality disorder (Behavior Problems) 9 11 Difficulty with concentration/attention 2 10 Aggressive reaction 4 9 Insomnia 7 8 Difficulty with memory 0 5 Confusion 3 4 Psychomotor slowing 2 3 Resistance Mechanism Disorders Infection viral 3 7 Respiratory System Disorders Pneumonia 1 5 Skin and Appendages Disorders Skin Disorder 2 3 Urinary System Disorders Urinary incontinence 2 4 * Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Migraine Adults In the four multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine (which included 35 pediatric patients 12 to 15 years of age), most adverse reactions occurred more frequently during the titration period than during the maintenance period. The most common adverse reactions with immediate-release topiramate 100 mg in the clinical trials for the preventive treatment of migraine of predominantly adults that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 6). Table 6 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any immediate-release topiramate group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (100 mg/day).

analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants). Other Adverse Reactions Observed During Clinical Trials Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect. Laboratory Test Abnormalities Adult Patients In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride, and ammonia, immediate-release topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions (5.4 , 5.13 )] . Controlled trials of adjunctive topiramate treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate versus 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate versus 1% placebo), and decreased serum potassium (0.4% topiramate versus 0.1% placebo). Pediatric Patients In pediatric patients (1 to 24 months) receiving adjunctive topiramate for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, alkaline phosphatase, and total protein. The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis) and potassium with immediate-release topiramate (vs. placebo) [see Use in Specific Populations (8.4) ] . Topiramate extended-release capsules are not indicated for partial-onset seizures in pediatric patients less than 6 years of age. In pediatric patients (ranging from 6 to 17 years of age) receiving immediate-release topiramate for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils. The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations ( 8.4) ] . Topiramate extended-release capsules are not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age.

hils. The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations ( 8.4) ] . Topiramate extended-release capsules are not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of immediate-release topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole-General Disorders: oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3) ] , hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions ( 5.13) ] , hypothermia with concomitant valproic acid [see Warnings and Precautions 5.15) ] . Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions ( 5. 12 )] , pemphigus Urinary System Disorders: kidney stones, nephrocalcinosis [see Warnings and Precautions ( 5.14 )] Vision disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions ( 5.1 )] , maculopathy Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.

<table width="504.2pt" cellspacing="0" cellpadding="0" border="1"><col width="504.2pt"/><col/><col/><col/><col/><tbody><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 3: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trial in Adult and Pediatric Patients</content></paragraph></td></tr><tr><td rowspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body System/ Adverse Reaction</content></paragraph></td><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Age Group</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Pediatric </content></paragraph><paragraph><content styleCode="bold">(6 to 15 Years) </content></paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Adult </content></paragraph><paragraph><content styleCode="bold">(Age &#x2265;16 Years)</content></paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Immediate-release Topiramate Daily</content></paragraph><paragraph><content styleCode="bold">Dosage Group (mg/day)</content></paragraph><paragraph><content styleCode="bold"> 50 400 50 400</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=74)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=77)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=160)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=159)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body as a Whole-General Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Asthenia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fever</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Leg pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3"

prule Lrule Rrule"><paragraph>Leg pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Paresthesia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>21</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>40</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Ataxia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hypoesthesia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hypertonia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Involuntary Muscle contraction </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vertigo</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastro-intestinal System Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Constipation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diarrhea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule T

otrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diarrhea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule T oprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Gastritis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dry mouth</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Liver and Biliary System Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Increase in Gamma-GT </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Weight loss</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Platelet, Bleeding &amp; Clotting Disorders </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Epistaxis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anorexia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anxiety </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" B

ule Lrule Rrule"><paragraph>14</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anxiety </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" B otrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cognitive problems</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Confusion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Depression </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Difficulty with concentration or attention </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Difficulty with memory </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Insomnia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Decrease in libido</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mood problems</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Personality disorder (behavior problems) </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Psychomotor sl

><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Psychomotor sl owing</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Somnolence </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10 </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Red Blood Cell Disorders </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anemia </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Reproductive Disorders, Female</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Intermenstrual bleeding </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vaginal hemorrhage</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Resistance Mechanism Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Viral infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" B

e Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" B otrule Toprule Lrule Rrule"><paragraph>Bronchitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Upper respiratory tract infection </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rhinitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sinusitis </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Skin and Appendages Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Alopecia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pruritus</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rash</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Acne</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Special Senses Other, Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Taste perversion</paragraph></td><td styleCode=" Botrule Toprule Lrul

paragraph><content styleCode="bold">Special Senses Other, Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Taste perversion</paragraph></td><td styleCode=" Botrule Toprule Lrul e Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Urinary System Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cystitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Micturition frequency </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Renal calculus</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Urinary incontinence </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Vascular (Extracardiac) Disorders </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Flushing </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr></tbody></table>

Toprule Lrule Rrule"><paragraph>Flushing </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="6.65in"/><col/><col/><tbody><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 4: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults ^{*, &#x2020;}</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Topiramate</content></paragraph><paragraph><content styleCode="bold">Dosage (mg/day)</content></paragraph><paragraph><content styleCode="bold">200 to 400 </content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body System/Adverse Reaction</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=291)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=183)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body as a Whole-General Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Asthenia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Back pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Chest pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Influenza-like symptoms</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>25</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Ataxia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule

Lrule Rrule"><paragraph>25</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Ataxia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Speech disorders/Related speech problems</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Paresthesia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nystagmus</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Tremor</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Language problems</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Coordination abnormal</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Gait abnormal</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastro-Intestinal System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspepsia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Constipation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Weight loss </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Somnolence</paragraph></td><td styleCode=" Botrule Toprule Lr

Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Somnolence</paragraph></td><td styleCode=" Botrule Toprule Lr ule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>29</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nervousness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Psychomotor slowing</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Difficulty with memory</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Confusion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anorexia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Difficulty with concentration/attention</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mood problems</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Agitation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Aggressive reaction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Emotional liability</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cognitive problems</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Reproductive Disorders, Female</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Breast pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rhinitis</paragraph></td><td styleCode=

Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rhinitis</paragraph></td><td styleCode= " Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pharyngitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sinusitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Vision Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vision abnormal</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diplopia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo</paragraph><paragraph><content styleCode="bold">^&#x2020;</content>Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.</paragraph></td></tr></tbody></table>

" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pharyngitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sinusitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Vision Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vision abnormal</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diplopia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo</paragraph><paragraph><content styleCode="bold">^&#x2020;</content>Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="6.65in"/><col/><col/><tbody><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients 2 to 15 Years of Age^{*, &#x2020;}</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Topiramate</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body System/ Adverse Reaction</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=101)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=98)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body as a Whole-General Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Injury</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Gait abnormal</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Ataxia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hyperkinesia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Speech disorders/Related speech problems</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastro-Intestinal System Disorders</content>

problems</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastro-Intestinal System Disorders</content> </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Saliva increased</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Constipation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Gastroenteritis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Weight loss </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Platelet, Bleeding &amp; Clotting Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Purpura</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Epistaxis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Somnolence</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>26</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anorexia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>24</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nervousness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Personality disorder (Behavior Problems)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Difficulty with concentration/attention</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td styleCode=" Botrule Toprule L

ph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Difficulty with concentration/attention</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td styleCode=" Botrule Toprule L rule Rrule"><paragraph>Aggressive reaction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Insomnia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Difficulty with memory</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Confusion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Psychomotor slowing</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Resistance Mechanism Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Infection viral</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pneumonia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Skin and Appendages Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Skin Disorder</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Urinary System Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Urinary incontinence</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo</paragraph><paragraph><content styleCode="bold">^&#x2020;</content>Values represent the percentage of patients reporting a given adverse reaction.

Lrule Rrule"><paragraph>^*Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo</paragraph><paragraph><content styleCode="bold">^&#x2020;</content>Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category</paragraph></td></tr></tbody></table>

Lrule Rrule"><paragraph>^*Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo</paragraph><paragraph><content styleCode="bold">^&#x2020;</content>Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="6.65in"/><col/><col/><col/><tbody><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 6: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults^{*,&#x2020;,&#x2021;}</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Topiramate Dosage (mg/day)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">50</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">100</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body System/ Adverse Reaction</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=445)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=235)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=386)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body as a Whole-General Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Injury</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Paresthesia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>35</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>51</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule

Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hypoaesthesia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Language problems </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastro-Intestinal System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diarrhea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal pain </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspepsia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dry mouth </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Gastroenteritis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Weight loss</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Musculoskeletal System Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Arthralgia </paragraph

paragraph><content styleCode="bold">Musculoskeletal System Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Arthralgia </paragraph ></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anorexia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Somnolence</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Difficulty with memory</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Insomnia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Difficulty with concentration/attention</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mood problems</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anxiety</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Depression</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nervousness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Confusion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" B

ode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Confusion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" B otrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Psychomotor slowing </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Reproductive Disorders, Female</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Menstrual disorder</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Reproductive Disorders, Male</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Ejaculation premature</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Resistance Mechanism Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Viral Infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Upper respiratory tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sinusitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pharyngitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Coughing</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4<

graph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Coughing</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4< /paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Bronchitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspnea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Skin and Appendages Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pruritis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Special Sense Other, Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Taste perversion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Urinary System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Urinary tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Vision Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Blurred vision</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*Includes 35 adolescent patients age 12 to 15 years</paragraph><paragraph><content styleCode="bold">^&#x2020;</content> Values represent the percentage of patients reporting a given reaction.

><paragraph>2</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*Includes 35 adolescent patients age 12 to 15 years</paragraph><paragraph><content styleCode="bold">^&#x2020;</content> Values represent the percentage of patients reporting a given reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.</paragraph><paragraph><content styleCode="bold">^&#x2021;</content> Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for more than 50% of reactions coded as vision abnormal, a preferred term</paragraph></td></tr></tbody></table>

ategory.</paragraph><paragraph><content styleCode="bold">^&#x2021;</content> Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for more than 50% of reactions coded as vision abnormal, a preferred term</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="6.65in"/><col/><col/><col/><tbody><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 7: Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age^*&#x2020;</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Immediate-Release Topiramate Dosage</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">50 mg/day</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">100 mg/day</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body System/ Adverse Reaction</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=45)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=46)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=48)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body as a Whole - General Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fever</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Paresthesia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>19</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph

agraph>19</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph >6</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastrointestinal System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal pain </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Weight loss</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anorexia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Somnolence</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Insomnia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Resistance Mechanism Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Infection viral</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Upper respiratory tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>26</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>23</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rhinitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><parag

paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>26</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>23</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rhinitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><parag raph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sinusitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Coughing</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Special Senses Other, Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Taste perversion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Vision Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Conjunctivitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*35 adolescent patients aged 12 to &lt;16 years were also included in adverse reaction assessment for adults</paragraph><paragraph><content styleCode="bold">^&#x2020;</content> Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events.</paragraph></td></tr></tbody></table>

patients aged 12 to &lt;16 years were also included in adverse reaction assessment for adults</paragraph><paragraph><content styleCode="bold">^&#x2020;</content> Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events.</paragraph></td></tr></tbody></table> <table width="504.2pt" cellspacing="0" cellpadding="0" border="1"><col width="504.2pt"/><col/><col/><col/><col/><tbody><tr><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 3: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trial in Adult and Pediatric Patients</content></paragraph></td></tr><tr><td rowspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body System/ Adverse Reaction</content></paragraph></td><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Age Group</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Pediatric </content></paragraph><paragraph><content styleCode="bold">(6 to 15 Years) </content></paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Adult </content></paragraph><paragraph><content styleCode="bold">(Age &#x2265;16 Years)</content></paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Immediate-release Topiramate Daily</content></paragraph><paragraph><content styleCode="bold">Dosage Group (mg/day)</content></paragraph><paragraph><content styleCode="bold"> 50 400 50 400</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=74)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=77)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=160)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">(N=159)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body as a Whole-General Disorders</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Asthenia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fever</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Leg pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3"

7 DRUG INTERACTIONS Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day ( 7.5 ) Monitor lithium levels if lithium is used with high-dose topiramate extended-release capsules ( 7.8 ) 7.1 Alcohol Alcohol use is contraindicated within 6 hours prior to and 6 hours after topiramate extended-release capsules administration [see Contraindications (4) and Warnings and Precautions ( 5.5 )] . 7.2 Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3) ] . Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions ( 5.13 , 5.15 ) and Clinical Pharmacology ( 12.3 )] . 7.3 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when topiramate extended-release capsules is given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology ( 12.3) ] . 7.4 CNS Depressants Concomitant administration of topiramate with other CNS depressant drugs or alcohol has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, topiramate extended-release capsules should be used with extreme caution if used in combination with alcohol and other CNS depressants [see Contraindications (4) and Warnings and Precautions ( 5.7) ] . 7.5 Oral Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with topiramate extended-release capsules. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology ( 12.3 )] . 7.6 Hydrochlorothiazide (HCTZ) Topiramate C max and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate extended-release capsules may require a decrease in the topiramate extended-release capsules dose [see Clinical Pharmacology (12.3) ] . 7.7 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial.

d-release capsules may require a decrease in the topiramate extended-release capsules dose [see Clinical Pharmacology (12.3) ] . 7.7 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate extended-release capsules is added to pioglitazone therapy or pioglitazone is added to topiramate extended-release capsules therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology ( 12.3 )] . 7.8 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose topiramate extended-release capsules [see Clinical Pharmacology ( 12.3 )] . 7.9 Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate extended-release capsules and any adjustments in amitriptyline dose should be made according to the patients’ clinical response and not on the basis of plasma levels [see Clinical Pharmacology ( 12.3) ]. 7.1 Alcohol Alcohol use is contraindicated within 6 hours prior to and 6 hours after topiramate extended-release capsules administration [see Contraindications (4) and Warnings and Precautions ( 5.5 )] . 7.2 Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3) ] . Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions ( 5.13 , 5.15 ) and Clinical Pharmacology ( 12.3 )] .

comitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions ( 5.13 , 5.15 ) and Clinical Pharmacology ( 12.3 )] . 7.3 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when topiramate extended-release capsules is given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology ( 12.3) ] . 7.4 CNS Depressants Concomitant administration of topiramate with other CNS depressant drugs or alcohol has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, topiramate extended-release capsules should be used with extreme caution if used in combination with alcohol and other CNS depressants [see Contraindications (4) and Warnings and Precautions ( 5.7) ] . 7.5 Oral Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with topiramate extended-release capsules. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology ( 12.3 )] . 7.6 Hydrochlorothiazide (HCTZ) Topiramate C max and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate extended-release capsules may require a decrease in the topiramate extended-release capsules dose [see Clinical Pharmacology (12.3) ] .

e (HCTZ) Topiramate C max and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate extended-release capsules may require a decrease in the topiramate extended-release capsules dose [see Clinical Pharmacology (12.3) ] . 7.7 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate extended-release capsules is added to pioglitazone therapy or pioglitazone is added to topiramate extended-release capsules therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology ( 12.3 )] . 7.8 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose topiramate extended-release capsules [see Clinical Pharmacology ( 12.3 )] . 7.9 Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate extended-release capsules and any adjustments in amitriptyline dose should be made according to the patients’ clinical response and not on the basis of plasma levels [see Clinical Pharmacology ( 12.3) ].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as topiramate extended-release capsules, during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/. Risk Summary Topiramate extended-release capsules can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age (SGA) [see Human Data] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data] . In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor. Topiramate extended-release capsules treatment can cause metabolic acidosis [see Warnings and Precautions ( 5.4) ] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4 )] .

ic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4 )] . Newborns of mothers treated with topiramate extended-release capsules should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery. Data Human Data Data from pregnancy registries indicate an increased risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy. In the NAAED pregnancy registry, the prevalence of oral clefts among topiramate-exposed infants (1.1%) was higher than the prevalence of infants exposed to reference AEDs (0.36%), or the prevalence in infants of mothers without epilepsy and without exposure to AEDs (0.12%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval=[CI] 4.0 to 23.0) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED, and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data When topiramate (0 mg/kg/day, 20 mg/kg/day, 100 mg/kg/day, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0 mg/kg/day, 20 mg/kg/day, 100 mg/kg/day, and 500 mg/kg/day or 0 mg/kg/day, 0.2 mg/kg/day, 2.5 mg/kg/day, 30 mg/kg/day, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 mg/kg/day and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater.

mg/kg/day and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0 mg/kg/day, 20 mg/kg/day, 60 mg/kg/day, and 180 mg/kg/day or 0 mg/kg/day, 10 mg/kg/day, 35 mg/kg/day, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0 mg/kg/day, 0.2 mg/kg/day, 4 mg/kg/day, 20 mg/kg/day, and 100 mg/kg/day or 0 mg/kg/day, 2 mg/kg/day, 20 mg/kg/day, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre-and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0 mg/kg/day, 0.2 mg/kg/day, 2.5 mg/kg/day, 30 mg/kg/day, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. 8.2 Lactation Risk Summary Topiramate is excreted in human milk [see Data] . The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for topiramate extended-release capsules and any potential adverse effects on the breastfed infant from topiramate extended-release capsules or from the underlying maternal condition. Data Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma. 8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks to the fetus of oral clefts and of being small for gestational age [see Drug Interactions ( 7.5 ) and Use in Specific Populations ( 8.1 )] . 8.4 Pediatric Use Seizures in Pediatric Patients 6 Years of Age and Older The safety and effectiveness of topiramate extended-release capsules for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Adverse Reactions ( 6.1) , Clinical Studies ( 14.2 , 14.3) ] .

mate extended-release capsules for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Adverse Reactions ( 6.1) , Clinical Studies ( 14.2 , 14.3) ] . The adverse reactions in pediatric patients treated for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome are similar to those seen in adults [see Warnings and Precautions (5) and Adverse Reactions (6 )] . These include, but are not limited to: ·oligohydrosis and hyperthermia [see Warnings and Precautions (5.3 )] dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.4 )] dose-related increased incidence of hyperammonemia [see Warnings and Precautions ( 5.13) ] Not Recommended for Pediatric Patients Younger than 6 Years of Age The safety and effectiveness of topiramate extended-release capsules for treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients younger than 6 years of age has not been established. Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, topiramate extended-release capsules is recommended only for children age 6 or older. The following pediatric use information for adjunctive treatment for partial-onset epilepsy in infants and toddlers (1 to 24 months) is based on studies conducted with immediate-release topiramate, which failed to demonstrate efficacy. Safety and effectiveness of immediate-release topiramate in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5 mg/kg, 15 mg/kg, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions ( 6.1 )] .

ents on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions ( 6.1 )] . Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Adverse Reactions ( 6.1 )] . The significance of these findings is uncertain. Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Adverse Reactions (6.1) ] . There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain. Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.13)] . Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions ( 5.4 ) and Adverse Reactions (6) ] . In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient’s underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions ( 5.7 )] . In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known. Other Pediatric Studies Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study [see Adverse Reactions ( 6.1 )] . A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28, 6 to15 years of age) versus levetiracetam (N=35, 4 to15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 8 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive.

ation were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 8 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect an immediate-release topiramate-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight). Table 8 Summary of Immediate-release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval) Annual Change in BMD Lumbar Spine (g/cm 2 ) -0.036 (-0.058, -0.014) Annual Change in BMD TBLH* (g/cm 2 ) -0.026 (-0.039, -0.012) Annual Change in Height (cm) (4 to 9 years, Primary Analysis Population for Height) ** -0.84 (-2.67, 0.99) Annual Change in Height (cm) (4 to 15 years) -0.75 (-2.21, 0.71) Annual Change in Height (cm) (10 to 15 years) -1.01 (-3.64, 1.61) Height Velocity (cm/year) (4 to 9 years) -1.00 (-2.76, 0.76) Height Velocity (cm/year) (4 to 15 years) -0.98 (-2.33, 0.37) Height Velocity (cm/year) (10 to 15 years) -0.96 (-3.24, 1.32) Annual Change in Weight (kg) -2.05 (-3.66, -0.45) * TBLH=total body less head ** Whereas no patients were randomized to 2 to 5 year age subgroup for immediate-release topiramate, 5 patients (4 to 5 years) were randomized to the active control group. Metabolic acidosis (serum bicarbonate <20 mEq/L) was observed in all immediate-release topiramate-treated patients at some time in the study [see Warnings and Precautions ( 5.4) ]. Over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate < 20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and ≥ 5mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 mg/day to 200 mg/day, or 2 mg/kg/day to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies ( 14.4 )] , a flexible dose (2 mg/kg/day to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase.

67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 3 [see Clinical Studies ( 14.4 )] . Efficacy of topiramate (2 mg/kg/day to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients 12 to 16 years of age) for 20 weeks. In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release topiramate that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions ( 6.1 )] . The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions ( 5.7) ] . Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions (5.4) ] . In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Adverse Reactions ( 6.1) ] . Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse that were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology ( 12.2 )] . Preventive Treatment of Migraine in Pediatric Patients 6 to 11 Years of Age Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. The risk for cognitive adverse reactions was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.7 )] . Juvenile Animal Studies When topiramate (30 mg/kg/day, 90 mg/kg/day, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis.

, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis. 8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2 . Estimate GFR should be measured prior to dosing [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3) ] . 8.6 Renal Impairment The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m 2 ) and severe (creatinine clearance less than 30 mL/min/1.73m 2 ) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . 8.7 Patients Undergoing Hemodialysis Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration ( 2.6 ) and Clinical Pharmacology ( 12.3 )] .

and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . 8.7 Patients Undergoing Hemodialysis Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration ( 2.6 ) and Clinical Pharmacology ( 12.3 )] . 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as topiramate extended-release capsules, during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/. Risk Summary Topiramate extended-release capsules can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age (SGA) [see Human Data] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data] . In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor. Topiramate extended-release capsules treatment can cause metabolic acidosis [see Warnings and Precautions ( 5.4) ] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4 )] .

mg/kg/day and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0 mg/kg/day, 20 mg/kg/day, 60 mg/kg/day, and 180 mg/kg/day or 0 mg/kg/day, 10 mg/kg/day, 35 mg/kg/day, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0 mg/kg/day, 0.2 mg/kg/day, 4 mg/kg/day, 20 mg/kg/day, and 100 mg/kg/day or 0 mg/kg/day, 2 mg/kg/day, 20 mg/kg/day, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre-and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0 mg/kg/day, 0.2 mg/kg/day, 2.5 mg/kg/day, 30 mg/kg/day, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD for epilepsy or migraine on a mg/m 2 basis.

f organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. 8.2 Lactation Risk Summary Topiramate is excreted in human milk [see Data] . The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for topiramate extended-release capsules and any potential adverse effects on the breastfed infant from topiramate extended-release capsules or from the underlying maternal condition. Data Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma. 8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks to the fetus of oral clefts and of being small for gestational age [see Drug Interactions ( 7.5 ) and Use in Specific Populations ( 8.1 )] .

8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks to the fetus of oral clefts and of being small for gestational age [see Drug Interactions ( 7.5 ) and Use in Specific Populations ( 8.1 )] . 8.4 Pediatric Use Seizures in Pediatric Patients 6 Years of Age and Older The safety and effectiveness of topiramate extended-release capsules for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Adverse Reactions ( 6.1) , Clinical Studies ( 14.2 , 14.3) ] . The adverse reactions in pediatric patients treated for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome are similar to those seen in adults [see Warnings and Precautions (5) and Adverse Reactions (6 )] . These include, but are not limited to: ·oligohydrosis and hyperthermia [see Warnings and Precautions (5.3 )] dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.4 )] dose-related increased incidence of hyperammonemia [see Warnings and Precautions ( 5.13) ] Not Recommended for Pediatric Patients Younger than 6 Years of Age The safety and effectiveness of topiramate extended-release capsules for treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients younger than 6 years of age has not been established. Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, topiramate extended-release capsules is recommended only for children age 6 or older. The following pediatric use information for adjunctive treatment for partial-onset epilepsy in infants and toddlers (1 to 24 months) is based on studies conducted with immediate-release topiramate, which failed to demonstrate efficacy. Safety and effectiveness of immediate-release topiramate in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5 mg/kg, 15 mg/kg, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%).

severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions ( 6.1 )] . Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Adverse Reactions ( 6.1 )] . The significance of these findings is uncertain. Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Adverse Reactions (6.1) ] . There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain. Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.13)] . Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions ( 5.4 ) and Adverse Reactions (6) ] . In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient’s underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions ( 5.7 )] . In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known. Other Pediatric Studies Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study [see Adverse Reactions ( 6.1 )] .

known. Other Pediatric Studies Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study [see Adverse Reactions ( 6.1 )] . A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28, 6 to15 years of age) versus levetiracetam (N=35, 4 to15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 8 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect an immediate-release topiramate-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight). Table 8 Summary of Immediate-release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval) Annual Change in BMD Lumbar Spine (g/cm 2 ) -0.036 (-0.058, -0.014) Annual Change in BMD TBLH* (g/cm 2 ) -0.026 (-0.039, -0.012) Annual Change in Height (cm) (4 to 9 years, Primary Analysis Population for Height) ** -0.84 (-2.67, 0.99) Annual Change in Height (cm) (4 to 15 years) -0.75 (-2.21, 0.71) Annual Change in Height (cm) (10 to 15 years) -1.01 (-3.64, 1.61) Height Velocity (cm/year) (4 to 9 years) -1.00 (-2.76, 0.76) Height Velocity (cm/year) (4 to 15 years) -0.98 (-2.33, 0.37) Height Velocity (cm/year) (10 to 15 years) -0.96 (-3.24, 1.32) Annual Change in Weight (kg) -2.05 (-3.66, -0.45) * TBLH=total body less head ** Whereas no patients were randomized to 2 to 5 year age subgroup for immediate-release topiramate, 5 patients (4 to 5 years) were randomized to the active control group. Metabolic acidosis (serum bicarbonate <20 mEq/L) was observed in all immediate-release topiramate-treated patients at some time in the study [see Warnings and Precautions ( 5.4) ]. Over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate < 20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and ≥ 5mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients.

uggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 mg/day to 200 mg/day, or 2 mg/kg/day to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies ( 14.4 )] , a flexible dose (2 mg/kg/day to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 3 [see Clinical Studies ( 14.4 )] . Efficacy of topiramate (2 mg/kg/day to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients 12 to 16 years of age) for 20 weeks. In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release topiramate that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions ( 6.1 )] . The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions ( 5.7) ] . Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions (5.4) ] . In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Adverse Reactions ( 6.1) ] . Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse that were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology ( 12.2 )] . Preventive Treatment of Migraine in Pediatric Patients 6 to 11 Years of Age Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age.

tablished for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. The risk for cognitive adverse reactions was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.7 )] . Juvenile Animal Studies When topiramate (30 mg/kg/day, 90 mg/kg/day, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis. 8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2 . Estimate GFR should be measured prior to dosing [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3) ] . 8.6 Renal Impairment The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m 2 ) and severe (creatinine clearance less than 30 mL/min/1.73m 2 ) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] .

in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m 2 ) and severe (creatinine clearance less than 30 mL/min/1.73m 2 ) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . 8.7 Patients Undergoing Hemodialysis Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration ( 2.6 ) and Clinical Pharmacology ( 12.3 )] .

<table cellspacing="0" cellpadding="0" border="1"><col width="1pt"/><col width="275.4pt"/><tbody><tr><td><paragraph><content styleCode="bold">Safety Parameter</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Treatment Difference in Least Square Means (95 % Confidence Interval)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in BMD Lumbar Spine (g/cm²)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">-0.036 (-0.058, -0.014)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in BMD TBLH* (g/cm²) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -0.026 (-0.039, -0.012)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in Height (cm) (4 to 9 years, Primary Analysis Population for Height) **</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -0.84 (-2.67, 0.99)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in Height (cm) (4 </content><content styleCode="bold">to 15 years) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">-0.75 (-2.21, 0.71)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in Height (cm) (10 </content><content styleCode="bold">to 15 years) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -1.01 (-3.64, 1.61)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Height Velocity (cm/year) (4 to 9 years)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -1.00 (-2.76, 0.76)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Height Velocity (cm/year) (4 to 15 years) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -0.98 (-2.33, 0.37)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Height Velocity (cm/year) (10 to 15 years)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -0.96 (-3.24, 1.32)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in Weight (kg) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -2.05 (-3.66, -0.45)</content></paragraph></td></tr></tbody></table>

tent></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in Weight (kg) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -2.05 (-3.66, -0.45)</content></paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="1pt"/><col width="275.4pt"/><tbody><tr><td><paragraph><content styleCode="bold">Safety Parameter</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Treatment Difference in Least Square Means (95 % Confidence Interval)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in BMD Lumbar Spine (g/cm²)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">-0.036 (-0.058, -0.014)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in BMD TBLH* (g/cm²) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -0.026 (-0.039, -0.012)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in Height (cm) (4 to 9 years, Primary Analysis Population for Height) **</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -0.84 (-2.67, 0.99)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in Height (cm) (4 </content><content styleCode="bold">to 15 years) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">-0.75 (-2.21, 0.71)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in Height (cm) (10 </content><content styleCode="bold">to 15 years) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -1.01 (-3.64, 1.61)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Height Velocity (cm/year) (4 to 9 years)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -1.00 (-2.76, 0.76)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Height Velocity (cm/year) (4 to 15 years) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -0.98 (-2.33, 0.37)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Height Velocity (cm/year) (10 to 15 years)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -0.96 (-3.24, 1.32)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Annual Change in Weight (kg) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> -2.05 (-3.66, -0.45)</content></paragraph></td></tr></tbody></table>

10 OVERDOSAGE Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate. Topiramate overdose has resulted in severe metabolic acidosis [see Warnings and Precautions ( 5.4) ] . A patient who ingested a dose of immediate-release topiramate between 96 g and 110 g was admitted to a hospital with a coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days. Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of topiramate extended-release capsules. In the event of overdose, topiramate extended-release capsules should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.

11 DESCRIPTION Topiramate, USP, is a sulfamate-substituted monosaccharide. Topiramate extended-release capsules are available as 200 mg capsules for oral administration. Topiramate is a white to off-white powder. Topiramate is freely soluble in polar organic solvents such as acetonitrile and acetone; and very slightly soluble to practically insoluble in non-polar organic solvents such as hexanes. Topiramate has the molecular formula C 12 H 21 NO 8 S and a molecular weight of 339.4. Topiramate is designated chemically as 2,3:4,5-Di- O -isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula: Topiramate extended-release capsules are an extended-release capsule. Topiramate extended-release capsules contain the following inactive ingredients: Sugar Spheres (contains sucrose and corn starch), Hypromellose, Povidone, Ethylcellulose, Titanium Dioxide, Talc. The capsule shells contain gelatin, titanium dioxide and colorants- FD&C Red #40, FD&C Yellow #6. Capsule shells are imprinted with black print that contains shellac, black iron oxide, propylene glycol, FD&C red #40, FD&C blue #2, FD&C blue #1 and D&C yellow #10. TOPIRAMATE ER CAPSULE

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate’s efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV. 12.2 Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 mg/kg to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP < 90 mm Hg, DBP < 50 mm Hg, SBP or DBP increases or decreases ≥ 20 mm Hg, and pulse increases or decreases ≥ 30 beats per minute. These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established. 12.3 Pharmacokinetics Absorption and Distribution Linear pharmacokinetics of topiramate from topiramate extended-release capsules were observed following a single oral dose over the range of 50 mg to 200 mg. At 25 mg, the pharmacokinetics of topiramate extended-release capsules is nonlinear possibly due to the binding of topiramate to carbonic anhydrase in red blood cells. The peak plasma concentrations (C max ) of topiramate occurred at approximately 24 hours following a single 200 mg oral dose of topiramate extended-release capsules. At steady-state, the (AUC 0-24 , C max , and C min ) of topiramate from topiramate extended-release capsules administered once-daily and the immediate-release tablet administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for topiramate extended-release capsules administered once-daily was approximately 26% and 42% in healthy subjects and in epileptic patients, respectively, compared to approximately 40% and 51%, respectively, for immediate-release topiramate [see Clinical Pharmacology ( 12.6 )]. Compared to the fasted state, high-fat meal increased the C max of topiramate by 37% and shortened the T max to approximately 8 hours following a single dose of topiramate extended-release capsules, while having no effect on the AUC.

, respectively, for immediate-release topiramate [see Clinical Pharmacology ( 12.6 )]. Compared to the fasted state, high-fat meal increased the C max of topiramate by 37% and shortened the T max to approximately 8 hours following a single dose of topiramate extended-release capsules, while having no effect on the AUC. Modeling of the observed single dose fed data with simulation to steady state showed that the effect on C max is significantly reduced following repeat administrations. Topiramate extended-release capsules can be taken without regard to meals. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of topiramate extended-release capsules. Specific Populations Renal Impairment The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73m 2 ) [see Dosage and Administration ( 2.5 )] . Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration ( 2.6) and Use in Specific Populations ( 8.7) ]. Hepatic Impairment Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Age, Gender and Race The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly.

n for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration ( 2.4 ) and Use in Specific Populations ( 8.5 )] . In a study of 13 healthy elderly subjects and 18 healthy young adults who received topiramate extended-release capsules, 30% higher mean C max and 44% higher AUC values were observed in elderly compared to young subjects. Elderly subjects exhibited shorter median T max at 16 hours versus 24 hours in young subjects. The apparent elimination half-life was similar across age groups. As recommended for all patients, dosage adjustment is indicated in elderly patients with a creatinine clearance rate less than 70 mL/min/1.73 m 2 ) [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.5 )] . Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of immediate-release topiramate were evaluated in patients ages 2 to <16 years of age. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients age 2 years to <16 years of age (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years of age) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Drug-Drug Interaction Studies In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that immediate-release topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. The same drug interactions can be expected with the use of topiramate extended-release capsules. Antiepileptic Drugs Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. Interaction of topiramate extended-release capsules and standard AEDs is not expected to differ from the experience with immediate-release topiramate products. In Table 9, the second column (AED concentration) describes what happens to the concentration of the co-administered AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone.

scribes what happens to the concentration of the co-administered AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 9: Summary of AED Interactions with Topiramate AED Coadministered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase* 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide † NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400mg per day 13% decrease NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate * =Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin † =Is not administered but is an active metabolite of carbamazepine Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), immediate-release topiramate, given in the absence of other medications at doses of 50 mg/day to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200 mg, 400 mg, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET, and there was no significant dose-dependent change in EE exposure for doses of 50 mg/day to 200 mg/day. The clinical significance of the changes observed is not known [see Drug Interactions ( 7.5) ] . Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination [see Drug Interactions ( 7.6 )] . Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin T max . The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate or topiramate extended-release capsules pharmacokinetics is unclear.

linical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate or topiramate extended-release capsules pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known [see Drug Interactions ( 7.7 )] . Glyburide A drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C max and 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced C max by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions ( 7.8 )] . Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of immediate-release topiramate [see Drug Interactions ( 7.9 )] . Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100 mg, 250 mg, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 mg and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine.

ay in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Diltiazem Co-administration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg/day) resulted in a 10% decrease in C max and 25% decrease in diltiazem AUC, 27% decrease in C max and 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate. 12.6 Relative Bioavailability of Topiramate Extended-Release Capsules Compared to Immediate-Release Topiramate Study in Healthy Normal Volunteers Topiramate extended-release capsules taken once a day provides steady state plasma levels comparable to immediate-release topiramate taken every 12 hours, when administered at the same total 200 mg daily dose. In a crossover study, 33 healthy subjects were titrated to a 200 mg dose of either topiramate extended-release capsules or immediate-release topiramate and were maintained at 200 mg per day for 10 days. The 90% CI for the ratios of AUC 0-24 , C max and C min , as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose) for multiple time points were within the 80 to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80 to 125% bioequivalence limits, except for the initial time points before 1.5 hours post-dose. Study in Patients with Epilepsy In a study in epilepsy patients treated with immediate-release topiramate alone or in combination with either enzyme-inducing or neutral AEDs who were switched to an equivalent daily dose of topiramate extended-release capsules, there was a 10% decrease in AUC 0-24 , C max , and C min on the first day after the switch in all patients. At steady state, AUC 0-24 and C max were comparable to immediate-release topiramate in all patients. While patients treated with topiramate extended-release capsules alone or in combination with neutral AEDs showed comparable C min at steady state, patients treated with enzyme-inducers showed a 10% decrease in C min. This difference is likely not clinically significant and probably due to the small number of patients on enzyme-inducers.

ted with topiramate extended-release capsules alone or in combination with neutral AEDs showed comparable C min at steady state, patients treated with enzyme-inducers showed a 10% decrease in C min. This difference is likely not clinically significant and probably due to the small number of patients on enzyme-inducers. 12.1 Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate’s efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV. 12.2 Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 mg/kg to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP < 90 mm Hg, DBP < 50 mm Hg, SBP or DBP increases or decreases ≥ 20 mm Hg, and pulse increases or decreases ≥ 30 beats per minute. These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established.

minute. These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established. 12.3 Pharmacokinetics Absorption and Distribution Linear pharmacokinetics of topiramate from topiramate extended-release capsules were observed following a single oral dose over the range of 50 mg to 200 mg. At 25 mg, the pharmacokinetics of topiramate extended-release capsules is nonlinear possibly due to the binding of topiramate to carbonic anhydrase in red blood cells. The peak plasma concentrations (C max ) of topiramate occurred at approximately 24 hours following a single 200 mg oral dose of topiramate extended-release capsules. At steady-state, the (AUC 0-24 , C max , and C min ) of topiramate from topiramate extended-release capsules administered once-daily and the immediate-release tablet administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for topiramate extended-release capsules administered once-daily was approximately 26% and 42% in healthy subjects and in epileptic patients, respectively, compared to approximately 40% and 51%, respectively, for immediate-release topiramate [see Clinical Pharmacology ( 12.6 )]. Compared to the fasted state, high-fat meal increased the C max of topiramate by 37% and shortened the T max to approximately 8 hours following a single dose of topiramate extended-release capsules, while having no effect on the AUC. Modeling of the observed single dose fed data with simulation to steady state showed that the effect on C max is significantly reduced following repeat administrations. Topiramate extended-release capsules can be taken without regard to meals. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of topiramate extended-release capsules. Specific Populations Renal Impairment The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73m 2 ) [see Dosage and Administration ( 2.5 )] . Hemodialysis Topiramate is cleared by hemodialysis.

69 mL/min/1.73m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73m 2 ) [see Dosage and Administration ( 2.5 )] . Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration ( 2.6) and Use in Specific Populations ( 8.7) ]. Hepatic Impairment Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Age, Gender and Race The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration ( 2.4 ) and Use in Specific Populations ( 8.5 )] . In a study of 13 healthy elderly subjects and 18 healthy young adults who received topiramate extended-release capsules, 30% higher mean C max and 44% higher AUC values were observed in elderly compared to young subjects. Elderly subjects exhibited shorter median T max at 16 hours versus 24 hours in young subjects. The apparent elimination half-life was similar across age groups. As recommended for all patients, dosage adjustment is indicated in elderly patients with a creatinine clearance rate less than 70 mL/min/1.73 m 2 ) [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.5 )] . Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of immediate-release topiramate were evaluated in patients ages 2 to <16 years of age. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients age 2 years to <16 years of age (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years of age) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose.

ng pediatric patients (down to 2 years of age) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Drug-Drug Interaction Studies In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that immediate-release topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. The same drug interactions can be expected with the use of topiramate extended-release capsules. Antiepileptic Drugs Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. Interaction of topiramate extended-release capsules and standard AEDs is not expected to differ from the experience with immediate-release topiramate products. In Table 9, the second column (AED concentration) describes what happens to the concentration of the co-administered AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 9: Summary of AED Interactions with Topiramate AED Coadministered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase* 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide † NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400mg per day 13% decrease NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate * =Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin † =Is not administered but is an active metabolite of carbamazepine Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), immediate-release topiramate, given in the absence of other medications at doses of 50 mg/day to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200 mg, 400 mg, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET, and there was no significant dose-dependent change in EE exposure for doses of 50 mg/day to 200 mg/day. The clinical significance of the changes observed is not known [see Drug Interactions ( 7.5) ] . Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly.

clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination [see Drug Interactions ( 7.6 )] . Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin T max . The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate or topiramate extended-release capsules pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known [see Drug Interactions ( 7.7 )] . Glyburide A drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C max and 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced C max by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions ( 7.8 )] . Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of immediate-release topiramate [see Drug Interactions ( 7.9 )] .

g multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of immediate-release topiramate [see Drug Interactions ( 7.9 )] . Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100 mg, 250 mg, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 mg and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Diltiazem Co-administration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg/day) resulted in a 10% decrease in C max and 25% decrease in diltiazem AUC, 27% decrease in C max and 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.

ed in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate. 12.6 Relative Bioavailability of Topiramate Extended-Release Capsules Compared to Immediate-Release Topiramate Study in Healthy Normal Volunteers Topiramate extended-release capsules taken once a day provides steady state plasma levels comparable to immediate-release topiramate taken every 12 hours, when administered at the same total 200 mg daily dose. In a crossover study, 33 healthy subjects were titrated to a 200 mg dose of either topiramate extended-release capsules or immediate-release topiramate and were maintained at 200 mg per day for 10 days. The 90% CI for the ratios of AUC 0-24 , C max and C min , as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose) for multiple time points were within the 80 to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80 to 125% bioequivalence limits, except for the initial time points before 1.5 hours post-dose. Study in Patients with Epilepsy In a study in epilepsy patients treated with immediate-release topiramate alone or in combination with either enzyme-inducing or neutral AEDs who were switched to an equivalent daily dose of topiramate extended-release capsules, there was a 10% decrease in AUC 0-24 , C max , and C min on the first day after the switch in all patients. At steady state, AUC 0-24 and C max were comparable to immediate-release topiramate in all patients. While patients treated with topiramate extended-release capsules alone or in combination with neutral AEDs showed comparable C min at steady state, patients treated with enzyme-inducers showed a 10% decrease in C min. This difference is likely not clinically significant and probably due to the small number of patients on enzyme-inducers.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis An increase in urinary bladder tumors was observed in mice given topiramate (0 mg/kg/day, 20 mg/kg/day, 75 mg/kg/day, and 300 mg/kg/day) in the diet for 21 months. An increase in the incidence of bladder tumors in males and females receiving 300 mg/kg was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy and approximately 4 times the MRHD for migraine (100 mg) on a mg/m 2 basis. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m 2 basis). Mutagenesis Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro ; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo . Impairment of Fertility No adverse effects on male or female fertility were observed in rats administered oral doses of up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2 basis) prior to and during mating and early pregnancy.

ytes in vitro or in rat bone marrow in vivo . Impairment of Fertility No adverse effects on male or female fertility were observed in rats administered oral doses of up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2 basis) prior to and during mating and early pregnancy. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis An increase in urinary bladder tumors was observed in mice given topiramate (0 mg/kg/day, 20 mg/kg/day, 75 mg/kg/day, and 300 mg/kg/day) in the diet for 21 months. An increase in the incidence of bladder tumors in males and females receiving 300 mg/kg was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy and approximately 4 times the MRHD for migraine (100 mg) on a mg/m 2 basis. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m 2 basis). Mutagenesis Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro ; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo . Impairment of Fertility No adverse effects on male or female fertility were observed in rats administered oral doses of up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2 basis) prior to and during mating and early pregnancy.

14 CLINICAL STUDIES 14.1 Bridging Study to Demonstrate Pharmacokinetic Equivalence between Extended-Release and Immediate-Release Topiramate Formulations The basis for approval of the extended-release formulation (topiramate extended-release capsules) included the studies described below using an immediate-release formulation and the demonstration of the pharmacokinetic equivalence of topiramate extended-release capsules to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see Clinical Pharmacology ( 12.6) ] . The clinical studies described in the following sections were conducted using immediate-release topiramate. 14.2 Monotherapy Epilepsy Patients With Partial-Onset or Primary Generalized Tonic-Clonic Seizures Adults and Pediatric Patients 10 Years of Age and Older The effectiveness of topiramate as initial monotherapy in adults and pediatric patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1). Study 1 was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg per day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day of topiramate. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty-eight percent of patients achieved the maximal dose of 400 mg/day for >2 weeks, and patients who did not tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use. Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure in Study 1 Pediatric Patients 6 to 9 Years of Age The conclusion that topiramate is effective as initial monotherapy in pediatric patients 6 to 9 years of age with partial-onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach using data from the controlled epilepsy trials conducted with immediate-release topiramate described in labeling. The approach consisted of first showing a similar exposure response relationship between pediatric patients down to 2 years of age and adults when immediate-release topiramate was given as adjunctive therapy [see Use in Specific Populations ( 8.4) ] . Similarity of exposure-response was demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy.

tric patients down to 2 years of age and adults when immediate-release topiramate was given as adjunctive therapy [see Use in Specific Populations ( 8.4) ] . Similarity of exposure-response was demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy. Specific dosing in pediatric patients 6 to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with immediate-release topiramate initial monotherapy [see Dosage and Administration (2.1)] . TOPIRAMATE ER CAPSULE 14.3 Adjunctive Therapy Epilepsy Adult Patients With Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for adults with partial-onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures. Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a pre-specified minimum number of partial-onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg/day or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 mg/day or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 mg/day or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 10. Pediatric Patients 6 to 16 Years of Age With Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for pediatric patients 6 to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures. Patients in Study 8 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 mg/day or 50 mg/day; the dose was then increased by 25 mg/day to 150 mg/day increments every other week until the assigned dosage of 125 mg/day, 175 mg/day, 225 mg/day or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases.

inning at 25 mg/day or 50 mg/day; the dose was then increased by 25 mg/day to 150 mg/day increments every other week until the assigned dosage of 125 mg/day, 175 mg/day, 225 mg/day or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period. Patients With Primary Generalized Tonic-Clonic Seizures The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 6 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo (see Table 11). Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg/day to 150 mg/day increments every other week until the assigned dose of 175 mg/day, 225 mg/day or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period. Patients With Lennox-Gastaut Syndrome The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10), comparing a single dosage of topiramate with placebo (see Table 11). Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4 week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity. Table 10: Immediate Release Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults With Partial-Onset Seizures * Target Topiramate Dosage (mg per day) Study Stabilization Dose Placebo † 200 400 600 800 1,000 2 N 42 42 40 41 -- -- Mean Dose 5.9 200 390 556 -- -- Median Dose 6.0 200 400 600 -- -- 3 N 44 -- -- 40 45 40 Mean Dose 9.7 -- -- 544 739 796 Median Dose 10.0 -- -- 600 800 1,000 4 N 23 -- 19 -- -- -- Mean Dose 3.8 -- 395 -- -- -- Median Dose 4.0 -- 400 -- -- -- 5 N 30 -- -- 28 -- -- Mean Dose 5.7 -- -- 522 -- -- Median Dose 6.0 -- -- 600 -- -- 6 N 28 -- -- -- 25 -- Mean Dose 8.0 -- -- -- 568 -- Median Dose 8.0 -- -- -- 600 -- 7 N 90 157 -- -- -- -- Mean Dose 8 200 -- -- -- -- Median Dose 8 200 -- -- -- -- * Dose-response studies were not conducted for other indications or pediatric partial-onset seizures † Placebo dosages are given as the number of tablets.

