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WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate hydrochloride oral solution has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride oral solution, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride oral solution, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout methylphenidate hydrochloride oral solution treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2)]. See full prescribing information for complete boxed warning.Methylphenidate hydrochloride oral solution has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride oral solution, can result in overdose and death (5.1, 9.2, 10). Before prescribing methylphenidate hydrochloride oral solution, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
1. INDICATIONS AND USAGE Methylphenidate hydrochloride oral solution is indicated for the treatment of: Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years of age and older Narcolepsy Methylphenidate hydrochloride oral solution is a central nervous system (CNS) stimulant indicated for the treatment of: Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years of age and older (1) Narcolepsy (1)
2. DOSAGE & ADMINISTRATION 2.1 Pretreatment Screening Prior to treating patients with methylphenidate hydrochloride oral solution, assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)]. the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome [see Warnings and Precautions (5.10)]. 2.2 General Dosing Information Pediatric Patients 6 years of Age and Older The recommended starting dosage is 5 mg orally twice daily before breakfast and lunch (preferably 30 to 45 minutes before meals). Increase the dosage gradually, in increments of 5 mg to 10 mg weekly. Daily dosage above 60 mg is not recommended. Adults Administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. The maximum recommended daily dose is 60 mg. The average dosage is 20 to 30 mg daily. For adult patients who are unable to sleep if medication is taken late in the day, administer the last dose before 6 p.m. 2.3 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage, or, if necessary, discontinue methylphenidate hydrochloride oral solution. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue methylphenidate hydrochloride oral solution. Pediatric patients 6 years and older: Starting dose is 5 mg twice daily (before breakfast and lunch); increase the dose 5 mg to 10 mg weekly; daily dosage above 60 mg is not recommended. (2.2) Adults: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Maximum recommended daily dosage is 60 mg. (2)
3. DOSAGE FORMS & STRENGTHS Methylphenidate hydrochloride oral solution is a colorless, grape flavored liquid available in a 500 mL bottle in the following strengths: 5 mg per 5 mL 10 mg per 5 mL Oral solution: 5 mg per 5 mL and 10 mg per 5 mL. (3)
4. CONTRAINDICATIONS SECTION Methylphenidate hydrochloride oral solution is contraindicated in patients: with known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride oral solution. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions (6)]. receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions (7)]. Known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride oral solution (4) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days (4)
5. WARNINGS AND PRECAUTIONS SECTION 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride oral solution has a high potential for abuse and misuse. The use of methylphenidate hydrochloride oral solution exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate hydrochloride oral solution can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride oral solution, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride oral solution, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate hydrochloride oral solution in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride oral solution to anyone else. Throughout methylphenidate hydrochloride oral solution treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate hydrochloride oral solution use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases. Monitor all methylphenidate hydrochloride oral solution-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Pre-Existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Illness CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating methylphenidate hydrochloride oral solution treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosages, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride oral solution.
a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride oral solution. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride oral solution-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, Including Raynaud’s Phenomenon CNS stimulants, including methylphenidate hydrochloride oral solution, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during methylphenidate hydrochloride oral solution treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride oral solution-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication-treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in methylphenidate hydrochloride oral solution-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. The safety and effectiveness of methylphenidate hydrochloride oral solution have not been established in pediatric patient less than 6 years of age. 5.8 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate hydrochloride oral solution -treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.9 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2)].