6 N 28 -- -- -- 25 -- Mean Dose 8.0 -- -- -- 568 -- Median Dose 8.0 -- -- -- 600 -- 7 N 90 157 -- -- -- -- Mean Dose 8 200 -- -- -- -- Median Dose 8 200 -- -- -- -- * Dose-response studies were not conducted for other indications or pediatric partial-onset seizures † Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day) In all adjunctive topiramate trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 11. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial. Table 11: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials Target Topiramate Dosage (mg per day) Study # # Placebo 200 400 600 800 1,000 ≈6 mg/kg/day* Partial Onset Seizures Studies in Adults 2 N 45 45 45 46 -- -- -- Median % Reduction 12 27 † 48 ‡ 45 § -- -- -- % Responders 18 24 44 ¶ 46 ¶ -- -- -- 3 N 47 -- -- 48 48 47 -- Median % Reduction 2 -- -- 41 § 41 § 36 § % Responders 9 -- -- 40 § 41 § 36 ¶ 4 N 24 -- 23 -- -- -- -- Median % Reduction 1 -- 41 # -- -- -- -- % Responders 8 -- 35 ¶ -- -- -- -- 5 N 30 -- -- 30 -- -- -- Median % Reduction -12 -- -- 46 Þ -- -- -- % Responders 10 -- -- 47 § -- -- -- 6 N 28 -- -- -- 28 -- -- Median % Reduction -21 -- -- -- 24 § -- -- % Responders 0 -- -- -- 43 § -- -- 7 N 91 168 -- -- -- -- -- Median % Reduction 20 44 § -- -- -- -- -- % Responders 24 45 § Partial Onset Seizures Studies in Pediatric Patients ß 8 N 45 -- -- -- -- -- 41 Median % Reduction 11 -- -- -- -- -- 33 ¶ % Responders 20 -- -- -- -- -- 39 Primary Generalized Tonic-Clonic à, ß 9 N 40 -- -- -- -- -- 39 Median % Reduction 9 -- -- -- -- -- 57 ¶ % Responders 20 -- -- -- -- -- 56 § Lennox-Gastaut Syndrome è, ß 10 N 49 -- -- -- -- -- 46 Median % Reduction -5 -- -- -- -- -- 15 ¶ % Responders 14 28 ð Improvement in Seizure Severity ø 28 52 ¶ Comparisons with placebo: *For Studies 8 and 9, specified target dosages (<9.3 mg/kg/day) were assigned based on subject’s weight to approximate a dosage of 6mg/kg per day; these dosages corresponded to mg/day dosages of 125 mg/day, 175 mg/day, 225 mg/day , and 400 mg/day † p= 0.080; ‡ p ≤ 0.010; § p ≤ 0.001; ¶ p ≤ 0.050; # p= 0.065; Þ p ≤ 0.005; ß Studies included pediatric patients 2 years of age and older, an age group for which topiramate extended-release capsules is not indicated [see Indications and Usage ( 1.2 ) and Use in Specific Populations ( 8.4 )] à Median % reduction and % responders are reported for PGTC seizures; è Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures ð p= 0.071; ø Percentage of subjects who were minimally, much, or very much improved from baseline. Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 mg per day to 100 mg per day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated. 14.4 Preventive Treatment of Migraine Adult Patients The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted in US (Study 11) or the US and Canada (Study 12) established the effectiveness of immediate-release topiramate in the preventive treatment of migraine.

4.4 Preventive Treatment of Migraine Adult Patients The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted in US (Study 11) or the US and Canada (Study 12) established the effectiveness of immediate-release topiramate in the preventive treatment of migraine. The design of both trials was identical, enrolling patients with a history of migraine with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, opthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventative medications before starting the baseline phase. Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, 200 mg/day (twice the recommended daily dosage for migraine prophylaxis) or placebo, and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period.). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate (according to migraines classified by IHS criteria) from the baseline phase to double-blind treatment period in each immediate-release topiramate treatment group compared to placebo in the Intent-To-Treat (ITT) population. In Study 11, a total of 469 patients (416 females, 53 males) ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of topiramate 50 mg/day, 100 mg/day and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the immediate-release topiramate 50 mg/day, 100 mg/day, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 2). The treatment differences between the immediate release topiramate 100 mg/day and 200 mg/day groups versus placebo were similar and statistically significant (p < 0.001 for both comparisons). In Study 12, a total of 468 patients (406 females, 62 males) ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of immediate-release topiramate 50 mg/day, 100 mg/day, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the immediate-release topiramate 50 mg/day, 100 mg/day, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 2). The differences between the immediate-release topiramate 100 mg and 200 mg per day groups versus placebo were similar and statistically significant (p = 0.008 and p < 0.001, respectively).

ate-release topiramate 50 mg/day, 100 mg/day, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 2). The differences between the immediate-release topiramate 100 mg and 200 mg per day groups versus placebo were similar and statistically significant (p = 0.008 and p < 0.001, respectively). In both studies there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race. For patients withdrawing from immediate-release topiramate, daily dosages were decreased in weekly intervals by 25 mg/day to 50 mg/day. Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents) Pediatric Patients 12 to 17 Years of Age The effectiveness of immediate-release topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial (Study 13). The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]). Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and ≤14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12 week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Approximately 80% or more patients in each treatment group completed the study. The median average daily dosages were 45 mg/day and 79 mg/day in the target dose groups of immediate-release topiramate 50 mg/day and 100 mg/day, respectively. Effectiveness of treatment was assessed by comparing each immediate-release topiramate treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint). The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 12. The 100 mg immediate-release topiramate dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate. The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3.0 for 100 mg immediate-release topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p=0.0087).

te, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3.0 for 100 mg immediate-release topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p=0.0087). Table 12: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set) Category Placebo (N=33) Immediate-Release Topiramate 50 mg/day (N=35) Immediate-Release Topiramate 100 mg/day (N=35) Baseline Median 3.6 4.0 4.0 Last 12 Weeks of Double-Blind Phase Median 2.3 2.3 1.0 Percent Reduction (%) Median 44.4 44.6 72.2 P-value versus Placebo *,† 0.7975 0.0164 ‡ * P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject’s stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate. † P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure. ‡ Indicates p-value is <0.05 (two-sided). TOPIRAMATE ER CAPSULE 14.1 Bridging Study to Demonstrate Pharmacokinetic Equivalence between Extended-Release and Immediate-Release Topiramate Formulations The basis for approval of the extended-release formulation (topiramate extended-release capsules) included the studies described below using an immediate-release formulation and the demonstration of the pharmacokinetic equivalence of topiramate extended-release capsules to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see Clinical Pharmacology ( 12.6) ] . The clinical studies described in the following sections were conducted using immediate-release topiramate.

inetic equivalence of topiramate extended-release capsules to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see Clinical Pharmacology ( 12.6) ] . The clinical studies described in the following sections were conducted using immediate-release topiramate. 14.2 Monotherapy Epilepsy Patients With Partial-Onset or Primary Generalized Tonic-Clonic Seizures Adults and Pediatric Patients 10 Years of Age and Older The effectiveness of topiramate as initial monotherapy in adults and pediatric patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1). Study 1 was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg per day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day of topiramate. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty-eight percent of patients achieved the maximal dose of 400 mg/day for >2 weeks, and patients who did not tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use. Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure in Study 1 Pediatric Patients 6 to 9 Years of Age The conclusion that topiramate is effective as initial monotherapy in pediatric patients 6 to 9 years of age with partial-onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach using data from the controlled epilepsy trials conducted with immediate-release topiramate described in labeling. The approach consisted of first showing a similar exposure response relationship between pediatric patients down to 2 years of age and adults when immediate-release topiramate was given as adjunctive therapy [see Use in Specific Populations ( 8.4) ] . Similarity of exposure-response was demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy. Specific dosing in pediatric patients 6 to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with immediate-release topiramate initial monotherapy [see Dosage and Administration (2.1)] . TOPIRAMATE ER CAPSULE

e was given as initial monotherapy. Specific dosing in pediatric patients 6 to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with immediate-release topiramate initial monotherapy [see Dosage and Administration (2.1)] . TOPIRAMATE ER CAPSULE 14.3 Adjunctive Therapy Epilepsy Adult Patients With Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for adults with partial-onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures. Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a pre-specified minimum number of partial-onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg/day or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 mg/day or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 mg/day or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 10. Pediatric Patients 6 to 16 Years of Age With Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for pediatric patients 6 to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures. Patients in Study 8 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 mg/day or 50 mg/day; the dose was then increased by 25 mg/day to 150 mg/day increments every other week until the assigned dosage of 125 mg/day, 175 mg/day, 225 mg/day or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

5 mg/day to 150 mg/day increments every other week until the assigned dosage of 125 mg/day, 175 mg/day, 225 mg/day or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period. Patients With Primary Generalized Tonic-Clonic Seizures The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 6 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo (see Table 11). Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg/day to 150 mg/day increments every other week until the assigned dose of 175 mg/day, 225 mg/day or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period. Patients With Lennox-Gastaut Syndrome The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10), comparing a single dosage of topiramate with placebo (see Table 11). Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4 week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity. Table 10: Immediate Release Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults With Partial-Onset Seizures * Target Topiramate Dosage (mg per day) Study Stabilization Dose Placebo † 200 400 600 800 1,000 2 N 42 42 40 41 -- -- Mean Dose 5.9 200 390 556 -- -- Median Dose 6.0 200 400 600 -- -- 3 N 44 -- -- 40 45 40 Mean Dose 9.7 -- -- 544 739 796 Median Dose 10.0 -- -- 600 800 1,000 4 N 23 -- 19 -- -- -- Mean Dose 3.8 -- 395 -- -- -- Median Dose 4.0 -- 400 -- -- -- 5 N 30 -- -- 28 -- -- Mean Dose 5.7 -- -- 522 -- -- Median Dose 6.0 -- -- 600 -- -- 6 N 28 -- -- -- 25 -- Mean Dose 8.0 -- -- -- 568 -- Median Dose 8.0 -- -- -- 600 -- 7 N 90 157 -- -- -- -- Mean Dose 8 200 -- -- -- -- Median Dose 8 200 -- -- -- -- * Dose-response studies were not conducted for other indications or pediatric partial-onset seizures † Placebo dosages are given as the number of tablets.

6 N 28 -- -- -- 25 -- Mean Dose 8.0 -- -- -- 568 -- Median Dose 8.0 -- -- -- 600 -- 7 N 90 157 -- -- -- -- Mean Dose 8 200 -- -- -- -- Median Dose 8 200 -- -- -- -- * Dose-response studies were not conducted for other indications or pediatric partial-onset seizures † Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day) In all adjunctive topiramate trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 11. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial. Table 11: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials Target Topiramate Dosage (mg per day) Study # # Placebo 200 400 600 800 1,000 ≈6 mg/kg/day* Partial Onset Seizures Studies in Adults 2 N 45 45 45 46 -- -- -- Median % Reduction 12 27 † 48 ‡ 45 § -- -- -- % Responders 18 24 44 ¶ 46 ¶ -- -- -- 3 N 47 -- -- 48 48 47 -- Median % Reduction 2 -- -- 41 § 41 § 36 § % Responders 9 -- -- 40 § 41 § 36 ¶ 4 N 24 -- 23 -- -- -- -- Median % Reduction 1 -- 41 # -- -- -- -- % Responders 8 -- 35 ¶ -- -- -- -- 5 N 30 -- -- 30 -- -- -- Median % Reduction -12 -- -- 46 Þ -- -- -- % Responders 10 -- -- 47 § -- -- -- 6 N 28 -- -- -- 28 -- -- Median % Reduction -21 -- -- -- 24 § -- -- % Responders 0 -- -- -- 43 § -- -- 7 N 91 168 -- -- -- -- -- Median % Reduction 20 44 § -- -- -- -- -- % Responders 24 45 § Partial Onset Seizures Studies in Pediatric Patients ß 8 N 45 -- -- -- -- -- 41 Median % Reduction 11 -- -- -- -- -- 33 ¶ % Responders 20 -- -- -- -- -- 39 Primary Generalized Tonic-Clonic à, ß 9 N 40 -- -- -- -- -- 39 Median % Reduction 9 -- -- -- -- -- 57 ¶ % Responders 20 -- -- -- -- -- 56 § Lennox-Gastaut Syndrome è, ß 10 N 49 -- -- -- -- -- 46 Median % Reduction -5 -- -- -- -- -- 15 ¶ % Responders 14 28 ð Improvement in Seizure Severity ø 28 52 ¶ Comparisons with placebo: *For Studies 8 and 9, specified target dosages (<9.3 mg/kg/day) were assigned based on subject’s weight to approximate a dosage of 6mg/kg per day; these dosages corresponded to mg/day dosages of 125 mg/day, 175 mg/day, 225 mg/day , and 400 mg/day † p= 0.080; ‡ p ≤ 0.010; § p ≤ 0.001; ¶ p ≤ 0.050; # p= 0.065; Þ p ≤ 0.005; ß Studies included pediatric patients 2 years of age and older, an age group for which topiramate extended-release capsules is not indicated [see Indications and Usage ( 1.2 ) and Use in Specific Populations ( 8.4 )] à Median % reduction and % responders are reported for PGTC seizures; è Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures ð p= 0.071; ø Percentage of subjects who were minimally, much, or very much improved from baseline. Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 mg per day to 100 mg per day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated.

r, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 mg per day to 100 mg per day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated. 14.4 Preventive Treatment of Migraine Adult Patients The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted in US (Study 11) or the US and Canada (Study 12) established the effectiveness of immediate-release topiramate in the preventive treatment of migraine. The design of both trials was identical, enrolling patients with a history of migraine with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, opthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventative medications before starting the baseline phase. Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, 200 mg/day (twice the recommended daily dosage for migraine prophylaxis) or placebo, and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period.). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate (according to migraines classified by IHS criteria) from the baseline phase to double-blind treatment period in each immediate-release topiramate treatment group compared to placebo in the Intent-To-Treat (ITT) population. In Study 11, a total of 469 patients (416 females, 53 males) ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of topiramate 50 mg/day, 100 mg/day and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the immediate-release topiramate 50 mg/day, 100 mg/day, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 2). The treatment differences between the immediate release topiramate 100 mg/day and 200 mg/day groups versus placebo were similar and statistically significant (p < 0.001 for both comparisons). In Study 12, a total of 468 patients (406 females, 62 males) ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of immediate-release topiramate 50 mg/day, 100 mg/day, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups.

erage daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of immediate-release topiramate 50 mg/day, 100 mg/day, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the immediate-release topiramate 50 mg/day, 100 mg/day, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 2). The differences between the immediate-release topiramate 100 mg and 200 mg per day groups versus placebo were similar and statistically significant (p = 0.008 and p < 0.001, respectively). In both studies there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race. For patients withdrawing from immediate-release topiramate, daily dosages were decreased in weekly intervals by 25 mg/day to 50 mg/day. Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents) Pediatric Patients 12 to 17 Years of Age The effectiveness of immediate-release topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial (Study 13). The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]). Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and ≤14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12 week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Approximately 80% or more patients in each treatment group completed the study. The median average daily dosages were 45 mg/day and 79 mg/day in the target dose groups of immediate-release topiramate 50 mg/day and 100 mg/day, respectively. Effectiveness of treatment was assessed by comparing each immediate-release topiramate treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint). The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 12. The 100 mg immediate-release topiramate dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate. The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3.0 for 100 mg immediate-release topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p=0.0087).

te, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3.0 for 100 mg immediate-release topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p=0.0087). Table 12: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set) Category Placebo (N=33) Immediate-Release Topiramate 50 mg/day (N=35) Immediate-Release Topiramate 100 mg/day (N=35) Baseline Median 3.6 4.0 4.0 Last 12 Weeks of Double-Blind Phase Median 2.3 2.3 1.0 Percent Reduction (%) Median 44.4 44.6 72.2 P-value versus Placebo *,† 0.7975 0.0164 ‡ * P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject’s stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate. † P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure. ‡ Indicates p-value is <0.05 (two-sided). TOPIRAMATE ER CAPSULE

<table cellspacing="0" cellpadding="0" border="1"><col width="6.65in"/><col/><col/><col/><col/><col/><col/><col/><tbody><tr><td colspan="8" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 10: Immediate Release Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults With Partial-Onset Seizures^*</content></paragraph></td></tr><tr><td colspan="8" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Target Topiramate Dosage (mg per day)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Study</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Stabilization Dose</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo^&#x2020;</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">200</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">400</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">600</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">800</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">1,000</content></paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>42</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>42</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>40</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mean Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>200</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>390</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>556</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>200</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>400</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>600</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44</

/paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44</ paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>40</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>40</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mean Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>544</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>739</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>796</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>600</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>800</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1,000</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>23</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>19</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mean Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>395</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>400</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>30</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</para

agraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>30</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</para graph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>28</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mean Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>522</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>600</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>28</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>25</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mean Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>568</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>600</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>90</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>157</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td

ph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>90</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>157</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td ><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mean Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>200</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>200</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td colspan="8" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">^*</content> Dose-response studies were not conducted for other indications or pediatric partial-onset seizures</paragraph><paragraph><content styleCode="bold">^&#x2020;</content> Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day)</paragraph></td></tr></tbody></table>

><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mean Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>200</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>200</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td colspan="8" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">^*</content> Dose-response studies were not conducted for other indications or pediatric partial-onset seizures</paragraph><paragraph><content styleCode="bold">^&#x2020;</content> Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day)</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="504.9pt"/><col/><col/><col/><col/><col/><col/><col/><col/><col/><col/><tbody><tr><td colspan="11" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 11: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials</content></paragraph></td></tr><tr><td colspan="11" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Target Topiramate Dosage (mg per day)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Study #</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">#</content></paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">200</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">400</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">600</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">800</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">1,000</content></paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">&#x2248;6 mg/kg/day*</content></paragraph></td></tr><tr><td colspan="11" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Partial Onset Seizures Studies in Adults</content></paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>46</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median % Reduction</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>27^&#x2020;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>48^&#x2021;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45^&#xA7;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>% Responders</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>24</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44<sup

d></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>% Responders</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>24</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44<sup >&#xB6;</sup></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>46^&#xB6;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>47</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>48</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>48</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>47</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median % Reduction</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41^&#xA7;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41^&#xA7;</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>36^&#xA7;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>% Responders</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>40^&#xA7;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41^&#xA7;</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>36^&#xB6;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>24</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>23</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median % Reduction</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41^#</paragraph></td><td styleCode=" Botrule

e"><paragraph>Median % Reduction</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41^#</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>% Responders</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>35^&#xB6;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>30</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>30</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median % Reduction</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>-12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>46^&#xDE;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>% Responders</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>47^&#xA7;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>28</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule To

yleCode=" Botrule Toprule Lrule Rrule"><paragraph>28</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule To prule Lrule Rrule"><paragraph>28</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median % Reduction</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>-21</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>24^&#xA7;</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>% Responders</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>43^&#xA7;</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>91</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>168</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median % Reduction</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44^&#xA7;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>% Responders</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>24</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45^&#xA7;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td colspan="11" styleCode=" Botrule Toprule Lrule Rru

paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td colspan="11" styleCode=" Botrule Toprule Lrule Rru le"><paragraph><content styleCode="bold">Partial Onset Seizures Studies in Pediatric Patients^&#xDF;</content></paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median % Reduction</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33^&#xB6;</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>% Responders</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>39</paragraph></td></tr><tr><td colspan="11" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Primary Generalized Tonic-Clonic^{&#xE0;, &#xDF;}</content></paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>40</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>39</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median % Reduction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Bot

ode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Bot rule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>57^&#xB6;</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>% Responders</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>56^&#xA7;</paragraph></td></tr><tr><td colspan="11" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Lennox-Gastaut Syndrome^{&#xE8;, &#xDF;}</content></paragraph></td></tr><tr><td rowspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>49</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>46</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median % Reduction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>-5</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15^&#xB6;</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>% Responders</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>28^&#xF0;</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Improvement in Seizure Severity^&#xF8;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>28</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>52<sup>&#xB

td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>52^{&#xB 6;}</paragraph></td></tr><tr><td colspan="11" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Comparisons with placebo:</paragraph><paragraph>*For Studies 8 and 9, specified target dosages (&lt;9.3 mg/kg/day) were assigned based on subject&#x2019;s weight to approximate a dosage of 6mg/kg per day; these dosages corresponded to mg/day dosages of 125 mg/day, 175 mg/day, 225 mg/day , and 400 mg/day</paragraph><paragraph>^&#x2020;p= 0.080; </paragraph><paragraph>^&#x2021;p &#x2264; 0.010; </paragraph><paragraph>^&#xA7;p &#x2264; 0.001; </paragraph><paragraph>^&#xB6;p &#x2264; 0.050; </paragraph><paragraph>^#p= 0.065; </paragraph><paragraph>^&#xDE;p &#x2264; 0.005; </paragraph><paragraph>^&#xDF;Studies included pediatric patients 2 years of age and older, an age group for which topiramate extended-release capsules is not indicated <content styleCode="italics">[see Indications and Usage (<linkHtml href="#www.splportal.comLINK_7d868b49-1157-4bbe-8a81-87d3d7e9ac23">1.2</linkHtml>)</content><content styleCode="italics">and Use in Specific Populations (<linkHtml href="#www.splportal.comLINK_916f38a7-8120-4f83-a121-cb8dc49742ff">8.4</linkHtml>)]</content></paragraph><paragraph>^&#xE0;Median % reduction and % responders are reported for PGTC seizures; </paragraph><paragraph>^&#xE8;Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures</paragraph><paragraph>^&#xF0;p= 0.071; </paragraph><paragraph>^&#xF8;Percentage of subjects who were minimally, much, or very much improved from baseline.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr></tbody></table>

Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="1pt"/><col/><col/><col/><tbody><tr><td colspan="4"><paragraph><content styleCode="bold">Table 12: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Category</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo (N=33)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Immediate-Release Topiramate </content></paragraph><paragraph><content styleCode="bold">50 mg/day (N=35)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Immediate-Release Topiramate </content></paragraph><paragraph><content styleCode="bold">100 mg/day (N=35)</content></paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Baseline</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Last 12 Weeks of Double-Blind Phase</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Percent Reduction (%)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44.6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>72.2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>P-value versus Placebo ^*,&#x2020;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.7975</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.0164 ^&#x2021;</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>^*P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject&#x2019;s stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate.</paragraph><paragraph>^&#x2020;P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure.</paragraph><paragraph>^&#x2021; Indicates p-value is &lt;0.05 (two-sided).</paragraph></td></tr></tbody></table>

k rate during baseline period as a covariate.</paragraph><paragraph>^&#x2020;P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure.</paragraph><paragraph>^&#x2021; Indicates p-value is &lt;0.05 (two-sided).</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="6.65in"/><col/><col/><col/><col/><col/><col/><col/><tbody><tr><td colspan="8" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Table 10: Immediate Release Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults With Partial-Onset Seizures^*</content></paragraph></td></tr><tr><td colspan="8" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Target Topiramate Dosage (mg per day)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Study</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Stabilization Dose</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo^&#x2020;</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">200</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">400</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">600</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">800</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">1,000</content></paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>42</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>42</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>40</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>41</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mean Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>200</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>390</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>556</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Median Dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6.0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>200</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>400</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>600</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>--</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44</

16 HOW SUPPLIED 16.1 How Supplied Topiramate extended-release capsules are available as: 200 mg (yellow opaque cap and white opaque body) topiramate extended-release capsules (black print “par” on the cap and “C368” on the body) Bottles of 30….NDC-10370-368-11 Bottles of 100…NDC-10370-368-01 Bottles of 500...NDC-10370-368-05 16.2 Storage and Handling Topiramate extended-release capsules should be stored in well closed containers at 20º to 25°C (68º to 77°F) [see USP Controlled Room Temperature]. Protect from moisture and light. 16.1 How Supplied Topiramate extended-release capsules are available as: 200 mg (yellow opaque cap and white opaque body) topiramate extended-release capsules (black print “par” on the cap and “C368” on the body) Bottles of 30….NDC-10370-368-11 Bottles of 100…NDC-10370-368-01 Bottles of 500...NDC-10370-368-05 16.2 Storage and Handling Topiramate extended-release capsules should be stored in well closed containers at 20º to 25°C (68º to 77°F) [see USP Controlled Room Temperature]. Protect from moisture and light.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration Instructions Counsel patients to swallow topiramate extended-release capsules whole and intact. Topiramate extended-release capsules should not be sprinkled on food, chewed, or crushed [see Dosage and Administration ( 2.7 )] . Consumption of Alcohol Advise patients to completely avoid consumption of alcohol at least 6 hours prior to and 6 hours after taking topiramate extended-release capsules [see Warnings and Precautions ( 5.5 )] . Eye Disorders Advise patients taking topiramate extended-release capsules to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain [see Warnings and Precautions ( 5.1 , 5.2 )] . Oligohydrosis and Hyperthermia Counsel patients that topiramate extended-release capsules, especially pediatric patients, can cause decreased sweating and increased body temperature, especially in hot weather, and they should seek medical attention if this is noticed [see Warnings and Precautions ( 5.3 )] . Metabolic Acidosis Inform patients about the potentially significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus [see Warnings and Precautions ( 5.4 )] . Suicidal Behavior and Ideation Counsel patients, their caregivers, and families that AEDs, including topiramate extended-release capsules, may increase the risk of suicidal thoughts and behavior and they should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers [see Warnings and Precautions ( 5.6 )] . Interference With Cognitive and Motor Performance Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects and advise them not to drive or operate machinery until they have gained sufficient experience on topiramate extended-release capsules to gauge whether it adversely affects their mental performance, motor performance, and/or vision [see Warnings and Precautions ( 5.7 )] . Advise patients that even when taking topiramate extended-release capsules or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, counsel all patients taking topiramate extended-release capsules for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Physicians should discuss the appropriate level of caution with their patients, before patients with epilepsy engage in such activities.

emselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Physicians should discuss the appropriate level of caution with their patients, before patients with epilepsy engage in such activities. Fetal Toxicity Counsel pregnant women and women of childbearing potential that use of topiramate extended-release capsules during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be small for their gestational age [see Use in Specific Populations ( 8.1 )] . There may also be risks to the fetus from chronic metabolic acidosis with use of topiramate extended-release capsules during pregnancy [see Warnings and Precautions ( 5.4 , 5.8 )] . When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing birth control with topiramate [see Warnings and Precautions ( 5.8 ) and Drug Interactions ( 7.5) ] . Encourage pregnant women using topiramate extended-release capsules to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations ( 8.1 )] . Decrease in Bone Mineral Density Inform the patient or caregiver that long-term treatment with topiramate extended-release capsules can decrease bone formation and increase bone resorption in children [see Warnings and Precautions ( 5.10 )] . Negative Effects on Growth (Height and Weight) Discuss with the patient or caregiver that long-term topiramate extended-release capsules treatment may attenuate growth as reflected by slower height increase and weight gain in pediatric patients [see Warnings and Precautions ( 5.11) ] . Serious Skin Reactions Inform patients about the signs of serious skin reactions. Instruct patients to immediately inform their healthcare provider at the first appearance of skin rash [see Warnings and Precautions ( 5.12 )] . Hyperammonemia and Encephalopathy Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Patients should be instructed to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see Warnings and Precautions ( 5.13 )] . Kidney Stones Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation [see Warnings and Precautions ( 5.14) ] . Hypothermia Counsel patients that topiramate extended-release capsules can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction [see Warnings and Precautions ( 5.15 )] .

MEDICATION GUIDE Dispense with Medication Guide available at: www.endo.com/products Topiramate (toe pyre’ a mate) Extended-Release Capsules What is the most important information I should know about topiramate extended-release capsules? Take topiramate extended-release capsules whole. Do not sprinkle topiramate extended-release capsules on food, or break, crush, dissolve, or chew topiramate extended-release capsules before swallowing. If you cannot swallow topiramate extended-release capsules whole, tell your healthcare provider. You may need a different medicine. Do not drink alcohol within 6 hours prior to and 6 hours after topiramate extended-release capsules administration. Topiramate extended-release capsules may cause eye problems. Serious eye problems include: any sudden decrease in vision with or without eye pain and redness, a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma). These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms, including any new problems with your vision. Topiramate extended-release capsules may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. If a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away. Topiramate extended-release capsules can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will: feel tired not feel hungry (loss of appetite) feel changes in heartbeat have trouble thinking clearly Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with topiramate extended-release capsules. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis. Like other antiepileptic drugs, topiramate extended-release capsules may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying trouble sleeping (insomnia) attempts to commit suicide new or worse irritability new or worse depression acting aggressive, being angry, or violent new or worse anxiety acting on dangerous impulses feeling agitated or restless an extreme increase in activity and talking (mania) panic attacks other unusual changes in behavior or mood Do not stop topiramate extended-release capsules without first talking to a healthcare provider. Stopping topiramate extended-release capsules suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions?

topping topiramate extended-release capsules suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Topiramate extended-release capsules can harm your unborn baby. If you take topiramate extended-release capsules during pregnancy, your baby has a higher risk for birth defects called cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant. Cleft lip and cleft palate may happen even in children born to women who are not taking any medicines and do not have other risk factors. There may be other medicines to treat your condition that have a lower chance of birth defects. All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of topiramate extended-release capsules. If the decision is made to use topiramate extended-release capsules, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your doctor about the best kind of birth control to use while you are taking topiramate extended-release capsules. Tell your healthcare provider right away if you become pregnant while taking topiramate extended-release capsules. You and your healthcare provider should decide if you will continue to take topiramate extended-release capsules while you are pregnant. If you take topiramate extended-release capsules during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. Talk to your healthcare provider if you have questions about this risk during pregnancy. Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if topiramate extended-release capsules have caused metabolic acidosis during your pregnancy. Pregnancy Registry: If you become pregnant while taking topiramate extended-release capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of topiramate extended-release capsules and other antiepileptic drugs during pregnancy. Topiramate extended-release capsules may decrease the density of bones when used over a long period. Topiramate extended-release capsules may slow height increase and weight gain in children and adolescents when used over a long period. What are topiramate extended-release capsules? Topiramate extended-release capsules are a prescription medicine used: to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic seizures) in people 6 years and older, with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 6 years and older to prevent migraine headaches in adults and adolescents 12 years of age and older.

6 years and older, with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 6 years and older to prevent migraine headaches in adults and adolescents 12 years of age and older. Before taking topiramate extended-release capsules, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems, or suicidal thoughts or behavior have kidney problems, kidney stones, or are getting kidney dialysis have a history of metabolic acidosis (too much acid in the blood) have liver problems have weak, brittle or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density) have lung or breathing problems have eye problems, especially glaucoma have diarrhea have a growth problem are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet are having surgery are pregnant or plan to become pregnant are breastfeeding. Topiramate passes into your breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the topiramate that passes into breast milk can cause other serious harm to your baby. Talk to your healthcare provider about the best way to feed your baby if you take topiramate extended-release capsules. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially, tell your healthcare provider if you take: Valproic acid (such as DEPAKENE ® or DEPAKOTE ® ) any medicines that impair or decrease your thinking, concentration, or muscle coordination birth control pills. Topiramate extended-release capsules may make your birth control pills less effective. Tell your healthcare provider if your menstrual bleeding changes while you are taking birth control pills and topiramate extended-release capsules. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider. How should I take topiramate extended-release capsules? Take topiramate extended-release capsules exactly as prescribed. Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider. Take topiramate extended-release capsules whole. Do not sprinkle topiramate extended-release capsules on food, or break, crush, dissolve, or chew topiramate extended-release capsules before swallowing. Topiramate extended-release capsules can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking topiramate extended-release capsules. If you take too much topiramate extended-release capsules, call your healthcare provider right away or go to the nearest emergency room. Talk to your health care provider on what you should do if you miss a dose. Do not stop taking topiramate extended-release capsules without talking to your healthcare provider. Stopping topiramate extended-release capsules suddenly may cause serious problems. If you have epilepsy and you stop taking topiramate extended-release capsules suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking topiramate extended-release capsules slowly. Your healthcare provider may do blood tests while you take topiramate extended-release capsules. What should I avoid while taking topiramate extended-release capsules? Do not drink alcohol within 6 hours before or 6 hours after taking topiramate extended-release capsules.

ng topiramate extended-release capsules slowly. Your healthcare provider may do blood tests while you take topiramate extended-release capsules. What should I avoid while taking topiramate extended-release capsules? Do not drink alcohol within 6 hours before or 6 hours after taking topiramate extended-release capsules. Topiramate extended-release capsules and alcohol can cause serious side effects such as severe sleepiness and dizziness and an increase in seizures. Do not drive a car or operate heavy machinery until you know how topiramate extended-release capsules affect you. Topiramate extended-release capsules can slow your thinking and motor skills and may affect vision. What are the possible side effects of topiramate extended-release capsules? Topiramate extended-release capsules may cause serious side effects, including: See “What is the most important information I should know about topiramate extended-release capsules?” Serious skin reactions. Topiramate extended-release capsules may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). Topiramate extended-release capsules may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters. High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when topiramate extended-release capsules is taken with a medicine called valproic acid (DEPAKENE ® and DEPAKOTE ® ). Kidney stones. Drink plenty of fluids when taking topiramate extended-release capsules to decrease your chances of getting kidney stones. Low body temperature. Taking topiramate extended-release capsules when you are also taking valproic acid cause a drop in body temperature to less than 95ºF, feeling tired, confusion, or coma. Effects on thinking and alertness. Topiramate extended-release capsules may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. Topiramate extended-release capsules may cause depression or mood problems, tiredness, and sleepiness. Dizziness or loss of muscle coordination. Call your healthcare provider right away if you have any of the symptoms above. The most common side effects of topiramate extended-release capsules include: tingling of the arms and legs (paresthesia) nervousness fever not feeling hungry speech problems tiredness nausea dizziness sleepiness/drowsiness weight loss slow reactions difficulty with memory abnormal vision upper respiratory tract infection diarrhea a change in the way foods taste pain in abdomen decreased feeling or sensitivity, especially in the skin Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of topiramate extended-release capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Endo at 1-800-828-9393. How should I store topiramate extended-release capsules? Store topiramate extended-release capsules at 20º to 25°C (68º to 77°F) [see USP Controlled Room Temperature]. Keep topiramate extended-release capsules in a tightly closed container. Keep topiramate extended-release capsules dry and away from moisture and light. Keep topiramate extended-release capsules and all medicines out of the reach of children. General information about the safe and effective use of topiramate extended-release capsules . Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

es dry and away from moisture and light. Keep topiramate extended-release capsules and all medicines out of the reach of children. General information about the safe and effective use of topiramate extended-release capsules . Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use topiramate extended-release capsules for a condition for which it was not prescribed. Do not give topiramate extended-release capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about topiramate extended-release capsules that is written for health professionals. What are the ingredients in topiramate extended-release capsules? Active ingredient: topiramate Inactive ingredients: Sugar Spheres (contains sucrose and corn starch), Hypromellose, Povidone, Ethylcellulose, Titanium Dioxide and Talc Capsule shells: Gelatin, titanium dioxide and colorants. Colorants: FD&C Red #40 FD&C Yellow #6 Capsule shells are imprinted with black print that contains shellac, black iron oxide, propylene glycol, FD&C Red #40, FD&C Blue #2, FD&C Blue #1 and D&C Yellow #10. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Endo. For more information, go to www.endo.com or call 1-800-828-9393. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Endo USA Malvern, PA 19355 U.S.A. Made in India Neutral Code: MP/DRUGS/25/82/2020 ©2024 Endo, Inc. or one of its affiliates. OS365-01-74-04 Revised: 05/2024

1 INDICATIONS AND USAGE QUDEXY XR is indicated for: Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older ( 1.1 ); adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut Syndrome in patients 2 years of age and older ( 1.2 ) Preventive treatment of migraine in patients 12 years of age and older ( 1.3 ) 1.1 Monotherapy Epilepsy QUDEXY XR is indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older. 1.2 Adjunctive Therapy Epilepsy QUDEXY XR is indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut Syndrome in patients 2 years of age and older. 1.3 Migraine QUDEXY XR is indicated for the preventive treatment of migraine in patients 12 years of age and older.

2 DOSAGE AND ADMINISTRATION QUDEXY XR initial dose, titration, and recommended maintenance dose varies by indication and age group. See Full Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) Capsules may be swallowed whole or opened and sprinkled on a spoonful of soft food ( 2.6 ) 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older The recommended dose for QUDEXY XR monotherapy in adults and pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate QUDEXY XR according to the following schedule (see Table 1 ). Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10 Years of Age and Older QUDEXY XR Once Daily Dose Week 1 50 mg Week 2 100 mg Week 3 150 mg Week 4 200 mg Week 5 300 mg Week 6 400 mg Pediatric Patients 2 to 9 Years of Age Dosing in patients 2 to 9 years of age is based on weight. During the titration period, the initial dose of QUDEXY XR is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day in the second week. Dosage can be increased by 25 mg to 50 mg once daily each subsequent week, as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to 7 weeks. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 mg to 50 mg once daily weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (see Table 2 ). Table 2: Monotherapy Target Total Daily Maintenance Dosing for Patients 2 to 9 Years of Age Weight (kg) Total Daily Dose (mg/day) Minimum Maintenance Dose Total Daily Dose (mg/day) Maximum Maintenance Dose Up to 11 150 250 12 to 22 200 300 23 to 31 200 350 32 to 38 250 350 Greater than 38 250 400 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Older) The recommended total daily dose of QUDEXY XR as adjunctive therapy in adults with partial-onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily, and with primary generalized tonic-clonic seizures is 400 mg orally once daily. Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures. Pediatric Patients 2 to 16 Years of Age The recommended total daily dose of QUDEXY XR as adjunctive therapy for pediatric patients 2 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day.

n a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day. 2.3 Dosing for the Preventive Treatment of Migraine The recommended total daily dose of QUDEXY XR as treatment for the preventive treatment of migraine in patients 12 years of age and older is 100 mg once daily. The recommended titration rate for QUDEXY XR for the preventive treatment of migraine is as follows: Table 3: Preventive Treatment of Migraine Titration Schedule for Patients 12 Years of Age and Older QUDEXY XR Once Daily Dose Week 1 25 mg Week 2 50 mg Week 3 75 mg Week 4 100 mg Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustment can be used. 2.4 Dosing in Patients with Renal Impairment In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose of QUDEXY XR is recommended [see Use in Specific Populations (8.5 , 8.6) , Clinical Pharmacology (12.3) ]. 2.5 Dosing in Patients Undergoing Hemodialysis To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of QUDEXY XR may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . 2.6 Administration Instructions QUDEXY XR capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed or crushed. It should not be stored for further use. QUDEXY XR can be taken without regard to meals [see Clinical Pharmacology (12.3) ] .