d at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.9 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2)]. Prescribe methylphenidate hydrochloride oral solution to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride oral solution-treated patients with a history of abnormally increased IOP or open-angle glaucoma. 5.10 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2)]. Before initiating methylphenidate hydrochloride oral solution, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride oral solution-treated patients for the emergence or worsening of tics or Tourette’s syndrome and discontinue treatment if clinically appropriate. Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. (5.2) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. (5.3) Psychiatric Adverse Reactions: Prior to initiating methylphenidate hydrochloride oral solution, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride oral solution (5.4) Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention. (5.5) Peripheral Vasculopathy, Including Raynaud’s Phenomenon: Careful observation for digital changes is necessary during methylphenidate hydrochloride oral solution treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. (5.6) Long-Term Suppression of Growth in Pediatric Patients: Closely monitor (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. (5.7) Acute Angle Closure Glaucoma: Methylphenidate hydrochloride oral solution-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. (5.8) Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe methylphenidate hydrochloride oral solution to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open-angle glaucoma. (5.9) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating methylphenidate hydrochloride oral solution, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. (5.10)
6. ADVERSE REACTIONS SECTION The following adverse reactions are discussed in more detail in other sections of the labeling: Abuse, misuse, and addiction [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)] Known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride oral solution [see Contraindications (4)] Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications (4), Drug Interactions (7)] Risks to patients with serious cardiac disease [see Warnings and Precautions (5.2)] Increased blood pressure and heart rate [see Warnings and Precautions (5.3)] Psychiatric adverse reactions [see Warnings and Precautions (5.4)] Priapism [see Warnings and Precautions (5.5)] Peripheral vasculopathy, including Raynaud’s phenomenon [see Warnings and Precautions (5.6)] Long-term suppression of growth in pediatric patients [see Warnings and Precautions (5.7)] Acute angle closure glaucoma [see Warnings and Precautions (5.8)] Increased intraocular pressure and glaucoma [see Warnings and Precautions (5.9)] Motor and verbal tics, and worsening of Tourette’s syndrome [see Warnings and Precautions (5.10)] The following adverse reactions associated with the use of methylphenidate containing products were identified in clinical studies, postmarketing reports, or literature. Because some of these reactions were 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.
ethylphenidate containing products were identified in clinical studies, postmarketing reports, or literature. Because some of these reactions were 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. Infections and infestations: nasopharyngitis Blood and the lymphatic system disorders: leukopenia, thrombocytopenia, anemia, pancytopenia Immune system disorders: hypersensitivity reactions, including angioedema and anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas Metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients Psychiatric disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, affect lability, mania, disorientation, libido changes Nervous system disorders: headache, dizziness, tremor, dyskinesia including choreoatheetoid movements, drowsiness, convulsions, cerebral arteritis and/or occlusion, serotonin syndrome in combination with serotonergic drugs, migraine, motor and verbal tics Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, mydriasis, increased intraocular pressure Cardiac disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris, sudden cardiac death, myocardial infarction, bradycardia, extrasystole Respiratory, thoracic and mediastinal disorders: cough, pharyngolaryngeal pain, dyspnea Gastrointestinal disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia, diarrhea General disorders: fatigue, hyperpyrexia Hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura angioneurotic edema, erythema, fixed drug eruption Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, rhabdomyolysis, myalgia, muscle twitching Renal and urinary disorders: hematuria Reproductive system and breast disorders: gynecomastia Urogenital disorders: priapism Vascular disorders: peripheral coldness, Raynaud’s phenomenon Investigations: weight loss Common adverse reactions: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain.(6) To report SUSPECTED ADVERSE REACTIONS, contact KVK-Tech, Inc. at 1-800-862-3895 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7. DRUG INTERACTIONS SECTION 7.1 Clinically Important Drug Interactions with Methylphenidate Hydrochloride Oral Solution Table 1 presents clinically important drug interactions with methylphenidate hydrochloride oral solution Table 1: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Oral Solution Monoamine Oxidase Inhibitors (MAOI) Clinical Impact: Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride oral solution, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4)]. Intervention: Concomitant use of methylphenidate hydrochloride oral solution with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical Impact: Methylphenidate hydrochloride oral solution may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3)]. Intervention: Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical Impact: Concomitant use of halogenated anesthetics and methylphenidate hydrochloride oral solution may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention: Avoid use of methylphenidate hydrochloride oral solution in patients being treated with anesthetics on the day of surgery. Risperidone Clinical Impact: Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS) Intervention: Monitor for signs of EPS. • Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. (7.1)
<table width="100%"><caption>Table 1: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Oral Solution</caption><tbody><tr><td colspan="2">Monoamine Oxidase Inhibitors (MAOI)</td></tr><tr><td>Clinical Impact:</td><td>Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride oral solution, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4)].</td></tr><tr><td>Intervention:</td><td>Concomitant use of methylphenidate hydrochloride oral solution with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated.</td></tr><tr><td colspan="2">Antihypertensive Drugs</td></tr><tr><td>Clinical Impact:</td><td>Methylphenidate hydrochloride oral solution may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3)].</td></tr><tr><td>Intervention:</td><td>Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.</td></tr><tr><td colspan="2">Halogenated Anesthetics</td></tr><tr><td>Clinical Impact:</td><td>Concomitant use of halogenated anesthetics and methylphenidate hydrochloride oral solution may increase the risk of sudden blood pressure and heart rate increase during surgery.</td></tr><tr><td>Intervention:</td><td>Avoid use of methylphenidate hydrochloride oral solution in patients being treated with anesthetics on the day of surgery.</td></tr><tr><td colspan="2">Risperidone</td></tr><tr><td>Clinical Impact:</td><td>Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS)</td></tr><tr><td>Intervention:</td><td>Monitor for signs of EPS.</td></tr></tbody></table>
8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Published studies and post marketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations). No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 12 and 19 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adults on a mg/m2 basis. However, spina bifida was observed in rabbits at a dose 65 times the MRHD given to adults. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 7 times the MRHD given to adults (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride oral solution, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 65 times the MRHD of 60 mg/day given to adults on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (19 times the MRHD given to adults on a mg/m2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (12 times the MRHD of 60 mg/day given to adults on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (4 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (7 times the MRHD of 60 mg/day given to adults on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adults on a mg/m2 basis). 8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight -adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7.
adults on a mg/m2 basis). 8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight -adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride oral solution and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride oral solution or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride oral solution for the treatment of ADHD have been established in pediatric patients six years of age and older. The safety and effectiveness of methylphenidate hydrochloride oral solution in pediatric patients under six years of age have not been established. The long-term efficacy of methylphenidate in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride oral solution. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.6)]. Juvenile Animal Toxicity Data In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 -14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats (5 mg/kg/day) is less than the MRHD given to children on a mg/m2 basis. The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Methylphenidate hydrochloride oral solution has not been studied in the geriatric population.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate hydrochloride oral solution contains methylphenidate hydrochloride, a Schedule II controlled substance. 9.2 Abuse Methylphenidate hydrochloride oral solution has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. Methylphenidate hydrochloride oral solution can be diverted for non medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride oral solution, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses and or unapproved methods of administration, such as snorting or injection. 9.3 Dependence Physical Dependence Methylphenidate hydrochloride oral solution may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride oral solution include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate hydrochloride oral solution may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
10. OVERDOSAGE SECTION Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