3 DOSAGE FORMS AND STRENGTHS QUDEXY XR (topiramate) extended-release capsules are available in the following strengths and colors: 25 mg: light pink and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "25 mg" on the body in black ink 50 mg: golden yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "50 mg" on the body in black ink 100 mg: reddish brown and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "100 mg" on the body in black ink 150 mg: pale yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "150 mg" on the body in black ink 200 mg: brown and grey capsules, printed with "UPSHER-SMITH" on the cap in white ink and "200 mg" on the body in black ink Extended-release capsules: 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg ( 3 )

4 CONTRAINDICATIONS QUDEXY XR is contraindicated in patients with a history of hypersensitivity reaction to topiramate, QUDEXY XR, or any of the inactive ingredients of QUDEXY XR. Anaphylaxis and angioedema have occurred with topiramate [see Warnings and Precautions (5.13) ]. History of hypersensitivity reaction to topiramate, QUDEXY XR, or any of the inactive ingredients of QUDEXY XR (4, 5.13)

5 WARNINGS AND PRECAUTIONS Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue QUDEXY XR as soon as possible ( 5.1 ) Visual field defects: consider discontinuation of QUDEXY XR ( 5.2 ) Oligohydrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients ( 5.3 ) Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of QUDEXY XR if clinically appropriate ( 5.4 ) Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.5 ) Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur ( 5.6 ) Fetal Toxicity: use during pregnancy can cause major congenital malformations, including but not limited to cleft lip and/or palate and being small for gestational age ( 5.7 ) Withdrawal of AEDs: withdraw QUDEXY XR gradually ( 5.8 ) Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients ( 5.9 ) Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy ( 5.10 ) Serious skin reactions: If SJS or TEN is suspected, discontinue QUDEXY XR ( 5.11 ) Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur ( 5.12 ) Kidney stones: avoid use with other carbonic anhydrase inhibitors, drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.13 ) Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use ( 5.14 ) 5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of QUDEXY XR as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of QUDEXY XR, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation.

ield Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with topiramate, consideration should be given to discontinuing the drug. 5.3 Oligohydrosis and Hyperthermia Oligohydrosis (decreased sweating), infrequently resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures. The majority of the reports have been in pediatric patients. Patients (especially pediatric patients) treated with QUDEXY XR should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when QUDEXY XR is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. 5.4 Metabolic Acidosis QUDEXY XR can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by QUDEXY XR. QUDEXY XR-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of QUDEXY XR. Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials, for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial-onset seizures was as high as 67% for immediate-release topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and ≥5 mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤ 2% for placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions (5.9 , 5.13) ] . A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that topiramate decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions (5.9) , Use in Specific Populations (8.4) ] .

s lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions (5.9) , Use in Specific Populations (8.4) ] . Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24-months old patients. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4) ] . QUDEXY XR treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions (5.7) , Use in Specific Populations (8.1) ] . Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients Measurement of baseline and periodic serum bicarbonate during QUDEXY XR treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing QUDEXY XR (using dose tapering). If the decision is made to continue patients on QUDEXY XR in the face of persistent acidosis, alkali treatment should be considered. 5.5 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including QUDEXY XR increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs. Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing QUDEXY XR or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.6 Cognitive/Neuropsychiatric Adverse Reactions Immediate-release topiramate can cause cognitive/neuropsychiatric adverse reactions and therefore these are expected to be caused by QUDEXY XR. The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue. Adult Patients Cognitive Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction. In adult epilepsy adjunctive controlled trials, which used rapid titration (100 to 200 mg/day weekly increments) and target immediate-release topiramate doses of 200 mg to 1000 mg/day, 56% of patients in the 800 mg/day and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200 to 400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase. In the monotherapy epilepsy-controlled trial conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day. In the 6-month controlled trials for the preventive treatment of migraine, which used a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration.

on of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations treated with topiramate [see Warnings and Precautions (5.5) ] . Somnolence/Fatigue Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue appeared dose-related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both somnolence and fatigue were dose-related and more common in the titration phase. Pediatric Patients In pediatric epilepsy trials (adjunctive and monotherapy), the incidence of cognitive/neuropsychiatric adverse reactions was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems, and language problems. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in topiramate-treated patients compared to placebo. The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during the titration period and sometimes persisted for various durations after completion of titration. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 13 [see Clinical Studies (14.5) ] . Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency. 5.7 Fetal Toxicity QUDEXY XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformation, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations (8.1) ] . Consider the benefits and risks of QUDEXY XR when administering this drug in women of childbearing potential, particularly when QUDEXY XR is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.1) , Patient Counseling Information (17) ] .

lations (8.1) ] . Consider the benefits and risks of QUDEXY XR when administering this drug in women of childbearing potential, particularly when QUDEXY XR is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.1) , Patient Counseling Information (17) ] . QUDEXY XR should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus [see Use in Specific Populations (8.1) ] . 5.8 Withdrawal of Antiepileptic Drugs In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including QUDEXY XR, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14) ] . In situations where rapid withdrawal of QUDEXY XR is medically required, appropriate monitoring is recommended. 5.9 Decrease in Bone Mineral Density Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations (8.4) ]. Twenty-one percent of immediate-release topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of -0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions (5.4) ] . Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in immediate-release topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium. 5.10 Negative Effects on Growth (Height and Weight) Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on growth (i.e., height and weight) [see Use in Specific Populations (8.4) ] . Although continued growth was observed in both treatment groups, the immediate-release topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all topiramate age subgroups. Growth (height and weight) of children receiving prolonged QUDEXY XR therapy should be carefully monitored. 5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking topiramate. DRESS may be fatal or life-threatening.

carefully monitored. 5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking topiramate. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. QUDEXY XR should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.12 Serious Skin Reactions Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. QUDEXY XR should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed, and alternative therapy should be considered. Inform patients about the signs of serious skin reactions. 5.13 Anaphylaxis and Angioedema Hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with topiramate in the postmarketing setting. If a hypersensitivity reaction occurs, discontinue QUDEXY XR and initiate appropriate therapy [see Contraindications (4) ] . 5.14 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions (6.2) ] . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Post-marketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions (7.1) ] . Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose. Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial-onset epilepsy and this was not due to a pharmacokinetic interaction. In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.

olism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. 5.15 Kidney Stones Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 to 24 months old with epilepsy, 7% developed kidney or bladder stones. QUDEXY XR is not approved for treatment of epilepsy in pediatric patients less than 2 years old [see Use in Specific Populations (8.4) ] . Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions (5.4) ] . The concomitant use of QUDEXY XR with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in immediate-release topiramate-treated pediatric patients in one-year active-controlled study [see Use in Specific Populations (8.4) ] . This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. 5.16 Hypothermia with Concomitant Valproic Acid Use Hypothermia, defined as a drop-in body core temperature to <35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.1) ] . Consideration should be given to stopping QUDEXY XR or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

<table width="75%"><caption>Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</caption><col width="16%" align="left" valign="bottom"/><col width="21%" align="center" valign="bottom"/><col width="21%" align="center" valign="bottom"/><col width="21%" align="center" valign="bottom"/><col width="21%" align="center" valign="bottom"/><thead><tr styleCode="First Last"><th align="left">Indication</th><th align="center">Placebo Patients with Events per 1,000 Patients</th><th align="center">Drug Patients with Events per 1,000 Patients</th><th align="center">Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients</th><th align="center">Risk Difference: Additional Drug Patients with Events per 1,000 Patients</th></tr></thead><tbody><tr><td align="left">Epilepsy</td><td align="center">1.0</td><td align="center">3.4</td><td align="center">3.5</td><td align="center">2.4</td></tr><tr><td align="left">Psychiatric</td><td align="center">5.7</td><td align="center">8.5</td><td align="center">1.5</td><td align="center">2.9</td></tr><tr styleCode="Botrule"><td align="left">Other</td><td align="center">1.0</td><td align="center">1.8</td><td align="center">1.9</td><td align="center">0.9</td></tr><tr><td align="left">Total</td><td align="center">2.4</td><td align="center">4.3</td><td align="center">1.8</td><td align="center">1.9</td></tr></tbody></table>

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1) ] Visual Field Defects [see Warnings and Precautions (5.2) ] Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.3) ] Metabolic Acidosis [see Warnings and Precautions (5.4) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.5) ] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.6) ] Decrease in Bone Mineral Density [see Warnings and Precautions (5.9) ] Negative Effects on Growth (Height and Weight) [see Warnings and Precautions (5.10) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan • Hypersensitivity Reactions [see Warnings and Precautions (5.11) ] Serious Skin Reactions [see Warnings and Precautions (5.12) ] Anaphylaxis and Angioedema [see Warnings and Precautions (5.13) ] Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use [see Warnings and Precautions (5.14) ] Kidney Stones [see Warnings and Precautions (5.15) ] Hypothermia with Concomitant Valproic Acid Use [see Warnings and Precautions (5.16) ] The data described in section 6.1 were obtained using immediate-release topiramate tablets. Epilepsy : The most common (≥10% more frequent than placebo or low-dose topiramate) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision and fever ( 6.1 ) Migraine : Most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain and upper respiratory tract infection ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience with Immediate-Release Topiramate Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Monotherapy Epilepsy Adults 16 Years of Age and Older The most common adverse reactions in the controlled trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were: paresthesia, weight loss, and anorexia (see Table 5 ) . Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia. Pediatric Patients 6 to 15 Years of Age The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were fever and weight loss (see Table 5 ).

omnia, somnolence, and paresthesia. Pediatric Patients 6 to 15 Years of Age The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were fever and weight loss (see Table 5 ). Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than in the 50 mg/day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion. Table 5 represents the incidence of adverse reactions occurring in at least 3% of the adult and pediatric patients treated with 400 mg/day immediate-release topiramate and occurring with greater incidence than 50 mg/day topiramate. Table 5: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trials (Study 1) in Adult and Pediatric Patients Age Group Pediatric (6 to 15 Years) Adult (Age ≥16 Years) Immediate-release Topiramate Daily Dosage Group (mg/day) 50 400 50 400 Body System/ Adverse Reaction (N=74) % (N=77) % (N=160) % (N=159) % Body as a Whole-General Disorders Asthenia 0 3 4 6 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Paresthesia 3 12 21 40 Dizziness 13 14 Ataxia 3 4 Hypoesthesia 4 5 Hypertonia 0 3 Involuntary muscle contraction 0 3 Vertigo 0 3 Gastro-Intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Dry mouth 1 3 Liver and Biliary System Disorders Increase in gamma-GT 1 3 Metabolic and Nutritional Disorders Weight loss 7 17 6 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Anorexia 4 14 Anxiety 4 6 Cognitive problems 1 6 1 4 Confusion 0 3 Depression 0 3 7 9 Difficulty with concentration or attention 7 10 7 8 Difficulty with memory 1 3 6 11 Insomnia 8 9 Decrease in libido 0 3 Mood problems 1 8 2 5 Personality disorder (behavior problems) 0 3 Psychomotor slowing 3 5 Somnolence 10 15 Red Blood Cell Disorders Anemia 1 3 Reproductive Disorders, Female Intermenstrual bleeding 0 3 Vaginal hemorrhage 0 3 Resistance Mechanism Disorders Infection 3 8 2 3 Viral infection 3 6 6 8 Respiratory System Disorders Bronchitis 1 5 3 4 Upper respiratory tract infection 16 18 Rhinitis 5 6 2 4 Sinusitis 1 4 Skin and Appendages Disorders Alopecia 1 4 3 4 Pruritus 1 4 Rash 3 4 1 4 Acne 2 3 Special Senses Other, Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Micturition frequency 0 3 Renal calculus 0 3 Urinary incontinence 1 3 Vascular (Extracardiac) Disorders Flushing 0 5 Adjunctive Therapy Epilepsy .Adults 16 Years of Age and Older In pooled controlled clinical trials in adults with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with immediate-release topiramate at dosages of 200 to 400 mg/day (recommended dosage range) and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to immediate-release topiramate or placebo. The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200 to 400 mg/day topiramate group with an incidence higher (≥ 10%) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (Table 6). Table 6 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day topiramate and was greater than placebo incidence.

o group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (Table 6). Table 6 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day topiramate and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended topiramate dosing (i.e., 600 mg to 1000 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (200 mg to 400 mg daily) range. Table 6: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. Body System/ Adverse Reaction Topiramate Dosage (mg/day) Placebo (N=291) 200 to 400 (N=183) Body as a Whole-General Disorders Fatigue 13 15 Asthenia 1 6 Back pain 4 5 Chest pain 3 4 Influenza-like symptoms 2 3 Central & Peripheral Nervous System Disorders Dizziness 15 25 Ataxia 7 16 Speech disorders/Related speech problems 2 13 Paresthesia 4 11 Nystagmus 7 10 Tremor 6 9 Language problems 1 6 Coordination abnormal 2 4 Gait abnormal 1 3 Gastro-Intestinal System Disorders Nausea 8 10 Dyspepsia 6 7 Abdominal pain 4 6 Constipation 2 4 Metabolic and Nutritional Disorders Weight loss 3 9 Psychiatric Disorders Somnolence 12 29 Nervousness 6 16 Psychomotor slowing 2 13 Difficulty with memory 3 12 Confusion 5 11 Anorexia 4 10 Difficulty with concentration/attention 2 6 Mood problems 2 4 Agitation 2 3 Aggressive reaction 2 3 Emotional lability 1 3 Cognitive problems 1 3 Reproductive Disorders Breast pain 2 4 Respiratory System Disorders Rhinitis 6 7 Pharyngitis 2 6 Sinusitis 4 5 Vision Disorders Vision abnormal 2 13 Diplopia 5 10 In controlled clinical trials in adults, 11% of patients receiving immediate-release topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg/day. Adverse reactions associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia. .Pediatric Patients 2 to 15 Years of Age In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with immediate-release topiramate at dosages of 5 mg to 9 mg/kg/day (recommended dose range) and 101 patients received placebo. The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg to 9 mg/kg/day immediate-release topiramate group with an incidence higher (≥ 10%) than in the placebo group were: fatigue and somnolence (see Table 7 ). Table 7 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg to 9 mg/kg/day (recommended dose range) of immediate-release topiramate and was greater than placebo incidence. Table 7: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Pediatric Patients 2 to 15 Years of Age Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. , Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.

trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. , Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. Body System/ Placebo Topiramate Adverse Reaction (N=101) (N=98) Body as a Whole-General Disorders Fatigue 5 16 Injury 13 14 Central & Peripheral Nervous System Disorders Gait abnormal 5 8 Ataxia 2 6 Hyperkinesia 4 5 Dizziness 2 4 Speech disorders/Related speech problems 2 4 Gastro-Intestinal System Disorders Nausea 5 6 Saliva increased 4 6 Constipation 4 5 Gastroenteritis 2 3 Metabolic and Nutritional Disorders Weight loss 1 9 Platelet, Bleeding, & Clotting Disorders Purpura 4 8 Epistaxis 1 4 Psychiatric Disorders Somnolence 16 26 Anorexia 15 24 Nervousness 7 14 Personality disorder (behavior problems) 9 11 Difficulty with concentration/attention 2 10 Aggressive reaction 4 9 Insomnia 7 8 Difficulty with memory 0 5 Confusion 3 4 Psychomotor slowing 2 3 Resistance Mechanism Disorders Infection viral 3 7 Respiratory System Disorders Pneumonia 1 5 Skin and Appendages Disorders Skin disorder 2 3 Urinary System Disorders Urinary incontinence 2 4 None of the pediatric patients who received topiramate adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Migraine Adults In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine clinical trials for the preventive treatment of migraine (which included 35 adolescent patients age 12 to 15 years of age), most of the adverse reactions with topiramate were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period. The most common adverse reactions with immediate-release topiramate 100 mg in clinical trials for the preventive treatment of migraine of predominantly adults that were seen at an incidence higher (≥5%) than in the placebo group were paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 8 ). Table 8 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any immediate-release topiramate treatment group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). Table 8: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults Includes 35 adolescent patients age 12 to 15 years. , Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.

, Placebo-Controlled, Migraine Trials in Adults Includes 35 adolescent patients age 12 to 15 years. , Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. Topiramate Dosage (mg/day) Body System/ Placebo (N=445) 50 (N=235) 100 (N=386) Adverse Reaction % % % Body as a Whole-General Disorders Fatigue 11 14 15 Injury 7 9 6 Central & Peripheral Nervous System Disorders Paresthesia 6 35 51 Dizziness 10 8 9 Hypoesthesia 2 6 7 Language problems 2 7 6 Gastro-Intestinal System Disorders Nausea 8 9 13 Diarrhea 4 9 11 Abdominal pain 5 6 6 Dyspepsia 3 4 5 Dry mouth 2 2 3 Gastroenteritis 1 3 3 Metabolic and Nutritional Disorders Weight loss 1 6 9 Musculoskeletal System Disorders Arthralgia 2 7 3 Psychiatric Disorders Anorexia 6 9 15 Somnolence 5 8 7 Difficulty with memory 2 7 7 Insomnia 5 6 7 Difficulty with concentration/attention 2 3 6 Mood problems 2 3 6 Anxiety 3 4 5 Depression 4 3 4 Nervousness 2 4 4 Confusion 2 2 3 Psychomotor slowing 1 3 2 Reproductive Disorders, Female Menstrual disorder 2 3 2 Reproductive Disorders, Male Ejaculation premature 0 3 0 Resistance Mechanism Disorders Viral infection 3 4 4 Respiratory System Disorders Upper respiratory tract infection 12 13 14 Sinusitis 6 10 6 Pharyngitis 4 5 6 Coughing 2 2 4 Bronchitis 2 3 3 Dyspnea 2 1 3 Skin and Appendages Disorders Pruritus 2 4 2 Special Sense Other, Disorders Taste perversion 1 15 8 Urinary System Disorders Urinary tract infection 2 4 2 Vision Disorders Blurred vision Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term. 2 4 2 Of the 1,135 patients exposed to immediate-release topiramate in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo-treated patients. The adverse reactions associated with discontinuing therapy in the immediate-release topiramate-treated patients in these studies included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%). Patients treated in these studies experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, immediate-release topiramate 50 mg, 100 mg, and 200 mg groups, respectively. Pediatric Patients 12 to 17 Years of Age In five, randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine, most of the adverse reactions with immediate-release topiramate occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period. In four, fixed-dose, double-blind clinical trials for the preventive treatment of migraine in immediate-release topiramate-treated pediatric patients 12 to 17 years of age, the most common adverse reactions immediate-release topiramate 100 mg that were seen at an incidence higher (≥ 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 9 ).

n immediate-release topiramate-treated pediatric patients 12 to 17 years of age, the most common adverse reactions immediate-release topiramate 100 mg that were seen at an incidence higher (≥ 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 9 ). Table 9 shows adverse reactions from the pediatric trial [Study 13; see Clinical Studies (14.5) ] in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of immediate-release topiramate, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years of age) were treated with placebo or 50 mg, 100 mg, or 200 mg of immediate-release topiramate [see Clinical Studies (14.5) ]. Table 9 also shows adverse reactions in pediatric patients in the controlled migraine trials when the incidence in an immediate-release topiramate dose group was at least 5% or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 9 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose-related and greater at higher than recommended immediate-release topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dose (100 mg daily). Table 9: Adverse Reactions in Pooled, Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults. , Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. , Included studies MIG-3006, MIGR-001, MIGR-002 and MIGR-003. Topiramate Dosage Placebo 50 mg/day 100 mg/day Body System/ Adverse Reaction (N=45) % (N=46) % (N=48) % Body as a Whole-General Disorders Fatigue 7 7 8 Fever 2 4 6 Central & Peripheral Nervous System Disorders Paresthesia 7 20 19 Dizziness 4 4 6 Gastro-Intestinal System Disorders Abdominal pain 9 7 15 Nausea 4 4 8 Metabolic and Nutritional Disorders Weight loss 2 7 4 Psychiatric Disorders Anorexia 4 9 10 Somnolence 2 2 6 Insomnia 2 9 2 Resistance Mechanism Disorders Infection viral 4 4 8 Respiratory System Disorders Upper respiratory tract infection 11 26 23 Rhinitis 2 7 6 Sinusitis 2 9 4 Coughing 0 7 2 Special Senses Other, Disorders Taste perversion 2 2 6 Vision Disorders Conjunctivitis 4 7 4 In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of immediate-release topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one immediate-release topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%). Increased Risk for Bleeding Topiramate is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse reaction for topiramate than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages.

analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants). Other Adverse Reactions Observed During Clinical Trials Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect. Laboratory Test Abnormalities Adult Patients In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride and ammonia, immediate-release topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions (5.4 , 5.12) ] . Controlled trials of adjunctive topiramate treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate versus 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate versus 1% placebo), and decreased serum potassium (0.4% topiramate versus 0.1% placebo). Pediatric Patients In pediatric patients (1 to 24 months) receiving adjunctive topiramate for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, blood urea nitrogen (BUN), alkaline phosphatase, and total protein. The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis), and potassium with immediate-release (vs placebo) [see Use in Specific Populations (8.4) ] . QUDEXY XR is not indicated for partial-onset seizures in pediatric patients less than 2 years of age. In pediatric patients (ranging from 6 to 17 years of age) receiving immediate-release topiramate for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils, The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations (8.4) ] . QUDEXY XR is not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age. 6.2 Clinical Trials Experience with QUDEXY XR Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the QUDEXY XR study, a dose of 200 mg per day was administered to a limited number of patients; therefore, these results cannot be directly compared to immediate-release topiramate experience. The safety data presented below are from 249 patients with partial epilepsy on concomitant AEDs who participated in the QUDEXY XR study [see Clinical Studies (14.4) ] .

day was administered to a limited number of patients; therefore, these results cannot be directly compared to immediate-release topiramate experience. The safety data presented below are from 249 patients with partial epilepsy on concomitant AEDs who participated in the QUDEXY XR study [see Clinical Studies (14.4) ] . Table 10 displays the incidence of adverse reactions that occurred in ≥2% of patients and numerically greater than placebo. Table 10: Incidence (≥2%) of Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trial in Patients With Partial-Onset Seizures Body System/ Adverse Reaction Placebo (N=125) QUDEXY XR (200 mg) (N=124) General Disorders Fatigue 5 6 Asthenia 1 2 Irritability 1 2 Nervous System Disorders Somnolence 2 12 Dizziness 6 7 Paresthesia 2 7 Aphasia 0 2 Dysarthria 1 2 Memory impairment 1 2 Psychiatric Disorder Psychomotor retardation 0 2 Cardiovascular Disorders, General Hypertension 1 3 Metabolic and Nutritional Disorders Weight decrease 0 7 Decreased appetite 2 4 Anorexia 1 2 In the controlled clinical study using QUDEXY XR, 8.9% of patients who received QUDEXY XR and 4.0% who received placebo discontinued as a result of adverse reactions. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of immediate-release topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole–General Disorders : immediate hypersensitivity reactions (including anaphylaxis and angioedema [see Warnings and Precautions (5.13) ] , delayed hypersensitivity reactions (including facial swelling, lip swelling, periorbital swelling, tongue swelling), oligohydrosis and hyperthermia [see Warnings and Precautions (5.3) ] , hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions (5.14) ] , hypothermia with concomitant valproic acid [see Warnings and Precautions (5.16) ] Gastrointestinal System Disorders : hepatic failure (including fatalities), hepatitis, pancreatitis Skin and Appendage Disorders : bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions (5.12) ] , pemphigus Urinary System Disorders : kidney stones, nephrocalcinosis [see Warnings and Precautions (5.4 , 5.13) ] Vision Disorders : acute myopia, secondary angle closure glaucoma [see Warnings and Precautions (5.1) ] , maculopathy Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with Vitamin K antagonist anticoagulant medications such as warfarin.

<table ID="t5" width="75%"><caption>Table 5: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trials (Study 1) in Adult and Pediatric Patients</caption><colgroup><col width="48%" align="left" valign="top"/><col width="12%" align="center" valign="top"/><col width="14%" align="center" valign="top"/><col width="14%" align="center" valign="top"/><col width="12%" align="center" valign="top"/></colgroup><thead><tr><th align="left"/><th colspan="4" align="center">Age Group</th></tr><tr><th align="left"/><th styleCode="Botrule" colspan="2" align="center">Pediatric (6 to 15 Years)</th><th styleCode="Botrule" colspan="2" align="center">Adult (Age &#x2265;16 Years)</th></tr><tr><th align="left"/><th colspan="4" align="center">Immediate-release Topiramate Daily Dosage Group (mg/day)</th></tr><tr><th align="left"/><th styleCode="Botrule" align="center">50</th><th styleCode="Botrule" align="center">400</th><th styleCode="Botrule" align="center">50</th><th styleCode="Botrule" align="center">400</th></tr><tr><th align="left">Body System/ Adverse Reaction</th><th align="center">(N=74) %</th><th align="center">(N=77) %</th><th align="center">(N=160) %</th><th align="center">(N=159) %</th></tr></thead><tbody><tr><td align="left"><content styleCode="bold">Body as a Whole-General Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Asthenia</td><td align="center">0</td><td align="center">3</td><td align="center">4</td><td align="center">6</td></tr><tr><td align="left">Fever</td><td align="center">1</td><td align="center">12</td><td align="center"/><td align="center"/></tr><tr><td align="left">Leg pain</td><td align="center"/><td align="center"/><td align="center">2</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Paresthesia</td><td align="center">3</td><td align="center">12</td><td align="center">21</td><td align="center">40</td></tr><tr><td align="left">Dizziness</td><td align="center"/><td align="center"/><td align="center">13</td><td align="center">14</td></tr><tr><td align="left">Ataxia</td><td align="center"/><td align="center"/><td align="center">3</td><td align="center">4</td></tr><tr><td align="left">Hypoesthesia</td><td align="center"/><td align="center"/><td align="center">4</td><td align="center">5</td></tr><tr><td align="left">Hypertonia</td><td align="center"/><td align="center"/><td align="center">0</td><td align="center">3</td></tr><tr><td align="left">Involuntary muscle contraction</td><td align="center">0</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left">Vertigo</td><td align="center">0</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left"><content styleCode="bold">Gastro-Intestinal System Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Constipation</td><td align="center"/><td align="center"/><td align="center">1</td><td align="center">4</td></tr><tr><td align="left">Diarrhea</td><td align="center">8</td><td align="center">9</td><td align="center"/><td align="center"/></tr><tr><td align="left">Gastritis</td><td align="center"/><td align="center"/><td

Constipation</td><td align="center"/><td align="center"/><td align="center">1</td><td align="center">4</td></tr><tr><td align="left">Diarrhea</td><td align="center">8</td><td align="center">9</td><td align="center"/><td align="center"/></tr><tr><td align="left">Gastritis</td><td align="center"/><td align="center"/><td align="center">0</td><td align="center">3</td></tr><tr><td align="left">Dry mouth</td><td align="center"/><td align="center"/><td align="center">1</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Liver and Biliary System Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Increase in gamma-GT</td><td align="center"/><td align="center"/><td align="center">1</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Weight loss</td><td align="center">7</td><td align="center">17</td><td align="center">6</td><td align="center">17</td></tr><tr><td align="left"><content styleCode="bold">Platelet, Bleeding &amp; Clotting Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Epistaxis</td><td align="center">0</td><td align="center">4</td><td align="center"/><td align="center"/></tr><tr><td align="left"><content styleCode="bold">Psychiatric Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Anorexia</td><td align="center"/><td align="center"/><td align="center">4</td><td align="center">14</td></tr><tr><td align="left">Anxiety</td><td align="center"/><td align="center"/><td align="center">4</td><td align="center">6</td></tr><tr><td align="left">Cognitive problems</td><td align="center">1</td><td align="center">6</td><td align="center">1</td><td align="center">4</td></tr><tr><td align="left">Confusion</td><td align="center">0</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left">Depression</td><td align="center">0</td><td align="center">3</td><td align="center">7</td><td align="center">9</td></tr><tr><td align="left">Difficulty with concentration or attention</td><td align="center">7</td><td align="center">10</td><td align="center">7</td><td align="center">8</td></tr><tr><td align="left">Difficulty with memory</td><td align="center">1</td><td align="center">3</td><td align="center">6</td><td align="center">11</td></tr><tr><td align="left">Insomnia</td><td align="center"/><td align="center"/><td align="center">8</td><td align="center">9</td></tr><tr><td align="left">Decrease in libido</td><td align="center"/><td align="center"/><td align="center">0</td><td align="center">3</td></tr><tr><td align="left">Mood problems</td><td align="center">1</td><td align="center">8</td><td align="center">2</td><td align="center">5</td></tr><tr><td align="left">Personality disorder (behavior problems)</td><td align="center">0</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left">Psychomotor slowing</td><td align="center"/><td align="center"/><td align="center">3</td><td align="center">5</td></tr><tr><td align="left">Somnolence</td><td align="center"/><td align="center"/><td align="center">10</td><td align="center">15</td></tr><tr><td align="left"><content styleCode="bold">Red Blood Cell Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Anemia</td><td align="center">1</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left"><content sty

gn="left"><content styleCode="bold">Red Blood Cell Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Anemia</td><td align="center">1</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left"><content sty leCode="bold">Reproductive Disorders, Female</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Intermenstrual bleeding</td><td align="center">0</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left">Vaginal hemorrhage</td><td align="center"/><td align="center"/><td align="center">0</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Resistance Mechanism Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Infection</td><td align="center">3</td><td align="center">8</td><td align="center">2</td><td align="center">3</td></tr><tr><td align="left">Viral infection</td><td align="center">3</td><td align="center">6</td><td align="center">6</td><td align="center">8</td></tr><tr><td align="left"><content styleCode="bold">Respiratory System Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Bronchitis</td><td align="center">1</td><td align="center">5</td><td align="center">3</td><td align="center">4</td></tr><tr><td align="left">Upper respiratory tract infection</td><td align="center">16</td><td align="center">18</td><td align="center"/><td align="center"/></tr><tr><td align="left">Rhinitis</td><td align="center">5</td><td align="center">6</td><td align="center">2</td><td align="center">4</td></tr><tr><td align="left">Sinusitis</td><td align="center">1</td><td align="center">4</td><td align="center"/><td align="center"/></tr><tr><td align="left"><content styleCode="bold">Skin and Appendages Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Alopecia</td><td align="center">1</td><td align="center">4</td><td align="center">3</td><td align="center">4</td></tr><tr><td align="left">Pruritus</td><td align="center"/><td align="center"/><td align="center">1</td><td align="center">4</td></tr><tr><td align="left">Rash</td><td align="center">3</td><td align="center">4</td><td align="center">1</td><td align="center">4</td></tr><tr><td align="left">Acne</td><td align="center"/><td align="center"/><td align="center">2</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Special Senses Other, Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Taste perversion</td><td align="center"/><td align="center"/><td align="center">3</td><td align="center">5</td></tr><tr><td align="left"><content styleCode="bold">Urinary System Disorders</content></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Cystitis</td><td align="center"/><td align="center"/><td align="center">1</td><td align="center">3</td></tr><tr><td align="left">Micturition frequency</td><td align="center">0</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left">Renal calculus</td><td align="center"/><td align="center"/><td align="center">0</td><td align="center">3</td></tr><tr><td align="left">Urinary incontinence</td><td align="center">1</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left"><content styleCode="bold">Vascular (Extracardiac) Disorders</content></td><td align="center"/><td align="center

n="center">0</td><td align="center">3</td></tr><tr><td align="left">Urinary incontinence</td><td align="center">1</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left"><content styleCode="bold">Vascular (Extracardiac) Disorders</content></td><td align="center"/><td align="center "/><td align="center"/><td align="center"/></tr><tr><td align="left">Flushing</td><td align="center">0</td><td align="center">5</td><td align="center"/><td align="center"/></tr></tbody></table>

n="center">0</td><td align="center">3</td></tr><tr><td align="left">Urinary incontinence</td><td align="center">1</td><td align="center">3</td><td align="center"/><td align="center"/></tr><tr><td align="left"><content styleCode="bold">Vascular (Extracardiac) Disorders</content></td><td align="center"/><td align="center "/><td align="center"/><td align="center"/></tr><tr><td align="left">Flushing</td><td align="center">0</td><td align="center">5</td><td align="center"/><td align="center"/></tr></tbody></table> <table width="85%"><caption>Table 6: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults <footnote ID="K4130">Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.</footnote></caption><colgroup><col width="60%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/></colgroup><thead><tr><th rowspan="2" align="left" valign="bottom">Body System/ Adverse Reaction</th><th align="center"/><th styleCode="Botrule" align="center">Topiramate Dosage (mg/day)</th></tr><tr><th align="center">Placebo (N=291)</th><th align="center">200 to 400 (N=183)</th></tr></thead><tbody><tr><td align="left"><content styleCode="bold">Body as a Whole-General Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Fatigue</td><td align="center">13</td><td align="center">15</td></tr><tr><td align="left">Asthenia</td><td align="center">1</td><td align="center">6</td></tr><tr><td align="left">Back pain</td><td align="center">4</td><td align="center">5</td></tr><tr><td align="left">Chest pain</td><td align="center">3</td><td align="center">4</td></tr><tr><td align="left">Influenza-like symptoms</td><td align="center">2</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Dizziness</td><td align="center">15</td><td align="center">25</td></tr><tr><td align="left">Ataxia</td><td align="center">7</td><td align="center">16</td></tr><tr><td align="left">Speech disorders/Related speech problems</td><td align="center">2</td><td align="center">13</td></tr><tr><td align="left">Paresthesia</td><td align="center">4</td><td align="center">11</td></tr><tr><td align="left">Nystagmus</td><td align="center">7</td><td align="center">10</td></tr><tr><td align="left">Tremor</td><td align="center">6</td><td align="center">9</td></tr><tr><td align="left">Language problems</td><td align="center">1</td><td align="center">6</td></tr><tr><td align="left">Coordination abnormal</td><td align="center">2</td><td align="center">4</td></tr><tr><td align="left">Gait abnormal</td><td align="center">1</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Gastro-Intestinal System Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Nausea</td><td align="center">8</td><td align="center">10</td></tr><tr><td align="left">Dyspepsia</td><td align="center">6</td><td align="center">7</td></tr><tr><td align="left">Abdominal pain</td><td align="center">4</td><td align="center">6</td></tr><tr><td align="left">Constipation</td><td align="center">2</td><td align="center">4</td></tr><tr><td align="left"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Weight loss</td><td align="center">3</td><td align="center">9</td></tr><tr><td align="left"><content styleCode="bold">Psychiatric Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Somnolence</td><td align="center">12</td><td align="center">29</td></tr><tr><td align="left">Nervousness</td><td align="center">6</td><td align="center">16</td></tr><tr><td align="left">Psychomotor slowing</td><td align="center">2</t

orders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Somnolence</td><td align="center">12</td><td align="center">29</td></tr><tr><td align="left">Nervousness</td><td align="center">6</td><td align="center">16</td></tr><tr><td align="left">Psychomotor slowing</td><td align="center">2</t d><td align="center">13</td></tr><tr><td align="left">Difficulty with memory</td><td align="center">3</td><td align="center">12</td></tr><tr><td align="left">Confusion</td><td align="center">5</td><td align="center">11</td></tr><tr><td align="left">Anorexia</td><td align="center">4</td><td align="center">10</td></tr><tr><td align="left">Difficulty with concentration/attention</td><td align="center">2</td><td align="center">6</td></tr><tr><td align="left">Mood problems</td><td align="center">2</td><td align="center">4</td></tr><tr><td align="left">Agitation</td><td align="center">2</td><td align="center">3</td></tr><tr><td align="left">Aggressive reaction</td><td align="center">2</td><td align="center">3</td></tr><tr><td align="left">Emotional lability</td><td align="center">1</td><td align="center">3</td></tr><tr><td align="left">Cognitive problems</td><td align="center">1</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Reproductive Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Breast pain</td><td align="center">2</td><td align="center">4</td></tr><tr><td align="left"><content styleCode="bold">Respiratory System Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Rhinitis</td><td align="center">6</td><td align="center">7</td></tr><tr><td align="left">Pharyngitis</td><td align="center">2</td><td align="center">6</td></tr><tr><td align="left">Sinusitis</td><td align="center">4</td><td align="center">5</td></tr><tr><td align="left"><content styleCode="bold">Vision Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Vision abnormal</td><td align="center">2</td><td align="center">13</td></tr><tr><td align="left">Diplopia</td><td align="center">5</td><td align="center">10</td></tr></tbody></table>

d align="left"><content styleCode="bold">Vision Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Vision abnormal</td><td align="center">2</td><td align="center">13</td></tr><tr><td align="left">Diplopia</td><td align="center">5</td><td align="center">10</td></tr></tbody></table> <table ID="t7" width="60%"><caption>Table 7: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Pediatric Patients 2 to 15 Years of Age <footnote ID="K4516">Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.</footnote>^,<footnote ID="K4520">Values represent the percentage of patients reporting a given adverse reaction.

rials in Pediatric Patients 2 to 15 Years of Age <footnote ID="K4516">Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.</footnote>^,<footnote ID="K4520">Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.</footnote></caption><colgroup><col width="60%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/></colgroup><thead><tr><th align="left">Body System/</th><th align="center">Placebo</th><th align="center">Topiramate</th></tr><tr><th align="left">Adverse Reaction</th><th align="center">(N=101)</th><th align="center">(N=98)</th></tr></thead><tbody><tr><td align="left"><content styleCode="bold">Body as a Whole-General Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Fatigue</td><td align="center">5</td><td align="center">16</td></tr><tr><td align="left">Injury</td><td align="center">13</td><td align="center">14</td></tr><tr><td align="left"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Gait abnormal</td><td align="center">5</td><td align="center">8</td></tr><tr><td align="left">Ataxia</td><td align="center">2</td><td align="center">6</td></tr><tr><td align="left">Hyperkinesia</td><td align="center">4</td><td align="center">5</td></tr><tr><td align="left">Dizziness</td><td align="center">2</td><td align="center">4</td></tr><tr><td align="left">Speech disorders/Related speech problems</td><td align="center">2</td><td align="center">4</td></tr><tr><td align="left"><content styleCode="bold">Gastro-Intestinal System Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Nausea</td><td align="center">5</td><td align="center">6</td></tr><tr><td align="left">Saliva increased</td><td align="center">4</td><td align="center">6</td></tr><tr><td align="left">Constipation</td><td align="center">4</td><td align="center">5</td></tr><tr><td align="left">Gastroenteritis</td><td align="center">2</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Weight loss</td><td align="center">1</td><td align="center">9</td></tr><tr><td align="left"><content styleCode="bold">Platelet, Bleeding, &amp; Clotting Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Purpura</td><td align="center">4</td><td align="center">8</td></tr><tr><td align="left">Epistaxis</td><td align="center">1</td><td align="center">4</td></tr><tr><td align="left"><content styleCode="bold">Psychiatric Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Somnolence</td><td align="center">16</td><td align="center">26</td></tr><tr><td align="left">Anorexia</td><td align="center">15</td><td align="center">24</td></tr><tr><td align="left">Nervousness</td><td align="center">7</td><td align="center">14</td></tr><tr><td align="left">Personality disorder (behavior problems)</td><td align="center">9</td><td align="center">11</td></tr><tr><td align="left">Difficulty with concentration/attention</td><td align="center">2</td><td align="center">10</td></tr><tr><td align="left">Aggressive reaction</td><td align="center">4</td><td align="center">9</td></tr><tr><td align="left">Insomnia</td><td align="center">7</td><td align="center">8</td></tr><tr><td align="left">Difficulty with memory</td><td align="center">0</td>

d><td align="center">2</td><td align="center">10</td></tr><tr><td align="left">Aggressive reaction</td><td align="center">4</td><td align="center">9</td></tr><tr><td align="left">Insomnia</td><td align="center">7</td><td align="center">8</td></tr><tr><td align="left">Difficulty with memory</td><td align="center">0</td> <td align="center">5</td></tr><tr><td align="left">Confusion</td><td align="center">3</td><td align="center">4</td></tr><tr><td align="left">Psychomotor slowing</td><td align="center">2</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Resistance Mechanism Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Infection viral</td><td align="center">3</td><td align="center">7</td></tr><tr><td align="left"><content styleCode="bold">Respiratory System Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Pneumonia</td><td align="center">1</td><td align="center">5</td></tr><tr><td align="left"><content styleCode="bold">Skin and Appendages Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Skin disorder</td><td align="center">2</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Urinary System Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Urinary incontinence</td><td align="center">2</td><td align="center">4</td></tr></tbody></table> <table ID="t8" width="75%"><caption>Table 8: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults <footnote ID="K4863">Includes 35 adolescent patients age 12 to 15 years.</footnote>^,<footnote ID="K4867">Values represent the percentage of patients reporting a given adverse reaction.

rexia</td><td align="center">6</td><td align="center">9</td><td align="center">15</td></tr><tr><td align="left">Somnolence</td><td align="center">5</td><td align="center">8</td><td align="center">7</td></tr><tr><td align="left">Difficulty with memory</td><td align="center">2</td><td align="center">7</td><td align="cent er">7</td></tr><tr><td align="left">Insomnia</td><td align="center">5</td><td align="center">6</td><td align="center">7</td></tr><tr><td align="left">Difficulty with concentration/attention</td><td align="center">2</td><td align="center">3</td><td align="center">6</td></tr><tr><td align="left">Mood problems</td><td align="center">2</td><td align="center">3</td><td align="center">6</td></tr><tr><td align="left">Anxiety</td><td align="center">3</td><td align="center">4</td><td align="center">5</td></tr><tr><td align="left">Depression</td><td align="center">4</td><td align="center">3</td><td align="center">4</td></tr><tr><td align="left">Nervousness</td><td align="center">2</td><td align="center">4</td><td align="center">4</td></tr><tr><td align="left">Confusion</td><td align="center">2</td><td align="center">2</td><td align="center">3</td></tr><tr><td align="left">Psychomotor slowing</td><td align="center">1</td><td align="center">3</td><td align="center">2</td></tr><tr><td colspan="4" align="left"><content styleCode="bold">Reproductive Disorders, Female</content></td></tr><tr><td align="left">Menstrual disorder</td><td align="center">2</td><td align="center">3</td><td align="center">2</td></tr><tr><td colspan="4" align="left"><content styleCode="bold">Reproductive Disorders, Male</content></td></tr><tr><td align="left">Ejaculation premature</td><td align="center">0</td><td align="center">3</td><td align="center">0</td></tr><tr><td colspan="4" align="left"><content styleCode="bold">Resistance Mechanism Disorders</content></td></tr><tr><td align="left">Viral infection</td><td align="center">3</td><td align="center">4</td><td align="center">4</td></tr><tr><td colspan="4" align="left"><content styleCode="bold">Respiratory System Disorders</content></td></tr><tr><td align="left">Upper respiratory tract infection</td><td align="center">12</td><td align="center">13</td><td align="center">14</td></tr><tr><td align="left">Sinusitis</td><td align="center">6</td><td align="center">10</td><td align="center">6</td></tr><tr><td align="left">Pharyngitis</td><td align="center">4</td><td align="center">5</td><td align="center">6</td></tr><tr><td align="left">Coughing</td><td align="center">2</td><td align="center">2</td><td align="center">4</td></tr><tr><td align="left">Bronchitis</td><td align="center">2</td><td align="center">3</td><td align="center">3</td></tr><tr><td align="left">Dyspnea</td><td align="center">2</td><td align="center">1</td><td align="center">3</td></tr><tr><td colspan="4" align="left"><content styleCode="bold">Skin and Appendages Disorders</content></td></tr><tr><td align="left">Pruritus</td><td align="center">2</td><td align="center">4</td><td align="center">2</td></tr><tr><td align="left"><content styleCode="bold">Special Sense Other, Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left">Taste perversion</td><td align="center">1</td><td align="center">15</td><td align="center">8</td></tr><tr><td colspan="4" align="left"><content styleCode="bold">Urinary System Disorders</content></td></tr><tr><td align="left">Urinary tract infection</td><td align="center">2</td><td align="center">4</td><td align="center">2</td></tr><tr><td colspan="4" align="left"><content styleCode="bold">Vision Disorders</content></td></tr><tr styleCode="Botrule Last"><td align="left">Blurred vision <footnote ID="K5342">Blurred vision was the most common term considered as vision abnormal.

gn="center">2</td><td align="center">4</td><td align="center">2</td></tr><tr><td colspan="4" align="left"><content styleCode="bold">Vision Disorders</content></td></tr><tr styleCode="Botrule Last"><td align="left">Blurred vision <footnote ID="K5342">Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for &gt;50% of reactions coded as vision abnormal, a preferred term.</footnote></td><td align="center">2</td><td align="center">4</td><td align="center">2</td></tr></tbody></table>

gn="center">2</td><td align="center">4</td><td align="center">2</td></tr><tr><td colspan="4" align="left"><content styleCode="bold">Vision Disorders</content></td></tr><tr styleCode="Botrule Last"><td align="left">Blurred vision <footnote ID="K5342">Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for &gt;50% of reactions coded as vision abnormal, a preferred term.</footnote></td><td align="center">2</td><td align="center">4</td><td align="center">2</td></tr></tbody></table> <table ID="t9" width="75%"><caption>Table 9: Adverse Reactions in Pooled, Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age <footnote ID="K5397">35 adolescent patients aged 12 to &lt;16 years were also included in adverse reaction assessment for adults.</footnote>^,<footnote ID="K5401">Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events.</footnote>^,<footnote ID="K5405">Included studies MIG-3006, MIGR-001, MIGR-002 and MIGR-003.</footnote></caption><colgroup><col width="50%" align="left" valign="top"/><col width="16%" align="center" valign="top"/><col width="18%" align="center" valign="top"/><col width="16%" align="center" valign="top"/></colgroup><thead><tr><th colspan="2" align="left"/><th colspan="2" align="center">Topiramate Dosage</th></tr><tr><th align="left"/><th align="center">Placebo</th><th align="center">50 mg/day</th><th align="center">100 mg/day</th></tr><tr><th align="left">Body System/ Adverse Reaction</th><th align="center">(N=45) %</th><th align="center">(N=46) %</th><th align="center">(N=48) %</th></tr></thead><tbody><tr><td align="left"><content styleCode="bold">Body as a Whole-General Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Fatigue</td><td align="center">7</td><td align="center">7</td><td align="center">8</td></tr><tr><td align="left"> Fever</td><td align="center">2</td><td align="center">4</td><td align="center">6</td></tr><tr><td align="left"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Paresthesia</td><td align="center">7</td><td align="center">20</td><td align="center">19</td></tr><tr><td align="left"> Dizziness</td><td align="center">4</td><td align="center">4</td><td align="center">6</td></tr><tr><td align="left"><content styleCode="bold">Gastro-Intestinal System Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Abdominal pain</td><td align="center">9</td><td align="center">7</td><td align="center">15</td></tr><tr><td align="left"> Nausea</td><td align="center">4</td><td align="center">4</td><td align="center">8</td></tr><tr><td align="left"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Weight loss</td><td align="center">2</td><td align="center">7</td><td align="center">4</td></tr><tr><td align="left"><content styleCode="bold">Psychiatric Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Anorexia</td><td align="center">4</td><td align="center">9</td><td align="center">10</td></tr><tr><td align="left"> Somnolence</td><td align="center">2</td><td align="center">2</td><td align="center">6</td></tr><tr><td align="left"> Insomnia</td><td align="center">2</td><td align="center">9</td><td align="center">2</td></tr><tr><td align="left"><content styleCode="bold">Resistance Mechanism Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Infection viral</td><td align="center">4</td><td align="center">4</td><td align="center">8</td></tr><tr><td align="left"><content styleCode="bold">Respiratory System D

ent styleCode="bold">Resistance Mechanism Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Infection viral</td><td align="center">4</td><td align="center">4</td><td align="center">8</td></tr><tr><td align="left"><content styleCode="bold">Respiratory System D isorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Upper respiratory tract infection</td><td align="center">11</td><td align="center">26</td><td align="center">23</td></tr><tr><td align="left"> Rhinitis</td><td align="center">2</td><td align="center">7</td><td align="center">6</td></tr><tr><td align="left"> Sinusitis</td><td align="center">2</td><td align="center">9</td><td align="center">4</td></tr><tr><td align="left"> Coughing</td><td align="center">0</td><td align="center">7</td><td align="center">2</td></tr><tr><td align="left"><content styleCode="bold">Special Senses Other, Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Taste perversion</td><td align="center">2</td><td align="center">2</td><td align="center">6</td></tr><tr><td align="left"><content styleCode="bold">Vision Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Conjunctivitis</td><td align="center">4</td><td align="center">7</td><td align="center">4</td></tr></tbody></table>

er">2</td><td align="center">6</td></tr><tr><td align="left"><content styleCode="bold">Vision Disorders</content></td><td align="center"/><td align="center"/><td align="center"/></tr><tr><td align="left"> Conjunctivitis</td><td align="center">4</td><td align="center">7</td><td align="center">4</td></tr></tbody></table> <table width="50%"><caption>Table 10: Incidence (&#x2265;2%) of Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trial in Patients With Partial-Onset Seizures</caption><colgroup><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/></colgroup><thead><tr styleCode="First Last"><th align="left" valign="bottom">Body System/ Adverse Reaction</th><th align="center" valign="bottom">Placebo (N=125)</th><th align="center">QUDEXY XR (200 mg) (N=124)</th></tr></thead><tbody><tr><td align="left"><content styleCode="bold">General Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Fatigue</td><td align="center">5</td><td align="center">6</td></tr><tr><td align="left">Asthenia</td><td align="center">1</td><td align="center">2</td></tr><tr><td align="left">Irritability</td><td align="center">1</td><td align="center">2</td></tr><tr><td align="left"><content styleCode="bold">Nervous System Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Somnolence</td><td align="center">2</td><td align="center">12</td></tr><tr><td align="left">Dizziness</td><td align="center">6</td><td align="center">7</td></tr><tr><td align="left">Paresthesia</td><td align="center">2</td><td align="center">7</td></tr><tr><td align="left">Aphasia</td><td align="center">0</td><td align="center">2</td></tr><tr><td align="left">Dysarthria</td><td align="center">1</td><td align="center">2</td></tr><tr><td align="left">Memory impairment</td><td align="center">1</td><td align="center">2</td></tr><tr><td align="left"><content styleCode="bold">Psychiatric Disorder</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Psychomotor retardation</td><td align="center">0</td><td align="center">2</td></tr><tr><td align="left"><content styleCode="bold">Cardiovascular Disorders, General</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Hypertension</td><td align="center">1</td><td align="center">3</td></tr><tr><td align="left"><content styleCode="bold">Metabolic and Nutritional Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td align="left">Weight decrease</td><td align="center">0</td><td align="center">7</td></tr><tr><td align="left">Decreased appetite</td><td align="center">2</td><td align="center">4</td></tr><tr><td align="left">Anorexia</td><td align="center">1</td><td align="center">2</td></tr></tbody></table>

7 DRUG INTERACTIONS Oral contraceptives: decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day ( 7.4 ) Monitor lithium levels if lithium is used with high-dose QUDEXY XR ( 7.7 ) 7.1 Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed [see Clinical Pharmacology (12.3) ] . Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.12 , 5.14) , Clinical Pharmacology (12.3) ]. 7.2 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when QUDEXY XR is given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology (12.3) ]. 7.3 CNS Depressants Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, QUDEXY XR should be used with extreme caution if used in combination with alcohol and other CNS depressants. 7.4 Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with QUDEXY XR. Patients taking estrogen-containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology (12.3) ] . 7.5 Hydrochlorothiazide (HCTZ) Topiramate C max and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to QUDEXY XR may require a decrease in the QUDEXY XR dose [see Clinical Pharmacology (12.3) ] . 7.6 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when QUDEXY XR is added to pioglitazone therapy or pioglitazone is added to QUDEXY XR therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology (12.3) ] . 7.7 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose QUDEXY XR [see Clinical Pharmacology (12.3) ] .

adequate control of their diabetic disease state [see Clinical Pharmacology (12.3) ] . 7.7 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose QUDEXY XR [see Clinical Pharmacology (12.3) ] . 7.8 Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of QUDEXY XR and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as QUDEXY XR, during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/. Risk Summary QUDEXY XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data ]. SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data ] . All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor . QUDEXY XR treatment can cause metabolic acidosis [see Warnings and Precautions (5.4) ]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor.

see Warnings and Precautions (5.4) ]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4) ]. Newborns of mothers treated with QUDEXY XR should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery. Data Human Data Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in the United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval=[CI] 5.9 to 26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED, and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data When topiramate (0, 20, 100, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) were increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis.

A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre- and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. 8.2 Lactation Risk Summary Topiramate is excreted in human milk [see Data ]. The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for QUDEXY XR and any potential adverse effects on the breastfed infant from QUDEXY XR or from the underlying maternal condition. Data Human Data Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma. 8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions (7.4) , and Use in Specific Populations (8.1) ].

Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions (7.4) , and Use in Specific Populations (8.1) ]. 8.4 Pediatric Use Adjunctive Treatment for Epilepsy Pediatric Patients 2 Years of Age and Older The safety and effectiveness of QUDEXY XR as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome have been established in pediatric patients 2 years of age and older and is based on controlled trials with immediate-release topiramate [see Adverse Reactions (6.1) and Clinical Studies (14.3 , 14.4 )] . The adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults [see Warnings and Precautions (5) and Adverse Reactions (6) ] . These include, but are not limited to: oligohydrosis and hyperthermia [see Warnings and Precautions (5.3) ] dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.4) ] dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.12) ] Pediatric Patients Below the Age of 2 Years The following pediatric use information is based on studies conducted with immediate-release topiramate. Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions/toxicities not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions (6.1) ] . Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%).

Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose-related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Adverse Reactions (6.1) ] . The significance of these findings is uncertain. Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6% for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Adverse Reactions (6.1) ] . There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain. Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.12) ]. Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions (5.4) , Adverse Reactions (6.1) ] . In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions (5.6) ] . In this open-label, uncontrolled study, the mortality was 37 deaths/1,000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 to 24 months) with partial epilepsy is not known. Monotherapy Treatment of Epilepsy Pediatric Patients 2 Years of Age and Older The safety and effectiveness of QUDEXY XR as monotherapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures have been established in pediatric patients aged 2 years and older and is based on controlled trials with immediate-release topiramate [see Adverse Reactions (6.1) , Clinical Studies (14.1) ] . A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28, 6 to 15 years of age) versus levetiracetam (N=35, 4 to 15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 11 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect a topiramate induced attenuation of the key safety outcomes.

amate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect a topiramate induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight). Table 11: Summary of Immediate-Release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval) Annual Change in BMD Lumbar Spine (g/cm 2 ) -0.036 (-0.058, -0.014) Annual Change in BMD TBLH TBLH = total body less head (g/cm 2 ) -0.026 (-0.039, -0.012) Annual Change in Height (cm) (4 to 9 years, Primary Analysis Population for Height) Whereas no patients were randomized to 2 to 5 year of age subgroup for immediate-release topiramate, 5 patients (4 to 5 years) were randomized to the active control group. -0.84 (-2.67, 0.99) Annual Change in Height (cm) (4 to 15 years) -0.75 (-2.21, 0.71) Annual Change in Height (cm) (10 to 15 years) -1.01 (-3.64, 1.61) Height Velocity (cm/year) (4 to 9 years) 1.00 (-2.76, 0.76) Height Velocity (cm/year) (4 to 15 years) -0.98 (-2.33, 0.37) Height Velocity (cm/year) (10 to 15 years) -0.96 (-3.24, 1.32) Annual Change in Weight (kg) -2.05 (-3.66, -0.45) Metabolic acidosis (serum bicarbonate < 20 mEq/L) was observed in all immediate-release topiramate-treated patients at some time in the study [see Warnings and Precautions (5.4) ] . Over the whole study, 76% more immediate-release topiramate -treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate < 20 mEq/L) compared to levetiracetam treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and ≥ 5 mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. Pediatric Patients Below the Age of 2 Years Safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy. Preventive Treatment of Migraine Pediatric Patients 12 to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies (14.5) ] , a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase.

67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 13 [see Clinical Studies (14.5) ]. Efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients (12 to 16 years of age) for 20 weeks. In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release topiramate that were seen at an incidence higher (≥ 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions (6.1) ] . The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions (5.6) ]. Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions (5.4) ] . In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Warnings and Precautions (5.4) and Adverse Reactions (6.1) ] . Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology (12.2) ]. Pediatric Patients Below the Age of 12 Years Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. The risk for cognitive adverse reaction was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.6) ] . Juvenile Animal Studies When topiramate (0, 30, 90 or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis.

90 or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis. 8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2 . Estimate GFR should be measured prior to dosing [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73 m 2 ) and severe (creatinine clearance less than 30 mL/min/1.73 m 2 ) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . 8.7 Patients Undergoing Hemodialysis Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] .

<table ID="t11" width="75%"><caption>Table 11: Summary of Immediate-Release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes</caption><colgroup><col width="50%" align="left" valign="middle"/><col width="50%" align="center" valign="middle"/></colgroup><thead><tr styleCode="First Last"><th styleCode="Lrule Rrule" align="center" valign="top">Safety Parameter</th><th styleCode="Rrule" align="center" valign="top">Treatment Difference in Least Square Means (95 % Confidence Interval)</th></tr></thead><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" align="left"><content styleCode="bold">Annual Change in BMD Lumbar Spine (g/cm ²) </content></td><td styleCode="Rrule" align="center"><content styleCode="bold">-0.036 (-0.058, -0.014)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left"><content styleCode="bold">Annual Change in BMD TBLH <footnote ID="K6959">TBLH = total body less head</footnote>(g/cm ²) </content></td><td styleCode="Rrule" align="center"><content styleCode="bold">-0.026 (-0.039, -0.012)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left"><content styleCode="bold">Annual Change in Height (cm) (4 to 9 years, Primary Analysis Population for Height) <footnote ID="K6979">Whereas no patients were randomized to 2 to 5 year of age subgroup for immediate-release topiramate, 5 patients (4 to 5 years) were randomized to the active control group.</footnote></content></td><td styleCode="Rrule" align="center"><content styleCode="bold">-0.84 (-2.67, 0.99)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left"><content styleCode="bold">Annual Change in Height (cm) (4 to 15 years)</content></td><td styleCode="Rrule" align="center"><content styleCode="bold">-0.75 (-2.21, 0.71)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left"><content styleCode="bold">Annual Change in Height (cm) (10 to 15 years)</content></td><td styleCode="Rrule" align="center"><content styleCode="bold">-1.01 (-3.64, 1.61)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left"><content styleCode="bold">Height Velocity (cm/year) (4 to 9 years)</content></td><td styleCode="Rrule" align="center"><content styleCode="bold">1.00 (-2.76, 0.76)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left"><content styleCode="bold">Height Velocity (cm/year) (4 to 15 years)</content></td><td styleCode="Rrule" align="center"><content styleCode="bold">-0.98 (-2.33, 0.37)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left"><content styleCode="bold">Height Velocity (cm/year) (10 to 15 years)</content></td><td styleCode="Rrule" align="center"><content styleCode="bold">-0.96 (-3.24, 1.32)</content></td></tr><tr><td styleCode="Lrule Rrule" align="left"><content styleCode="bold">Annual Change in Weight (kg)</content></td><td styleCode="Rrule" align="center"><content styleCode="bold">-2.05 (-3.66, -0.45)</content></td></tr></tbody></table>

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as QUDEXY XR, during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/. Risk Summary QUDEXY XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data ]. SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data ] . All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor . QUDEXY XR treatment can cause metabolic acidosis [see Warnings and Precautions (5.4) ]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4) ].

lic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4) ]. Newborns of mothers treated with QUDEXY XR should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery. Data Human Data Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in the United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval=[CI] 5.9 to 26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED, and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data When topiramate (0, 20, 100, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) were increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day.

on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre- and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis.

8.4 Pediatric Use Adjunctive Treatment for Epilepsy Pediatric Patients 2 Years of Age and Older The safety and effectiveness of QUDEXY XR as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome have been established in pediatric patients 2 years of age and older and is based on controlled trials with immediate-release topiramate [see Adverse Reactions (6.1) and Clinical Studies (14.3 , 14.4 )] . The adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults [see Warnings and Precautions (5) and Adverse Reactions (6) ] . These include, but are not limited to: oligohydrosis and hyperthermia [see Warnings and Precautions (5.3) ] dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.4) ] dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.12) ] Pediatric Patients Below the Age of 2 Years The following pediatric use information is based on studies conducted with immediate-release topiramate. Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions/toxicities not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions (6.1) ] . Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%).

8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2 . Estimate GFR should be measured prior to dosing [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] .

10 OVERDOSAGE Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate. Topiramate overdose has resulted in severe metabolic acidosis [see Warnings and Precautions (5.4) ] . A patient who ingested a dose of immediate-release topiramate between 96 g and 110 g was admitted to a hospital with a coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days. Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of QUDEXY XR. Therefore, in the event of QUDEXY XR overdose, QUDEXY XR should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.

11 DESCRIPTION Topiramate, USP, is a sulfamate-substituted monosaccharide. QUDEXY XR (topiramate) extended-release capsules are available as 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg capsules for oral administration as whole capsules or opened and sprinkled onto a spoonful of soft food. Topiramate is a white to off-white powder. Topiramate is freely soluble in polar organic solvents such as acetonitrile and acetone; and very slightly soluble to practically insoluble in non-polar organic solvents such as hexanes. Topiramate has the molecular formula C 12 H 21 NO 8 S and a molecular weight of 339.4. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula: QUDEXY XR (topiramate) extended-release capsules contain beads of topiramate in a capsule. The inactive ingredients are microcrystalline cellulose, hypromellose 2910, ethylcellulose, diethyl phthalate. In addition, the capsule shells for all strengths contain hypromellose 2910, titanium dioxide, black iron oxide, red iron oxide and/or yellow iron oxide, black pharmaceutical ink, and white pharmaceutical ink (200 mg only). Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV. 12.2 Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP < 90 mm Hg, DBP < 50 mm Hg, SBP or DBP increases or decreases ≥ 20 mm Hg, and pulse increases or decreases ≥ 30 beats per minute. These changes were often dose-related and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established. 12.3 Pharmacokinetics Absorption and Distribution The pharmacokinetics of QUDEXY XR are linear with dose proportional increases in plasma concentration when administered as a single oral dose over the range of 50 mg to 1,400 mg. At 25 mg, the pharmacokinetics of QUDEXY XR are nonlinear, possibly due to the binding of topiramate to carbonic anhydrase in red blood cells. QUDEXY XR sprinkled on a spoonful of soft food is bioequivalent to the intact capsule formulation. Following a single 200 mg oral dose of QUDEXY XR, peak plasma concentrations (T max ) occurred approximately 20 hours after dosing. Steady-state was reached in about 5 days following daily dosing of QUDEXY XR in subjects with normal renal function, with a T max of approximately 6 hours. At steady-state, the plasma exposure (AUC 0–24hr , C max , and C min ) of topiramate from QUDEXY XR administered once daily and the immediate-release topiramate tablets administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for QUDEXY XR administered once daily was approximately 40% in healthy subjects, compared to approximately 53% for immediate-release topiramate [see Clinical Pharmacology (12.6) ] . Compared to the fasted state, high-fat meal had no effect on bioavailability (AUC and C max ) but delayed the T max by approximately 4 hours following a single dose of QUDEXY XR.

s approximately 40% in healthy subjects, compared to approximately 53% for immediate-release topiramate [see Clinical Pharmacology (12.6) ] . Compared to the fasted state, high-fat meal had no effect on bioavailability (AUC and C max ) but delayed the T max by approximately 4 hours following a single dose of QUDEXY XR. QUDEXY XR can be taken without regard to meals. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean effective half-life of QUDEXY XR is approximately 56 hours. Steady-state is reached in about 5 days after QUDEXY XR dosing in subjects with normal renal function. Specific Populations Renal Impairment The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73 m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73 m 2 ) [see Dosage and Administration (2.4 , 2.6) ] . Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counter flow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration (2.5) and Use in Specific Populations (8.7) ] . Hepatic Impairment Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Age, Gender and Race The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults.

l clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration (2.3) , Use in Specific Populations (8.5) ] . Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of immediate-release topiramate were evaluated in patients age 2 years to less than 16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1,217 subjects including 258 pediatric patients age 2 years to less than 16 years (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Pediatric Patients with Obesity A population PK analysis of topiramate was conducted in 129 children <21 years of age with and without obesity to evaluate the potential impact of obesity on plasma topiramate exposures. Obesity was defined as BMI ≥95th percentile for age and sex based on CDC-recommended BMI-for-age growth charts for males and females. Using the currently recommended dosing regimens, children with obesity are likely to have median values of average concentration at steady-state, and trough concentration at steady-state that are up to 20% lower and 19% lower, respectively, compared to children without obesity. Dosage adjustment according to obesity status is not necessary.. Drug Interactions In vitro s studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Antiepileptic Drugs Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 12. Interaction of QUDEXY XR and standard AEDs is not expected to differ from the experience with immediate-release topiramate products. In Table 12, the second column (AED concentration) describes what happens to the concentration of the co‑administered AED listed in the first column when topiramate was added. The third column (topiramate concentration) describes how the co‑administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone.

cribes what happens to the concentration of the co‑administered AED listed in the first column when topiramate was added. The third column (topiramate concentration) describes how the co‑administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 12: Summary of AED Interactions with Topiramate AED Co‑administered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide Is not administered, but is an active metabolite of carbamazepine. NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400 mg per day 13% decrease NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg per day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg per day. The clinical significance of the changes observed is not known [see Drug Interactions (7.4) ] . Digoxin In a single-dose study, serum digoxin AUC decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination. Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0–12h increased by 18% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin T max . The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly.

ed when administered with metformin. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known. Glyburide A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C max and a 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15% and C max was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions (7.7) ] . Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of topiramate. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9- hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg per day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg per day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg per day dose of topiramate in the same study.

sing of topiramate (200 mg per day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg per day dose of topiramate in the same study. Diltiazem Coadministration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg per day) resulted in a 10% decrease in C max and 25% decrease in diltiazem AUC, a 27% decrease in C max and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg per day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate. 12.6 Relative Bioavailability of QUDEXY XR Compared to Immediate-Release Topiramate in Healthy Volunteers QUDEXY XR, taken once daily, provides similar steady-state topiramate concentrations to immediate-release topiramate taken every 12 hours, when administered at the same total daily dose. In a healthy volunteer, multiple-dose crossover study, the 90% CI for the ratios of AUC 0–24 , C max and C min , as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose)) for multiple time points were within the 80% to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80% to 125% bioequivalence limits, except for the initial time points before 3 hours and at 8 hours post-dose, which is not expected to have a significant clinical impact. The effects of switching between QUDEXY XR and immediate-release topiramate were also evaluated in the same multiple-dose, crossover, comparative bioavailability study. In healthy subjects switched from immediate-release topiramate given every 12 hours to QUDEXY XR given once daily, similar concentrations were maintained immediately after the formulation switch. On the first day following the switch, there were no significant differences in AUC 0–24 , C max , and C min , as the 90% CI for the ratios were contained within the 80% to 125% equivalence limits.

12.2 Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP < 90 mm Hg, DBP < 50 mm Hg, SBP or DBP increases or decreases ≥ 20 mm Hg, and pulse increases or decreases ≥ 30 beats per minute. These changes were often dose-related and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established.

12.3 Pharmacokinetics Absorption and Distribution The pharmacokinetics of QUDEXY XR are linear with dose proportional increases in plasma concentration when administered as a single oral dose over the range of 50 mg to 1,400 mg. At 25 mg, the pharmacokinetics of QUDEXY XR are nonlinear, possibly due to the binding of topiramate to carbonic anhydrase in red blood cells. QUDEXY XR sprinkled on a spoonful of soft food is bioequivalent to the intact capsule formulation. Following a single 200 mg oral dose of QUDEXY XR, peak plasma concentrations (T max ) occurred approximately 20 hours after dosing. Steady-state was reached in about 5 days following daily dosing of QUDEXY XR in subjects with normal renal function, with a T max of approximately 6 hours. At steady-state, the plasma exposure (AUC 0–24hr , C max , and C min ) of topiramate from QUDEXY XR administered once daily and the immediate-release topiramate tablets administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for QUDEXY XR administered once daily was approximately 40% in healthy subjects, compared to approximately 53% for immediate-release topiramate [see Clinical Pharmacology (12.6) ] . Compared to the fasted state, high-fat meal had no effect on bioavailability (AUC and C max ) but delayed the T max by approximately 4 hours following a single dose of QUDEXY XR. QUDEXY XR can be taken without regard to meals. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean effective half-life of QUDEXY XR is approximately 56 hours. Steady-state is reached in about 5 days after QUDEXY XR dosing in subjects with normal renal function. Specific Populations Renal Impairment The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73 m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73 m 2 ) [see Dosage and Administration (2.4 , 2.6) ] . Hemodialysis Topiramate is cleared by hemodialysis.

n/1.73 m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73 m 2 ) [see Dosage and Administration (2.4 , 2.6) ] . Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counter flow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration (2.5) and Use in Specific Populations (8.7) ] . Hepatic Impairment Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Age, Gender and Race The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration (2.3) , Use in Specific Populations (8.5) ] . Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of immediate-release topiramate were evaluated in patients age 2 years to less than 16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1,217 subjects including 258 pediatric patients age 2 years to less than 16 years (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Pediatric Patients with Obesity A population PK analysis of topiramate was conducted in 129 children <21 years of age with and without obesity to evaluate the potential impact of obesity on plasma topiramate exposures. Obesity was defined as BMI ≥95th percentile for age and sex based on CDC-recommended BMI-for-age growth charts for males and females.

A population PK analysis of topiramate was conducted in 129 children <21 years of age with and without obesity to evaluate the potential impact of obesity on plasma topiramate exposures. Obesity was defined as BMI ≥95th percentile for age and sex based on CDC-recommended BMI-for-age growth charts for males and females. Using the currently recommended dosing regimens, children with obesity are likely to have median values of average concentration at steady-state, and trough concentration at steady-state that are up to 20% lower and 19% lower, respectively, compared to children without obesity. Dosage adjustment according to obesity status is not necessary.. Drug Interactions In vitro s studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Antiepileptic Drugs Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 12. Interaction of QUDEXY XR and standard AEDs is not expected to differ from the experience with immediate-release topiramate products. In Table 12, the second column (AED concentration) describes what happens to the concentration of the co‑administered AED listed in the first column when topiramate was added. The third column (topiramate concentration) describes how the co‑administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 12: Summary of AED Interactions with Topiramate AED Co‑administered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide Is not administered, but is an active metabolite of carbamazepine. NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400 mg per day 13% decrease NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg per day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg per day. The clinical significance of the changes observed is not known [see Drug Interactions (7.4) ] . Digoxin In a single-dose study, serum digoxin AUC decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly.

clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination. Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0–12h increased by 18% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin T max . The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known. Glyburide A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C max and a 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15% and C max was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions (7.7) ] . Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of topiramate. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).

g per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of topiramate. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9- hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg per day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg per day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg per day dose of topiramate in the same study. Diltiazem Coadministration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg per day) resulted in a 10% decrease in C max and 25% decrease in diltiazem AUC, a 27% decrease in C max and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg per day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.

<table width="60%"><caption>Table 12: Summary of AED Interactions with Topiramate</caption><tbody><tr><td styleCode="Botrule"><paragraph><content styleCode="bold">AED</content></paragraph><content styleCode="bold">Co&#x2011;administered</content></td><td styleCode="Botrule"><paragraph><content styleCode="bold">AED</content></paragraph><content styleCode="bold">Concentration</content></td><td styleCode="Botrule"><content styleCode="bold">Topiramate Concentration </content></td></tr><tr><td>Phenytoin</td><td>NC or 25% increase <footnote ID="fn_4d6e31bd-8eb1-402d-857a-4df8fac82e5a">Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.</footnote></td><td>48% decrease</td></tr><tr><td>Carbamazepine (CBZ)</td><td>NC</td><td>40% decrease</td></tr><tr><td>CBZ epoxide <footnote ID="fn_c7a7cbb5-0b11-4e63-92b9-cfffa4d3854a">Is not administered, but is an active metabolite of carbamazepine.</footnote></td><td>NC</td><td>NE</td><td/></tr><tr><td>Valproic acid</td><td>11% decrease</td><td>14% decrease</td></tr><tr><td>Phenobarbital</td><td>NC</td><td>NE</td></tr><tr><td>Primidone</td><td>NC</td><td>NE</td><td/></tr><tr><td>Lamotrigine</td><td>NC at TPM doses up to 400 mg per day</td><td>13% decrease</td></tr></tbody></table>

13 NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis An increase in urinary bladder tumors was observed in mice given topiramate (0, 20, 75, and 300 mg/kg/day) in the diet for 21 months. An increase in the incidence of bladder tumors in males and females receiving 300 mg/kg/day was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy (400 mg) and approximately 4 times the MRHD for migraine (100 mg) on a mg/m 2 basis. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m 2 basis). Mutagenesis Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro ; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo . Impairment of Fertility No adverse effects on male or female fertility were observed in rats administered topiramate orally at doses up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2 basis) prior to and during mating and early pregnancy.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis An increase in urinary bladder tumors was observed in mice given topiramate (0, 20, 75, and 300 mg/kg/day) in the diet for 21 months. An increase in the incidence of bladder tumors in males and females receiving 300 mg/kg/day was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy (400 mg) and approximately 4 times the MRHD for migraine (100 mg) on a mg/m 2 basis. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m 2 basis). Mutagenesis Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro ; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo . Impairment of Fertility No adverse effects on male or female fertility were observed in rats administered topiramate orally at doses up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m 2 basis) prior to and during mating and early pregnancy.

14 CLINICAL STUDIES 14.1 Extended-Release: Bridging Study to Demonstrate Pharmacokinetic Equivalence between Extended-Release (QUDEXY XR) and Immediate-Release Topiramate Formulations Although a controlled clinical trial was performed (Study 14) [see Clinical Studies (14.4) ] , the basis for approval of the extended-release formulation (QUDEXY XR) included the studies described below using an immediate-release formulation [see Clinical Studies (14.2 , 14.3 , 14.5) ] and the demonstration of the pharmacokinetic equivalence of QUDEXY XR to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see Clinical Pharmacology (12.6) ] . 14.2 Monotherapy Epilepsy Patients with Partial-Onset or Primary Generalized Tonic-Clonic Seizures Adults and Pediatric Patients 10 Years of Age and Older The effectiveness of topiramate as initial monotherapy in adults and pediatric patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1). Study 1 was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day of topiramate. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty-eight percent of patients achieved the maximal dose of 400 mg/day for >2 weeks, and patients who did not tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use. Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure in Study 1 Figure 1 Pediatric Patients 2 to 9 Years of Age The conclusion that topiramate is effective as initial monotherapy in pediatric patients 2 to 9 years of age with partial-onset or primary generalized tonic-clonic seizures was based on a pharmacometrics bridging approach using data from the controlled epilepsy trials conducted with immediate-release topiramate described in labeling. This approach consisted of first showing a similar exposure-response relationship between pediatric patients down to 2 years of age and adults when immediate-release topiramate was given as adjunctive therapy. Similarity of exposure-response was also demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy.

re-response relationship between pediatric patients down to 2 years of age and adults when immediate-release topiramate was given as adjunctive therapy. Similarity of exposure-response was also demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy. Specific dosing in pediatric patients 2 to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with immediate-release topiramate initial monotherapy [see Dosage and Administration (2.1) ] . 14.3 Adjunctive Therapy Epilepsy Adult Patients with Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for adults with partial-onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial-onset seizures, with or without secondarily generalized seizures. Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a pre-specified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose and the actual mean and median doses in the stabilization period are shown in Table 13. Pediatric Patients 2 to 16 Years of Age with Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for pediatric patients 2 to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures (see Table 14 ). Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial-onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate tablets in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period. Patients with Primary Generalized Tonic-Clonic Seizures The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo (see Table 14 ). Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225, or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period. Patients with Lennox-Gastaut Syndrome The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10) comparing a single dosage of topiramate with placebo (see Table 14 ). Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week, then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity. Table 13: Immediate-Release Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults with Partial-Onset Seizures Dose-response studies were not conducted for other indications or pediatric partial-onset seizures. Target Topiramate Dosage (mg/day) Study Stabilization Dose Placebo Placebo dosages are given as the number of tablets.

Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults with Partial-Onset Seizures Dose-response studies were not conducted for other indications or pediatric partial-onset seizures. Target Topiramate Dosage (mg/day) Study Stabilization Dose Placebo Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day) 200 400 600 800 1,000 2 N 42 42 40 41 -- -- Mean Dose 5.9 200 390 556 -- -- Median Dose 6.0 200 400 600 -- -- 3 N 44 -- -- 40 45 40 Mean Dose 9.7 -- -- 544 739 796 Median Dose 10.0 -- -- 600 800 1,000 4 N 23 -- 19 -- -- -- Mean Dose 3.8 -- 395 -- -- -- Median Dose 4.0 -- 400 -- -- -- 5 N 30 -- -- 28 -- -- Mean Dose 5.7 -- -- 522 -- -- Median Dose 6.0 -- -- 600 -- -- 6 N 28 -- -- -- 25 -- Mean Dose 7.9 -- -- -- 568 -- Median Dose 8 -- -- -- 600 -- 7 N 90 157 -- -- -- -- Mean Dose 8 200 -- -- -- -- Median Dose 8 200 -- -- -- -- In all adjunctive topiramate trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 14. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial. Table 14: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials Target Topiramate Dosage (mg per day) Study # # Placebo 200 400 600 800 1,000 ≈6 mg/kg/day For Studies 8 and 9, specified target dosages (less than 9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6 mg/kg/day; these dosages corresponded to mg per day dosages of 125 mg per day, 175 mg per day, 225 mg per day, and 400 mg per day. Comparisons with placebo: Partial-Onset Seizures Studies in Adults 2 N 45 45 45 46 -- -- -- Median % Reduction 12 27 p=0.080; 48 p ≤ 0.010; 45 p ≤ 0.001; -- -- -- % Responders 18 24 44 p ≤ 0.050; 46 -- -- -- 3 N 47 -- -- 48 48 47 -- Median % Reduction 2 -- -- 41 41 36 % Responders 9 -- -- 40 41 36 4 N 24 -- 23 -- -- -- -- Median % Reduction 1 -- 41 p=0.065; -- -- -- -- % Responders 8 -- 35 -- -- -- -- 5 N 30 -- -- 30 -- -- -- Median % Reduction -12 -- -- 46 p ≤0.005; -- -- -- % Responders 10 -- -- 47 -- -- -- 6 N 28 -- -- -- 28 -- -- Median % Reduction -21 -- -- -- 24 -- -- % Responders 0 -- -- -- 43 -- -- 7 N 91 168 -- -- -- -- -- Median % Reduction 20 44 -- -- -- -- -- % Responders 24 45 Partial-Onset Seizures Studies in Pediatric Patients 8 N 45 -- -- -- -- -- 41 Median % Reduction 11 -- -- -- -- -- 33 % Responders 20 -- -- -- -- -- 39 Primary Generalized Tonic-Clonic Median % reduction and % responders are reported for PGTC seizures 9 N 40 -- -- -- -- -- 39 Median % Reduction 9 -- -- -- -- -- 57 % Responders 20 -- -- -- -- -- 56 Lennox-Gastaut Syndrome Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures 10 N 49 -- -- -- -- -- 46 Median % Reduction -5 -- -- -- -- -- 15 % Responders 14 28 p=0.071 Improvement in Seizure Severity Percent of subjects who were minimally, much, or very much improved from baseline. 28 52 Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 to 100 mg/day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated.

nction of gender, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 to 100 mg/day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated. 14.4 Extended-Release: Adjunctive Therapy in Adult Patients with Partial-Onset Seizures with QUDEXY XR The effectiveness of QUDEXY XR as an adjunctive treatment for adults (18 to 75 years of age) was evaluated in a randomized, international, multi-center, double-blind, parallel-group, placebo-controlled trial in patients with a history of partial-onset seizures, with or without secondary generalization (Study 14). Patients with partial-onset seizures on a stable dose of 1 to 3 AEDs entered into an 8-week baseline period. Patients who experienced at least 8 partial onset seizures, with or without secondary generalization, and no more than 21 consecutive seizure free days during the 8-week baseline phase were randomly assigned to placebo or QUDEXY XR administered once daily in addition to their concomitant AEDs. Following randomization, 249 patients began the double-blind treatment phase, which consisted of an initial 3-week titration period followed by an 8-week maintenance period. During the titration period, patients received QUDEXY XR or placebo beginning at 50 mg once daily; the dose was increased at weekly intervals by 50 mg once daily, or the placebo equivalent, until a final dose of 200 mg once daily was achieved. Patients then entered the maintenance period at the assigned dose of 200 mg once daily, or its placebo equivalent. The percent reduction in the frequency of partial-onset seizure, baseline period compared to the treatment phase, was the primary endpoint. Data was analyzed by the Wilcoxon rank-sum test, with the criteria of statistical significance of p<0.05. The results of the analysis are presented in Table 15. The median percent reduction in seizure rate was 39.5% in patients taking QUDEXY XR (N=124) and 21.7% in patients taking placebo (N=125). This difference was statistically significant. Table 15: Percent Reduction From Baseline in Partial-Onset Seizure Frequency During 11-week Treatment Period in Study 14 Study End Point QUDEXY XR (N=124) Placebo (N=125) Median Percent Reduction from Baseline Statistically Significant by the Wilcoxon rank-sum test 39.5% 21.7% Figure 2 shows the change from baseline during titration plus maintenance (11 weeks) in partial-onset seizure frequency by category for patients treated with QUDEXY XR and placebo. Patients in whom the seizure frequency increased are shown as "worse." Patients in whom the seizure frequency decreased are shown in four categories of reduction in seizure frequency. Figure 2: Proportion of Patients by Category of Seizure Response to QUDEXY XR and Placebo Figure 2 14.5 Preventive Treatment of Migraine Adult Patients The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted in the US (Study 11) or the US and Canada (Study 12) established the effectiveness of immediate-release topiramate in the preventive treatment of migraine. The design of both trials was identical, enrolling patients with a history of migraine, with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventive medications before starting the baseline phase.

HS) diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventive medications before starting the baseline phase. Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either topiramate 50 mg/day, 100 mg/day, 200 mg/day (twice the recommended daily dosage for the preventive treatment of migraine), or placebo and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate (according to migraines classified by IHS criteria) from the baseline phase to double-blind treatment period in each immediate-release topiramate treatment group compared to placebo in the Intent-To-Treat (ITT) population. In Study 11, a total of 469 patients (416 females, 53 males), ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of topiramate 50, 100, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the immediate-release topiramate 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 3 ). The treatment differences between the immediate-release topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p<0.001 for both comparisons). In Study 12, a total of 468 patients (406 females, 62 males), ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of immediate-release topiramate 50, 100, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the immediate-release topiramate 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 3 ). The differences between the immediate-release topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p=0.008 and p <0.001, respectively). In both studies, there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race. For patients withdrawing from immediate-release topiramate, daily dosages were decreased in weekly intervals by 25 to 50 mg/day.

reatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race. For patients withdrawing from immediate-release topiramate, daily dosages were decreased in weekly intervals by 25 to 50 mg/day. Figure 3: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents) Figure 3 Pediatric Patients 12 to 17 Years of Age The effectiveness of immediate-release topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial (Study 13). The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]). Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and ≤14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Approximately 80% or more patients in each treatment group completed the study. The median average daily dosages were 45 and 79 mg/day in the target dose groups of immediate-release topiramate 50 and 100 mg/day, respectively. Effectiveness of treatment was assessed by comparing each immediate-release topiramate treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint). The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 16. The 100 mg immediate-release topiramate dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate. The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3.0 for 100 mg immediate-release topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p = 0.0087). Table 16: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set) Category Placebo (N=33) Topiramate 50 mg/day (N=35) Topiramate 100 mg/day (N=35) Baseline Median 3.6 4.0 4.0 Last 12 Weeks of Double-Blind Phase Median 2.3 2.3 1.0 Percent Reduction (%) Median 44.4 44.6 72.2 P-value versus Placebo P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject's stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate. , P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure. 0.7975 0.0164 Indicates p-value is < 0.05 (two-sided).

<table ID="t13" width="75%"><caption>Table 13: Immediate-Release Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults with Partial-Onset Seizures <footnote ID="K8588">Dose-response studies were not conducted for other indications or pediatric partial-onset seizures.</footnote></caption><colgroup><col width="11%" align="center" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="11%" align="center" valign="middle"/><col width="11%" align="center" valign="middle"/><col width="11%" align="center" valign="middle"/><col width="12%" align="center" valign="middle"/><col width="12%" align="center" valign="middle"/><col width="12%" align="center" valign="middle"/></colgroup><thead><tr><th align="center"/><th align="left"/><th align="center"/><th styleCode="Botrule" colspan="5" align="center">Target Topiramate Dosage (mg/day)</th></tr><tr><th align="center">Study</th><th align="center">Stabilization Dose</th><th align="center">Placebo <footnote ID="K8639">Placebo dosages are given as the number of tablets.

ign="center"/><th align="left"/><th align="center"/><th styleCode="Botrule" colspan="5" align="center">Target Topiramate Dosage (mg/day)</th></tr><tr><th align="center">Study</th><th align="center">Stabilization Dose</th><th align="center">Placebo <footnote ID="K8639">Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day)</footnote></th><th align="center">200</th><th align="center">400</th><th align="center">600</th><th align="center">800</th><th align="center">1,000</th></tr></thead><tbody><tr><td styleCode="Botrule" rowspan="3" align="center">2</td><td align="left">N</td><td align="center">42</td><td align="center">42</td><td align="center">40</td><td align="center">41</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Mean Dose</td><td align="center">5.9</td><td align="center">200</td><td align="center">390</td><td align="center">556</td><td align="center">--</td><td align="center">--</td></tr><tr styleCode="Botrule"><td align="left">Median Dose</td><td align="center">6.0</td><td align="center">200</td><td align="center">400</td><td align="center">600</td><td align="center">--</td><td align="center">--</td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">3</td><td align="left">N</td><td align="center">44</td><td align="center">--</td><td align="center">--</td><td align="center">40</td><td align="center">45</td><td align="center">40</td></tr><tr><td align="left">Mean Dose</td><td align="center">9.7</td><td align="center">--</td><td align="center">--</td><td align="center">544</td><td align="center">739</td><td align="center">796</td></tr><tr styleCode="Botrule"><td align="left">Median Dose</td><td align="center">10.0</td><td align="center">--</td><td align="center">--</td><td align="center">600</td><td align="center">800</td><td align="center">1,000</td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">4</td><td align="left">N</td><td align="center">23</td><td align="center">--</td><td align="center">19</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Mean Dose</td><td align="center">3.8</td><td align="center">--</td><td align="center">395</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr styleCode="Botrule"><td align="left">Median Dose</td><td align="center">4.0</td><td align="center">--</td><td align="center">400</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">5</td><td align="left">N</td><td align="center">30</td><td align="center">--</td><td align="center">--</td><td align="center">28</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Mean Dose</td><td align="center">5.7</td><td align="center">--</td><td align="center">--</td><td align="center">522</td><td align="center">--</td><td align="center">--</td></tr><tr styleCode="Botrule"><td align="left">Median Dose</td><td align="center">6.0</td><td align="center">--</td><td align="center">--</td><td align="center">600</td><td align="center">--</td><td align="center">--</td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">6</td><td align="left">N</td><td align="center">28</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">25</td><td align="center">--</td></tr><tr><td align="left">Mean Dose</td><td align="center">7.9</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">568</td><td align="center">--</td></tr><tr styleCode="Botrule"><td align="left">Median Dose</td><td align

td align="center">25</td><td align="center">--</td></tr><tr><td align="left">Mean Dose</td><td align="center">7.9</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">568</td><td align="center">--</td></tr><tr styleCode="Botrule"><td align="left">Median Dose</td><td align ="center">8</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">600</td><td align="center">--</td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">7</td><td align="left">N</td><td align="center">90</td><td align="center">157</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Mean Dose</td><td align="center">8</td><td align="center">200</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Median Dose</td><td align="center">8</td><td align="center">200</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr></tbody></table>

align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Median Dose</td><td align="center">8</td><td align="center">200</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr></tbody></table> <table ID="t14" width="75%"><caption>Table 14: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials</caption><colgroup><col width="10%" align="center" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="10%" align="center" valign="middle"/><col width="10%" align="center" valign="middle"/><col width="10%" align="center" valign="middle"/><col width="10%" align="center" valign="middle"/><col width="10%" align="center" valign="middle"/><col width="10%" align="center" valign="middle"/><col width="10%" align="center" valign="middle"/></colgroup><thead><tr><th align="center"/><th align="left"/><th align="center"/><th styleCode="Botrule" colspan="6" align="center">Target Topiramate Dosage (mg per day)</th></tr><tr><th align="center" valign="bottom">Study #</th><th align="center" valign="bottom">#</th><th align="center" valign="bottom">Placebo</th><th align="center" valign="bottom">200</th><th align="center" valign="bottom">400</th><th align="center" valign="bottom">600</th><th align="center" valign="bottom">800</th><th align="center" valign="bottom">1,000</th><th align="center" valign="bottom">&#x2248;6 mg/kg/day <footnote ID="K9056">For Studies 8 and 9, specified target dosages (less than 9.3 mg/kg/day) were assigned based on subject&apos;s weight to approximate a dosage of 6 mg/kg/day; these dosages corresponded to mg per day dosages of 125 mg per day, 175 mg per day, 225 mg per day, and 400 mg per day.</footnote></th></tr></thead><tbody><tr styleCode="First Last"><td colspan="9" align="left">Comparisons with placebo:</td></tr></tbody><tbody><tr styleCode="Botrule First"><td colspan="9" align="left"><content styleCode="bold">Partial-Onset Seizures Studies in Adults</content></td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">2</td><td align="left">N</td><td align="center">45</td><td align="center">45</td><td align="center">45</td><td align="center">46</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Median % Reduction</td><td align="center">12</td><td align="center">27 <footnote ID="K9103">p=0.080;</footnote></td><td align="center">48 <footnote ID="K9107">p &#x2264; 0.010;</footnote></td><td align="center">45 <footnote ID="t13f4">p &#x2264; 0.001;</footnote></td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr styleCode="Botrule"><td align="left">% Responders</td><td align="center">18</td><td align="center">24</td><td align="center">44 <footnote ID="t13f5">p &#x2264; 0.050;</footnote></td><td align="center">46 <footnoteRef IDREF="t13f5"/></td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">3</td><td align="left">N</td><td align="center">47</td><td align="center">--</td><td align="center">--</td><td align="center">48</td><td align="center">48</td><td align="center">47</td><td align="center">--</td></tr><tr><td align="left">Median % Reduction</td><td align="center">2</td><td align="center">--</td><td align="center">--</td><td align="center">41 <footnoteRef IDREF="t13f4"/></td><td align="center">41 <footnoteRef IDREF="t13f4"/></td><td align="center">36 <footnoteRef IDREF="t13f4"/></td><td align="center"/></tr><tr styleCode="Botrule"><td align="left">% Responders</td><td align="center">9</td><td align="center">--</td><td align="center">--</td><td align="center">40 <footnoteRef IDREF="t13f4"/></td><t

gn="center">41 <footnoteRef IDREF="t13f4"/></td><td align="center">36 <footnoteRef IDREF="t13f4"/></td><td align="center"/></tr><tr styleCode="Botrule"><td align="left">% Responders</td><td align="center">9</td><td align="center">--</td><td align="center">--</td><td align="center">40 <footnoteRef IDREF="t13f4"/></td><t d align="center">41 <footnoteRef IDREF="t13f4"/></td><td align="center">36 <footnoteRef IDREF="t13f5"/></td><td align="center"/></tr><tr><td styleCode="Botrule" rowspan="3" align="center">4</td><td align="left">N</td><td align="center">24</td><td align="center">--</td><td align="center">23</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Median % Reduction</td><td align="center">1</td><td align="center">--</td><td align="center">41 <footnote ID="K9247">p=0.065;</footnote></td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr styleCode="Botrule"><td align="left">% Responders</td><td align="center">8</td><td align="center">--</td><td align="center">35 <footnoteRef IDREF="t13f5"/></td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">5</td><td align="left">N</td><td align="center">30</td><td align="center">--</td><td align="center">--</td><td align="center">30</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Median % Reduction</td><td align="center">-12</td><td align="center">--</td><td align="center">--</td><td align="center">46 <footnote ID="K9313">p &#x2264;0.005;</footnote></td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr styleCode="Botrule"><td align="left">% Responders</td><td align="center">10</td><td align="center">--</td><td align="center">--</td><td align="center">47 <footnoteRef IDREF="t13f4"/></td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">6</td><td align="left">N</td><td align="center">28</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">28</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Median % Reduction</td><td align="center">-21</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">24 <footnoteRef IDREF="t13f4"/></td><td align="center">--</td><td align="center">--</td></tr><tr styleCode="Botrule"><td align="left">% Responders</td><td align="center">0</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">43 <footnoteRef IDREF="t13f4"/></td><td align="center">--</td><td align="center">--</td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">7</td><td align="left">N</td><td align="center">91</td><td align="center">168</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr><td align="left">Median % Reduction</td><td align="center">20</td><td align="center">44 <footnoteRef IDREF="t13f4"/></td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td></tr><tr styleCode="Botrule"><td align="left">% Responders</td><td align="center">24</td><td align="center">45 <footnoteRef IDREF="t13f4"/></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr styleCode="Botrule"><td colspan="9" align="left"><content styleCode="bold">Partial-Onset Seizures Studies in Pediatric Patients</content></td

center">24</td><td align="center">45 <footnoteRef IDREF="t13f4"/></td><td align="center"/><td align="center"/><td align="center"/><td align="center"/><td align="center"/></tr><tr styleCode="Botrule"><td colspan="9" align="left"><content styleCode="bold">Partial-Onset Seizures Studies in Pediatric Patients</content></td ></tr><tr><td styleCode="Botrule" rowspan="3" align="center">8</td><td align="left">N</td><td align="center">45</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">41</td></tr><tr><td align="left">Median % Reduction</td><td align="center">11</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">33 <footnoteRef IDREF="t13f5"/></td></tr><tr styleCode="Botrule"><td align="left">% Responders</td><td align="center">20</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">39</td></tr><tr styleCode="Botrule"><td colspan="9" align="left"><content styleCode="bold">Primary Generalized Tonic-Clonic <footnote ID="K9544">Median % reduction and % responders are reported for PGTC seizures</footnote></content></td></tr><tr><td styleCode="Botrule" rowspan="3" align="center">9</td><td align="left">N</td><td align="center">40</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">39</td></tr><tr><td align="left">Median % Reduction</td><td align="center">9</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">57 <footnoteRef IDREF="t13f5"/></td></tr><tr styleCode="Botrule"><td align="left">% Responders</td><td align="center">20</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">56 <footnoteRef IDREF="t13f4"/></td></tr><tr styleCode="Botrule"><td colspan="9" align="left"><content styleCode="bold">Lennox-Gastaut Syndrome <footnote ID="K9618">Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures</footnote></content></td></tr><tr><td styleCode="Botrule" rowspan="4" align="center">10</td><td align="left">N</td><td align="center">49</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">46</td></tr><tr><td align="left">Median % Reduction</td><td align="center">-5</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">--</td><td align="center">15 <footnoteRef IDREF="t13f5"/></td></tr><tr><td align="left">% Responders</td><td align="center">14</td><td align="center"/><td align="center"/><td align="center"/><td align="center"/><td align="center"/><td align="center">28 <footnote ID="K9676">p=0.071</footnote></td></tr><tr><td align="left">Improvement in Seizure Severity <footnote ID="K9682">Percent of subjects who were minimally, much, or very much improved from baseline.</footnote></td><td align="center">28</td><td align="center"/><td align="center"/><td align="center"/><td align="center"/><td align="center"/><td align="center">52 <footnoteRef IDREF="t13f5"/></td></tr></tbody></table>

footnote ID="K9682">Percent of subjects who were minimally, much, or very much improved from baseline.</footnote></td><td align="center">28</td><td align="center"/><td align="center"/><td align="center"/><td align="center"/><td align="center"/><td align="center">52 <footnoteRef IDREF="t13f5"/></td></tr></tbody></table> <table width="50%"><caption>Table 15: Percent Reduction From Baseline in Partial-Onset Seizure Frequency During 11-week Treatment Period in Study 14</caption><colgroup><col width="50%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/></colgroup><thead><tr styleCode="First Last"><th align="left" valign="bottom">Study End Point</th><th align="center">QUDEXY XR (N=124)</th><th align="center">Placebo (N=125)</th></tr></thead><tbody><tr styleCode="First Last"><td align="left">Median Percent Reduction from Baseline <footnote ID="K9753">Statistically Significant by the Wilcoxon rank-sum test</footnote></td><td align="center">39.5%</td><td align="center">21.7%</td></tr></tbody></table>

4)</th><th align="center">Placebo (N=125)</th></tr></thead><tbody><tr styleCode="First Last"><td align="left">Median Percent Reduction from Baseline <footnote ID="K9753">Statistically Significant by the Wilcoxon rank-sum test</footnote></td><td align="center">39.5%</td><td align="center">21.7%</td></tr></tbody></table> <table width="75%"><caption>Table 16: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set)</caption><col align="left" valign="top" width="36%"/><col align="center" valign="top" width="10%"/><col align="center" valign="top" width="27%"/><col align="center" valign="top" width="27%"/><thead><tr><th>Category</th><th>Placebo (N=33) </th><th>Topiramate 50 mg/day (N=35) </th><th>Topiramate 100 mg/day (N=35) </th></tr></thead><tbody><tr><td><content styleCode="bold">Baseline</content></td><td/><td/><td/></tr><tr><td>Median</td><td>3.6</td><td>4.0</td><td>4.0</td></tr><tr><td><content styleCode="bold">Last 12 Weeks of Double-Blind Phase</content></td><td/><td/><td/></tr><tr><td>Median</td><td>2.3</td><td>2.3</td><td>1.0</td></tr><tr><td><content styleCode="bold">Percent Reduction (%)</content></td><td/><td/><td/></tr><tr><td>Median</td><td>44.4</td><td>44.6</td><td>72.2</td></tr><tr><td>P-value versus Placebo <footnote ID="K9965">P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject&apos;s stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate.</footnote>^,<footnote ID="K9969">P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure.</footnote></td><td/><td>0.7975</td><td>0.0164 <footnote ID="K9976">Indicates p-value is &lt; 0.05 (two-sided).</footnote></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied QUDEXY ® XR (topiramate) extended-release capsules contain beads of topiramate in a capsule and are available in the following strengths and colors: 25 mg: light pink and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "25 mg" on the body in black ink. 25 mg capsules are supplied in the following package configurations: Bottles of 30 with desiccant and a child-resistant closure, NDC 0245-1071-30 Bottles of 90 with desiccant and a child-resistant closure, NDC 0245-1071-90 50 mg: golden yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "50 mg" on the body in black ink. 50 mg capsules are supplied in the following package configurations: Bottles of 30 with desiccant and a child-resistant closure, NDC 0245-1072-30 Bottles of 90 with desiccant and a child-resistant closure, NDC 0245-1072-90 100 mg: reddish brown and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "100 mg" on the body in black ink. 100 mg capsules are supplied in the following package configurations: Bottles of 30 with desiccant and a child-resistant closure, NDC 0245-1074-30 Bottles of 90 with desiccant and a child-resistant closure, NDC 0245-1074-90 150 mg: pale yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "150 mg" on the body in black ink. 150 mg capsules are supplied in the following package configurations: Bottles of 30 with desiccant and a child-resistant closure, NDC 0245-1075-30 Bottles of 90 with desiccant and a child-resistant closure, NDC 0245-1075-90 200 mg: brown and grey capsules, printed with "UPSHER-SMITH" on the cap in white ink and "200 mg" on the body in black ink. 200 mg capsules are supplied in the following package configurations: Bottles of 30 with desiccant and a child-resistant closure, NDC 0245-1073-30 Bottles of 90 with desiccant and a child-resistant closure, NDC 0245-1073-90 16.2 Storage and Handling QUDEXY XR (topiramate) extended-release capsules should be stored in a tightly closed container at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture.