11. DESCRIPTION Methylphenidate hydrochloride oral solution contains methylphenidate hydrochloride a CNS stimulant. It is available as 5 mg/5 mL and 10 mg/5 mL strengths for oral administration. Chemically, methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is: Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Each mL of methylphenidate hydrochloride oral solution 5 mg/5 mL contains 1 mg of methylphenidate hydrochloride USP. Each mL of methylphenidate hydrochloride oral solution 10 mg/5 mL contains 2 mg of methylphenidate hydrochloride USP. Methylphenidate hydrochloride oral solution also contains the following inactive ingredients: artificial grape flavor, glycerin, hydrochloric acid, maltitol syrup, propylene glycol, purified water, sodium hydroxide, and sorbitol. Hydrochloric acid may be added to adjust pH. figure01chemicalstructure
12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in subjects taking methylphenidate hydrochloride oral solution. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride oral solution, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of 40 mg dexmethylphenidate hydrochloride extended-release capsule in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship. 12.3 Pharmacokinetics Absorption Following a single dose administration of 20 mg methylphenidate hydrochloride oral solution and 20 mg tablet of methylphenidate hydrochloride in healthy volunteers under fasted conditions, time to peak plasma concentration (Tmax) of methylphenidate was at 1 to 2 hours after dosing, and: The mean peak plasma concentration (Cmax) of methylphenidate was 9.1 ng/mL and 9.8 ng/mL, respectively. The mean area under concentration curve (AUC) of methylphenidate was 46.7 hour*ng/mL and 50.0 hour*ng/mL, respectively. Effect of Food Ingestion of a high-fat meal with methylphenidate hydrochloride oral solution increased methylphenidate mean Cmax and AUC by about 13% and 25%, respectively. Time to Cmax (Tmax) was delayed by approximately 1 hour. Distribution Plasma protein binding is 10% to 33%. The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate. Elimination The mean terminal half-life (t½) of methylphenidate was 2.7 hours following administration of 20 mg methylphenidate hydrochloride oral solution. The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. Metabolism Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. Specific Populations Male and Female Patients, Racial Groups, and Age The effect of gender, race, and age on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride oral solution administration have not been studied. Patients with Renal Impairment Methylphenidate hydrochloride oral solution has not been studied in patients with renal impairment.
Racial Groups, and Age The effect of gender, race, and age on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride oral solution administration have not been studied. Patients with Renal Impairment Methylphenidate hydrochloride oral solution has not been studied in patients with renal impairment. Since renal clearance is not an important route of methylphenidate clearance, renal impairment is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride oral solution. Patients with Hepatic Impairment Methylphenidate hydrochloride oral solution has not been studied in patients with hepatic impairment. Since methylphenidate is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body, hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate hydrochloride oral solution.
13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 5 times the maximum recommended human dose (MRHD) of 60 mg/kg given to adults on a mg/m2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 7 times the MRHD (adults) on a mg/m2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 13 times the maximum recommended human dose of 60 mg/day given to adults on a mg/m2 basis.
16. HOW SUPPLIED/STORAGE AND HANDLING How Supplied Methylphenidate hydrochloride oral solution is a colorless, grape flavored liquid available in the following strengths: 5 mg per 5 mL Bottles of 500 mL . . . . . . . . NDC 10702-163-50 10 mg per 5 mL Bottles of 500 mL . . . . . . . . NDC 10702-164-50 Storage and Handling Store at 20° to 25°C (68° to 77°F), with excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in tight container with a child-resistant closure.
17. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of methylphenidate hydrochloride oral solution, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2), Overdosage (10)]. Advise patients to store methylphenidate hydrochloride oral solution in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride oral solution to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with methylphenidate hydrochloride oral solution use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)]. Increased Blood Pressure and Heart Rate Instruct patients that methylphenidate hydrochloride oral solution can elevate blood pressure and heart rate [see Warnings and Precautions (5.3)]. Psychiatric Adverse Reactions Advise patients that methylphenidate hydrochloride oral solution, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)]. Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5)]. Circulation Problems in Fingers and Toes (Peripheral Vasculopathy, Including Raynauds Phenomenon) Instruct patients about the risk of peripheral vasculopathy, including Raynauds phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride oral solution. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)]. Long-Term Suppression of Growth in Pediatric Patients Advise patients that methylphenidate hydrochloride oral solution may cause slowing of growth and weight loss in pediatric patients [see Warnings and Precautions (5.7)]. Increased Intraocular Pressure (IOP) and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with methylphenidate hydrochloride oral solution [see Warnings and Precautions (5.9)]. Motor and Verbal Tics, and Worsening of Tourettes Syndrome Advise patients that motor and verbal tics and worsening of Tourettes syndrome may occur during treatment with methylphenidate hydrochloride oral solution. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourettes syndrome occurs [see Warnings and Precautions (5.10)]. Manufactured By: KVK-Tech, Inc. 110 Terry Drive Newtown, PA 18940 Item ID# 6226/05 Manufacturers Code: 10702 03/2026 figure05companylogo
MEDICATION GUIDE Methylphenidate Hydrochloride Oral Solution CII (meth″ il fen′ i date hye″ droe klor′ ide) What is the most important information I should know about methylphenidate hydrochloride oral solution? Methylphenidate hydrochloride oral solution may cause serious side effects, including: • Abuse, misuse, and addiction. Methylphenidate hydrochloride oral solution has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride oral solution, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride oral solution or when it is used in ways that are not approved, such as snorting or injection. o Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride oral solution and will monitor you or your child during treatment. o Methylphenidate hydrochloride oral solution may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. o Do not give methylphenidate hydrochloride oral solution to anyone else. See “What is methylphenidate hydrochloride oral solution?” for more information. o Keep methylphenidate hydrochloride oral solution in a safe place and properly dispose of any unused medicine. See “How should I store methylphenidate hydrochloride oral solution?” for more information. o Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. • Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting treatment with methylphenidate hydrochloride oral solution. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with methylphenidate hydrochloride oral solution. • Increased blood pressure and heart rate. Your healthcare provider should check your or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride oral solution. • Mental (psychiatric) problems, including: o new or worse behavior and thought problems o new or worse bipolar illness o new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with methylphenidate hydrochloride oral solution, especially hearing voices, seeing or believing things that are not real, or new manic symptoms What is methylphenidate hydrochloride oral solution?
healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with methylphenidate hydrochloride oral solution, especially hearing voices, seeing or believing things that are not real, or new manic symptoms What is methylphenidate hydrochloride oral solution? Methylphenidate hydrochloride oral solution is a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. Methylphenidate hydrochloride oral solution may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. It is not known if methylphenidate hydrochloride oral solution is safe and effective for use in children under 6 years of age. Methylphenidate hydrochloride oral solution is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep methylphenidate hydrochloride oral solution in a safe place to protect it from theft. Never give your methylphenidate hydrochloride oral solution to anyone else, because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride oral solution may harm others and is against the law. Do note take methylphenidate hydrochloride oral solution if you or your child are: • allergic to methylphenidate hydrochloride or any of the ingredients in methylphenidate hydrochloride oral solution. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride oral solution. • taking, or have stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI). Before taking methylphenidate hydrochloride oral solution tell your healthcare provider about all your medical conditions, including if you or your child: • have heart problems, heart disease, heart defects, or high blood pressure • have mental problems including psychosis, mania, bipolar illness, or depression, or have a family history of suicide, bipolar illness, or depression • have circulation problems in fingers and toes • have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) • have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome • are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride oral solution will harm the unborn baby. • are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride oral solution passes into breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate hydrochloride oral solution. Tell your healthcare provider about all the medicines that you take or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride oral solution and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with methylphenidate hydrochloride oral solution. Your healthcare provider will decide whether methylphenidate hydrochloride oral solution can be taken with other medicines. Especially tell your healthcare provider if you or your child take a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI). Know the medicines that you take or your child take. Keep a list of your medicines with you to show your healthcare provider and pharmacist. Do not start any new medicine during treatment with methylphenidate hydrochloride oral solution without talking to your healthcare provider first.