16.2 Storage and Handling QUDEXY XR (topiramate) extended-release capsules should be stored in a tightly closed container at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture.

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide). Administration Instructions Counsel patients to swallow QUDEXY XR capsules whole or carefully open and sprinkle the entire contents on a spoonful of soft food. This drug/food mixture should be swallowed immediately and not chewed. Do not store drug/food mixture for future use [see Dosage and Administration (2.6) ] . Eye Disorders Advise patients taking QUDEXY XR to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain [see Warnings and Precautions (5.1 and 5.2) ] . Oligohydrosis and Hyperthermia Closely monitor QUDEXY XR-treated patients, especially pediatric patients, for evidence of decreased sweating and increased body temperature, especially in hot weather. Counsel patients to contact their healthcare professionals immediately if they develop a high or persistent fever, or decreased sweating [see Warnings and Precautions (5.3) ] . Metabolic Acidosis Warn patients about the potential significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) , (8.4) ]. Suicidal Behavior and Ideation Counsel patients, their caregivers, and families that AEDs, including QUDEXY XR, may increase the risk of suicidal thoughts and behavior and they should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Instruct patients to immediately report behaviors of concern to their healthcare providers [see Warnings and Precautions (5.5) ] . Interference with Cognitive and Motor Performance Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, visual effects, and advise patients not to drive or operate machinery until they have gained sufficient experience on QUDEXY XR to gauge whether it adversely affects their mental performance, motor performance, and/or vision [see Warnings and Precautions (5.6) ] . Even when taking QUDEXY XR, or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, advise all patients taking QUDEXY XR for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Discuss the appropriate level of caution with patients, before patients with epilepsy engage in such activities. Fetal Toxicity Inform pregnant women and women of childbearing potential that use of QUDEXY XR during pregnancy can cause fetal harm. QUDEXY XR increased the risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be small for their gestational age.

XR increased the risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be small for their gestational age. There may also be risks to the fetus from chronic metabolic acidosis with use of QUDEXY XR during pregnancy [see Warnings and Precautions (5.4) , (5.7) , Use in Specific Populations (8.1) ] . When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using QUDEXY XR, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing or progestin-only contraceptives with topiramate [see Drug Interactions (7.4) ] . Encourage pregnant women using QUDEXY XR to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1) ] . Decrease in Bone Mineral Density Inform the patient or caregiver that long-term treatment with QUDEXY XR can decrease bone formation and increase bone resorption in children [see Warnings and Precautions (5.9) ] . Negative Effects on Growth (Height and Weight) Discuss with the patient or caregiver that long-term QUDEXY XR treatment may attenuate growth as reflected by slower height increase and weight gain in pediatric patients [see Warnings and Precautions (5.10) ] . Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related. Advise patients to report such reactions to a healthcare provider immediately [see Warnings and Precautions (5.11)] . Serious Skin Reactions Inform patients about the signs of serious skin reactions. Instruct patients to immediately inform their healthcare provider at the first appearance of skin rash [see Warnings and Precautions (5.12) ]. Anaphylaxis and Angioedema Inform patients about the signs and symptoms of hypersensitivity reactions such as anaphylaxis and angioedema, which can occur with QUDEXY XR. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.13) ] . Hyperammonemia and Encephalopathy Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see Warnings and Precautions (5.14) ] . Kidney Stones Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation [see Warnings and Precautions (5.15) ] . Hypothermia Counsel patients that QUDEXY XR can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature.

he risk of kidney stone formation [see Warnings and Precautions (5.15) ] . Hypothermia Counsel patients that QUDEXY XR can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction [see Warnings and Precautions (5.16) ] . Distributed by UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 Qudexy is a registered trademark of Upsher-Smith Laboratories, LLC. All other marks are property of their respective owners.

Medication Guide This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 3/2025 MEDICATION GUIDE QUDEXY ® XR (cue-DEKS-ee ex-arr) (topiramate) Extended-Release Capsules, for oral use What is the most important information I should know about QUDEXY XR? QUDEXY XR may cause eye problems. Serious eye problems include: any sudden decrease in vision with or without eye pain and redness, a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma). These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms, including any new problems with your vision. QUDEXY XR may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. If you have a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away. QUDEXY XR can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will: feel tired not feel hungry (loss of appetite) feel changes in heartbeat have trouble thinking clearly Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with QUDEXY XR. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis. Like other antiepileptic drugs, QUDEXY XR may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Do not stop QUDEXY XR without first talking to a healthcare provider. Stopping QUDEXY XR suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. QUDEXY XR can harm your unborn baby. If you take QUDEXY XR during pregnancy, your baby has a higher risk for birth including cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant. Birth defects may happen even in children born to women who are not taking any medicines and do not have other risk factors.

you take QUDEXY XR during pregnancy, your baby has a higher risk for birth including cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant. Birth defects may happen even in children born to women who are not taking any medicines and do not have other risk factors. There may be other medicines to treat your condition that have a lower chance of birth defects. All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of QUDEXY XR. If the decision is made to use QUDEXY XR, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your healthcare provider about the best kind of birth control to use while you are taking QUDEXY XR. Tell your healthcare provider right away if you become pregnant while taking QUDEXY XR. You and your healthcare provider should decide if you will continue to take QUDEXY XR while you are pregnant. If you take QUDEXY XR during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. Talk to your healthcare provider if you have any questions about this risk during pregnancy. Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if QUDEXY XR has caused metabolic acidosis during your pregnancy. Pregnancy Registry: If you become pregnant while taking QUDEXY XR, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of QUDEXY XR and other antiepileptic drugs during pregnancy. QUDEXY XR may decrease the density of bones when used over a long period. QUDEXY XR may slow height increase and weight gain in children and adolescents when used over a long period. What is QUDEXY XR? QUDEXY XR is a prescription medicine used: to treat certain types of seizures (partial-onset seizures and primary generalized tonic-clonic seizures) in adults and children 2 years of age and older, with other medicines to treat certain types of seizures (partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 2 years of age and older, to prevent migraine headaches in adults and adolescents 12 years of age and older. Who should not take QUDEXY XR? Do not take QUDEXY XR if you are allergic to topiramate. QUDEXY XR, or any of the ingredients in QUDEXY XR. See the end of this Medication Guide for a complete list of ingredients in QUDEXY XR. What should I tell my healthcare provider before taking QUDEXY XR? Before taking QUDEXY XR, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems or suicidal thoughts or behavior have kidney problems, kidney stones or are getting kidney dialysis have a history of metabolic acidosis (too much acid in the blood) have liver problems have weak, brittle or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density) have lung or breathing problems have eye problems, especially glaucoma have diarrhea have a growth problem are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet are having surgery are pregnant or plan to become pregnant are breastfeeding or plan to breastfeed. QUDEXY XR passes into breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the QUDEXY XR that passes into breast milk can cause other serious harm to your baby. Talk to your healthcare provider about the best way to feed your baby if you take QUDEXY XR.

e breastfeeding or plan to breastfeed. QUDEXY XR passes into breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the QUDEXY XR that passes into breast milk can cause other serious harm to your baby. Talk to your healthcare provider about the best way to feed your baby if you take QUDEXY XR. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. QUDEXY XR and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: Valproic acid (such as DEPAKOTE ® ) any medicines that impair or decrease your thinking, concentration, or muscle coordination birth control that contains hormones (such as pills, implants, patches or injections). QUDEXY XR may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you are using birth control and QUDEXY XR. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider. How should I take QUDEXY XR? Take QUDEXY XR exactly as your healthcare provider tells you to. Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider. QUDEXY XR capsules may be swallowed whole or, if you cannot swallow the capsule whole, you may carefully open the QUDEXY XR capsule and sprinkle the medicine on a spoonful of soft food like applesauce. Swallow the food and medicine mixture right away. Do not store the food and medicine mixture to use later. Do not crush or chew QUDEXY XR before swallowing. Drink plenty fluids during the day. This may help prevent kidney stones while taking QUDEXY XR. If you take too much QUDEXY XR, call your healthcare provider right away or go to the nearest emergency room. QUDEXY XR can be taken before, during, or after a meal. If you miss a single dose of QUDEXY XR, take it as soon as you can. If you have missed more than one dose, you should call your healthcare provider for advice. Do not stop taking QUDEXY XR without talking to your healthcare provider. Stopping QUDEXY XR suddenly may cause serious problems. If you have epilepsy and you stop taking QUDEXY XR suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking QUDEXY XR slowly. Your healthcare provider may do blood tests while you take QUDEXY XR. What should I avoid while taking QUDEXY XR? You should not drink alcohol while taking QUDEXY XR. QUDEXY XR and alcohol can affect each other causing side effects such as sleepiness and dizziness. Do not drive a car or operate machinery until you know how QUDEXY XR affects you. QUDEXY XR can slow your thinking and motor skills and may affect vision. What are the possible side effects of QUDEXY XR? QUDEXY XR may cause serious side effects, including: See " What is the most important information I should know about QUDEXY XR? " High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when QUDEXY XR is taken with a medicine called valproic acid (DEPAKOTE ® ). Kidney stones. Drink plenty of fluids when taking QUDEXY XR to decrease your chances of getting kidney stones. Low body temperature. Taking QUDEXY XR when you are also taking valproic acid can cause a drop-in body temperature to less than 95°F, or can cause tiredness, confusion, or coma. Effects on thinking and alertness.

ney stones. Drink plenty of fluids when taking QUDEXY XR to decrease your chances of getting kidney stones. Low body temperature. Taking QUDEXY XR when you are also taking valproic acid can cause a drop-in body temperature to less than 95°F, or can cause tiredness, confusion, or coma. Effects on thinking and alertness. QUDEXY XR may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. QUDEXY XR may cause depression or mood problems, tiredness, and sleepiness. Dizziness or loss of muscle coordination. Severe multiorgan reactions. Treatment with QUDEXY XR may cause a serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death, particularly if it is not treated as early as possible. Contact your healthcare provider or get medical help right away if you have: o blistering and peeling of your skin or skin rash o fever or swollen glands that do not go away o hives o swelling of your face, eyes, lips, tongue, or throat o sores in your mouth, o trouble swallowing or breathing o dark urine o yellowing of the skin or whites of the eyes Serious skin reactions . QUDEXY XR may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). QUDEXY XR may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters. Anaphylaxis and angioedema. Serious allergic reactions can happen after you take QUDEXY XR. Get emergency help right awawy if you have swelling of the face, lips, eyes, tomgue, or throat, or trouble swallowing or breathing. Call your healthcare provider right away if you have any of the symptoms above. The most common side effects of QUDEXY XR include: tingling of the arms and legs (paresthesia) not feeling hungry weight loss nervousness nausea speech problems tiredness dizziness sleepiness/drowsiness a change in the way foods taste upper respiratory tract infection decreased feeling or sensitivity, especially on the skin slow reactions difficulty with memory fever abnormal vision diarrhea pain in the abdomen Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of QUDEXY XR. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Upsher-Smith Laboratories, LLC at 1-855-899-9180. How should I store QUDEXY XR? Store QUDEXY XR capsules at room temperature between 68°F to 77°F (20°C to 25°C). Keep QUDEXY XR in a tightly closed container. Keep QUDEXY XR dry and away from moisture. Keep QUDEXY XR and all medicines out of the reach of children. General information about the safe and effective use of QUDEXY XR. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use QUDEXY XR for a condition for which it was not prescribed. Do not give QUDEXY XR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about QUDEXY XR that is written for health professionals. What are the ingredients in QUDEXY XR? Active ingredient: topiramate Inactive ingredients: microcrystalline cellulose, hypromellose 2910, ethylcellulose, diethyl phthalate, titanium dioxide, black iron oxide, red iron oxide and/or yellow iron oxide, black pharmaceutical ink, and white pharmaceutical ink (200 mg only).

What are the ingredients in QUDEXY XR? Active ingredient: topiramate Inactive ingredients: microcrystalline cellulose, hypromellose 2910, ethylcellulose, diethyl phthalate, titanium dioxide, black iron oxide, red iron oxide and/or yellow iron oxide, black pharmaceutical ink, and white pharmaceutical ink (200 mg only). Distributed by: UPSHER-SMITH LABORATORIES, LLC , Maple Grove, MN 55369 Qudexy is a registered trademark of Upsher-Smith Laboratories, LLC. All other marks are property of their respective owners. This product may be covered by one or more U.S. patent(s). See www.uslpatents.com. For more information, go to www.upsher-smith.com or call UPSHER-SMITH LABORATORIES, LLC at 1-888-650-3789.

<table width="100%"><colgroup><col width="30%" align="left" valign="top"/><col width="30%" align="left" valign="top"/><col width="6%" align="left" valign="top"/><col width="34%" align="left" valign="top"/></colgroup><tfoot><tr styleCode="First Last"><td colspan="3" align="left">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td colspan="1" align="left">Revised: 3/2025</td></tr></tfoot><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" colspan="4" align="center"><paragraph><content styleCode="bold">MEDICATION GUIDE QUDEXY ^&#xAE;XR (cue-DEKS-ee ex-arr) (topiramate) Extended-Release Capsules, for oral use </content></paragraph></td></tr><tr><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">What is the most important information I should know about QUDEXY XR?</content></paragraph><paragraph><content styleCode="bold">QUDEXY XR may cause eye problems.</content>Serious eye problems include:</paragraph><list listType="unordered" styleCode="Disc"><item>any sudden decrease in vision with or without eye pain and redness,</item><item>a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma).</item></list><paragraph>These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms, including any new problems with your vision.</paragraph><paragraph/><paragraph><content styleCode="bold">QUDEXY XR may cause decreased sweating and increased body temperature (fever). </content>People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. If you have a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away.</paragraph><paragraph/><paragraph><content styleCode="bold">QUDEXY XR can increase the level of acid in your blood (metabolic acidosis). </content>If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms.

your blood (metabolic acidosis). </content>If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will:</paragraph><list listType="unordered" styleCode="Disc"><item>feel tired</item><item>not feel hungry (loss of appetite)</item><item>feel changes in heartbeat</item><item>have trouble thinking clearly</item></list><paragraph>Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with QUDEXY XR.</paragraph><paragraph>If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis.</paragraph><paragraph/><paragraph><content styleCode="bold">Like other antiepileptic drugs, QUDEXY XR may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.</content></paragraph><paragraph><content styleCode="bold">Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:</content></paragraph></td></tr><tr><td styleCode="Lrule" align="left"><list listType="unordered" styleCode="Circle"><item>thoughts about suicide or dying</item><item>attempts to commit suicide</item><item>new or worse depression</item><item>new or worse anxiety</item></list></td><td align="left"><list listType="unordered" styleCode="Circle"><item>feeling agitated or restless</item><item>panic attacks</item><item>trouble sleeping (insomnia)</item><item>new or worse irritability</item></list></td><td styleCode="Rrule" colspan="2" align="left"><list listType="unordered" styleCode="Circle"><item>acting aggressive, being angry, or violent</item><item>acting on dangerous impulses</item><item>an extreme increase in activity and talking (mania)</item><item>other unusual changes in behavior or mood</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">Do not stop QUDEXY XR without first talking to a healthcare provider.</content></paragraph><list listType="unordered" styleCode="Disc"><item>Stopping QUDEXY XR suddenly can cause serious problems.</item><item>Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.</item></list><paragraph><content styleCode="bold">How can I watch for early symptoms of suicidal thoughts and actions?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.</item><item>Keep all follow-up visits with your healthcare provider as scheduled.</item><item>Call your healthcare provider between visits as needed, especially if you are worried about symptoms.</item></list><paragraph><content styleCode="bold">QUDEXY XR can harm your unborn baby.</content></paragraph><list listType="unordered" styleCode="Disc"><item>If you take QUDEXY XR during pregnancy, your baby has a higher risk for birth including cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant.</item><item>Birth defects may happen even in children born to women who are not taking any medicines and do not have other risk factors.</item><item>There may be other medicines to treat your condition that have a lower chance of birth defects.</item><item>All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of QUDEXY XR.

who are not taking any medicines and do not have other risk factors.</item><item>There may be other medicines to treat your condition that have a lower chance of birth defects.</item><item>All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of QUDEXY XR. If the decision is made to use QUDEXY XR, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your healthcare provider about the best kind of birth control to use while you are taking QUDEXY XR.</item><item>Tell your healthcare provider right away if you become pregnant while taking QUDEXY XR. You and your healthcare provider should decide if you will continue to take QUDEXY XR while you are pregnant.</item><item>If you take QUDEXY XR during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. Talk to your healthcare provider if you have any questions about this risk during pregnancy.</item><item>Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if QUDEXY XR has caused metabolic acidosis during your pregnancy.</item><item>Pregnancy Registry: If you become pregnant while taking QUDEXY XR, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of QUDEXY XR and other antiepileptic drugs during pregnancy.</item></list><paragraph>QUDEXY XR may decrease the density of bones when used over a long period. QUDEXY XR may slow height increase and weight gain in children and adolescents when used over a long period.</paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">What is QUDEXY XR?</content></paragraph><paragraph>QUDEXY XR is a prescription medicine used:</paragraph><list listType="unordered" styleCode="Disc"><item>to treat certain types of seizures (partial-onset seizures and primary generalized tonic-clonic seizures) in adults and children 2 years of age and older,</item><item>with other medicines to treat certain types of seizures (partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 2 years of age and older,</item><item>to prevent migraine headaches in adults and adolescents 12 years of age and older.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">Who should not take QUDEXY XR? Do not take QUDEXY XR if you are allergic to topiramate.</content></paragraph><paragraph><content styleCode="bold"/>QUDEXY XR, or any of the ingredients in QUDEXY XR.

/td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">Who should not take QUDEXY XR? Do not take QUDEXY XR if you are allergic to topiramate.</content></paragraph><paragraph><content styleCode="bold"/>QUDEXY XR, or any of the ingredients in QUDEXY XR. See the end of this Medication Guide for a complete list of ingredients in QUDEXY XR.</paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">What should I tell my healthcare provider before taking QUDEXY XR?</content></paragraph><paragraph><content styleCode="bold">Before taking QUDEXY XR, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered" styleCode="Disc"><item>have or have had depression, mood problems or suicidal thoughts or behavior</item><item>have kidney problems, kidney stones or are getting kidney dialysis</item><item>have a history of metabolic acidosis (too much acid in the blood)</item><item>have liver problems</item><item>have weak, brittle or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density)</item><item>have lung or breathing problems</item><item>have eye problems, especially glaucoma</item><item>have diarrhea</item><item>have a growth problem</item><item>are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet</item><item>are having surgery</item><item>are pregnant or plan to become pregnant</item><item>are breastfeeding or plan to breastfeed. QUDEXY XR passes into breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the QUDEXY XR that passes into breast milk can cause other serious harm to your baby. Talk to your healthcare provider about the best way to feed your baby if you take QUDEXY XR.</item></list><paragraph>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. QUDEXY XR and other medicines may affect each other causing side effects.</paragraph><paragraph>Especially tell your healthcare provider if you take:</paragraph><list listType="unordered" styleCode="Disc"><item>Valproic acid (such as DEPAKOTE ^&#xAE;)</item><item>any medicines that impair or decrease your thinking, concentration, or muscle coordination</item><item>birth control that contains hormones (such as pills, implants, patches or injections). QUDEXY XR may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you are using birth control and QUDEXY XR.</item></list><paragraph>Ask your healthcare provider if you are not sure if your medicine is listed above.</paragraph><paragraph>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.</paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">How should I take QUDEXY XR?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Take QUDEXY XR exactly as your healthcare provider tells you to.</item><item>Your healthcare provider may change your dose. <content styleCode="bold">Do not </content>change your dose without talking to your healthcare provider.</item><item>QUDEXY XR capsules may be swallowed whole or, if you cannot swallow the capsule whole, you may carefully open the QUDEXY XR capsule and sprinkle the medicine on a spoonful of soft food like applesauce.<list listType="unordered" styleCode="Circle"><item>Swallow the food and medicine mixture right away.

ider.</item><item>QUDEXY XR capsules may be swallowed whole or, if you cannot swallow the capsule whole, you may carefully open the QUDEXY XR capsule and sprinkle the medicine on a spoonful of soft food like applesauce.<list listType="unordered" styleCode="Circle"><item>Swallow the food and medicine mixture right away. <content styleCode="bold">Do not </content>store the food and medicine mixture to use later.</item><item>Do not crush or chew QUDEXY XR before swallowing.</item></list></item><item>Drink plenty fluids during the day. This may help prevent kidney stones while taking QUDEXY XR.</item><item>If you take too much QUDEXY XR, call your healthcare provider right away or go to the nearest emergency room.</item><item>QUDEXY XR can be taken before, during, or after a meal.</item><item>If you miss a single dose of QUDEXY XR, take it as soon as you can. If you have missed more than one dose, you should call your healthcare provider for advice.</item><item>Do not stop taking QUDEXY XR without talking to your healthcare provider. Stopping QUDEXY XR suddenly may cause serious problems. If you have epilepsy and you stop taking QUDEXY XR suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking QUDEXY XR slowly.</item><item>Your healthcare provider may do blood tests while you take QUDEXY XR.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">What should I avoid while taking QUDEXY XR?</content></paragraph><list listType="unordered" styleCode="Disc"><item>You should not drink alcohol while taking QUDEXY XR. QUDEXY XR and alcohol can affect each other causing side effects such as sleepiness and dizziness.</item><item>Do not drive a car or operate machinery until you know how QUDEXY XR affects you. QUDEXY XR can slow your thinking and motor skills and may affect vision.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">What are the possible side effects of QUDEXY XR?</content></paragraph><paragraph><content styleCode="bold">QUDEXY XR may cause serious side effects, including:</content></paragraph><paragraph>See &quot; <linkHtml href="#info">What is the most important information I should know about QUDEXY XR?</linkHtml>&quot;</paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">High blood ammonia levels. </content>High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when QUDEXY XR is taken with a medicine called valproic acid (DEPAKOTE ^&#xAE;).</item><item><content styleCode="bold">Kidney stones. </content>Drink plenty of fluids when taking QUDEXY XR to decrease your chances of getting kidney stones.</item><item><content styleCode="bold">Low body temperature.</content>Taking QUDEXY XR when you are also taking valproic acid can cause a drop-in body temperature to less than 95&#xB0;F, or can cause tiredness, confusion, or coma.</item><item><content styleCode="bold">Effects on thinking and alertness. </content>QUDEXY XR may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. QUDEXY XR may cause depression or mood problems, tiredness, and sleepiness.</item><item><content styleCode="bold">Dizziness or loss of muscle coordination. </content></item><item><content styleCode="bold">Severe multiorgan reactions.</content> Treatment with QUDEXY XR may cause a serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells.

tent styleCode="bold">Dizziness or loss of muscle coordination. </content></item><item><content styleCode="bold">Severe multiorgan reactions.</content> Treatment with QUDEXY XR may cause a serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death, particularly if it is not treated as early as possible. Contact your healthcare provider or get medical help right away if you have: o blistering and peeling of your skin or skin rash o fever or swollen glands that do not go away o hives o swelling of your face, eyes, lips, tongue, or throat o sores in your mouth, o trouble swallowing or breathing o dark urine o yellowing of the skin or whites of the eyes</item><item><content styleCode="bold">Serious skin reactions</content>. QUDEXY XR may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). QUDEXY XR may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters.</item><item><content styleCode="bold">Anaphylaxis and angioedema.</content> Serious allergic reactions can happen after you take QUDEXY XR. Get emergency help right awawy if you have swelling of the face, lips, eyes, tomgue, or throat, or trouble swallowing or breathing.</item></list><paragraph>Call your healthcare provider right away if you have any of the symptoms above.</paragraph><paragraph><content styleCode="bold">The most common side effects of QUDEXY XR include:</content></paragraph></td></tr><tr><td styleCode="Lrule" align="left"><list listType="unordered" styleCode="Circle"><item>tingling of the arms and legs (paresthesia)</item><item>not feeling hungry</item><item>weight loss</item><item>nervousness</item><item>nausea</item></list></td><td colspan="2" align="left"><list listType="unordered" styleCode="Circle"><item>speech problems</item><item>tiredness</item><item>dizziness</item><item>sleepiness/drowsiness</item><item>a change in the way foods taste</item><item>upper respiratory tract infection</item><item>decreased feeling or sensitivity, especially on the skin</item></list></td><td styleCode="Rrule" align="left"><list listType="unordered" styleCode="Circle"><item>slow reactions</item><item>difficulty with memory</item><item>fever</item><item>abnormal vision</item><item>diarrhea</item><item>pain in the abdomen</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph>Tell your healthcare provider about any side effect that bothers you or that does not go away.</paragraph><paragraph>These are not all the possible side effects of QUDEXY XR. For more information, ask your healthcare provider or pharmacist.</paragraph><paragraph>Call your doctor for medical advice about side effects.

h>Tell your healthcare provider about any side effect that bothers you or that does not go away.</paragraph><paragraph>These are not all the possible side effects of QUDEXY XR. For more information, ask your healthcare provider or pharmacist.</paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph><paragraph>You may also report side effects to Upsher-Smith Laboratories, LLC at 1-855-899-9180.</paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">How should I store QUDEXY XR?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Store QUDEXY XR capsules at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item><item>Keep QUDEXY XR in a tightly closed container.</item><item>Keep QUDEXY XR dry and away from moisture.</item><item><content styleCode="bold">Keep QUDEXY XR and all medicines out of the reach of children.</content></item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">General information about the safe and effective use of QUDEXY XR.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use QUDEXY XR for a condition for which it was not prescribed. Do not give QUDEXY XR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about QUDEXY XR that is written for health professionals.</paragraph></td></tr><tr><td styleCode="Lrule Rrule" colspan="4" align="left"><paragraph><content styleCode="bold">What are the ingredients in QUDEXY XR?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content>topiramate</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content>microcrystalline cellulose, hypromellose 2910, ethylcellulose, diethyl phthalate, titanium dioxide, black iron oxide, red iron oxide and/or yellow iron oxide, black pharmaceutical ink, and white pharmaceutical ink (200 mg only).</paragraph><paragraph>Distributed by: <content styleCode="bold">UPSHER-SMITH LABORATORIES, LLC</content>, Maple Grove, MN 55369 Qudexy is a registered trademark of Upsher-Smith Laboratories, LLC. All other marks are property of their respective owners. This product may be covered by one or more U.S. patent(s). See www.uslpatents.com. For more information, go to www.upsher-smith.com or call UPSHER-SMITH LABORATORIES, LLC at 1-888-650-3789.</paragraph></td></tr></tbody></table>

1 INDICATIONS AND USAGE Topiramate extended-release capsules are indicated for: • Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older ( 1.1 ); adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut Syndrome in patients 2 years of age and older ( 1.2 ) • Preventive treatment of migraine in patients 12 years of age and older ( 1.3 ) 1.1 Monotherapy Epilepsy Topiramate extended-release capsules are indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older. 1.2 Adjunctive Therapy Epilepsy Topiramate extended-release capsules are indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut Syndrome in patients 2 years of age and older. 1.3 Migraine Topiramate extended-release capsules are indicated for the preventive treatment of migraine in patients 12 years of age and older .

2 DOSAGE AND ADMINISTRATION • Topiramate extended-release capsule initial dose, titration, and recommended maintenance dose varies by indication and age group. See Full Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) • Capsules may be swallowed whole or opened and sprinkled on a spoonful of soft food ( 2.6 ) 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older The recommended dose for topiramate extended-release capsules monotherapy in adults and pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate topiramate extended-release capsules according to the following schedule (see Table 1). Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10 Years of Age and Older Topiramate Extended-Release Capsules Once Daily Dose Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 50 mg 100 mg 150 mg 200 mg 300 mg 400 mg Pediatric Patients 2 to 9 Years of Age Dosing in patients 2 to 9 years of age is based on weight. During the titration period, the initial dose of topiramate extended-release capsules is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day in the second week. Dosage can be increased by 25 mg to 50 mg once daily each subsequent week, as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to 7 weeks. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 mg to 50 mg once daily weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (see Table 2). Table 2: Monotherapy Target Total Daily Maintenance Dosing for Patients 2 to 9 Years of Age Weight (kg) Total Daily Dose (mg/day) Minimum Maintenance Dose Total Daily Dose (mg/day) Maximum Maintenance Dose Up to 11 150 250 12 to 22 200 300 23 to 31 200 350 32 to 38 250 350 Greater than 38 250 400 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Older) The recommended total daily dose of topiramate extended-release capsules as adjunctive therapy in adults with partial-onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily, and with primary generalized tonic-clonic seizures is 400 mg orally once daily. Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures. Pediatric Patients 2 to 16 Years of Age The recommended total daily dose of topiramate extended-release capsules as adjunctive therapy for pediatric patients 2 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome.

gin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day. 2.3 Dosing for the Preventive Treatment of Migraine The recommended total daily dose of topiramate extended-release capsules as treatment for the preventive treatment of migraine in patients 12 years of age and older is 100 mg once daily. The recommended titration rate for topiramate extended-release capsules for the preventive treatment of migraine is as follows: Table 3: Preventive Treatment of Migraine Titration Schedule for Patients 12 Years of Age and Older Topiramate Extended-Release Capsules Once Daily Dose Week 1 25 mg Week 2 50 mg Week 3 75 mg Week 4 100 mg Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustment can be used. 2.4 Dosing in Patients with Renal Impairment In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose of topiramate extended-release capsules is recommended [see Use in Specific Populations ( 8.5 , 8.6 ), Clinical Pharmacology ( 12.3 )]. 2.5 Dosing in Patients Undergoing Hemodialysis To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate extended-release capsules may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. 2.6 Administration Instructions Topiramate extended-release capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed or crushed. It should not be stored for further use. Topiramate extended-release capsules can be taken without regard to meals [see Clinical Pharmacology ( 12.3 )].

3 DOSAGE FORMS AND STRENGTHS Topiramate Extended-Release Capsules are available in the following strengths and colors: • 25 mg: flesh colored cap printed with “G” in black ink and light grey body printed with “367” in black ink. • 50 mg: light orange cap printed with “G” in black ink and light grey body printed with “368” in black ink. • 100 mg: reddish orange cap printed with “G” in black ink and light grey body printed with “369” in black ink. • 150 mg: grey cap printed with “G” in black ink and light grey body printed with “370” in black ink. • 200 mg: brown cap printed with “G” in black ink and light grey body printed with “371” in black ink. Extended-release capsules: 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg ( 3 )

4 CONTRAINDICATIONS Topiramate extended-release capsules is contraindicated in patients with a history of hypersensitivity reaction to topiramate, topiramate extended-release capsules, or any of the inactive ingredients of topiramate extended-release capsules. Anaphylaxis and angioedema have occurred with topiramate [see Warnings and Precautions ( 5.13 )]. History of hypersensitivity reaction to topiramate, topiramate extended-release capsule, or any of the inactive ingredients of topiramate extended-release capsule ( 4 , 5.13 )

5 WARNINGS AND PRECAUTIONS • Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue topiramate extended-release capsules as soon as possible ( 5.1 ) • Visual field defects: consider discontinuation of topiramate extended-release capsules ( 5.2 ) • Oligohydrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients ( 5.3 ) • Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of topiramate extended-release capsules if clinically appropriate ( 5.4 ) • Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.5 ) • Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur ( 5.6 ) • Fetal Toxicity: use during pregnancy can cause major congenital malformations, including but not limited to cleft lip and/or palate, and being small for gestational age ( 5.7 ) • Withdrawal of AEDs: withdraw topiramate extended-release capsules gradually ( 5.8 ) • Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients ( 5.9 ) • Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy ( 5.10 ) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity, serious skin reactions, anaphylaxis, and angioedema: Discontinue topiramate extended-release capsules if an alternative etiology cannot be established. ( 5.11 , 5.12 , 5.13 ) • Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur ( 5.14 ) • Kidney stones: avoid use with other carbonic anhydrase inhibitors, drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.15 ) • Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use ( 5.16 ) 5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate extended-release capsules as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate extended-release capsules, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

psules as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate extended-release capsules, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with topiramate, consideration should be given to discontinuing the drug. 5.3 Oligohydrosis and Hyperthermia Oligohydrosis (decreased sweating), infrequently resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures. The majority of the reports have been in pediatric patients. Patients (especially pediatric patients) treated with topiramate extended-release capsules should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate extended-release capsules are prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. 5.4 Metabolic Acidosis Topiramate extended-release capsules can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by topiramate extended-release capsules. Topiramate extended-release capsules-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of topiramate. Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials, for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial-onset seizures was as high as 67% for immediate-release topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤ 2% for placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions ( 5.9 , 5.13)] .

ng cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions ( 5.9 , 5.13)] . A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that topiramate decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions ( 5.9 ), Use in Specific Populations ( 8.4 )] . Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24-months old patients. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations ( 8.4 )]. Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions ( 5.7 ), Use in Specific Populations ( 8.1 )]. Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered. 5.5 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including topiramate extended-release capsule increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

dal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs. Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing topiramate extended-release capsules or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.6 Cognitive/Neuropsychiatric Adverse Reactions Immediate-release topiramate can cause cognitive/neuropsychiatric adverse reactions and therefore these are expected to be caused by topiramate extended-release capsules. The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue. Adult Patients Cognitive Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction. In adult epilepsy adjunctive controlled trials, which used rapid titration (100 to 200 mg/day weekly increments) and target immediate-release topiramate doses of 200 mg to 1,000 mg/day, 56% of patients in the 800 mg/day and 1,000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200 to 400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase. In the monotherapy epilepsy-controlled trial conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day.

se events began during titration and persisted into the maintenance phase. In the monotherapy epilepsy-controlled trial conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day. In the 6-month controlled trials for the preventive treatment of migraine, which used a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations treated with topiramate [see Warnings and Precautions ( 5.5 )]. Somnolence/Fatigue Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue appeared dose-related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both somnolence and fatigue were dose-related and more common in the titration phase. Pediatric Patients In pediatric epilepsy trials (adjunctive and monotherapy), the incidence of cognitive/neuropsychiatric adverse reactions was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems, and language problems. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in topiramate-treated patients compared to placebo. The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during the titration period and sometimes persisted for various durations after completion of titration. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 13 [see Clinical Studies ( 14.5 )]. Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency. 5.7 Fetal Toxicity Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformation, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA).

can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformation, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations ( 8.1 )]. Consider the benefits and risks of topiramate extended-release capsules when administering this drug in women of childbearing potential, particularly when topiramate extended-release capsules are considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations ( 8.1 ), Patient Counseling Information ( 17 )]. Topiramate extended-release capsules should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus [see Use in Specific Populations ( 8.1 )]. 5.8 Withdrawal of Antiepileptic Drugs In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including topiramate extended-release capsules, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14)]. In situations where rapid withdrawal of topiramate extended-release capsules are medically required, appropriate monitoring is recommended. 5.9 Decrease in Bone Mineral Density Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations ( 8.4 )]. Twenty-one percent of immediate-release topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of -0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions ( 5.4 )]. Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in immediate-release topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium. 5.10 Negative Effects on Growth (Height and Weight) Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on growth (i.e., height and weight) [see Use in Specific Populations ( 8.4 )] . Although continued growth was observed in both treatment groups, the immediate-release topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group.

onotherapy on growth (i.e., height and weight) [see Use in Specific Populations ( 8.4 )] . Although continued growth was observed in both treatment groups, the immediate-release topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all topiramate age subgroups. Growth (height and weight) of children receiving prolonged topiramate extended-release capsules therapy should be carefully monitored. 5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking topiramate. DRESS may be fatal or lifethreatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. topiramate extended-release capsules should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.12 Serious Skin Reactions Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. Topiramate extended-release capsules should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions. 5.13 Anaphylaxis and Angioedema Hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with topiramate in the postmarketing setting. If a hypersensitivity reaction occurs, discontinue topiramate extended-release capsules and initiate appropriate therapy [see Contraindications ( 4 )] . 5.14 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions ( 6.2 )] . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Post-marketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions ( 7.1 )]. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo.

ed with discontinuation of treatment. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose. Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial-onset epilepsy and this was not due to a pharmacokinetic interaction. In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. 5.15 Kidney Stones Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 to 24 months old with epilepsy, 7% developed kidney or bladder stones. Topiramate extended-release capsules are not approved for treatment of epilepsy in pediatric patients less than 2 years old [see Use in Specific Populations ( 8.4 )] . Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions ( 5.4 )]. The concomitant use of topiramate extended-release capsules with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in immediate-release topiramate-treated pediatric patients in one-year active-controlled study [see Use in Specific Populations ( 8.4 )] . This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. 5.16 Hypothermia with Concomitant Valproic Acid Use Hypothermia, defined as a drop-in body core temperature to <35ºC (95ºF), has been reported in association with topiramate use with concomitant valproic acid both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions ( 7.1 )].

te use with concomitant valproic acid both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions ( 7.1 )]. Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

<table ID="_RefID418" width="100%"><caption> Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis </caption><col width="17%"/><col width="17%"/><col width="19%"/><col width="22%"/><col width="24%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Indication</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo Patients</content> <content styleCode="bold"> with Events per 1,000 Patients</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Drug Patients with</content> <content styleCode="bold"> Events per 1,000</content> <content styleCode="bold"> Patients</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Relative Risk:</content> <content styleCode="bold"> Incidence of</content> <content styleCode="bold"> Events in</content> <content styleCode="bold"> Drug Patients/</content> <content styleCode="bold"> Incidence in</content> <content styleCode="bold"> Placebo Patients</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Risk Difference:</content> <content styleCode="bold">Additional Drug</content> <content styleCode="bold">Patients with</content> <content styleCode="bold">Events per</content> <content styleCode="bold">1,000 Patients</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Epilepsy</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.4</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Psychiatric</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.9</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Other</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.9</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Total</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4.3</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1.8</paragraph></td><

aragraph>Total</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4.3</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1.8</paragraph></td>< td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1.9</paragraph></td></tr></tbody></table>

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: • Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions ( 5.1 )] • Visual Field Defects [see Warnings and Precautions ( 5.2 )] • Oligohydrosis and Hyperthermia [see Warnings and Precautions ( 5.3 )] • Metabolic Acidosis [see Warnings and Precautions ( 5.4 )] • Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.5 )] • Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions ( 5.6 )] • Decrease in Bone Mineral Density [see Warnings and Precautions ( 5.9 )] • Negative Effects on Growth (Height and Weight) [see Warnings and Precautions ( 5.10 )] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions ( 5.11 )] • Serious Skin Reactions [see Warnings and Precautions ( 5.12 )] • Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.13 )] • Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) [see Warnings and Precautions ( 5.14 )] • Kidney Stones [see Warnings and Precautions ( 5.15 )] • Hypothermia with Concomitant Valproic Acid Use [see Warnings and Precautions ( 5.16 )] The data described in section 6.1 were obtained using immediate-release topiramate tablets. Epilepsy: The most common (≥10% more frequent than placebo or low-dose topiramate) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision and fever ( 6.1 ) Migraine: Most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain and upper respiratory tract infection ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience with Immediate-Release Topiramate Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Monotherapy Epilepsy Adults 16 Years of Age and Older The most common adverse reactions in the controlled trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were: paresthesia, weight loss, and anorexia (see Table 5). Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia. Pediatric Patients 6 to 15 Years of Age The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were fever and weight loss (see Table 5).

somnia, somnolence, and paresthesia. Pediatric Patients 6 to 15 Years of Age The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were fever and weight loss (see Table 5). Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than in the 50 mg/day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion. Table 5 represents the incidence of adverse reactions occurring in at least 3% of the adult and pediatric patients treated with 400 mg/day immediate-release topiramate and occurring with greater incidence than 50 mg/day topiramate. Table 5: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trials (Study 1) in Adult and Pediatric Patients Body System/ Adverse Reaction Age Group Pediatric (6 to 15 Years) Adult (Age ≥16 Years) Immediate-release Topiramate Daily Dosage Group (mg/day) 50 400 50 400 (N=74) % (N=77) % (N=160) % (N=159) % Body as a Whole-General Disorders Asthenia 0 3 4 6 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Paresthesia 3 12 21 40 Dizziness 13 14 Ataxia 3 4 Hypoesthesia 4 5 Hypertonia 0 3 Involuntary muscle contraction 0 3 Vertigo 0 3 Gastro-Intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Dry mouth 1 3 Liver and Biliary System Disorders Increase in gaamma-GT 1 3 Metabolic and Nutritional Disorders Weight loss 7 17 6 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Anorexia 4 14 Anxiety 4 6 Cognitive problems 1 6 1 4 Confusion 0 3 Depression 0 3 7 9 Difficulty with concentration or attention 7 10 7 8 Difficulty with memory 1 3 6 11 Insomnia 8 9 Decrease in libido 0 3 Mood problems 1 8 2 5 Personality disorder (behavior problems) 0 3 Psychomotor slowing 3 5 Somnolence 10 15 Red Blood Cell Disorders Anemia 1 3 Reproductive Disorders, Female Intermenstrual bleeding 0 3 Vaginal hemorrhage 0 3 Resistance Mechanism Disorders Infection 3 8 2 3 Viral infection 3 6 6 8 Respiratory System Disorders Bronchitis 1 5 3 4 Upper respiratory tract infection 16 18 Rhinitis 5 6 2 4 Sinusitis 1 4 Skin and Appendages Disorders Alopecia 1 4 3 4 Pruritus 1 4 Rash 3 4 1 4 Acne 2 3 Special Senses Other, Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Micturition frequency 0 3 Renal calculus 0 3 Urinary incontinence 1 3 Vascular (Extracardiac) Disorders Flushing 0 5 Adjunctive Therapy Epilepsy Adults 16 Years of Age and Older In pooled controlled clinical trials in adults with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with immediate-release topiramate at dosages of 200 to 400 mg/day (recommended dosage range) and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to immediate-release topiramate or placebo. The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200 to 400 mg/day topiramate group with an incidence higher (≥ 10%) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (Table 6). Table 6 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day topiramate and was greater than placebo incidence.

o group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (Table 6). Table 6 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day topiramate and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended topiramate dosing (i.e., 600 mg to 1,000 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (200 mg to 400 mg daily) range. Table 6: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults a Body System/ Adverse Reaction Topiramate Dosage (mg/day) Placebo (N=291) 200 to 400 (N=183) Body as a Whole-General Disorders Fatigue 13 15 Asthenia 1 6 Back pain 4 5 Chest pain 3 4 Influenza-like symptoms 2 3 Central & Peripheral Nervous System Disorders Dizziness 15 25 Ataxia 7 16 Speech disorders/Related speech problems 2 13 Paresthesia 4 11 Nystagmus 7 10 Tremor 6 9 Language problems 1 6 Coordination abnormal 2 4 Gait abnormal 1 3 Gastro-Intestinal System Disorders Nausea 8 10 Dyspepsia 6 7 Abdominal pain 4 6 Constipation 2 4 Metabolic and Nutritional Disorders Weight loss 3 9 Psychiatric Disorders Somnolence 12 29 Nervousness 6 16 Psychomotor slowing 2 13 Difficulty with memory 3 12 Confusion 5 11 Anorexia 4 10 Difficulty with concentration/attention 2 6 Mood problems 2 4 Agitation 2 3 Aggressive reaction 2 3 Emotional lability 1 3 Cognitive problems 1 3 Reproductive Disorders Breast pain 2 4 Respiratory System Disorders Rhinitis 6 7 Pharyngitis 2 6 Sinusitis 4 5 Vision Disorders Vision abnormal 2 13 Diplopia 5 10 a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo In controlled clinical trials in adults, 11% of patients receiving immediate-release topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg/day. Adverse reactions associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia. Pediatric Patients 2 to 15 Years of Age In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with immediate-release topiramate at dosages of 5 mg to 9 mg/kg/day (recommended dose range) and 101 patients received placebo. The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg to 9 mg/kg/day immediate-release topiramate group with an incidence higher (≥ 10%) than in the placebo group were: fatigue and somnolence (see Table 7). Table 7 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg to 9 mg/kg/day (recommended dose range) of immediate-release topiramate and was greater than placebo incidence.

than in the placebo group were: fatigue and somnolence (see Table 7). Table 7 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg to 9 mg/kg/day (recommended dose range) of immediate-release topiramate and was greater than placebo incidence. Table 7: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Pediatric Patients 2 to 15 Years of Age a,b Body System/ Adverse Reaction Placebo (N=101) Topiramate (N=98) Body as a Whole-General Disorders Fatigue 5 16 Injury 13 14 Central & Peripheral Nervous System Disorders Gait abnormal 5 8 Ataxia 2 6 Hyperkinesia 4 5 Dizziness 2 4 Speech disorders/Related speech problems 2 4 Gastro-Intestinal System Disorders Nausea 5 6 Saliva increased 4 6 Constipation 4 5 Gastroenteritis 2 3 Metabolic and Nutritional Disorders Weight loss 1 9 Platelet, Bleeding, & Clotting Disorders Purpura 4 8 Epistaxis 1 4 Psychiatric Disorders Somnolence 16 26 Anorexia 15 24 Nervousness 7 14 Personality disorder (behavior problems) 9 11 Difficulty with concentration/attention 2 10 Aggressive reaction 4 9 Insomnia 7 8 Difficulty with memory 0 5 Confusion 3 4 Psychomotor slowing 2 3 Resistance Mechanism Disorders Infection viral 3 7 Respiratory System Disorders Pneumonia 1 5 Skin and Appendages Disorders Skin disorder 2 3 Urinary System Disorders Urinary incontinence 2 4 a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo b Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category None of the pediatric patients who received topiramate adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Migraine Adults In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine clinical trials for the preventive treatment of migraine (which included 35 adolescent patients age 12 to 15 years of age), most of the adverse reactions with topiramate were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period. The most common adverse reactions with immediate-release topiramate 100 mg in clinical trials for the preventive treatment of migraine of predominantly adults that were seen at an incidence higher (≥5%) than in the placebo group were paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 8). Table 8 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any immediate-release topiramate treatment group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily).

idence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). Table 8: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults a,b Topiramate Dosage (mg/day) Body System/ Adverse Reaction Placebo (N=445) % 50 (N=235) % 100 (N=386) % Body as a Whole-General Disorders Fatigue 11 14 15 Injury 7 9 6 Central & Peripheral Nervous System Disorders Paresthesia 6 35 51 Dizziness 10 8 9 Hypoesthesia 2 6 7 Language problems 2 7 6 Gastro-Intestinal System Disorders Nausea 8 9 13 Diarrhea 4 9 11 Abdominal pain 5 6 6 Dyspepsia 3 4 5 Dry mouth 2 2 3 Gastroenteritis 1 3 3 Metabolic and Nutritional Disorders Weight loss 1 6 9 Musculoskeletal System Disorders Arthralgia 2 7 3 Psychiatric Disorders Anorexia 6 9 15 Somnolence 5 8 7 Difficulty with memory 2 7 7 Insomnia 5 6 7 Difficulty with concentration/attention 2 3 6 Mood problems 2 3 6 Anxiety 3 4 5 Depression 4 3 4 Nervousness 2 4 4 Confusion 2 2 3 Psychomotor slowing 1 3 2 Reproductive Disorders, Female Menstrual disorder 2 3 2 Reproductive Disorders, Male Ejaculation premature 0 3 0 Resistance Mechanism Disorders Viral infection 3 4 4 Respiratory System Disorders Upper respiratory tract infection 12 13 14 Sinusitis 6 10 6 Pharyngitis 4 5 6 Coughing 2 2 4 Bronchitis 2 3 3 Dyspnea 2 1 3 Skin and Appendages Disorders Pruritus 2 4 2 Special Sense Other, Disorders Taste perversion 1 15 8 Urinary System Disorders Urinary tract infection 2 4 2 Vision Disorders Blurred vision c 2 4 2 a Includes 35 adolescent patients age 12 to 15 years. b Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. c Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term. Of the 1,135 patients exposed to immediate-release topiramate in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo-treated patients. The adverse reactions associated with discontinuing therapy in the immediate-release topiramate-treated patients in these studies included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%). Patients treated in these studies experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, immediate-release topiramate 50 mg, 100 mg, and 200 mg groups, respectively. Pediatric Patients 12 to 17 Years of Age In five, randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine, most of the adverse reactions with immediate-release topiramate occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period. In four, fixed-dose, double-blind clinical trials for the preventive treatment of migraine in immediate-release topiramate-treated pediatric patients 12 to 17 years of age, the most common adverse reactions immediate-release topiramate 100 mg that were seen at an incidence higher (≥ 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 9).

in immediate-release topiramate-treated pediatric patients 12 to 17 years of age, the most common adverse reactions immediate-release topiramate 100 mg that were seen at an incidence higher (≥ 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 9). Table 9 shows adverse reactions from the pediatric trial [Study 13; see Clinical Studies (14.5) ], in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of immediate-release topiramate, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years of age) were treated with placebo or 50 mg, 100 mg, or 200 mg of immediate-release topiramate [see Clinical Studies (14.5)]. Table 9 also shows adverse reactions in pediatric patients in the controlled migraine trials when the incidence in an immediate-release topiramate dose group was at least 5% or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 9 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose-related and greater at higher than recommended immediate-release topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dose (100 mg daily). Table 9: Adverse Reactions in Pooled, Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age a,b,c Body System/ Adverse Reaction Placebo (N=45) % Topiramate Dosage 50 mg/day (N=46) % 100 mg/day (N=48) % Body as a Whole-General Disorders Fatigue 7 7 8 Fever 2 4 6 Central & Peripheral Nervous System Disorders Paresthesia 7 20 19 Dizziness 4 4 6 Gastro-Intestinal System Disorders Abdominal pain 9 7 15 Nausea 4 4 8 Metabolic and Nutritional Disorders Weight loss 2 7 4 Psychiatric Disorders Anorexia 4 9 10 Somnolence 2 2 6 Insomnia 2 9 2 Resistance Mechanism Disorders Infection viral 4 4 8 Respiratory System Disorders Upper respiratory tract infection 11 26 23 Rhinitis 2 7 6 Sinusitis 2 9 4 Coughing 0 7 2 Special Senses Other, Disorders Taste perversion 2 2 6 Vision Disorders Conjunctivitis 4 7 4 a 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults. b Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. c Included studies MIG-3006, MIGR-001, MIGR-002 and MIGR-003 In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of immediate-release topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one immediate-release topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%). Increased Risk for Bleeding Topiramate is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse reaction for topiramate than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages.

analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants). Other Adverse Reactions Observed During Clinical Trials Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect. Laboratory Test Abnormalities Adult Patients In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride and ammonia, immediate-release topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions ( 5.4 , 5.14 )] . Controlled trials of adjunctive topiramate treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate versus 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate versus 1% placebo), and decreased serum potassium (0.4% topiramate versus 0.1% placebo). Pediatric Patients In pediatric patients (1 to 24 months) receiving adjunctive topiramate for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, blood urea nitrogen (BUN), alkaline phosphatase, and total protein. The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis), and potassium with immediate-release (vs placebo) [see Use in Specific Populations ( 8.4 )]. Topiramate extended-release capsules are not indicated for partial-onset seizures in pediatric patients less than 2 years of age. In pediatric patients (ranging from 6 to 17 years of age) receiving immediate-release topiramate for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils, The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations ( 8.4 )] . Topiramate extended-release capsules are not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age. 6.2 Clinical Trials Experience with Topiramate Extended-Release Capsules Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the topiramate extended-release capsules study, a dose of 200 mg per day was administered to a limited number of patients; therefore, these results cannot be directly compared to immediate-release topiramate experience.

the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the topiramate extended-release capsules study, a dose of 200 mg per day was administered to a limited number of patients; therefore, these results cannot be directly compared to immediate-release topiramate experience. The safety data presented below are from 249 patients with partial epilepsy on concomitant AEDs who participated in the topiramate extended-release capsules study [see Clinical Studies ( 14.4 )]. Table 10 displays the incidence of adverse reactions that occurred in ≥2% of patients and numerically greater than placebo. Table 10: Incidence (≥2%) of Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trial in Patients With Partial-Onset Seizures Body System/ Adverse Reaction Placebo (N=125) Topiramate Extended-Release Capsules (200 mg) (N=124) General Disorders Fatigue 5 6 Asthenia 1 2 Irritability 1 2 Nervous System Disorders Somnolence 2 12 Dizziness 6 7 Paresthesia 2 7 Aphasia 0 2 Dysarthria 1 2 Memory impairment 1 2 Psychiatric Disorder Psychomotor retardation 0 2 Cardiovascular Disorders, General Hypertension 1 3 Metabolic and Nutritional Disorders Weight decrease 0 7 Decreased appetite 2 4 Anorexia 1 2 In the controlled clinical study using topiramate extended-release capsules, 8.9% of patients who received topiramate extended-release capsules and 4% who received placebo discontinued as a result of adverse reactions. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole-General Disorders: immediate hypersensitivity reactions (including anaphylaxis and angioedema [see Warnings and Precautions ( 5.13 )] , delayed hypersensitivity reactions (including facial swelling, lip swelling, periorbital swelling, tongue swelling), oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3 )], hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions ( 5.14 )] , hypothermia with concomitant valproic acid [see Warnings and Precautions ( 5.16 )] Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions ( 5.12 )] , pemphigus, urticaria Urinary System Disorders: kidney stones, nephrocalcinosis [see Warnings and Precautions ( 5.4 , 5.13 )] Vision Disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions ( 5.1 )] , maculopathy Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with Vitamin K antagonist anticoagulant medications such as warfarin.

<table cellpadding="0pt" width="100%"><col width="27%"/><col width="25%"/><col width="23%"/><col width="9%"/><col width="15%"/><thead><tr><th align="left" rowspan="5" styleCode="Toprule " valign="middle"><content styleCode="bold">Body System/</content> <content styleCode="bold">Adverse Reaction</content></th><th align="center" colspan="4" styleCode="Toprule " valign="middle"><content styleCode="bold">Age Group</content></th></tr><tr><th align="center" colspan="2" styleCode="Botrule " valign="middle"><content styleCode="bold">Pediatric</content> <content styleCode="bold">(6 to 15 Years)</content></th><th align="center" colspan="2" styleCode="Botrule " valign="middle"><content styleCode="bold">Adult</content> <content styleCode="bold">(Age &#x2265;16 Years)</content></th></tr><tr><th align="center" colspan="4" valign="middle"><content styleCode="bold">Immediate-release Topiramate Daily Dosage Group (mg/day)</content></th></tr><tr><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">50</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">400</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">50</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">400</content></th></tr><tr><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">(N=74)</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">(N=77)</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">(N=160)</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">(N=159)</content> <content styleCode="bold">%</content></th></tr></thead><tbody><tr><td colspan="5" styleCode="Toprule " valign="middle"><paragraph><content styleCode="bold">Body as a Whole-General Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Asthenia</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Fever</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>12</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Leg pain</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Paresthesia</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>12</paragraph></td><td align="center" valign="middle"><paragraph>21</paragraph></td><td align="center" valign="mid

ign="middle"><list listType="unordered"><item><caption> </caption>Paresthesia</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>12</paragraph></td><td align="center" valign="middle"><paragraph>21</paragraph></td><td align="center" valign="mid dle"><paragraph>40</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Dizziness</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>13</paragraph></td><td align="center" valign="middle"><paragraph>14</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Ataxia</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Hypoesthesia</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Hypertonia</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Involuntary muscle contraction</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Vertigo</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Gastro-Intestinal System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Constipation</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Diarrhea</item></list></td><td align="center" valign="middle"><paragraph>8</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Gastritis</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Dry mouth</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Liver and Biliary System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Increase in gaamma-GT</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode=

="unordered"><item><caption> </caption>Increase in gaamma-GT</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode= "bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Weight loss</item></list></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>17</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>17</paragraph></td></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Platelet, Bleeding &amp; Clotting Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Epistaxis</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Anorexia</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>14</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Anxiety</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Cognitive problems</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Confusion</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Depression</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Difficulty with concentration or attention</item></list></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>10</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Difficulty with memory</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>11</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Insomnia</item></list></td><td valign="middle"/><td valign="middl

align="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>11</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Insomnia</item></list></td><td valign="middle"/><td valign="middl e"/><td align="center" valign="middle"><paragraph>8</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Decrease in libido</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Mood problems</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Personality disorder (behavior problems)</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Psychomotor slowing</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Somnolence</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>10</paragraph></td><td align="center" valign="middle"><paragraph>15</paragraph></td></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Red Blood Cell Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Anemia</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Reproductive Disorders, Female</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Intermenstrual bleeding</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Vaginal hemorrhage</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Resistance Mechanism Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Infection</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Viral infection</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" v

n="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Viral infection</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" v align="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Bronchitis</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Upper respiratory tract infection</item></list></td><td align="center" valign="middle"><paragraph>16</paragraph></td><td align="center" valign="middle"><paragraph>18</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Rhinitis</item></list></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Sinusitis</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Skin and Appendages Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Alopecia</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Pruritus</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Rash</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Acne</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Special Senses Other, Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Taste perversion</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td colspan="5" valign="middle"

r><td valign="middle"><list listType="unordered"><item><caption> </caption>Taste perversion</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td colspan="5" valign="middle" ><paragraph><content styleCode="bold">Urinary System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Cystitis</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Micturition frequency</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Renal calculus</item></list></td><td valign="middle"/><td valign="middle"/><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Urinary incontinence</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td valign="middle"/><td valign="middle"/></tr><tr><td colspan="5" valign="middle"><paragraph><content styleCode="bold">Vascular (Extracardiac) Disorders</content></paragraph></td></tr><tr><td styleCode="Botrule " valign="middle"><list listType="unordered"><item><caption> </caption>Flushing</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>5</paragraph></td><td styleCode="Botrule " valign="middle"/><td styleCode="Botrule " valign="middle"/></tr></tbody></table>

aption> </caption>Flushing</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>5</paragraph></td><td styleCode="Botrule " valign="middle"/><td styleCode="Botrule " valign="middle"/></tr></tbody></table> <table cellpadding="0pt" width="100%"><col width="36%"/><col width="34%"/><col width="30%"/><thead><tr><th align="left" rowspan="2" styleCode="Toprule " valign="middle"><content styleCode="bold">Body System/</content> <content styleCode="bold">Adverse Reaction</content></th><th align="left" styleCode="Toprule " valign="middle"/><th align="center" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Topiramate Dosage</content> <content styleCode="bold">(mg/day)</content></th></tr><tr><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=291)</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">200 to 400</content> <content styleCode="bold">(N=183)</content></th></tr></thead><tbody><tr><td colspan="3" styleCode="Toprule " valign="middle"><paragraph><content styleCode="bold">Body as a Whole-General Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Fatigue</item></list></td><td align="center" valign="middle"><paragraph>13</paragraph></td><td align="center" valign="middle"><paragraph>15</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Asthenia</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Back pain</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Chest pain</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Influenza-like symptoms</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Dizziness</item></list></td><td align="center" valign="middle"><paragraph>15</paragraph></td><td align="center" valign="middle"><paragraph>25</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Ataxia</item></list></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>16</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Speech disorders/Related speech problems</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>13</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Paresthesia</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>11</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Nystagmus</item></list></td><td align="center" valign="middle"><paragraph>7</paragraph></td><t

em></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>11</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Nystagmus</item></list></td><td align="center" valign="middle"><paragraph>7</paragraph></td><t d align="center" valign="middle"><paragraph>10</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Tremor</item></list></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Language problems</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Coordination abnormal</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Gait abnormal</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Gastro-Intestinal System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Nausea</item></list></td><td align="center" valign="middle"><paragraph>8</paragraph></td><td align="center" valign="middle"><paragraph>10</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Dyspepsia</item></list></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Abdominal pain</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Constipation</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Weight loss</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Somnolence</item></list></td><td align="center" valign="middle"><paragraph>12</paragraph></td><td align="center" valign="middle"><paragraph>29</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Nervousness</item></list></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>16</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Psychomotor slowing</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>13</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Difficulty with memory</item></list></td><td ali

em><caption> </caption>Psychomotor slowing</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>13</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Difficulty with memory</item></list></td><td ali gn="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>12</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Confusion</item></list></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>11</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Anorexia</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>10</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Difficulty with concentration/attention</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Mood problems</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Agitation</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Aggressive reaction</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Emotional lability</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Cognitive problems</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Reproductive Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Breast pain</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Rhinitis</item></list></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Pharyngitis</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Sinusitis</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Vision Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </c

align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Vision Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </c aption>Vision abnormal</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>13</paragraph></td></tr><tr><td styleCode="Botrule " valign="middle"><list listType="unordered"><item><caption> </caption>Diplopia</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>10</paragraph></td></tr></tbody></table>

tr><tr><td styleCode="Botrule " valign="middle"><list listType="unordered"><item><caption> </caption>Diplopia</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>10</paragraph></td></tr></tbody></table> <table cellpadding="0pt" width="98.74%"><col width="51%"/><col width="18%"/><col width="31%"/><thead><tr><th align="left" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Body System/</content> <content styleCode="bold">Adverse Reaction</content></th><th align="center" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=101)</content></th><th align="center" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Topiramate</content> <content styleCode="bold">(N=98)</content></th></tr></thead><tbody><tr><td colspan="3" styleCode="Toprule " valign="middle"><paragraph><content styleCode="bold">Body as a Whole-General Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Fatigue</item></list></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>16</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Injury</item></list></td><td align="center" valign="middle"><paragraph>13</paragraph></td><td align="center" valign="middle"><paragraph>14</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Gait abnormal</item></list></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Ataxia</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Hyperkinesia</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Dizziness</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Speech disorders/Related speech problems</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Gastro-Intestinal System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Nausea</item></list></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Saliva increased</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Constipation</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td val

d align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Constipation</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td val ign="middle"><list listType="unordered"><item><caption> </caption> Gastroenteritis</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Weight loss</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Platelet, Bleeding, &amp; Clotting Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Purpura</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Epistaxis</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Somnolence</item></list></td><td align="center" valign="middle"><paragraph>16</paragraph></td><td align="center" valign="middle"><paragraph>26</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Anorexia</item></list></td><td align="center" valign="middle"><paragraph>15</paragraph></td><td align="center" valign="middle"><paragraph>24</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Nervousness</item></list></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>14</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Personality disorder (behavior problems)</item></list></td><td align="center" valign="middle"><paragraph>9</paragraph></td><td align="center" valign="middle"><paragraph>11</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Difficulty with concentration/attention</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>10</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Aggressive reaction</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Insomnia</item></list></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Difficulty with memory</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Confusion</item></list></td><td align="center" valig

ion> </caption> Difficulty with memory</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Confusion</item></list></td><td align="center" valig n="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Psychomotor slowing</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Resistance Mechanism Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Infection viral</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Pneumonia</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Skin and Appendages Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Skin disorder</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Urinary System Disorders</content></paragraph></td></tr><tr><td styleCode="Botrule " valign="middle"><list listType="unordered"><item><caption> </caption> Urinary incontinence</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>4</paragraph></td></tr></tbody></table>

tyleCode="Botrule " valign="middle"><list listType="unordered"><item><caption> </caption> Urinary incontinence</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>4</paragraph></td></tr></tbody></table> <table cellpadding="0pt" width="92.1%"><col width="45%"/><col width="20%"/><col width="17%"/><col width="17%"/><thead><tr><th align="left" colspan="2" styleCode="Toprule " valign="middle"/><th align="center" colspan="2" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Topiramate Dosage (mg/day)</content></th></tr><tr><th align="left" styleCode="Botrule " valign="middle"><content styleCode="bold">Body System/</content> <content styleCode="bold">Adverse Reaction</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">Placebo (N=445)</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">50</content> <content styleCode="bold">(N=235)</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">100</content> <content styleCode="bold">(N=386)</content> <content styleCode="bold">%</content></th></tr></thead><tbody><tr><td colspan="4" styleCode="Toprule " valign="middle"><paragraph><content styleCode="bold">Body as a Whole-General Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Fatigue</item></list></td><td align="center" valign="middle"><paragraph>11</paragraph></td><td align="center" valign="middle"><paragraph>14</paragraph></td><td align="center" valign="middle"><paragraph>15</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Injury</item></list></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Paresthesia</item></list></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>35</paragraph></td><td align="center" valign="middle"><paragraph>51</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Dizziness</item></list></td><td align="center" valign="middle"><paragraph>10</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Hypoesthesia</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Language problems</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Gastro-Intestinal System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Nausea</item></list></td><td align="center" valign="middle"><paragraph>8</paragraph></td><td align="center" val

colspan="4" valign="middle"><paragraph><content styleCode="bold">Gastro-Intestinal System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Nausea</item></list></td><td align="center" valign="middle"><paragraph>8</paragraph></td><td align="center" val ign="middle"><paragraph>9</paragraph></td><td align="center" valign="middle"><paragraph>13</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Diarrhea</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td><td align="center" valign="middle"><paragraph>11</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Abdominal pain</item></list></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Dyspepsia</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Dry mouth</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Gastroenteritis</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Weight loss</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Musculoskeletal System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Arthralgia</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Anorexia</item></list></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td><td align="center" valign="middle"><paragraph>15</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Somnolence</item></list></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Difficulty with memory</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td al

td align="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Difficulty with memory</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td al ign="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Insomnia</item></list></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Difficulty with concentration/attention</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Mood problems</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Anxiety</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Depression</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Nervousness</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Confusion</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Psychomotor slowing</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Reproductive Disorders, Female</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Menstrual disorder</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Reproductive Disorders, Male</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Ejaculation premature</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>0</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Resistance

jaculation premature</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>0</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Resistance Mechanism Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Viral infection</item></list></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Upper respiratory tract infection</item></list></td><td align="center" valign="middle"><paragraph>12</paragraph></td><td align="center" valign="middle"><paragraph>13</paragraph></td><td align="center" valign="middle"><paragraph>14</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Sinusitis</item></list></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>10</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Pharyngitis</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Coughing</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Bronchitis</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Dyspnea</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Skin and Appendages Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Pruritus</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Special Sense Other, Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Taste perversion</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>15</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Urinary System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Urinary tract infection</item></list></td><td align="center" valign="middle"><para

aragraph>8</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Urinary System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>Urinary tract infection</item></list></td><td align="center" valign="middle"><para graph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Vision Disorders</content></paragraph></td></tr><tr><td styleCode="Botrule " valign="middle"><list listType="unordered"><item><caption> </caption>Blurred vision^c</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>2</paragraph></td></tr></tbody></table>

lurred vision^c</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>2</paragraph></td></tr></tbody></table> <table cellpadding="0pt" width="93.2%"><col width="32%"/><col width="15%"/><col width="32%"/><col width="21%"/><thead><tr><th align="left" rowspan="2" styleCode="Toprule " valign="middle"><content styleCode="bold">Body System/</content> <content styleCode="bold">Adverse Reaction</content></th><th align="center" rowspan="2" styleCode="Toprule " valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=45)</content> <content styleCode="bold">%</content></th><th align="center" colspan="2" styleCode="Toprule " valign="middle"><content styleCode="bold">Topiramate Dosage</content></th></tr><tr><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">50 mg/day</content> <content styleCode="bold">(N=46)</content> <content styleCode="bold">%</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">100 mg/day</content> <content styleCode="bold">(N=48)</content> <content styleCode="bold">%</content></th></tr></thead><tbody><tr><td colspan="4" styleCode="Toprule " valign="middle"><paragraph><content styleCode="bold">Body as a Whole-General Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Fatigue</item></list></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Fever</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Paresthesia</item></list></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>20</paragraph></td><td align="center" valign="middle"><paragraph>19</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Dizziness</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Gastro-Intestinal System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Abdominal pain</item></list></td><td align="center" valign="middle"><paragraph>9</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>15</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Nausea</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> <

lign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> < /caption> Weight loss</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Anorexia</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td><td align="center" valign="middle"><paragraph>10</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Somnolence</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Insomnia</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Resistance Mechanism Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Infection viral</item></list></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td><td align="center" valign="middle"><paragraph>8</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Respiratory System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Upper respiratory tract infection</item></list></td><td align="center" valign="middle"><paragraph>11</paragraph></td><td align="center" valign="middle"><paragraph>26</paragraph></td><td align="center" valign="middle"><paragraph>23</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Rhinitis</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Sinusitis</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>9</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Coughing</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td colspan="4" valign="middle"><paragraph><content styleCode="bold">Special Senses Other, Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Taste perversion</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>2</p

aph><content styleCode="bold">Special Senses Other, Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Taste perversion</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>2</p aragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><paragraph><content styleCode="bold">Vision Disorders</content></paragraph></td><td valign="middle"/><td valign="middle"/><td valign="middle"/></tr><tr><td styleCode="Botrule " valign="middle"><list listType="unordered"><item><caption> </caption> Conjunctivitis</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>7</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>4</paragraph></td></tr></tbody></table>

</caption> Conjunctivitis</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>7</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>4</paragraph></td></tr></tbody></table> <table ID="_RefID459" cellpadding="0pt" width="91.66%"><caption>Table 10: Incidence (&#x2265;2%) of Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trial in Patients With Partial-Onset Seizures </caption><col width="42%"/><col width="21%"/><col width="37%"/><thead><tr><th align="left" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Body System/</content> <content styleCode="bold">Adverse Reaction</content></th><th align="center" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=125)</content></th><th align="center" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Topiramate Extended-Release Capsules</content> <content styleCode="bold">(200 mg)</content> <content styleCode="bold">(N=124)</content></th></tr></thead><tbody><tr><td colspan="3" styleCode="Toprule " valign="middle"><paragraph><content styleCode="bold">General Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Fatigue</item></list></td><td align="center" valign="middle"><paragraph>5</paragraph></td><td align="center" valign="middle"><paragraph>6</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Asthenia</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Irritability</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Somnolence</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>12</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Dizziness</item></list></td><td align="center" valign="middle"><paragraph>6</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Paresthesia</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Aphasia</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Dysarthria</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Memory impairment</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Psychiatric Disorder</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption>

r" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Psychiatric Disorder</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Psychomotor retardation</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>2</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Cardiovascular Disorders, General</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Hypertension</item></list></td><td align="center" valign="middle"><paragraph>1</paragraph></td><td align="center" valign="middle"><paragraph>3</paragraph></td></tr><tr><td colspan="3" valign="middle"><paragraph><content styleCode="bold">Metabolic and Nutritional Disorders</content></paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Weight decrease</item></list></td><td align="center" valign="middle"><paragraph>0</paragraph></td><td align="center" valign="middle"><paragraph>7</paragraph></td></tr><tr><td valign="middle"><list listType="unordered"><item><caption> </caption> Decreased appetite</item></list></td><td align="center" valign="middle"><paragraph>2</paragraph></td><td align="center" valign="middle"><paragraph>4</paragraph></td></tr><tr><td styleCode="Botrule " valign="middle"><list listType="unordered"><item><caption> </caption> Anorexia</item></list></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>2</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS • Contraceptives: decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day ( 7.4 ) • Monitor lithium levels if lithium is used with high-dose topiramate extended-release capsules ( 7.7 ) 7.1 Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed [see Clinical Pharmacology ( 12.3 )]. Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions ( 5.12 , 5.14 ), Clinical Pharmacology ( 12.3 )]. 7.2 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when topiramate extended-release capsules are given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology ( 12.3 )]. 7.3 CNS Depressants Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, topiramate extended-release capsules should be used with extreme caution if used in combination with alcohol and other CNS depressants. 7.4 Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with topiramate extended-release capsules. Patients taking estrogen-containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology ( 12.3 )]. 7.5 Hydrochlorothiazide (HCTZ) Topiramate C max and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate extended-release capsules may require a decrease in the topiramate extended-release capsules dose [see Clinical Pharmacology ( 12.3 )] . 7.6 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate extended-release capsules are added to pioglitazone therapy or pioglitazone is added to topiramate extended-release capsules therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology ( 12.3 )] . 7.7 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose topiramate extended-release capsules [see Clinical Pharmacology ( 12.3 )].

iabetic disease state [see Clinical Pharmacology ( 12.3 )] . 7.7 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose topiramate extended-release capsules [see Clinical Pharmacology ( 12.3 )]. 7.8 Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate extended-release capsules and any adjustments in amitriptyline dose should be made according to the patient’s clinical response and not on the basis of plasma levels [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as topiramate extended-release capsules, during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/ . Risk Summary Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data] . All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor. Topiramate treatment can cause metabolic acidosis [see Warnings and Precautions (5.4)]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor.

[see Warnings and Precautions (5.4)]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4)]. Newborns of mothers treated with topiramate should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery. Data Human Data Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in the United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval=[CI] 5.9 to 26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10 th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED, and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data When topiramate (0, 20, 100, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) were increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis.

A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre- and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. 8.2 Lactation Risk Summary Topiramate is excreted in human milk [see Data]. The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for topiramate extended-release capsules and any potential adverse effects on the breastfed infant from topiramate extended-release capsules or from the underlying maternal condition. Data Human Data Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma. 8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions ( 7.4 ) and Use in Specific Populations ( 8.1 )].

eproductive Potential Contraception Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions ( 7.4 ) and Use in Specific Populations ( 8.1 )]. 8.4 Pediatric Use Adjunctive Treatment for Epilepsy Pediatric Patients 2 Years of Age and Older The safety and effectiveness of topiramate extended-release capsules as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome have been established in pediatric patients 2 years of age and older and is based on controlled trials with immediate-release topiramate [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.3 , 14.4 )]. The adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults [see Warnings and Precautions ( 5 ) and Adverse Reactions ( 6 )]. These include, but are not limited to: • oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3 )] • dose-related increased incidence of metabolic acidosis [see Warnings and Precautions ( 5.4 )] • dose-related increased incidence of hyperammonemia [see Warnings and Precautions ( 5.12 )] Pediatric Patients Below the Age of 2 Years The following pediatric use information is based on studies conducted with immediate-release topiramate. Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions/toxicities not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions ( 6.1 )].

ients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions ( 6.1 )]. Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose-related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Adverse Reactions ( 6.1 )]. The significance of these findings is uncertain. Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6% for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Adverse Reactions ( 6.1 )]. There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain. Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.14)]. Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )]. In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions ( 5.6 )]. In this open-label, uncontrolled study, the mortality was 37 deaths/1,000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 to 24 months) with partial epilepsy is not known. Monotherapy Treatment for Epilepsy Pediatric Patients 2 Years of Age and Older The safety and effectiveness of topiramate extended-release capsules as monotherapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures have been established in pediatric patients aged 2 years and older and is based on controlled trials with immediate-release topiramate [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.1 )] . A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28, 6 to 15 years of age) versus levetiracetam (N=35, 4 to 15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers.

ducted to assess effects of immediate-release topiramate (N=28, 6 to 15 years of age) versus levetiracetam (N=35, 4 to 15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 11 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect a topiramate induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight). Table 11: Summary of Immediate-Release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval) Annual Change in BMD Lumbar Spine (g/cm 2 ) -0.036 (-0.058, -0.014) Annual Change in BMD TBLH* (g/cm 2 ) -0.026 (-0.039, -0.012) Annual Change in Height (cm) (4 to 9 years, Primary Analysis Population for Height)** -0.84 (-2.67, 0.99) Annual Change in Height (cm) (4 to 15 years) -0.75 (-2.21, 0.71) Annual Change in Height (cm) (10 to 15 years) -1.01 (-3.64, 1.61) Height Velocity (cm/year) (4 to 9 years) 1 (-2.76, 0.76) Height Velocity (cm/year) (4 to 15 years) -0.98 (-2.33, 0.37) Height Velocity (cm/year) (10 to 15 years) -0.96 (-3.24, 1.32) Annual Change in Weight (kg) -2.05 (-3.66, -0.45) * TBLH = total body less head ** Whereas no patients were randomized to 2 to 5 year of age subgroup for immediate-release topiramate, 5 patients (4 to 5 years) were randomized to the active control group. Metabolic acidosis (serum bicarbonate < 20 mEq/L) was observed in all immediate-release topiramate-treated patients at some time in the study [see Warnings and Precautions ( 5.4 )] . Over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate < 20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and ≥ 5 mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. Pediatric Patients Below the Age of 2 Years Safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy. Preventive Treatment of Migraine Pediatric Patients 12 to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day.

ive Treatment of Migraine Pediatric Patients 12 to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies ( 14.5 )] , a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 13 [see Clinical Studies ( 14.5 )] . Efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients (12 to 16 years of age) for 20 weeks. In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release topiramate that were seen at an incidence higher (≥ 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions ( 6.1 )]. The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions ( 5.6 )]. Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions ( 5.4 )]. In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )]. Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology ( 12.2 )]. Pediatric Patients Below the Age of 12 Years Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients.

frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. The risk for cognitive adverse reaction was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions ( 5.6 )]. Juvenile Animal Studies When topiramate (0, 30, 90 or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis. 8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2 . Estimate GFR should be measured prior to dosing [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )]. 8.6 Renal Impairment The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73 m 2 ) and severe (creatinine clearance less than 30 mL/min/1.73 m 2 ) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )]. 8.7 Patients Undergoing Hemodialysis Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )].

<table cellpadding="0pt" width="100%"><col width="55%"/><col width="45%"/><thead><tr><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Safety Parameter</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Treatment Difference in Least Square Means (95 % Confidence Interval)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Annual Change in BMD Lumbar Spine (g/cm²)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">-0.036 (-0.058, -0.014)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Annual Change in BMD TBLH* (g/cm²)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">-0.026 (-0.039, -0.012)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Annual Change in Height (cm) (4 to 9 years, Primary Analysis Population for Height)**</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">-0.84 (-2.67, 0.99)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Annual Change in Height (cm) (4 to 15 years)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">-0.75 (-2.21, 0.71)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Annual Change in Height (cm) (10 to 15 years)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">-1.01 (-3.64, 1.61)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Height Velocity (cm/year) (4 to 9 years)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">1 (-2.76, 0.76)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Height Velocity (cm/year) (4 to 15 years)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">-0.98 (-2.33, 0.37)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Height Velocity (cm/year) (10 to 15 years)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">-0.96 (-3.24, 1.32)</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Annual Change in Weight (kg)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">-2.05 (-3.66, -0.45)</content></paragraph></td></tr></tbody></table>

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as topiramate extended-release capsules, during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/ . Risk Summary Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data] . All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients. Labor or Delivery Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor. Topiramate treatment can cause metabolic acidosis [see Warnings and Precautions (5.4)]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor.

A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre- and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis.

8.4 Pediatric Use Adjunctive Treatment for Epilepsy Pediatric Patients 2 Years of Age and Older The safety and effectiveness of topiramate extended-release capsules as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome have been established in pediatric patients 2 years of age and older and is based on controlled trials with immediate-release topiramate [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.3 , 14.4 )]. The adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults [see Warnings and Precautions ( 5 ) and Adverse Reactions ( 6 )]. These include, but are not limited to: • oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3 )] • dose-related increased incidence of metabolic acidosis [see Warnings and Precautions ( 5.4 )] • dose-related increased incidence of hyperammonemia [see Warnings and Precautions ( 5.12 )] Pediatric Patients Below the Age of 2 Years The following pediatric use information is based on studies conducted with immediate-release topiramate. Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions/toxicities not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions ( 6.1 )].

frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients. The risk for cognitive adverse reaction was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions ( 5.6 )]. Juvenile Animal Studies When topiramate (0, 30, 90 or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis.

8.5 Geriatric Use Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2 . Estimate GFR should be measured prior to dosing [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )].

10 OVERDOSAGE Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate. Topiramate overdose has resulted in severe metabolic acidosis [see Warnings and Precautions ( 5.4 )]. A patient who ingested a dose of immediate-release topiramate between 96 g and 110 g was admitted to a hospital with a coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days. Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of topiramate extended-release capsules. Therefore, in the event of topiramate extended-release capsules overdose, topiramate extended-release capsules should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.

11 DESCRIPTION Topiramate, USP is a sulfamate-substituted monosaccharide. Topiramate Extended-Release Capsules are available as 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg capsules for oral administration as whole capsules or opened and sprinkled onto a spoonful of soft food. Topiramate, USP is a white to off-white powder. Topiramate, USP is freely soluble in dichloromethane. Topiramate, USP has the molecular formula C 12 H 21 NO 8 S and a molecular weight of 339.36 g/mol. Topiramate, USP is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula: Topiramate Extended-Release Capsules contain pellets of topiramate, USP in a capsule. The inactive ingredients are D&C red No.30, ethylcellulose, FD&C red No.40, hypromellose, microcrystalline cellulose, polyethylene glycol and talc. The capsule shell for Topiramate Extended-Release Capsules, 25 mg contains black iron oxide, hypromellose, red iron oxide and titanium dioxide. The capsule shell for Topiramate Extended-Release Capsules, 50 mg contains black iron oxide, hypromellose, red iron oxide, titanium dioxide, and yellow iron oxide. The capsule shell for Topiramate Extended-Release Capsules, 100 mg contains black iron oxide, hypromellose, red iron oxide and titanium dioxide. The capsule shell for Topiramate Extended-Release Capsules, 150 mg contains black iron oxide, hypromellose, and titanium dioxide. The capsule shell for Topiramate Extended-Release Capsules, 200 mg contains black iron oxide, hypromellose, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink has the following components: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate’s efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV. 12.2 Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP < 90 mm Hg, DBP < 50 mm Hg, SBP or DBP increases or decreases ≥ 20 mm Hg, and pulse increases or decreases ≥ 30 beats per minute. These changes were often dose-related and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established. 12.3 Pharmacokinetics Absorption and Distribution The pharmacokinetics of topiramate extended-release capsules are linear with dose proportional increases in plasma concentration when administered as a single oral dose over the range of 50 mg to 1,400 mg. At 25 mg, the pharmacokinetics of topiramate extended-release capsules are nonlinear, possibly due to the binding of topiramate to carbonic anhydrase in red blood cells. Topiramate extended-release capsules sprinkled on a spoonful of soft food is bioequivalent to the intact capsule formulation. Following a single 200 mg oral dose of topiramate extended-release, peak plasma concentrations (T max ) occurred approximately 20 hours after dosing. Steady-state was reached in about 5 days following daily dosing of topiramate extended-release in subjects with normal renal function, with a T max of approximately 6 hours. At steady-state, the plasma exposure (AUC 0-24hr , C max , and C min ) of topiramate from topiramate extended-release administered once daily and the immediate-release topiramate tablets administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for topiramate extended-release administered once daily was approximately 40% in healthy subjects, compared to approximately 53% for immediate-release topiramate [see Clinical Pharmacology (12.6)].

s administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for topiramate extended-release administered once daily was approximately 40% in healthy subjects, compared to approximately 53% for immediate-release topiramate [see Clinical Pharmacology (12.6)]. Compared to the fasted state, high-fat meal had no effect on bioavailability (AUC and C max ) but delayed the T max by approximately 4 hours following a single dose of topiramate extended-release. Topiramate extended-release can be taken without regard to meals. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean effective half-life of topiramate extended-release capsules are approximately 56 hours. Steady-state is reached in about 5 days after topiramate extended-release capsules dosing in subjects with normal renal function. Specific Populations Renal Impairment The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73 m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73 m 2 ) [see Dosage and Administration ( 2.4 , 2.6 )]. Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counter flow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.7 )]. Hepatic Impairment Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Age, Gender and Race The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults.

Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration ( 2.3 ), Use in Specific Populations ( 8.5 )]. Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of immediate-release topiramate were evaluated in patients age 2 years to less than 16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1,217 subjects including 258 pediatric patients age 2 years to less than 16 years (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Pediatric Patients with Obesity A population PK analysis of topiramate was conducted in 129 children <21 years of age with and without obesity to evaluate the potential impact of obesity on plasma topiramate exposures. Obesity was defined as BMI ≥95th percentile for age and sex based on CDC-recommended BMI-for-age growth charts for males and females. Using the currently recommended dosing regimens, children with obesity are likely to have median values of average concentration at steady-state and trough concentration at steady-state that are up to 20% lower and 19% lower, respectively, compared to children without obesity. Dosage adjustment according to obesity status is not necessary. Drug Interactions In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Antiepileptic Drugs Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 12. Interaction of topiramate extended-release capsules and standard AEDs is not expected to differ from the experience with immediate-release topiramate products. In Table 12, the second column (AED concentration) describes what happens to the concentration of the co-administered AED listed in the first column when topiramate was added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone.

cribes what happens to the concentration of the co-administered AED listed in the first column when topiramate was added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 12: Summary of AED Interactions with Topiramate AED Co-administered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase a 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide b NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400 mg per day 13% decrease NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate ªPlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin ᵇIs not administered, but is an active metabolite of carbamazepine Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg per day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg per day. The clinical significance of the changes observed is not known [see Drug Interactions (7.4)]. Digoxin In a single-dose study, serum digoxin AUC decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination. Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0 to 12h increased by 18% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin T max . The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate extended-release capsules pharmacokinetics is unclear.

T max . The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate extended-release capsules pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known. Glyburide A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C max and a 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15% and C max was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions (7.7)]. Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of topiramate. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg per day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg per day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg per day dose of topiramate in the same study.

sing of topiramate (200 mg per day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg per day dose of topiramate in the same study. Diltiazem Coadministration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg per day) resulted in a 10% decrease in C max and 25% decrease in diltiazem AUC, a 27% decrease in C max and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg per day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate. 12.6 Relative Bioavailability of Topiramate Extended-Release Capsules Compared to Immediate-Release Topiramate in Healthy Volunteers Topiramate extended-release capsules, taken once daily, provides similar steady-state topiramate concentrations to immediate-release topiramate taken every 12 hours, when administered at the same total daily dose. In a healthy volunteer, multiple-dose crossover study, the 90% CI for the ratios of AUC 0-24 , C max and C min , as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose)) for multiple time points were within the 80% to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80% to 125% bioequivalence limits, except for the initial time points before 3 hours and at 8 hours post-dose, which is not expected to have a significant clinical impact. The effects of switching between topiramate extended-release capsules and immediate-release topiramate were also evaluated in the same multiple-dose, crossover, comparative bioavailability study. In healthy subjects switched from immediate-release topiramate given every 12 hours to topiramate extended-release capsules given once daily, similar concentrations were maintained immediately after the formulation switch. On the first day following the switch, there were no significant differences in AUC 0-24 , C max , and C min , as the 90% CI for the ratios were contained within the 80% to 125% equivalence limits.

12.1 Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate’s efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

12.3 Pharmacokinetics Absorption and Distribution The pharmacokinetics of topiramate extended-release capsules are linear with dose proportional increases in plasma concentration when administered as a single oral dose over the range of 50 mg to 1,400 mg. At 25 mg, the pharmacokinetics of topiramate extended-release capsules are nonlinear, possibly due to the binding of topiramate to carbonic anhydrase in red blood cells. Topiramate extended-release capsules sprinkled on a spoonful of soft food is bioequivalent to the intact capsule formulation. Following a single 200 mg oral dose of topiramate extended-release, peak plasma concentrations (T max ) occurred approximately 20 hours after dosing. Steady-state was reached in about 5 days following daily dosing of topiramate extended-release in subjects with normal renal function, with a T max of approximately 6 hours. At steady-state, the plasma exposure (AUC 0-24hr , C max , and C min ) of topiramate from topiramate extended-release administered once daily and the immediate-release topiramate tablets administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for topiramate extended-release administered once daily was approximately 40% in healthy subjects, compared to approximately 53% for immediate-release topiramate [see Clinical Pharmacology (12.6)]. Compared to the fasted state, high-fat meal had no effect on bioavailability (AUC and C max ) but delayed the T max by approximately 4 hours following a single dose of topiramate extended-release. Topiramate extended-release can be taken without regard to meals. Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean effective half-life of topiramate extended-release capsules are approximately 56 hours. Steady-state is reached in about 5 days after topiramate extended-release capsules dosing in subjects with normal renal function.

rance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean effective half-life of topiramate extended-release capsules are approximately 56 hours. Steady-state is reached in about 5 days after topiramate extended-release capsules dosing in subjects with normal renal function. Specific Populations Renal Impairment The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73 m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m 2 ) compared to subjects with normal renal function (creatinine clearance greater than 70 mL/min/1.73 m 2 ) [see Dosage and Administration ( 2.4 , 2.6 )]. Hemodialysis Topiramate is cleared by hemodialysis. Using a high-efficiency, counter flow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.7 )]. Hepatic Impairment Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Age, Gender and Race The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced [see Dosage and Administration ( 2.3 ), Use in Specific Populations ( 8.5 )]. Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of immediate-release topiramate were evaluated in patients age 2 years to less than 16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1,217 subjects including 258 pediatric patients age 2 years to less than 16 years (95 pediatric patients less than 10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.

ion for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Pediatric Patients with Obesity A population PK analysis of topiramate was conducted in 129 children <21 years of age with and without obesity to evaluate the potential impact of obesity on plasma topiramate exposures. Obesity was defined as BMI ≥95th percentile for age and sex based on CDC-recommended BMI-for-age growth charts for males and females. Using the currently recommended dosing regimens, children with obesity are likely to have median values of average concentration at steady-state and trough concentration at steady-state that are up to 20% lower and 19% lower, respectively, compared to children without obesity. Dosage adjustment according to obesity status is not necessary. Drug Interactions In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Antiepileptic Drugs Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 12. Interaction of topiramate extended-release capsules and standard AEDs is not expected to differ from the experience with immediate-release topiramate products. In Table 12, the second column (AED concentration) describes what happens to the concentration of the co-administered AED listed in the first column when topiramate was added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 12: Summary of AED Interactions with Topiramate AED Co-administered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase a 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide b NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400 mg per day 13% decrease NC=Less than 10% change in plasma concentration AED=Antiepileptic drug NE=Not evaluated TPM=topiramate ªPlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin ᵇIs not administered, but is an active metabolite of carbamazepine Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg per day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg per day. The clinical significance of the changes observed is not known [see Drug Interactions (7.4)]. Digoxin In a single-dose study, serum digoxin AUC decreased by 12% with concomitant topiramate administration.

xposure to NET and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg per day. The clinical significance of the changes observed is not known [see Drug Interactions (7.4)]. Digoxin In a single-dose study, serum digoxin AUC decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination. Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0 to 12h increased by 18% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin T max . The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate extended-release capsules pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC τ,ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite. The clinical significance of these findings is not known. Glyburide A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in C max and a 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15% and C max was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions (7.7)]. Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females).

sure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg per day [see Drug Interactions (7.7)]. Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg per day of topiramate. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg per day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg per day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg per day dose of topiramate in the same study. Diltiazem Coadministration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg per day) resulted in a 10% decrease in C max and 25% decrease in diltiazem AUC, a 27% decrease in C max and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg per day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.