oamine oxidase inhibitor (MAOI). Know the medicines that you take or your child take. Keep a list of your medicines with you to show your healthcare provider and pharmacist. Do not start any new medicine during treatment with methylphenidate hydrochloride oral solution without talking to your healthcare provider first. How should methylphenidate hydrochloride oral solution be taken? • Take methylphenidate hydrochloride oral solution exactly as prescribed by your healthcare provider. • Your healthcare provider may change the dose if needed. • Children 6 years of age and older: o Take methylphenidate hydrochloride oral solution by mouth 2 times a day before breakfast and lunch, 30 to 45 minutes before a meal, as prescribed by your healthcare provider. • Adults: o Take methylphenidate hydrochloride oral solution by mouth 2 or 3 times a day, 30 to 45 minutes before a meal, as prescribed by your healthcare provider. o For adults who have sleep problems when methylphenidate hydrochloride oral solution is taken late in the day, take your last dose of methylphenidate hydrochloride oral solution before 6 p.m. • If you or your child take too much methylphenidate hydrochloride oral solution, call your healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away What are the possible side effects of methylphenidate hydrochloride oral solution? Methylphenidate hydrochloride oral solution may cause serious side effects, including: • See “What is the most important information I should know about methylphenidate hydrochloride oral solution?” • Painful and prolonged erections (priapism). Priapism has happened in males who take products that contain methylphenidate. If you or your child develop priapism, get medical help right away. • Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon). Signs and symptoms may include: o fingers or toes may feel numb, cool, painful o fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes, or if you or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with methylphenidate hydrochloride oral solution. • Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with methylphenidate hydrochloride oral solution. Methylphenidate hydrochloride oral solution treatment may be stopped if your child is not growing or gaining weight. • Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. • New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride oral solution The most common side effects of methylphenidate hydrochloride oral solution include: • increased heart rate • irregular heart beat (palpitations) • headache • trouble sleeping • anxiety • sweating • weight loss • decreased appetite • dry mouth • nausea • stomach pain These are not all the possible side effects of methylphenidate hydrochloride oral solution. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 How should I store methylphenidate hydrochloride oral solution? • Store methylphenidate hydrochloride oral solution at room temperature between 20° to 25°C (68° to 77°F), with excursions permitted between 15° to 30°C (59° to 86°F).
medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 How should I store methylphenidate hydrochloride oral solution? • Store methylphenidate hydrochloride oral solution at room temperature between 20° to 25°C (68° to 77°F), with excursions permitted between 15° to 30°C (59° to 86°F). Store methylphenidate hydrochloride oral solution in a safe place, like a locked cabinet. • Protect from light and moisture. • Dispose of remaining, unused, or expired methylphenidate hydrochloride oral solution by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride oral solution with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away methylphenidate hydrochloride oral solution in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep methylphenidate hydrochloride oral solution and all medicines out of the reach of children. General information about the safe and effective use of methylphenidate hydrochloride oral solution. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use methylphenidate hydrochloride oral solution for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride oral solution to other people, even if they have the same symptoms. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about methylphenidate hydrochloride oral solution that is written for healthcare professionals. What are the ingredients in methylphenidate hydrochloride oral solution? Active Ingredient: methylphenidate hydrochloride USP Inactive Ingredients: artificial grape flavor, glycerin, hydrochloric acid, maltitol syrup, propylene glycol, purified water, sodium hydroxide, and sorbitol. Hydrochloric acid may be added to adjust pH. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured By: KVK-Tech, Inc. 110 Terry Drive Newtown, PA 18940 Item ID# 6226/05 Manufacturer’s Code: 10702 03/2026 figure02companylogo
<table width="100%"><tbody><tr><td><content styleCode="bold">What is the most important information I should know about methylphenidate hydrochloride oral solution?</content> <content styleCode="bold">Methylphenidate hydrochloride oral solution may cause serious side effects, including:</content> <content styleCode="bold">• Abuse, misuse, and addiction.</content>Methylphenidate hydrochloride oral solution has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride oral solution, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride oral solution or when it is used in ways that are not approved, such as snorting or injection. o Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride oral solution and will monitor you or your child during treatment. o Methylphenidate hydrochloride oral solution may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. o Do not give methylphenidate hydrochloride oral solution to anyone else. See <content styleCode="bold">“What is methylphenidate hydrochloride oral solution?”</content>for more information. o Keep methylphenidate hydrochloride oral solution in a safe place and properly dispose of any unused medicine. See <content styleCode="bold">“How should I store methylphenidate hydrochloride oral solution?”</content>for more information. o Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. • <content styleCode="bold">Risks for people with serious heart disease.</content>Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting treatment with methylphenidate hydrochloride oral solution. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with methylphenidate hydrochloride oral solution.</content> <content styleCode="bold">• Increased blood pressure and heart rate.</content> Your healthcare provider should check your or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride oral solution. • <content styleCode="bold">Mental (psychiatric) problems, including:</content> o new or worse behavior and thought problems o new or worse bipolar illness o new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.