<table cellpadding="0pt" width="96.24%"><col width="31%"/><col width="40%"/><col width="28%"/><thead><tr><th align="center" styleCode="Botrule Toprule " valign="bottom"><content styleCode="bold">AED</content> <content styleCode="bold">Co-administered</content></th><th align="center" styleCode="Botrule Toprule " valign="bottom"><content styleCode="bold">AED</content> <content styleCode="bold">Concentration</content></th><th align="center" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Topiramate </content> <content styleCode="bold">Concentration</content></th></tr></thead><tbody><tr><td align="center" styleCode="Toprule " valign="top"><paragraph>Phenytoin</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>NC or 25% increase^a</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>48% decrease</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>Carbamazepine (CBZ)</paragraph></td><td align="center" valign="top"><paragraph>NC</paragraph></td><td align="center" valign="top"><paragraph>40% decrease</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>CBZ epoxide^b</paragraph></td><td align="center" valign="top"><paragraph>NC</paragraph></td><td align="center" valign="top"><paragraph>NE</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>Valproic acid</paragraph></td><td align="center" valign="top"><paragraph>11% decrease</paragraph></td><td align="center" valign="top"><paragraph>14% decrease</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>Phenobarbital</paragraph></td><td align="center" valign="top"><paragraph>NC</paragraph></td><td align="center" valign="top"><paragraph>NE</paragraph></td></tr><tr><td align="center" valign="top"><paragraph>Primidone</paragraph></td><td align="center" valign="top"><paragraph>NC</paragraph></td><td align="center" valign="top"><paragraph>NE</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph>Lamotrigine</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>NC at TPM doses up to 400 mg per day</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>13% decrease</paragraph></td></tr></tbody></table>

14 CLINICAL STUDIES 14.1 Extended-Release: Bridging Study to Demonstrate Pharmacokinetic Equivalence between Extended-Release and Immediate-Release Topiramate Formulations Although a controlled clinical trial was performed (Study 14) [see Clinical Studies ( 14.4 )] , the basis for approval of the extended-release formulation (topiramate extended-release capsules) included the studies described below using an immediate-release formulation [see Clinical Studies ( 14.2 , 14.3 , 14.5 )] and the demonstration of the pharmacokinetic equivalence of topiramate extended-release capsules to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see Clinical Pharmacology ( 12.6 )]. 14.2 Monotherapy Epilepsy Patients with Partial-Onset or Primary Generalized Tonic-Clonic Seizures Adults and Pediatric Patients 10 Years of Age and Older The effectiveness of topiramate as initial monotherapy in adults and pediatric patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1). Study 1 was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day of topiramate. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty‑eight percent of patients achieved the maximal dose of 400 mg/day for ˃2 weeks, and patients who did not tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use. Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure in Study 1 Pediatric Patients 2 to 9 Years of Age The conclusion that topiramate is effective as initial monotherapy in pediatric patients 2 to 9 years of age with partial‑onset or primary generalized tonic-clonic seizures was based on a pharmacometrics bridging approach using data from the controlled epilepsy trials conducted with immediate-release topiramate described in labeling. This approach consisted of first showing a similar exposure-response relationship between pediatric patients down to 2 years of age and adults when immediate-release topiramate was given as adjunctive therapy. Similarity of exposure-response was also demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy.

re-response relationship between pediatric patients down to 2 years of age and adults when immediate-release topiramate was given as adjunctive therapy. Similarity of exposure-response was also demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy. Specific dosing in pediatric patients 2 to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with immediate-release topiramate initial monotherapy [see Dosage and Administration ( 2.1 )]. figure1 14.3 Adjunctive Therapy Epilepsy Adult Patients with Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for adults with partial-onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial‑onset seizures, with or without secondarily generalized seizures. Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a pre-specified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose and the actual mean and median doses in the stabilization period are shown in Table 13. Pediatric Patients 2 to 16 Years of Age with Partial ‑ Onset Seizures The effectiveness of topiramate as an adjunctive treatment for pediatric patients 2 to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures (see Table 14). Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial-onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate tablets in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients’ weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients’ weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period. Patients with Primary Generalized Tonic-Clonic Seizures The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo (see Table 14). Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225, or 400 mg/day based on patients’ body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period. Patients with Lennox-Gastaut Syndrome The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10) comparing a single dosage of topiramate with placebo (see Table 14). Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week, then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity. Table 13: Immediate-Release Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults with Partial-Onset Seizures a Study Stabilization Dose Placeboᵇ Target Topiramate Dosage (mg/day) 200 400 600 800 1,000 2 N Mean Dose Median Dose 42 5.9 6 42 200 200 40 390 400 41 556 600 -- -- -- -- -- -- 3 N Mean Dose Median Dose 44 9.7 10 -- -- -- -- -- -- 40 544 600 45 739 800 40 796 1,000 4 N Mean Dose Median Dose 23 3.8 4 -- -- -- 19 395 400 -- -- -- -- -- -- -- -- -- 5 N Mean Dose Median Dose 30 5.7 6 -- -- -- -- -- -- 28 522 600 -- -- -- -- -- -- 6 N Mean Dose Median Dose 28 7.9 8 -- -- -- -- -- -- -- -- -- 25 568 600 -- -- -- 7 N Mean Dose Median Dose 90 8 8 157 200 200 -- -- -- -- -- -- -- -- -- -- -- -- a Dose-response studies were not conducted for other indications or pediatric partial-onset seizures b Placebo dosages are given as the number of tablets.

-- 6 N Mean Dose Median Dose 28 7.9 8 -- -- -- -- -- -- -- -- -- 25 568 600 -- -- -- 7 N Mean Dose Median Dose 90 8 8 157 200 200 -- -- -- -- -- -- -- -- -- -- -- -- a Dose-response studies were not conducted for other indications or pediatric partial-onset seizures b Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 4 (4 tablets/day); Studies 2 and 5 (6 tablets/day); Studies 6 and 7 (8 tablets/day); Study 3 (10 tablets/day) In all adjunctive topiramate trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 14. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial. Table 14: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials Study # # Placebo Target Topiramate Dosage (mg per day) 200 400 600 800 1,000 ≈6mg/kg/day * Partial-Onset Seizures Studies in Adults 2 N Median % Reduction % Responders 45 12 18 45 27 a 24 45 48ᵇ 44ᵈ 46 45ᶜ 46ᵈ -- -- -- -- -- -- -- -- -- 3 N Median % Reduction % Responders 47 2 9 -- -- -- -- -- -- 48 41ᶜ 40ᶜ 48 41ᶜ 41ᶜ 47 36ᶜ 36ᵈ -- -- -- 4 N Median % Reduction % Responders 24 1 8 -- -- -- 23 41 e 35ᵈ -- -- -- -- -- -- -- -- -- -- -- -- 5 N Median% Reduction % Responders 30 -12 10 -- -- -- -- -- -- 30 46ᶠ 47ᶜ -- -- -- -- -- -- -- -- -- 6 N Median % Reduction % Responders 28 -21 0 -- -- -- -- -- -- -- -- -- 28 24ᶜ 43ᶜ -- -- -- -- -- -- 7 N Median % Reduction % Responders 91 20 24 168 44ᶜ 45ᶜ -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- Partial-Onset Seizures Studies in Pediatric Patients 8 N Median % Reduction % Responders 45 11 20 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 41 33ᵈ 39 Primary Generalized Tonic-Clonic h 9 N Median % Reduction % Responders 40 9 20 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 39 57ᵈ 56ᶜ Lennox-Gastaut Syndrome i 10 N Median % Reduction % Responders Improvement in Seizure Severityᶨ 49 -5 14 28 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 46 15ᵈ 28ᵍ 52ᵈ Comparisons with placebo: a p=0.080; b p ≤ 0.010; c p ≤ 0.001; d p ≤ 0.050; e p=0.065; f p ≤0.005; g p=0.071 h Median % reduction and % responders are reported for PGTC seizures i Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures j Percent of subjects who were minimally, much, or very much improved from baseline. *For Studies 8 and 9, specified target dosages (less than 9.3 mg/kg/day) were assigned based on subject’s weight to approximate a dosage of 6 mg/kg/day; these dosages corresponded to mg per day dosages of 125 mg per day, 175 mg per day, 225 mg per day, and 400 mg per day Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 to 100 mg/day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated. 14.4 Extended-Release: Adjunctive Therapy in Adult Patients with Partial-Onset Seizures with Topiramate Extended-Release Capsules The effectiveness of topiramate extended-release capsules as an adjunctive treatment for adults (18 to 75 years of age) was evaluated in a randomized, international, multi-center, double-blind, parallel-group, placebo-controlled trial in patients with a history of partial-onset seizures, with or without secondary generalization (Study 14).

topiramate extended-release capsules as an adjunctive treatment for adults (18 to 75 years of age) was evaluated in a randomized, international, multi-center, double-blind, parallel-group, placebo-controlled trial in patients with a history of partial-onset seizures, with or without secondary generalization (Study 14). Patients with partial-onset seizures on a stable dose of 1 to 3 AEDs entered into an 8-week baseline period. Patients who experienced at least 8 partial‑onset seizures, with or without secondary generalization, and no more than 21 consecutive seizure free days during the 8-week baseline phase were randomly assigned to placebo or topiramate extended-release capsules administered once daily in addition to their concomitant AEDs. Following randomization, 249 patients began the double-blind treatment phase, which consisted of an initial 3-week titration period followed by an 8-week maintenance period. During the titration period, patients received topiramate extended-release capsules or placebo beginning at 50 mg once daily; the dose was increased at weekly intervals by 50 mg once daily, or the placebo equivalent, until a final dose of 200 mg once daily was achieved. Patients then entered the maintenance period at the assigned dose of 200 mg once daily, or its placebo equivalent. The percent reduction in the frequency of partial-onset seizure, baseline period compared to the treatment phase, was the primary endpoint. Data was analyzed by the Wilcoxon rank-sum test, with the criteria of statistical significance of p<0.05. The results of the analysis are presented in Table 15. The median percent reduction in seizure rate was 39.5% in patients taking topiramate extended-release capsules (N=124) and 21.7% in patients taking placebo (N=125). This difference was statistically significant. Table 15: Percent Reduction From Baseline in Partial-Onset Seizure Frequency During 11-week Treatment Period in Study 14 Study End Point Topiramate Extended-Release Capsules (N=124) Placebo (N=125) Median Percent Reduction from Baseline a 39.5% 21.7% a Statistically Significant by the Wilcoxon rank-sum test Figure 2 shows the change from baseline during titration plus maintenance (11 weeks) in partial-onset seizure frequency by category for patients treated with topiramate extended-release capsules and placebo. Patients in whom the seizure frequency increased are shown as “worse.” Patients in whom the seizure frequency decreased are shown in four categories of reduction in seizure frequency. Figure 2: Proportion of Patients by Category of Seizure Response to Topiramate Extended-Release Capsules and Placebo figure2 14.5 Preventive Treatment of Migraine Adult Patients The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted in the US (Study 11) or the US and Canada (Study 12) established the effectiveness of immediate-release topiramate in the preventive treatment of migraine. The design of both trials was identical, enrolling patients with a history of migraine, with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventive medications before starting the baseline phase.

HS) diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventive medications before starting the baseline phase. Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either topiramate 50 mg/day, 100 mg/day, 200 mg/day (twice the recommended daily dosage for the preventive treatment of migraine), or placebo and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate (according to migraines classified by IHS criteria) from the baseline phase to double-blind treatment period in each immediate-release topiramate treatment group compared to placebo in the Intent-To-Treat (ITT) population. In Study 11, a total of 469 patients (416 females, 53 males), ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of topiramate 50, 100, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the immediate-release topiramate 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 3). The treatment differences between the immediate-release topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p<0.001 for both comparisons). In Study 12, a total of 468 patients (406 females, 62 males), ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of immediate-release topiramate 50, 100, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches per 28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the immediate-release topiramate 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 3). The differences between the immediate-release topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p=0.008 and p <0.001, respectively). In both studies, there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race. For patients withdrawing from immediate-release topiramate, daily dosages were decreased in weekly intervals by 25 to 50 mg/day.

reatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race. For patients withdrawing from immediate-release topiramate, daily dosages were decreased in weekly intervals by 25 to 50 mg/day. Figure 3: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents) Pediatric Patients 12 to 17 Years of Age The effectiveness of immediate-release topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial (Study 13). The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]). Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and ≤14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either immediate-release topiramate 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Approximately 80% or more patients in each treatment group completed the study. The median average daily dosages were 45 and 79 mg/day in the target dose groups of immediate-release topiramate 50 and 100 mg/day, respectively. Effectiveness of treatment was assessed by comparing each immediate-release topiramate treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint). The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 16. The 100 mg immediate-release topiramate dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate. The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3 for 100 mg immediate-release topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p = 0.0087). Table 16: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set) Category Placebo (N=33) Topiramate 50 mg/day (N=35) Topiramate 100 mg/day (N=35) Baseline Median 3.6 4 4 Last 12 Weeks of Double-Blind Phase Median 2.3 2.3 1 Percent Reduction (%) Median 44.4 44.6 72.2 P-value versus Placebo a,b 0.7975 0.0164 c a P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject's stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate. b P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure. c Indicates p-value is < 0.05 (two-sided). figure3

<table width="100%"><col width="8%"/><col width="16%"/><col width="11%"/><col width="10%"/><col width="16%"/><col width="11%"/><col width="10%"/><col width="16%"/><tbody><tr><td align="center" rowspan="2" styleCode="Toprule " valign="middle"><paragraph><content styleCode="bold">Study</content></paragraph></td><td rowspan="2" styleCode="Toprule " valign="middle"><paragraph><content styleCode="bold">Stabilization Dose</content></paragraph></td><td align="center" rowspan="2" styleCode="Toprule " valign="middle"><paragraph><content styleCode="bold">Placebo&#x1D47;</content></paragraph></td><td align="center" colspan="5" styleCode="Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Target Topiramate Dosage (mg/day)</content></paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph><content styleCode="bold">200</content></paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph><content styleCode="bold">400</content></paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph><content styleCode="bold">600</content></paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph><content styleCode="bold">800</content></paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph><content styleCode="bold">1,000</content></paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>2</paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N </paragraph><paragraph> Mean Dose </paragraph><paragraph> Median Dose</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>42</paragraph><paragraph>5.9</paragraph><paragraph>6</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>42 </paragraph><paragraph>200</paragraph><paragraph>200</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>40</paragraph><paragraph>390</paragraph><paragraph>400</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>41</paragraph><paragraph>556</paragraph><paragraph>600</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>3</paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N</paragraph><paragraph>Mean Dose</paragraph><paragraph>Median Dose</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>44</paragraph><paragraph>9.7</paragraph><paragraph>10</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>40</paragraph><paragraph>544</paragraph><paragraph>600</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>45</paragraph><paragraph>739</paragraph><paragraph>800</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>40</paragraph><paragraph>796</paragraph><paragraph>1,000</paragraph><

544</paragraph><paragraph>600</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>45</paragraph><paragraph>739</paragraph><paragraph>800</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>40</paragraph><paragraph>796</paragraph><paragraph>1,000</paragraph>< /td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>4</paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N</paragraph><paragraph> Mean Dose</paragraph><paragraph> Median Dose</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>23</paragraph><paragraph>3.8</paragraph><paragraph>4</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>19</paragraph><paragraph>395</paragraph><paragraph>400</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>5</paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N</paragraph><paragraph> Mean Dose</paragraph><paragraph> Median Dose</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>30</paragraph><paragraph>5.7</paragraph><paragraph>6</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>28</paragraph><paragraph>522</paragraph><paragraph>600</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>6</paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N</paragraph><paragraph> Mean Dose</paragraph><paragraph> Median Dose</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>28</paragraph><paragraph>7.9</paragraph><paragraph>8</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>25</paragraph><paragraph>568</paragraph><paragraph>600</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>7</paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N</paragraph><paragraph> Mean Dose</paragraph><paragraph> Median Dose</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>90</paragraph><paragraph>8</paragraph><paragrap

" styleCode="Botrule " valign="middle"><paragraph>7</paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N</paragraph><paragraph> Mean Dose</paragraph><paragraph> Median Dose</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>90</paragraph><paragraph>8</paragraph><paragrap h>8</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>157</paragraph><paragraph>200</paragraph><paragraph>200</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr></tbody></table>

ragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr></tbody></table> <table width="97.22%"><col width="7%"/><col width="15%"/><col width="9%"/><col width="8%"/><col width="15%"/><col width="8%"/><col width="8%"/><col width="15%"/><col width="14%"/><thead><tr><th align="center" rowspan="2" styleCode="Toprule " valign="middle"><content styleCode="bold">Study</content> <content styleCode="bold">#</content></th><th align="center" rowspan="2" styleCode="Toprule " valign="middle"><content styleCode="bold">#</content></th><th align="center" rowspan="2" styleCode="Toprule " valign="middle"><content styleCode="bold">Placebo</content></th><th align="center" colspan="6" styleCode="Botrule Toprule " valign="middle"><content styleCode="bold">Target Topiramate Dosage (mg per day)</content></th></tr><tr><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">200</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">400</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">600</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">800</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">1,000</content></th><th align="center" styleCode="Botrule " valign="middle"><content styleCode="bold">&#x2248;6mg/kg/day^*</content></th></tr></thead><tbody><tr><td colspan="9" styleCode="Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Partial-Onset Seizures Studies in Adults</content></paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>2 </paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N Median % Reduction % Responders</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>45 12 18</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>45 27^a 24</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>45 48&#x1D47; 44&#x1D48;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>46 45&#x1D9C; 46&#x1D48;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>3 </paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N Median % Reduction % Responders</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>47 2 9</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>48 41&#x1D9C; 40&#x1D9C;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>48 41&#x1D9C; 41&#x1D9C;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>47 36&#x1D9C; 36&#x1D48;</paragraph></td><td align="center" styleCode="Botrule " valign="mid

><paragraph>48 41&#x1D9C; 40&#x1D9C;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>48 41&#x1D9C; 41&#x1D9C;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>47 36&#x1D9C; 36&#x1D48;</paragraph></td><td align="center" styleCode="Botrule " valign="mid dle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>4 </paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N Median % Reduction % Responders</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>24 1 8</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>23 41^e 35&#x1D48;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>5 </paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N Median% Reduction % Responders</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>30 -12 10</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>30 46&#x1DA0; 47&#x1D9C;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>6 </paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N Median % Reduction % Responders</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>28 -21 0</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>28 24&#x1D9C; 43&#x1D9C;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>7 </paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N Median % Reduction % Responders</

d><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>7 </paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N Median % Reduction % Responders</ paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>91 20 24</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>168 44&#x1D9C; 45&#x1D9C;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td></tr><tr><td colspan="9" styleCode="Botrule " valign="middle"><paragraph><content styleCode="bold">Partial-Onset Seizures Studies in Pediatric Patients</content></paragraph></td></tr><tr><td align="center" valign="middle"><paragraph>8 </paragraph></td><td valign="middle"><paragraph>N Median % Reduction % Responders</paragraph></td><td align="center" valign="middle"><paragraph>45 11 20</paragraph></td><td align="center" valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" valign="middle"><paragraph>41 33&#x1D48; 39</paragraph></td></tr><tr><td colspan="9" styleCode="Botrule " valign="middle"><paragraph><content styleCode="bold">Primary Generalized Tonic-Clonic^h</content></paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>9 </paragraph></td><td styleCode="Botrule " valign="middle"><paragraph>N Median % Reduction % Responders</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>40 9 20</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>39 57&#x1D48; 56&#x1D9C;</paragraph></td></tr><tr><td colspan="9" styleCode="Botrule " valign="middle"><paragraph><content styleCode="bold">Lennox-Gastaut Syndromeⁱ</content></paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>10 </paragraph></td><td styleCode="Botrule " valign="middle"><p

9C;</paragraph></td></tr><tr><td colspan="9" styleCode="Botrule " valign="middle"><paragraph><content styleCode="bold">Lennox-Gastaut Syndromeⁱ</content></paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="middle"><paragraph>10 </paragraph></td><td styleCode="Botrule " valign="middle"><p aragraph>N Median % Reduction % Responders Improvement in Seizure Severity&#x1DA8;</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>49 -5 14 </paragraph><paragraph>28</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>--</paragraph><paragraph>--</paragraph><paragraph>--</paragraph></td><td align="center" styleCode="Botrule " valign="middle"><paragraph>46 15&#x1D48; 28&#x1D4D; </paragraph><paragraph>52&#x1D48;</paragraph></td></tr></tbody></table> <table width="100%"><col width="38%"/><col width="34%"/><col width="28%"/><tbody><tr><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Study End Point</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Topiramate Extended-Release Capsules</content></paragraph><paragraph><content styleCode="bold">(N=124)</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold"> (N=125)</content></paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Median Percent Reduction from Baseline^a</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>39.5%</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>21.7%</paragraph></td></tr></tbody></table>

d></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Median Percent Reduction from Baseline^a</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>39.5%</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>21.7%</paragraph></td></tr></tbody></table> <table width="100%"><col width="34%"/><col width="17%"/><col width="23%"/><col width="26%"/><tbody><tr><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Category</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N=33)</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Topiramate 50 mg/day</content></paragraph><paragraph><content styleCode="bold">(N=35)</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Topiramate 100 mg/day</content></paragraph><paragraph><content styleCode="bold">(N=35)</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Baseline</content></paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><list listType="unordered"><item><caption> </caption>Median</item></list></td><td align="center" valign="top"><paragraph>3.6</paragraph></td><td align="center" valign="top"><paragraph>4</paragraph></td><td align="center" valign="top"><paragraph>4</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Last 12 Weeks of Double-Blind Phase</content></paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><list listType="unordered"><item><caption> </caption>Median</item></list></td><td align="center" valign="top"><paragraph>2.3</paragraph></td><td align="center" valign="top"><paragraph>2.3</paragraph></td><td align="center" valign="top"><paragraph>1</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Percent Reduction (%)</content></paragraph></td><td valign="top"/><td valign="top"/><td valign="top"/></tr><tr><td valign="top"><list listType="unordered"><item><caption> </caption>Median</item></list></td><td align="center" valign="top"><paragraph>44.4</paragraph></td><td align="center" valign="top"><paragraph>44.6</paragraph></td><td align="center" valign="top"><paragraph>72.2</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><list listType="unordered"><item><caption> </caption>P-value versus Placebo^a,b</item></list></td><td styleCode="Botrule " valign="top"/><td align="center" styleCode="Botrule " valign="top"><paragraph>0.7975</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0.0164^c</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Topiramate Extended-Release Capsules contain pellets of topiramate in a capsule and are available in the following strengths and colors: 25 mg: flesh colored cap printed with “G” in black ink and light grey body printed with “367” in black ink. 25 mg capsules are supplied in the following package configurations: • Bottles of 30 with desiccant and a child-resistant closure, NDC 72603-120-01 50 mg: light orange cap printed with “G” in black ink and light grey body printed with “368” in black ink. 50 mg capsules are supplied in the following package configurations: • Bottles of 30 with desiccant and a child-resistant closure, NDC 72603-121-01 100 mg: reddish orange cap printed with “G” in black ink and light grey body printed with “369” in black ink. 100 mg capsules are supplied in the following package configurations: • Bottles of 30 with desiccant and a child-resistant closure, NDC 72603-122-01 150 mg: grey cap printed with “G” in black ink and light grey body printed with “370” in black ink. 150 mg capsules are supplied in the following package configurations: • Bottles of 30 with desiccant and a child-resistant closure, NDC 72603-123-01 200 mg: brown cap printed with “G” in black ink and light grey body printed with “371” in black ink. 200 mg capsules are supplied in the following package configurations: • Bottles of 30 with desiccant and a child-resistant closure, NDC 72603-124-01 16.2 Storage and Handling Topiramate Extended-Release Capsules should be stored in a tightly-closed container at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

16.2 Storage and Handling Topiramate Extended-Release Capsules should be stored in a tightly-closed container at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide). Administration Instructions Counsel patients to swallow topiramate extended-release capsules whole or carefully open and sprinkle the entire contents on a spoonful of soft food. This drug/food mixture should be swallowed immediately and not chewed. Do not store drug/food mixture for future use [see Dosage and Administration ( 2.6 )]. Eye Disorders Advise patients taking topiramate extended-release capsules to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain [see Warnings and Precautions ( 5.1 and 5.2 )]. Oligohydrosis and Hyperthermia Closely monitor topiramate extended-release capsules-treated patients, especially pediatric patients, for evidence of decreased sweating and increased body temperature, especially in hot weather. Counsel patients to contact their healthcare professionals immediately if they develop a high or persistent fever, or decreased sweating [see Warnings and Precautions ( 5.3 )]. Metabolic Acidosis Warn patients about the potential significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 ), ( 8.4 )]. Suicidal Behavior and Ideation Counsel patients, their caregivers, and families that AEDs, including topiramate extended-release capsules, may increase the risk of suicidal thoughts and behavior and they should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Instruct patients to immediately report behaviors of concern to their healthcare providers [see Warnings and Precautions ( 5.5 )]. Interference with Cognitive and Motor Performance Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, visual effects, and advise patients not to drive or operate machinery until they have gained sufficient experience on topiramate extended-release capsules to gauge whether it adversely affects their mental performance, motor performance, and/or vision [see Warnings and Precautions ( 5.6 )]. Even when taking topiramate extended-release capsules, or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, advise all patients taking topiramate extended-release capsules for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Discuss the appropriate level of caution with patients, before patients with epilepsy engage in such activities. Fetal Toxicity Inform pregnant women and women of childbearing potential that use of topiramate extended-release capsules during pregnancy can cause fetal harm.

will need to avoid such activities altogether. Discuss the appropriate level of caution with patients, before patients with epilepsy engage in such activities. Fetal Toxicity Inform pregnant women and women of childbearing potential that use of topiramate extended-release capsules during pregnancy can cause fetal harm. Topiramate extended-release capsules increased the risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be small for their gestational age. There may also be risks to the fetus from chronic metabolic acidosis with use of topiramate extended-release capsules during pregnancy [see Warnings and Precautions ( 5.4 ), ( 5.7 ), Use in Specific Populations ( 8.1 )]. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate extended-release capsules, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing or progestin-only contraceptives with topiramate [see Drug Interactions ( 7.4 )]. Encourage pregnant women using topiramate extended-release capsules to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations ( 8.1 )]. Decrease in Bone Mineral Density Inform the patient or caregiver that long-term treatment with topiramate extended-release capsules can decrease bone formation and increase bone resorption in children [see Warnings and Precautions ( 5.9 )] . Negative Effects on Growth (Height and Weight) Discuss with the patient or caregiver that long-term topiramate extended-release capsules treatment may attenuate growth as reflected by slower height increase and weight gain in pediatric patients [see Warnings and Precautions ( 5.10 )] . Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related. Advise patients to report such reactions to a healthcare provider immediately [see Warnings and Precautions ( 5.11 )] . Serious Skin Reactions Inform patients about the signs of serious skin reactions. Instruct patients to immediately inform their healthcare provider at the first appearance of skin rash [see Warnings and Precautions ( 5.12 )]. Anaphylaxis and Angioedema Inform patients about the signs and symptoms of hypersensitivity reactions such as anaphylaxis and angioedema, which can occur with topiramate extended-release capsules. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions ( 5.13 )]. Hyperammonemia and Encephalopathy Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see Warnings and Precautions ( 5.14 )].

omiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see Warnings and Precautions ( 5.14 )]. Kidney Stones Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation [see Warnings and Precautions ( 5.15 )]. Hypothermia Counsel patients that topiramate extended-release capsules can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction [see Warnings and Precautions ( 5.16 )]. Manufactured for: Northstar Rx LLC Memphis, TN 38141. Manufactured by: Glenmark Pharmaceuticals Limited India March 2026

MEDICATION GUIDE MEDICATION GUIDE Topiramate (toe pirʾ a mate) Extended-Release Capsules, for oral use What is the most important information I should know about topiramate extended-release capsules? Topiramate extended-release capsules may cause eye problems. Serious eye problems include: • any sudden decrease in vision with or without eye pain and redness, • a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma). These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms, including any new problems with your vision. Topiramate extended-release capsules may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. If you have a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away. Topiramate extended-release capsules can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will: • feel tired • not feel hungry (loss of appetite) • feel changes in heartbeat • have trouble thinking clearly Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with topiramate extended-release capsules. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis. Like other antiepileptic drugs, topiramate extended-release capsules may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: Do not stop topiramate extended-release capsules without first talking to a healthcare provider. • Stopping topiramate extended-release capsules suddenly can cause serious problems. • Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. • Keep all follow-up visits with your healthcare provider as scheduled. • Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Topiramate extended-release capsules can harm your unborn baby. • If you take topiramate extended-release capsules during pregnancy, your baby has a higher risk for birth defects including cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant. • Birth defects may happen even in children born to women who are not taking any medicines and do not have other risk factors. • There may be other medicines to treat your condition that have a lower chance of birth defects.

left palate. These defects can begin early in pregnancy, even before you know you are pregnant. • Birth defects may happen even in children born to women who are not taking any medicines and do not have other risk factors. • There may be other medicines to treat your condition that have a lower chance of birth defects. • All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of topiramate extended-release capsules. If the decision is made to use topiramate extended-release capsules, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your healthcare provider about the best kind of birth control to use while you are taking topiramate extended-release capsules. • Tell your healthcare provider right away if you become pregnant while taking topiramate extended-release capsules. You and your healthcare provider should decide if you will continue to take topiramate extended-release capsules while you are pregnant. • If you take topiramate extended-release capsules during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. Talk to your healthcare provider if you have any questions about this risk during pregnancy. • Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if topiramate extended-release capsules has caused metabolic acidosis during your pregnancy. • Pregnancy Registry: If you become pregnant while taking topiramate extended-release capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of topiramate extended-release capsules and other antiepileptic drugs during pregnancy. Topiramate extended-release capsules may decrease the density of bones when used over a long period. Topiramate extended-release capsules may slow height increase and weight gain in children and adolescents when used over a long period. What are topiramate extended-release capsules? Topiramate extended-release capsules are prescription medicine used: • to treat certain types of seizures (partial-onset seizures and primary generalized tonic-clonic seizures) in adults and children 2 years of age and older, • with other medicines to treat certain types of seizures (partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 2 years of age and older, • to prevent migraine headaches in adults and adolescents 12 years of age and older. Who should not take topiramate extended-release capsules? Do not take topiramate extended-release capsules if you are allergic to topiramate, topiramate extended-release capsules, or any of the ingredients in topiramate extended-release capsules See the end of this Medication Guide for a complete list of ingredients in topiramate extended-release capsules. What should I tell my healthcare provider before taking topiramate extended-release capsules?

piramate, topiramate extended-release capsules, or any of the ingredients in topiramate extended-release capsules See the end of this Medication Guide for a complete list of ingredients in topiramate extended-release capsules. What should I tell my healthcare provider before taking topiramate extended-release capsules? Before taking topiramate extended-release capsules, tell your healthcare provider about all of your medical conditions, including if you: • have or have had depression, mood problems or suicidal thoughts or behavior • have kidney problems, kidney stones or are getting kidney dialysis • have a history of metabolic acidosis (too much acid in the blood) • have liver problems • have weak, brittle or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density) • have lung or breathing problems • have eye problems, especially glaucoma • have diarrhea • have a growth problem • are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet • are having surgery • are pregnant or plan to become pregnant • are breastfeeding or plan to breastfeed. Topiramate passes into your breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the topiramate that passes into breast milk can cause other serious harm to your baby. Talk to your healthcare provider about the best way to feed your baby if you take topiramate extended-release capsules. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Topiramate extended-release capsules and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: • Valproic acid (such as DEPAKOTE ® ) • any medicines that impair or decrease your thinking, concentration, or muscle coordination • birth control that contains hormones (such as pills, implants, patches or injections). Topiramate extended-release capsules may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you are using birth control and topiramate extended-release capsules. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider. How should I take topiramate extended-release capsules? • Take topiramate extended-release capsules exactly as your healthcare provider tells you to. • Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider. • Topiramate extended-release capsules may be swallowed whole or, if you cannot swallow the capsule whole, you may carefully open the topiramate extended-release capsules and sprinkle the medicine on a spoonful of soft food like applesauce. o Swallow the food and medicine mixture right away. Do not store the food and medicine mixture to use later. o Do not crush or chew topiramate extended-release capsules before swallowing. • Drink plenty of fluids during the day. This may help prevent kidney stones while taking topiramate extended-release capsules. • If you take too much topiramate extended-release capsules, call your healthcare provider right away or go to the nearest emergency room. • Topiramate extended-release capsules can be taken before, during, or after a meal. • If you miss a single dose of topiramate extended-release capsules, take it as soon as you can. If you have missed more than one dose, you should call your healthcare provider for advice. • Do not stop taking topiramate extended-release capsules without talking to your healthcare provider.

re, during, or after a meal. • If you miss a single dose of topiramate extended-release capsules, take it as soon as you can. If you have missed more than one dose, you should call your healthcare provider for advice. • Do not stop taking topiramate extended-release capsules without talking to your healthcare provider. Stopping topiramate extended-release capsules suddenly may cause serious problems. If you have epilepsy and you stop taking topiramate extended-release capsules suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking topiramate extended-release capsules slowly. • Your healthcare provider may do blood tests while you take topiramate extended-release capsules. What should I avoid while taking topiramate extended-release capsules? • You should not drink alcohol while taking topiramate extended-release capsules. Topiramate extended-release capsules and alcohol can affect each other causing side effects such as sleepiness and dizziness. • Do not drive a car or operate machinery until you know how topiramate extended-release capsules affects you. Topiramate extended-release capsules can slow your thinking and motor skills and may affect vision. What are the possible side effects of topiramate extended-release capsules? Topiramate extended-release capsules may cause serious side effects, including: See "What is the most important information I should know about topiramate extended-release capsules?" • Effects on thinking and alertness. Topiramate extended-release capsules may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. Topiramate extended-release capsules may cause depression or mood problems, tiredness, and sleepiness. • Dizziness or loss of muscle coordination. • Severe multiorgan reactions. Treatment with topiramate extended-release capsules may cause a serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death, particularly if it is not treated as early as possible. Contact your healthcare provider or get medical help right away if you have: o blistering and peeling of your skin or skin rash o fever or swollen glands that do not go away o hives o swelling of your face, eyes, lips, tongue, or throat o sores in your mouth, o trouble swallowing or breathing o dark urine o yellowing of the skin or whites of the eyes • Serious skin reactions . Topiramate extended-release capsules may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). Topiramate extended-release capsules may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters. • Allergic Reactions. Serious allergic reactions can happen after you take topiramate extended-release capsules. Get emergency help right away if you have swelling of the face, lips, eyes, tongue, or throat, or trouble swallowing or breathing . • High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when topiramate extended-release capsules are taken with a medicine called valproic acid (DEPAKOTE®). Call your healthcare provider right away if you develop unexplained tiredness, vomiting, slowing of your thinking or reaction time, or changes in your mental activities. • Kidney stones. Drink plenty of fluids when taking topiramate extended-release capsules to decrease your chances of getting kidney stones. • Low body temperature.

lthcare provider right away if you develop unexplained tiredness, vomiting, slowing of your thinking or reaction time, or changes in your mental activities. • Kidney stones. Drink plenty of fluids when taking topiramate extended-release capsules to decrease your chances of getting kidney stones. • Low body temperature. Taking topiramate extended-release capsules when you are also taking valproic acid can cause a drop-in body temperature to less than 95ºF, or can cause tiredness, confusion, or coma. Call your healthcare provider right away if you have any of the symptoms above. The most common side effects of topiramate extended-release capsules include: Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of topiramate extended-release capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Northstar Rx LLC at 1-800-206-7821. How should I store topiramate extended-release capsules? • Store topiramate extended-release capsules at room temperature between 68°F to 77°F (20°C to 25°C). • Keep topiramate extended-release capsules in a tightly closed container. • Keep topiramate extended-release capsules dry and away from moisture. • Keep topiramate extended-release capsules and all medicines out of the reach of children. General information about the safe and effective use of topiramate extended-release capsules: Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use topiramate extended-release capsules for a condition for which it was not prescribed. Do not give topiramate extended-release capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about topiramate extended-release capsules that is written for health professionals. What are the ingredients in topiramate extended-release capsules? Active ingredient: topiramate, USP Inactive ingredients: D&C red No.30, ethylcellulose, FD&C red No.40, hypromellose, microcrystalline cellulose, polyethylene glycol and talc. The capsule shell for Topiramate Extended-Release Capsules, 25 mg contains black iron oxide, hypromellose, red iron oxide and titanium dioxide. The capsule shell for Topiramate Extended-Release Capsules, 50 mg contains black iron oxide, hypromellose, red iron oxide, titanium dioxide, and yellow iron oxide. The capsule shell for Topiramate Extended-Release Capsules, 100 mg contains black iron oxide, hypromellose, red iron oxide and titanium dioxide. The capsule shell for Topiramate Extended-Release Capsules, 150 mg contains black iron oxide, hypromellose, and titanium dioxide. The capsule shell for Topiramate Extended-Release Capsules, 200 mg contains black iron oxide, hypromellose, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink has the following components: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. This Medication Guide has been approved by the U.S. Food and Drug Administration. Trademarks are the property of their respective owners. Manufactured for: Northstar Rx LLC Memphis, TN 38141. Manufactured by: Glenmark Pharmaceuticals Limited India March 2026

<table width="100%"><col width="100%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">MEDICATION GUIDE</content></paragraph><paragraph><content styleCode="bold">Topiramate (toe pir&#x2BE; a mate)</content></paragraph><paragraph><content styleCode="bold">Extended-Release Capsules, for oral use</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about topiramate extended-release capsules?</content></paragraph><paragraph><content styleCode="bold">Topiramate extended-release capsules may cause eye problems.</content> Serious eye problems include:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>any sudden decrease in vision with or without eye pain and redness,</item><item><caption>&#x2022;</caption>a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma).</item></list><paragraph>These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms, including any new problems with your vision.</paragraph><paragraph><content styleCode="bold">Topiramate extended-release capsules may cause decreased sweating and increased body temperature (fever).</content> People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. If you have a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away.</paragraph><paragraph><content styleCode="bold">Topiramate extended-release capsules can increase the level of acid in your blood (metabolic acidosis).</content> If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms.

your blood (metabolic acidosis).</content> If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>feel tired</item><item><caption>&#x2022;</caption>not feel hungry (loss of appetite)</item><item><caption>&#x2022;</caption>feel changes in heartbeat</item><item><caption>&#x2022;</caption>have trouble thinking clearly</item></list><paragraph>Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with topiramate extended-release capsules.</paragraph><paragraph>If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis.</paragraph><paragraph><content styleCode="bold">Like other antiepileptic drugs, topiramate extended-release capsules may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.</content></paragraph><paragraph><content styleCode="bold">Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:</content></paragraph><paragraph><content styleCode="bold">Do not stop topiramate extended-release capsules without first talking to a healthcare provider.</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Stopping topiramate extended-release capsules suddenly can cause serious problems.</item><item><caption>&#x2022;</caption>Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.</item></list><paragraph><content styleCode="bold">How can I watch for early symptoms of suicidal thoughts and actions?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.</item><item><caption>&#x2022;</caption>Keep all follow-up visits with your healthcare provider as scheduled.</item><item><caption>&#x2022;</caption>Call your healthcare provider between visits as needed, especially if you are worried about symptoms.</item></list><paragraph><content styleCode="bold">Topiramate extended-release capsules can harm your unborn baby.</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>If you take topiramate extended-release capsules during pregnancy, your baby has a higher risk for birth defects including cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant.</item><item><caption>&#x2022;</caption>Birth defects may happen even in children born to women who are not taking any medicines and do not have other risk factors.</item><item><caption>&#x2022;</caption>There may be other medicines to treat your condition that have a lower chance of birth defects.</item><item><caption>&#x2022;</caption>All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of topiramate extended-release capsules. If the decision is made to use topiramate extended-release capsules, you should use effective birth control (contraception) unless you are planning to become pregnant.

men of childbearing age should talk to their healthcare providers about using other possible treatments instead of topiramate extended-release capsules. If the decision is made to use topiramate extended-release capsules, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your healthcare provider about the best kind of birth control to use while you are taking topiramate extended-release capsules.</item><item><caption>&#x2022;</caption>Tell your healthcare provider right away if you become pregnant while taking topiramate extended-release capsules. You and your healthcare provider should decide if you will continue to take topiramate extended-release capsules while you are pregnant.</item><item><caption>&#x2022;</caption>If you take topiramate extended-release capsules during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. Talk to your healthcare provider if you have any questions about this risk during pregnancy.</item><item><caption>&#x2022;</caption>Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if topiramate extended-release capsules has caused metabolic acidosis during your pregnancy.</item><item><caption>&#x2022;</caption>Pregnancy Registry: If you become pregnant while taking topiramate extended-release capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334.

our pregnancy.</item><item><caption>&#x2022;</caption>Pregnancy Registry: If you become pregnant while taking topiramate extended-release capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of topiramate extended-release capsules and other antiepileptic drugs during pregnancy.</item></list><paragraph>Topiramate extended-release capsules may decrease the density of bones when used over a long period.</paragraph><paragraph>Topiramate extended-release capsules may slow height increase and weight gain in children and adolescents when used over a long period.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are topiramate extended-release capsules?</content></paragraph><paragraph>Topiramate extended-release capsules are prescription medicine used:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>to treat certain types of seizures (partial-onset seizures and primary generalized tonic-clonic seizures) in adults and children 2 years of age and older,</item><item><caption>&#x2022;</caption>with other medicines to treat certain types of seizures (partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 2 years of age and older,</item><item><caption>&#x2022;</caption>to prevent migraine headaches in adults and adolescents 12 years of age and older.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Who should not take topiramate extended-release capsules?</content></paragraph><paragraph>Do not take topiramate extended-release capsules if you are allergic to topiramate, topiramate extended-release capsules, or any of the ingredients in topiramate extended-release capsules</paragraph><paragraph>See the end of this Medication Guide for a complete list of ingredients in topiramate extended-release capsules.</paragraph><paragraph><content styleCode="bold">What should I tell my healthcare provider before taking topiramate extended-release capsules?</content></paragraph><paragraph><content styleCode="bold">Before taking topiramate extended-release capsules, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have or have had depression, mood problems or suicidal thoughts or behavior</item><item><caption>&#x2022;</caption>have kidney problems, kidney stones or are getting kidney dialysis</item><item><caption>&#x2022;</caption>have a history of metabolic acidosis (too much acid in the blood)</item><item><caption>&#x2022;</caption>have liver problems</item><item><caption>&#x2022;</caption>have weak, brittle or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density)</item><item><caption>&#x2022;</caption>have lung or breathing problems</item><item><caption>&#x2022;</caption>have eye problems, especially glaucoma</item><item><caption>&#x2022;</caption>have diarrhea</item><item><caption>&#x2022;</caption>have a growth problem</item><item><caption>&#x2022;</caption>are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet</item><item><caption>&#x2022;</caption>are having surgery</item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant</item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. Topiramate passes into your breast milk. Breastfed babies may be sleepy or have diarrhea.

etogenic diet</item><item><caption>&#x2022;</caption>are having surgery</item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant</item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. Topiramate passes into your breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the topiramate that passes into breast milk can cause other serious harm to your baby. Talk to your healthcare provider about the best way to feed your baby if you take topiramate extended-release capsules.</item></list><paragraph>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Topiramate extended-release capsules and other medicines may affect each other causing side effects.</paragraph><paragraph>Especially tell your healthcare provider if you take:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Valproic acid (such as DEPAKOTE^&#xAE;)</item><item><caption>&#x2022;</caption>any medicines that impair or decrease your thinking, concentration, or muscle coordination</item><item><caption>&#x2022;</caption>birth control that contains hormones (such as pills, implants, patches or injections). Topiramate extended-release capsules may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you are using birth control and topiramate extended-release capsules.</item></list><paragraph>Ask your healthcare provider if you are not sure if your medicine is listed above.</paragraph><paragraph>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take topiramate extended-release capsules?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Take topiramate extended-release capsules exactly as your healthcare provider tells you to.</item><item><caption>&#x2022;</caption>Your healthcare provider may change your dose. <content styleCode="bold">Do not</content> change your dose without talking to your healthcare provider.</item><item><caption>&#x2022;</caption>Topiramate extended-release capsules may be swallowed whole or, if you cannot swallow the capsule whole, you may carefully open the topiramate extended-release capsules and sprinkle the medicine on a spoonful of soft food like applesauce.<list listType="unordered"><item><caption>o</caption>Swallow the food and medicine mixture right away. <content styleCode="bold">Do not</content> store the food and medicine mixture to use later.</item><item><caption>o</caption>Do not crush or chew topiramate extended-release capsules before swallowing.</item></list></item><item><caption>&#x2022;</caption>Drink plenty of fluids during the day. This may help prevent kidney stones while taking topiramate extended-release capsules.</item><item><caption>&#x2022;</caption>If you take too much topiramate extended-release capsules, call your healthcare provider right away or go to the nearest emergency room.</item><item><caption>&#x2022;</caption>Topiramate extended-release capsules can be taken before, during, or after a meal.</item><item><caption>&#x2022;</caption>If you miss a single dose of topiramate extended-release capsules, take it as soon as you can. If you have missed more than one dose, you should call your healthcare provider for advice.</item><item><caption>&#x2022;</caption>Do not stop taking topiramate extended-release capsules without talking to your healthcare provider.

miss a single dose of topiramate extended-release capsules, take it as soon as you can. If you have missed more than one dose, you should call your healthcare provider for advice.</item><item><caption>&#x2022;</caption>Do not stop taking topiramate extended-release capsules without talking to your healthcare provider. Stopping topiramate extended-release capsules suddenly may cause serious problems. If you have epilepsy and you stop taking topiramate extended-release capsules suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking topiramate extended-release capsules slowly.</item><item><caption>&#x2022;</caption>Your healthcare provider may do blood tests while you take topiramate extended-release capsules.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I avoid while taking topiramate extended-release capsules?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>You should not drink alcohol while taking topiramate extended-release capsules. Topiramate extended-release capsules and alcohol can affect each other causing side effects such as sleepiness and dizziness.</item><item><caption>&#x2022;</caption>Do not drive a car or operate machinery until you know how topiramate extended-release capsules affects you. Topiramate extended-release capsules can slow your thinking and motor skills and may affect vision.</item></list></td></tr><tr><td align="justify" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of topiramate extended-release capsules?</content></paragraph><paragraph><content styleCode="bold">Topiramate extended-release capsules may cause serious side effects, including:</content></paragraph><paragraph>See &quot;What is the most important information I should know about topiramate extended-release capsules?&quot;</paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Effects on thinking and alertness.</content> Topiramate extended-release capsules may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. Topiramate extended-release capsules may cause depression or mood problems, tiredness, and sleepiness.</item><item><caption>&#x2022;</caption><content styleCode="bold">Dizziness or loss of muscle coordination.</content></item><item><caption>&#x2022;</caption><content styleCode="bold">Severe multiorgan reactions. </content>Treatment with topiramate extended-release capsules may cause a serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death, particularly if it is not treated as early as possible. Contact your healthcare provider or get medical help right away if you have:</item><item><caption>o</caption>blistering and peeling of your skin or skin rash</item><item><caption>o</caption>fever or swollen glands that do not go away</item><item><caption>o</caption>hives</item><item><caption>o</caption>swelling of your face, eyes, lips, tongue, or throat</item><item><caption>o</caption>sores in your mouth,</item><item><caption>o</caption>trouble swallowing or breathing</item><item><caption>o</caption>dark urine</item><item><caption>o</caption>yellowing of the skin or whites of the eyes</item><item><caption>&#x2022;</caption><content styleCode="bold">Serious skin reactions</content>. Topiramate extended-release capsules may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome).

on>yellowing of the skin or whites of the eyes</item><item><caption>&#x2022;</caption><content styleCode="bold">Serious skin reactions</content>. Topiramate extended-release capsules may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). Topiramate extended-release capsules may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters.</item><item><caption>&#x2022;</caption><content styleCode="bold">Allergic Reactions. </content>Serious allergic reactions can happen after you take topiramate extended-release capsules. Get emergency help right away if you have swelling of the face, lips, eyes, tongue, or throat, or trouble swallowing or breathing<content styleCode="bold">.</content></item><item><caption>&#x2022;</caption><content styleCode="bold">High blood ammonia levels. </content>High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when topiramate extended-release capsules are taken with a medicine called valproic acid (DEPAKOTE&#xAE;). Call your healthcare provider right away if you develop unexplained tiredness, vomiting, slowing of your thinking or reaction time, or changes in your mental activities.</item><item><caption>&#x2022;</caption><content styleCode="bold">Kidney stones.</content> Drink plenty of fluids when taking topiramate extended-release capsules to decrease your chances of getting kidney stones.</item><item><caption>&#x2022;</caption><content styleCode="bold">Low body temperature.</content> Taking topiramate extended-release capsules when you are also taking valproic acid can cause a drop-in body temperature to less than 95&#xBA;F, or can cause tiredness, confusion, or coma.</item></list><paragraph>Call your healthcare provider right away if you have any of the symptoms above. </paragraph><paragraph><content styleCode="bold">The most common side effects of topiramate extended-release capsules include:</content></paragraph><paragraph>Tell your healthcare provider about any side effect that bothers you or that does not go away.</paragraph><paragraph>These are not all the possible side effects of topiramate extended-release capsules. For more information, ask your healthcare provider or pharmacist.</paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph><paragraph>You may also report side effects to Northstar Rx LLC at 1-800-206-7821.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store topiramate extended-release capsules?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Store topiramate extended-release capsules at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item><item><caption>&#x2022;</caption>Keep topiramate extended-release capsules in a tightly closed container.</item><item><caption>&#x2022;</caption>Keep topiramate extended-release capsules dry and away from moisture.</item><item><caption>&#x2022;</caption><content styleCode="bold">Keep topiramate extended-release capsules and all medicines out of the reach of children.</content></item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of topiramate extended-release capsules:</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

/td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of topiramate extended-release capsules:</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use topiramate extended-release capsules for a condition for which it was not prescribed. Do not give topiramate extended-release capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about topiramate extended-release capsules that is written for health professionals.</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in topiramate extended-release capsules?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content> topiramate, USP</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content> D&amp;C red No.30, ethylcellulose, FD&amp;C red No.40, hypromellose, microcrystalline cellulose, polyethylene glycol and talc.</paragraph><paragraph>The capsule shell for Topiramate Extended-Release Capsules, 25 mg contains black iron oxide, hypromellose, red iron oxide and titanium dioxide.</paragraph><paragraph>The capsule shell for Topiramate Extended-Release Capsules, 50 mg contains black iron oxide, hypromellose, red iron oxide, titanium dioxide, and yellow iron oxide.</paragraph><paragraph>The capsule shell for Topiramate Extended-Release Capsules, 100 mg contains black iron oxide, hypromellose, red iron oxide and titanium dioxide.</paragraph><paragraph>The capsule shell for Topiramate Extended-Release Capsules, 150 mg contains black iron oxide, hypromellose, and titanium dioxide.</paragraph><paragraph>The capsule shell for Topiramate Extended-Release Capsules, 200 mg contains black iron oxide, hypromellose, red iron oxide, titanium dioxide, and yellow iron oxide.</paragraph><paragraph>The imprinting ink has the following components: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.</paragraph><paragraph>This Medication Guide has been approved by the U.S. Food and Drug Administration.</paragraph><paragraph>Trademarks are the property of their respective owners.</paragraph><paragraph>Manufactured for:</paragraph><paragraph><content styleCode="bold">Northstar Rx LLC</content></paragraph><paragraph>Memphis, TN 38141.</paragraph><paragraph>Manufactured by:</paragraph><paragraph><content styleCode="bold">Glenmark Pharmaceuticals Limited</content></paragraph><paragraph>India</paragraph><paragraph>March 2026</paragraph></td></tr></tbody></table>

<table ID="ID590" width="590" styleCode="Noautorules"><col width="517"/><col width="73"/><tbody><tr><td align="left" valign="top">Contraindications ( <linkHtml href="#ID214">4</linkHtml>) </td><td align="left" valign="top">3/2026 </td></tr><tr><td align="left" valign="top">Warnings and Precautions ( <linkHtml href="#ID559">5.11</linkHtml>, <linkHtml href="#ID234">5.13</linkHtml>) </td><td align="left" valign="top">3/2026 </td></tr></tbody></table>

1 INDICATIONS AND USAGE Topiramate is indicated for: Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older ( 1.1 ); adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older ( 1.2 ) Preventive treatment of migraine in patients 12 years of age and older ( 1.3 ) 1.1 Monotherapy Epilepsy Topiramate tablets and topiramate capsules are indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older. 1.2 Adjunctive Therapy Epilepsy Topiramate tablets and topiramate capsules are indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older. 1.3 Migraine Topiramate tablets and topiramate capsules are indicated for the preventive treatment of migraine in patients 12 years of age and older.

2 DOSAGE AND ADMINISTRATION Topiramate initial dose, titration, and recommended maintenance dose varies by indication and age group. See Full Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older The recommended dose for topiramate monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses. The dose should be achieved by titration according to the following schedule (Table 1): Table 1 Monotherapy Titration Schedule for Adults and Pediatric Patients 10 years and older Morning Dose Evening Dose Week 1 25 mg 25 mg Week 2 50 mg 50 mg Week 3 75 mg 75 mg Week 4 100 mg 100 mg Week 5 150 mg 150 mg Week 6 200 mg 200 mg Pediatric Patients 2 to 9 Years of Age Dosing in patients 2 to 9 years of age is based on weight. During the titration period, the initial dose of topiramate is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day (25 mg twice daily) in the second week. Dosage can be increased by 25 mg/day to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5 weeks to 7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 mg/day to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight ( Table 2 ). Table 2 Monotherapy Target Total Daily Maintenance Dosing for Patients 2 to 9 Years of Age * Administered in two equally divided doses Weight (kg) Total Daily Dose (mg/day)* Minimum Maintenance Dose Total Daily Dose (mg/day)* Maximum Maintenance Dose Up to 11 150 250 12 to 22 200 300 23 to 31 200 350 32 to 38 250 350 Greater than 38 250 400 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Older) The recommended total daily dose of topiramate as adjunctive therapy in adults with partial-onset seizures or Lennox-Gastaut Syndrome is 200 mg/day to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. Topiramate should be initiated at 25 mg/day to 50 mg/day, followed by titration to an effective dose in increments of 25 mg/day to 50 mg/day every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures. Pediatric Patients 2 to 16 Years of Age The recommended total daily dose of topiramate as adjunctive therapy for pediatric patients 2 years to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg/day to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg/day (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.

(or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day. 2.3 Dosing for the Preventive Treatment of Migraine The recommended total daily dose of topiramate as treatment for patients 12 years of age and older for the preventive treatment of migraine is 100 mg/day administered in two divided doses (Table 3). The recommended titration rate for topiramate for the preventive treatment of migraine is as follows: Table 3 Preventive Treatment of Migraine Titration Schedule for Patients 12 Years of Age and Older Morning Dose Evening Dose Week 1 None 25 mg Week 2 25 mg 25 mg Week 3 25 mg 50 mg Week 4 50 mg 50 mg Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used. 2.4 Administration Information Topiramate can be taken without regard to meals. Topiramate Tablets Because of the bitter taste, tablets should not be broken. Topiramate Capsules Topiramate capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use. 2.5 Dosing in Patients with Renal Impairment In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose of topiramate is recommended [see Use in Specific Populations ( 8.5 , 8.6 ), Clinical Pharmacology ( 12.3 )] . 2.6 Dosing in Patients Undergoing Hemodialysis To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] .

3 DOSAGE FORMS AND STRENGTHS Tablets: 25 mg, 50 mg, 100 mg, and 200 mg ( 3 ) Sprinkle Capsules: 15 mg, 25 mg and 50 mg ( 3 ) Topiramate Tablets, USP 50 mg, white to off-white, round-shaped, biconvex, beveled-edge, film-coated tablets debossed with "ZD 15" on one side and plain on the other side.

4 CONTRAINDICATIONS History of hypersensitivity reaction to topiramate, topiramate, or any of the inactive ingredients of topiramate ( 4 , 5.13 ) Topiramate is contraindicated in patients with a history of hypersensitivity reaction to topiramate, topiramate, or any of the inactive ingredients of topiramate. Anaphylaxis and angioedema have occurred [see Warnings and Precautions ( 5.13 )] .

5 WARNINGS AND PRECAUTIONS Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue topiramate as soon as possible ( 5.1 ) Visual field defects: consider discontinuation of topiramate ( 5.2 ) Oligohidrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients ( 5.3 ) Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of topiramate if clinically appropriate ( 5.4 ) Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.5 ) Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur ( 5.6 ) Fetal Toxicity: use during pregnancy can cause major congenital malformations, including but not limited to cleft lip and/or palate and being small for gestational age ( 5.7 ) Withdrawal of AEDs: withdraw topiramate gradually ( 5.8 ) Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients ( 5.9 ) Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy ( 5.10 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multiorgan Hypersensitivity, serious skin reactions (SJS or TEN), anaphylaxis and angioedema: Discontinue Topiramate if an alternative etiology cannot be established ( 5.11 , 5.12 , 5.13 ) Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur ( 5.14 ) Kidney stones: avoid use with other carbonic anhydrase inhibitors, drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.15 ) Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use ( 5.16 ) 5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate.

ated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. 5.2 Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug. 5.3 Oligohidrosis and Hyperthermia Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures. The majority of the reports have been in pediatric patients. Patients (especially pediatric patients) treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. 5.4 Metabolic Acidosis Topiramate can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by topiramate. Topiramate-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of topiramate. Metabolic acidosis was commonly observed in adult and pediatric patients treated with topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials, for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial-onset seizures was as high as 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and ≥5 mEq/L decrease from pretreatment) in these trials was up to 11%, compared to < 2% for placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions ( 5.9 , 5.15 )] . A one-year, active-controlled study of pediatric patients treated with topiramate demonstrated that topiramate decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions ( 5.9 ), Use in Specific Populations ( 8.4 )] .

lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions ( 5.9 ), Use in Specific Populations ( 8.4 )] . Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 months old pediatrics. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations ( 8.4 )] . Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions ( 5.7 ), Use in Specific Populations ( 8.1 )] . Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered. 5.5 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs. Table 4 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing topiramate or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.6 Cognitive/Neuropsychiatric Adverse Reactions Topiramate can cause cognitive/neuropsychiatric adverse reactions. The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue. Adult Patients Cognitive-Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction. In adult epilepsy adjunctive controlled trials, which used rapid titration (100 mg/day to 200 mg/day weekly increments), and target topiramate doses of 200 mg/day to 1000 mg/day, 56% of patients in the 800 mg/day and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200 mg/day to 400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase. In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day and 26% for 400 mg/day. In the 6-month controlled trials for the preventive treatment of migraine, which used a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations [see Warnings and Precautions ( 5.5 )].

e reactions most commonly developed during titration and sometimes persisted after completion of titration. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations [see Warnings and Precautions ( 5.5 )]. Somnolence/Fatigue Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue, appeared dose related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both fatigue and somnolence were dose-related and more common in the titration phase. Pediatric Patients In pediatric epilepsy trials (adjunctive and monotherapy), the incidence of cognitive/neuropsychiatric adverse reactions was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems, and language problems. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in topiramate-treated patients compared to placebo. The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 13 [see Clinical Studies ( 14.3 )] . Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency. 5.7 Fetal Toxicity Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts) and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations ( 8.1 )] . Consider the benefits and the risks of topiramate when administering this drug in women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations ( 8.1 ), Patient Counseling Information ( 17 )] . Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk.

ildbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations ( 8.1 ), Patient Counseling Information ( 17 )] . Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations ( 8.1 )] . 5.8 Withdrawal of Antiepileptic Drugs In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including topiramate, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies ( 14 )] . In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended. 5.9 Decrease in Bone Mineral Density Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations ( 8.4 )] . Twenty-one percent of topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of –0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions ( 5.4 )] . Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium. 5.10 Negative Effects on Growth (Height and Weight) Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of topiramate monotherapy on growth (i.e., height and weight) [see Use in Specific Populations ( 8.4 )] . Although continued growth was observed in both treatment groups, the topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the topiramate group compared to the control group. Negative effects on weight and height were seen across all topiramate age subgroups. Growth (height and weight) of children receiving prolonged topiramate therapy should be carefully monitored. 5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking topiramate. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis or myositis sometimes resembling an acute viral infection. Eosinophilia is often present.

ESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Topiramate should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.12 Serious Skin Reactions Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. Topiramate should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions. 5.13 Anaphylaxis and Angioedema Hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with topiramate in the postmarketing setting. If a hypersensitivity reaction occurs, discontinuetopiramate and initiate appropriate therapy [see Contraindications ( 4 )]. 5.14 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions ( 6.2 )] . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions ( 7.1 )] . Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose. Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial-onset epilepsy and this was not due to a pharmacokinetic interaction. In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. 5.15 Kidney Stones Topiramate increases the risk of kidney stones.

deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. 5.15 Kidney Stones Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones. Topiramate is not approved for treatment of epilepsy in pediatric patients less than 2 years old [see Use in Specific Populations ( 8.4 )]. Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions ( 5.4 )] . The concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in topiramate-treated pediatric patients in a one-year active-controlled study [see Use in Specific Populations ( 8.4 )] . This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. 5.16 Hypothermia with Concomitant Valproic Acid Use Hypothermia, defined as a drop in body core temperature to < 35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions ( 7.1 )] . Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

<table ID="ID479" width="0" styleCode="Noautorules"><caption>Table 4 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</caption><col width="114"/><col width="126"/><col width="132"/><col width="156"/><col width="167"/><tbody><tr><td align="center" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">Indication</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Placebo Patients</content> <content styleCode="bold">with Events per</content> <content styleCode="bold">1,000 Patients</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Drug Patients with</content> <content styleCode="bold">Events per 1,000</content> <content styleCode="bold">Patients</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Relative Risk:</content> <content styleCode="bold">Incidence of Events</content> <content styleCode="bold">in Drug</content> <content styleCode="bold">Patients/Incidence</content> <content styleCode="bold">in Placebo Patients</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Risk Difference:</content> <content styleCode="bold">Additional Drug</content> <content styleCode="bold">Patients with</content> <content styleCode="bold">Events per 1,000</content> <content styleCode="bold">Patients</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Epilepsy </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3.4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3.5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.4 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Psychiatric </td><td align="center" styleCode=" Botrule Rrule" valign="top">5.7 </td><td align="center" styleCode=" Botrule Rrule" valign="top">8.5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Other </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.8 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.9 </td><td align="center" styleCode=" Botrule Rrule" valign="top">0.9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Total </td><td align="center" styleCode=" Botrule Rrule">2.4 </td><td align="center" styleCode=" Botrule Rrule">4.3 </td><td align="center" styleCode=" Botrule Rrule">1.8 </td><td align="center" styleCode=" Botrule Rrule">1.9 </td></tr></tbody></table>

6 ADVERSE REACTIONS Epilepsy: Most common (≥10% more frequent than placebo or low-dose topiramate) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision and fever ( 6.1) Migraine: Most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain and upper respiratory tract infection ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are discussed in more detail in other sections of the labeling: Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions ( 5.1 )] Visual Field Defects [see Warnings and Precautions ( 5.2 )] Oligohidrosis and Hyperthermia [see Warnings and Precautions ( 5.3 )] Metabolic Acidosis [see Warnings and Precautions ( 5.4 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.5 )] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions ( 5.6 )] Decrease of Bone Mineral Density [see Warnings and Precautions ( 5.9 )] Negative Effects on Growth (Height and Weight) [see Warnings and Precautions ( 5.10 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions ( 5.11 )] Serious Skin Reactions [see Warnings and Precautions ( 5.12 )] Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.13 )] Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use) [see Warnings and Precautions ( 5.14 )] Kidney Stones [see Warnings and Precautions ( 5.15 )] Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions ( 5.16 )] The data described in the following sections were obtained using topiramate tablets. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug, and may not reflect the incidence of adverse reactions observed in practice. Monotherapy Epilepsy Adults 16 Years of Age and Older The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher ( ≥ 10 %) than in the 50 mg/day group were: paresthesia, weight loss and anorexia (see Table 5). Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common ( ≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia. Pediatric Patients 6 to 15 Years of Age The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher ( ≥ 10%) than in the 50 mg/day group were fever and weight loss (see Table 5).

mnolence, and paresthesia. Pediatric Patients 6 to 15 Years of Age The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher ( ≥ 10%) than in the 50 mg/day group were fever and weight loss (see Table 5). Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common ( ≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions resulting in discontinuation were difficulty with concentration/attention, fever, flushing, and confusion. Table 5 presents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day topiramate and occurring with greater incidence than 50 mg/day topiramate. Table 5 Adverse Reactions in the High Dose Group As Compared to the Low Dose Group, in Monotherapy Epilepsy Trial (Study 1) in Adult and Pediatric Patients Body System Adverse Reaction Age Group Pediatric (6 to 15 Years) Adult (Age ≥ 16 Years) Topiramate Daily Dosage Group (mg/day) 50 400 50 400 (N=74) % (N=77) % (N=160) % (N=159) % Body as a Whole - General Disorders Asthenia 0 3 4 6 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Paresthesia 3 12 21 40 Dizziness 13 14 Ataxia 3 4 Hypoesthesia 4 5 Hypertonia 0 3 Involuntary muscle contractions 0 3 Vertigo 0 3 Gastro-Intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Dry mouth 1 3 Liver and Biliary System Disorders Increase in Gamma-GT 1 3 Metabolic and Nutritional Disorders Weight loss 7 17 6 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Anorexia 4 14 Anxiety 4 6 Cognitive problems 1 6 1 4 Confusion 0 3 Depression 0 3 7 9 Difficulty with concentration or attention 7 10 7 8 Difficulty with memory 1 3 6 11 Insomnia 8 9 Decrease in libido 0 3 Mood problems 1 8 2 5 Personality disorder (behavior problems) 0 3 Psychomotor slowing 3 5 Somnolence 10 15 Red Blood Cell Disorders Anemia 1 3 Reproductive Disorders, Female Intermenstrual bleeding 0 3 Vaginal hemorrhage 0 3 Resistance Mechanism Disorders Infection 3 8 2 3 Viral infection 3 6 6 8 Respiratory System Disorders Bronchitis 1 5 3 4 Upper respiratory tract infection 16 18 Rhinitis 5 6 2 4 Sinusitis 1 4 Skin and Appendages Disorders Alopecia 1 4 3 4 Pruritus 1 4 Rash 3 4 1 4 Acne 2 3 Special Senses Other, Disorders Taste perversion 3 5 Urinary System Disorders Cystitis 1 3 Micturition frequency 0 3 Renal calculus 0 3 Urinary incontinence 1 3 Vascular (Extracardiac) Disorders Flushing 0 5 Adjunctive Therapy Epilepsy Adults 16 Years of Age and Older In pooled controlled clinical trials in adults with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with topiramate at dosages of 200 mg/day to 400 mg/day (recommended dosage range) and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200 mg/day to 400 mg/day topiramate group with an incidence higher (≥ 10 %) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (Table 6). Table 6 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 mg/day to 400 mg/day topiramate and was greater than placebo incidence.

were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (Table 6). Table 6 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 mg/day to 400 mg/day topiramate and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended topiramate dosing (i.e., 600 mg to 1000 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (200 mg to 400 mg daily) range. Table 6 Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults a a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. Body System Adverse Reaction Placebo Topiramate Dosage (mg/day) 200 to 400 (N=291) (N=183) Body as a Whole-General Disorders Fatigue 13 15 Asthenia 1 6 Back pain 4 5 Chest pain 3 4 Influenza-like symptoms 2 3 Central & Peripheral Nervous System Disorders Dizziness 15 25 Ataxia 7 16 Speech disorders/Related speech problems 2 13 Paresthesia 4 11 Nystagmus 7 10 Tremor 6 9 Language problems 1 6 Coordination abnormal 2 4 Gait abnormal 1 3 Gastro-Intestinal System Disorders Nausea 8 10 Dyspepsia 6 7 Abdominal pain 4 6 Constipation 2 4 Metabolic and Nutritional Disorders Weight loss 3 9 Psychiatric Disorders Somnolence 12 29 Nervousness 6 16 Psychomotor slowing 2 13 Difficulty with memory 3 12 Confusion 5 11 Anorexia 4 10 Difficulty with concentration/attention 2 6 Mood problems 2 4 Agitation 2 3 Aggressive reaction 2 3 Emotional lability 1 3 Cognitive problems 1 3 Reproductive Disorders Breast pain 2 4 Respiratory System Disorders Rhinitis 6 7 Pharyngitis 2 6 Sinusitis 4 5 Vision Disorders Vision abnormal 2 13 Diplopia 5 10 In controlled clinical trials in adults, 11% of patients receiving topiramate 200 mg/day to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg/day. Adverse reactions associated with discontinuing topiramate included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue and paresthesia. Pediatric Patients 2 to 15 Years of Age In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with topiramate at dosages of 5 to 9 mg/kg/day (recommended dose range) and 101 patients received placebo. The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg/kg/day to 9 mg/kg/day topiramate group with an incidence higher (≥ 10 %) than in the placebo group were: fatigue and somnolence (Table 7). Table 7 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg/kg/day to 9 mg/kg/day (recommended dose range) of topiramate and was greater than placebo incidence. Table 7 Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Pediatric Patients 2 to 15 Years of Age a,b a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. b Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.

trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. b Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. Body System/ Adverse Reaction Placebo Topiramate (N=101) (N=98) % % Body as a Whole - General Disorders Fatigue 5 16 Injury 13 14 Central & Peripheral Nervous System Disorders Gait abnormal 5 8 Ataxia 2 6 Hyperkinesia 4 5 Dizziness 2 4 Speech disorders/Related speech problems 2 4 Gastro-Intestinal System Disorders Nausea 5 6 Saliva increased 4 6 Constipation 4 5 Gastroenteritis 2 3 Metabolic and Nutritional Disorders Weight loss 1 9 Platelet, Bleeding, & Clotting Disorders Purpura 4 8 Epistaxis 1 4 Psychiatric Disorders Somnolence 16 26 Anorexia 15 24 Nervousness 7 14 Personality disorder (behavior problems) 9 11 Difficulty with concentration/attention 2 10 Aggressive reaction 4 9 Insomnia 7 8 Difficulty with memory 0 5 Confusion 3 4 Psychomotor slowing 2 3 Resistance Mechanism Disorders Infection viral 3 7 Respiratory System Disorders Pneumonia 1 5 Skin and Appendages Disorders Skin disorder 2 3 Urinary System Disorders Urinary incontinence 2 4 None of the pediatric patients who received topiramate adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions. Migraine Adults In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine clinical trials for the preventive treatment of migraine (which included 35 pediatric patients 12 to 15 years of age), most adverse reactions occurred more frequently during the titration period than during the maintenance period. The most common adverse reactions with topiramate 100 mg in the clinical trials for the preventive treatment of migraine of predominantly adults that were seen at an incidence higher (≥5 %) than in the placebo group were: paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 8). Table 8 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any topiramate treatment group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). Table 8 Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults a,b a Includes 35 adolescent patients age 12 to 15 years. b Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. c Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term.

may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. c Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term. Body System /Adverse Reaction Placebo (N=445) % Topiramate Dosage (mg/day) 50 (N=235) % 100 (N=386) % Body as a Whole-General Disorders Fatigue 11 14 15 Injury 7 9 6 Central & Peripheral Nervous System Disorders Paresthesia 6 35 51 Dizziness 10 8 9 Hypoesthesia 2 6 7 Language problems 2 7 6 Gastro-Intestinal System Disorders Nausea 8 9 13 Diarrhea 4 9 11 Abdominal pain 5 6 6 Dyspepsia 3 4 5 Dry mouth 2 2 3 Gastroenteritis 1 3 3 Metabolic and Nutritional Disorders Weight loss 1 6 9 Musculoskeletal System Disorders Arthralgia 2 7 3 Psychiatric Disorders Anorexia 6 9 15 Somnolence 5 8 7 Difficulty with memory 2 7 7 Insomnia 5 6 7 Difficulty with concentration/ attention 2 3 6 Mood problems 2 3 6 Anxiety 3 4 5 Depression 4 3 4 Nervousness 2 4 4 Confusion 2 2 3 Psychomotor slowing 1 3 2 Reproductive Disorders, Female Menstrual disorder 2 3 2 Reproductive Disorders, Male Ejaculation premature 0 3 0 Resistance Mechanism Disorders Viral infection 3 4 4 Respiratory System Disorders Upper respiratory tract infection 12 13 14 Sinusitis 6 10 6 Pharyngitis 4 5 6 Coughing 2 2 4 Bronchitis 2 3 3 Dyspnea 2 1 3 Skin and Appendages Disorders Pruritus 2 4 2 Special Sense Other, Disorders Taste perversion 1 15 8 Urinary System Disorders Urinary tract infection 2 4 2 Vision Disorders Blurred vision c 2 4 2 Of the 1,135 patients exposed to topiramate in the adult placebo-controlled studies, 25% of topiramate-treated patients discontinued due to adverse reactions, compared to 10% of the 445 placebo-treated patients. The adverse reactions associated with discontinuing therapy in the topiramate-treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%). Patients treated with topiramate experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, topiramate 50, 100, and 200 mg groups, respectively. Pediatric Patients 12 to 17 Years of Age In five, randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine, most adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period. In four, fixed-dose, double-blind clinical trials for the preventive treatment of migraine in topiramate-treated pediatric patients 12 to 17 years of age, the most common adverse reactions with topiramate 100 mg that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 9). Table 9 shows adverse reactions from the pediatric trial (Study 13 [see Clinical Studies (14.3)] ) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of topiramate, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years of age) were treated with placebo or 50 mg, 100 mg or 200 mg of topiramate. Table 9 also shows adverse reactions in pediatric patients in the controlled migraine trials when the incidence in a topiramate dose group was at least 5 % or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 9 indicate a dose-dependent relationship.

100 mg or 200 mg of topiramate. Table 9 also shows adverse reactions in pediatric patients in the controlled migraine trials when the incidence in a topiramate dose group was at least 5 % or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 9 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose-related and greater at higher than recommended topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily). Table 9 Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age a,b,c a 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults (Tables 11 and 12) b Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. c Included studies MIG-3006, MIGR-001, MIGR-002 and MIGR-003 Body System/ Adverse Reaction Placebo (N=45) % Topiramate Dosage 50 mg/day 100 mg/day (N=46) (N=48) % % Body as a Whole – General Disorders Fatigue 7 7 8 Fever 2 4 6 Central & Peripheral Nervous System Disorders Paresthesia 7 20 19 Dizziness 4 4 6 Gastrointestinal System Disorders Abdominal pain 9 7 15 Nausea 4 4 8 Metabolic and Nutritional Disorders Weight loss 2 7 4 Psychiatric Disorders Anorexia 4 9 10 Somnolence 2 2 6 Insomnia 2 9 2 Resistance Mechanism Disorders Infection viral 4 4 8 Respiratory System Disorders Upper respiratory tract infection 11 26 23 Rhinitis 2 7 6 Sinusitis 2 9 4 Coughing 0 7 2 Special Senses Other, Disorders Taste perversion 2 2 6 Vision Disorders Conjunctivitis 4 7 4 In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%). Increased Risk for Bleeding Topiramate is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse reaction for topiramate than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients. Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants). Other Adverse Reactions Observed During Clinical Trials Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect. Laboratory Test Abnormalities Adult Patients In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride and ammonia, topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions ( 5.4 , 5.14 )].

ory Test Abnormalities Adult Patients In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride and ammonia, topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions ( 5.4 , 5.14 )]. Controlled trials of adjunctive topiramate treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate versus 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate versus 1% placebo), and decreased serum potassium (0.4 % topiramate versus 0.1 % placebo). Pediatric Patients In pediatric patients (1 month to 24 months) receiving adjunctive topiramate for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with topiramate (vs. placebo) for the following clinical laboratory analytes: creatinine, blood urea nitrogen (BUN), alkaline phosphatase, and total protein, The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis), and potassium with topiramate (vs. placebo) [see Use in Specific Populations ( 8.4 )]. Topiramate is not indicated for partial-onset seizures in pediatric patients less than 2 years of age. In pediatric patients (ranging from 6 years to 17 years of age) receiving topiramate for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with topiramate (vs. placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils, The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations ( 8.4 ) ] . Topiramate is not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole-General Disorders: immediate hypersensitivity reactions (including anaphylaxis and angioedema) [see Warnings and Precautions ( 5.13 )], delayed hypersensitivity reactions (including facial swelling, lip swelling, periorbital swelling, tongue swelling), oligohydrosis and hyperthermia [see Warnings and Precautions ( 5.3 )] , hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions ( 5.14 )], hypothermia with concomitant valproic acid [see Warnings and Precautions ( 5.16 )] Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions ( 5.12 )] , pemphigus, urticaria Urinary System Disorders: kidney stones, nephrocalcinosis [see Warnings and Precautions ( 5.4 , 5.15 )] Vision Disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions ( 5.1 )] , maculopathy Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.

<table ID="ID485" width="100%" styleCode="Noautorules"><caption>Table 5 Adverse Reactions in the High Dose Group As Compared to the Low Dose Group, in Monotherapy Epilepsy Trial (Study 1) in Adult and Pediatric Patients</caption><col width="313"/><col width="87"/><col width="87"/><col width="20"/><col width="82"/><col width="118"/><tbody><tr><td rowspan="5" align="left" styleCode="Lrule Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Body System</content> Adverse Reaction </td><td colspan="5" align="center" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">Age Group</content> </td></tr><tr><td colspan="3" align="center" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Pediatric (6 to 15 Years)</content> </td><td colspan="2" align="center" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">Adult</content> <content styleCode="bold">(Age </content>&#x2265; <content styleCode="bold">16 Years)</content> </td></tr><tr><td colspan="5" align="center" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Topiramate Daily Dosage Group (mg/day)</content> </td></tr><tr><td align="center" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">50</content> </td><td align="center" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">400</content> </td><td colspan="2" align="center" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">50</content> </td><td align="center" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">400</content> </td></tr><tr><td align="center" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">(N=74) %</content> </td><td align="center" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">(N=77) %</content> </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">(N=160)</content> <content styleCode="bold">%</content> </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">(N=159)</content> <content styleCode="bold">%</content> </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Body as a Whole - General Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Asthenia </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">4 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Fever </td><td align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode=" Lrule Botrule" valign="top">12 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Leg pain </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">2 </td><td align="center" styleCode="Lrule Botrule Rrule"

Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Leg pain </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">2 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Paresthesia </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td align="center" styleCode=" Lrule Botrule" valign="top">12 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">21 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">40 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Dizziness </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">13 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">14 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Ataxia </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Hypoesthesia </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">4 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Hypertonia </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Involuntary muscle contractions </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Vertigo </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Gastro-Intestinal System Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Constipation </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Diarrhea </td><td align="center" styleCode=" Lrule Botrule" valign="top">8 </td><td alig

e" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Diarrhea </td><td align="center" styleCode=" Lrule Botrule" valign="top">8 </td><td alig n="center" styleCode=" Lrule Botrule" valign="top">9 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Gastritis </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Dry mouth </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Liver and Biliary System Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Increase in Gamma-GT </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Metabolic and Nutritional Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Weight loss </td><td align="center" styleCode=" Lrule Botrule" valign="top">7 </td><td align="center" styleCode=" Lrule Botrule" valign="top">17 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">6 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">17 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Platelet, Bleeding &amp; Clotting Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Epistaxis </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">4 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Psychiatric Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Anorexia </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">4 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">14 </td></tr>

<tr><td align="left" styleCode=" Lrule Botrule" valign="top">Anorexia </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">4 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">14 </td></tr> <tr><td align="left" styleCode=" Lrule Botrule" valign="top">Anxiety </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">4 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Cognitive problems </td><td align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode=" Lrule Botrule" valign="top">6 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Confusion </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Depression </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">7 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">9 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Difficulty with concentration or attention </td><td align="center" styleCode=" Lrule Botrule" valign="top">7 </td><td align="center" styleCode=" Lrule Botrule" valign="top">10 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">7 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">8 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Difficulty with memory </td><td align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">6 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">11 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Insomnia </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">8 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">9 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Decrease in libido </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Mood problems </td><td align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode=" Lrule Botrule" valign="top">8 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">2 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Personality disorder (behavior problems) </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="to

tyleCode=" Lrule Botrule" valign="top">Personality disorder (behavior problems) </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="to p"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Psychomotor slowing </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Somnolence </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">10 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">15 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Red Blood Cell Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Anemia </td><td align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Reproductive Disorders, Female</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Intermenstrual bleeding </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Vaginal hemorrhage </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Resistance Mechanism Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Infection </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td align="center" styleCode=" Lrule Botrule" valign="top">8 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">2 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Viral infection </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td align="center" styleCode=" Lrule Botrule" valign="top">6 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">6 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">8 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Respiratory System Disorders</content> </t

" Lrule Botrule" valign="top">6 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">6 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">8 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Respiratory System Disorders</content> </t d><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Bronchitis </td><td align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode=" Lrule Botrule" valign="top">5 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Upper respiratory tract infection </td><td align="center" styleCode=" Lrule Botrule" valign="top">16 </td><td align="center" styleCode=" Lrule Botrule" valign="top">18 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Rhinitis </td><td align="center" styleCode=" Lrule Botrule" valign="top">5 </td><td align="center" styleCode=" Lrule Botrule" valign="top">6 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">2 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Sinusitis </td><td align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode=" Lrule Botrule" valign="top">4 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Skin and Appendages Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Alopecia </td><td align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode=" Lrule Botrule" valign="top">4 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Pruritus </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Rash </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td align="center" styleCode=" Lrule Botrule" valign="top">4 </td><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Acne </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">2 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Special Senses Other, Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="to

le" valign="top">2 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Special Senses Other, Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="to p"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Taste perversion </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Urinary System Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Cystitis </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Micturition frequency </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Renal calculus </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode="Lrule Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Urinary incontinence </td><td align="center" styleCode=" Lrule Botrule" valign="top">1 </td><td align="center" styleCode=" Lrule Botrule" valign="top">3 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top"><content styleCode="bold">Vascular (Extracardiac) Disorders</content> </td><td styleCode=" Lrule Botrule" valign="top"/><td styleCode=" Lrule Botrule" valign="top"/><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Botrule" valign="top">Flushing </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">5 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr></tbody></table>

left" styleCode=" Lrule Botrule" valign="top">Flushing </td><td align="center" styleCode=" Lrule Botrule" valign="top">0 </td><td align="center" styleCode=" Lrule Botrule" valign="top">5 </td><td colspan="2" styleCode=" Lrule Botrule" valign="top"/><td styleCode="Lrule Botrule Rrule" valign="top"/></tr></tbody></table> <table ID="ID258" width="543" styleCode="Noautorules"><caption>Table 6 Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults ^a</caption><col width="312"/><col width="93"/><col width="138"/><tfoot><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^aPatients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.

unctive Epilepsy Trials in Adults ^a</caption><col width="312"/><col width="93"/><col width="138"/><tfoot><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^aPatients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. </paragraph></td></tr></tfoot><tbody><tr><td align="center" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">Body System</content> Adverse Reaction </td><td align="center" styleCode=" Toprule Botrule Rrule"><content styleCode="bold">Placebo</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Topiramate</content> <content styleCode="bold">Dosage (mg/day)</content> <content styleCode="bold">200 to 400</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" valign="top"/><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">(N=291)</content> </td><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">(N=183)</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Body as a Whole-General Disorders</content> </td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Fatigue </td><td align="center" styleCode=" Botrule Rrule" valign="top">13 </td><td align="center" styleCode=" Botrule Rrule" valign="top">15 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Asthenia </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Back pain </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Chest pain </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Influenza-like symptoms </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content> </td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Dizziness </td><td align="center" styleCode=" Botrule Rrule" valign="top">15 </td><td align="center" styleCode=" Botrule Rrule" valign="top">25 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Ataxia </td><td align="center" styleCode=" Botrule Rrule" valign="top">7 </td><td align="center" styleCode=" Botrule Rrule" valign="top">16 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Speech disorders/Related speech problems </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">13 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Paresthesia </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">11 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nystagmus </td><td align="center" styleCode=" Botrule Rrule" valign="top">7 </td><td align="center" styleCode=" Botrule Rrule" valign="top">10 </td></t

ule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">11 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nystagmus </td><td align="center" styleCode=" Botrule Rrule" valign="top">7 </td><td align="center" styleCode=" Botrule Rrule" valign="top">10 </td></t r><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Tremor </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td><td align="center" styleCode=" Botrule Rrule" valign="top">9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Language problems </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Coordination abnormal </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Gait abnormal </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Gastro-Intestinal System Disorders</content> </td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nausea </td><td align="center" styleCode=" Botrule Rrule" valign="top">8 </td><td align="center" styleCode=" Botrule Rrule" valign="top">10 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Dyspepsia </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td><td align="center" styleCode=" Botrule Rrule" valign="top">7 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Abdominal pain </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Constipation </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Metabolic and Nutritional Disorders</content> </td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Weight loss </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Psychiatric Disorders</content> </td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Somnolence </td><td align="center" styleCode=" Botrule Rrule" valign="top">12 </td><td align="center" styleCode=" Botrule Rrule" valign="top">29 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nervousness </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td><td align="center" styleCode=" Botrule Rrule" valign="top">16 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Psychomotor slowing </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">13 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Difficulty with memory </td><td align="center" styleCode=" Botrule Rrul

Rrule" valign="top">Psychomotor slowing </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">13 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Difficulty with memory </td><td align="center" styleCode=" Botrule Rrul e" valign="top">3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">12 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Confusion </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">11 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Anorexia </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">10 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Difficulty with concentration/attention </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Mood problems </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Agitation </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Aggressive reaction </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Emotional lability </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Cognitive problems </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Reproductive Disorders</content> </td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Breast pain </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Respiratory System Disorders</content> </td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Rhinitis </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td><td align="center" styleCode=" Botrule Rrule" valign="top">7 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Pharyngitis </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Sinusitis </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Vision Disorders</content> </td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rr

styleCode=" Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Vision Disorders</content> </td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rr ule" valign="top">Vision abnormal </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">13 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Diplopia </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">10 </td></tr></tbody></table> <table ID="ID261" width="543" styleCode="Noautorules"><caption>Table 7 Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Pediatric Patients 2 to 15 Years of Age ^a,b</caption><col width="272"/><col width="135"/><col width="136"/><tfoot><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^aPatients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo. </paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^bValues represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.

o. </paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^bValues represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. </paragraph></td></tr></tfoot><tbody><tr><td rowspan="3" align="left" styleCode="Lrule Toprule Botrule Rrule"><content styleCode="bold">Body System/</content> Adverse Reaction </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Placebo</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Topiramate</content> </td></tr><tr><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">(N=101)</content> </td><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">(N=98)</content> </td></tr><tr><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">%</content> </td><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">%</content> </td></tr><tr><td colspan="3" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Body as a Whole - General Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Fatigue </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">16 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Injury </td><td align="center" styleCode=" Botrule Rrule" valign="top">13 </td><td align="center" styleCode=" Botrule Rrule" valign="top">14 </td></tr><tr><td colspan="3" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Gait abnormal </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">8 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Ataxia </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Hyperkinesia </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Dizziness </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Speech disorders/Related speech problems </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr><tr><td colspan="3" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Gastro-Intestinal System Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nausea </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Saliva increased </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Constipation </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td>

lign="top">Saliva increased </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Constipation </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td> <td align="center" styleCode=" Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Gastroenteritis </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td></tr><tr><td colspan="3" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Metabolic and Nutritional Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Weight loss </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">9 </td></tr><tr><td colspan="3" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Platelet, Bleeding, &amp; Clotting Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Purpura </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">8 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Epistaxis </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr><tr><td colspan="3" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Psychiatric Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Somnolence </td><td align="center" styleCode=" Botrule Rrule" valign="top">16 </td><td align="center" styleCode=" Botrule Rrule" valign="top">26 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Anorexia </td><td align="center" styleCode=" Botrule Rrule" valign="top">15 </td><td align="center" styleCode=" Botrule Rrule" valign="top">24 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nervousness </td><td align="center" styleCode=" Botrule Rrule" valign="top">7 </td><td align="center" styleCode=" Botrule Rrule" valign="top">14 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Personality disorder (behavior problems) </td><td align="center" styleCode=" Botrule Rrule" valign="top">9 </td><td align="center" styleCode=" Botrule Rrule" valign="top">11 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Difficulty with concentration/attention </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">10 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Aggressive reaction </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Insomnia </td><td align="center" styleCode=" Botrule Rrule" valign="top">7 </td><td align="center" styleCode=" Botrule Rrule" valign="top">8 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Difficulty with memory </td><td align="center" styleCode=" Botrule Rrule" valign="top">0 </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Confusion </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" s

">0 </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Confusion </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr><tr><td align="left" s tyleCode="Lrule Botrule Rrule" valign="top">Psychomotor slowing </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td></tr><tr><td colspan="3" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Resistance Mechanism Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Infection viral </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">7 </td></tr><tr><td colspan="3" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Respiratory System Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Pneumonia </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td></tr><tr><td colspan="3" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Skin and Appendages Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Skin disorder </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td></tr><tr><td colspan="3" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Urinary System Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Urinary incontinence </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr></tbody></table>

op"><content styleCode="bold">Urinary System Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Urinary incontinence </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">4 </td></tr></tbody></table> <table ID="ID577" width="591" styleCode="Noautorules"><caption>Table 8 Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults ^a,b</caption><col width="187"/><col width="108"/><col width="148"/><col width="148"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^aIncludes 35 adolescent patients age 12 to 15 years. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^bValues represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^cBlurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for &gt;50% of reactions coded as vision abnormal, a preferred term.

one adverse reaction category. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^cBlurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for &gt;50% of reactions coded as vision abnormal, a preferred term. </paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="center" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">Body System</content>/Adverse Reaction </td><td rowspan="2" align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=445)</content> <content styleCode="bold">%</content> </td><td colspan="2" align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Topiramate Dosage (mg/day)</content> </td></tr><tr><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">50</content> <content styleCode="bold">(N=235)</content> <content styleCode="bold">%</content> </td><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">100</content> <content styleCode="bold">(N=386)</content> <content styleCode="bold">%</content> </td></tr><tr><td colspan="4" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Body as a Whole-General Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Fatigue </td><td align="left" styleCode=" Botrule Rrule" valign="top">11 </td><td align="left" styleCode=" Botrule Rrule" valign="top">14 </td><td align="left" styleCode=" Botrule Rrule" valign="top">15 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Injury </td><td align="left" styleCode=" Botrule Rrule" valign="top">7 </td><td align="left" styleCode=" Botrule Rrule" valign="top">9 </td><td align="left" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td colspan="4" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Central &amp; Peripheral Nervous System Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Paresthesia </td><td align="left" styleCode=" Botrule Rrule" valign="top">6 </td><td align="left" styleCode=" Botrule Rrule" valign="top">35 </td><td align="left" styleCode=" Botrule Rrule" valign="top">51 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Dizziness </td><td align="left" styleCode=" Botrule Rrule" valign="top">10 </td><td align="left" styleCode=" Botrule Rrule" valign="top">8 </td><td align="left" styleCode=" Botrule Rrule" valign="top">9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Hypoesthesia </td><td align="left" styleCode=" Botrule Rrule" valign="top">2 </td><td align="left" styleCode=" Botrule Rrule" valign="top">6 </td><td align="left" styleCode=" Botrule Rrule" valign="top">7 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Language problems </td><td align="left" styleCode=" Botrule Rrule" valign="top">2 </td><td align="left" styleCode=" Botrule Rrule" valign="top">7 </td><td align="left" styleCode=" Botrule Rrule" valign="top">6 </td></tr><tr><td colspan="4" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Gastro-Intestinal System Disorders</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nausea </td><td align="left" styleCode=" Botrule Rrule" valign="top">8 </td><td align="left" styleCode=" Botrule Rrule" valign="top">9 </td><td align="left" styleCode=" Botrule Rrule" valign="top">13 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Diarrhea </td><td align="left" styleCode=" Botru