d thought problems o new or worse bipolar illness o new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. <content styleCode="bold">Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with methylphenidate hydrochloride oral solution, especially hearing voices, seeing or believing things that are not real, or new manic symptoms</content></td></tr><tr><td><content styleCode="bold">What is methylphenidate hydrochloride oral solution?</content> Methylphenidate hydrochloride oral solution is a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. Methylphenidate hydrochloride oral solution may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. It is not known if methylphenidate hydrochloride oral solution is safe and effective for use in children under 6 years of age. <content styleCode="bold">Methylphenidate hydrochloride oral solution is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs.</content>Keep methylphenidate hydrochloride oral solution in a safe place to protect it from theft. Never give your methylphenidate hydrochloride oral solution to anyone else, because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride oral solution may harm others and is against the law. </td></tr><tr><td><content styleCode="bold">Do note take methylphenidate hydrochloride oral solution if you or your child are:</content> • allergic to methylphenidate hydrochloride or any of the ingredients in methylphenidate hydrochloride oral solution. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride oral solution. • taking, or have stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI). </td></tr><tr><td><content styleCode="bold">Before taking methylphenidate hydrochloride oral solution tell your healthcare provider about all your medical conditions, including if you or your child:</content> • have heart problems, heart disease, heart defects, or high blood pressure • have mental problems including psychosis, mania, bipolar illness, or depression, or have a family history of suicide, bipolar illness, or depression • have circulation problems in fingers and toes • have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) • have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome • are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride oral solution will harm the unborn baby. • are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride oral solution passes into breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate hydrochloride oral solution. <content styleCode="bold">Tell your healthcare provider about all the medicines that you take or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</content> Methylphenidate hydrochloride oral solution and some medicines may interact with each other and cause serious side effects.
de="bold">Tell your healthcare provider about all the medicines that you take or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</content> Methylphenidate hydrochloride oral solution and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with methylphenidate hydrochloride oral solution. Your healthcare provider will decide whether methylphenidate hydrochloride oral solution can be taken with other medicines. <content styleCode="bold">Especially tell your healthcare provider if you or your child take</content>a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI). Know the medicines that you take or your child take. Keep a list of your medicines with you to show your healthcare provider and pharmacist. <content styleCode="bold">Do not start any new medicine during treatment with methylphenidate hydrochloride oral solution without talking to your healthcare provider first.</content></td></tr><tr><td><content styleCode="bold">How should methylphenidate hydrochloride oral solution be taken?</content> • Take methylphenidate hydrochloride oral solution exactly as prescribed by your healthcare provider. • Your healthcare provider may change the dose if needed. • <content styleCode="bold">Children 6 years of age and older:</content> o Take methylphenidate hydrochloride oral solution by mouth 2 times a day before breakfast and lunch, 30 to 45 minutes before a meal, as prescribed by your healthcare provider. • <content styleCode="bold">Adults:</content> o Take methylphenidate hydrochloride oral solution by mouth 2 or 3 times a day, 30 to 45 minutes before a meal, as prescribed by your healthcare provider. o For adults who have sleep problems when methylphenidate hydrochloride oral solution is taken late in the day, take your last dose of methylphenidate hydrochloride oral solution before 6 p.m. • If you or your child take too much methylphenidate hydrochloride oral solution, call your healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away </td></tr><tr><td><paragraph><content styleCode="bold">What are the possible side effects of methylphenidate hydrochloride oral solution?</content> <content styleCode="bold">Methylphenidate hydrochloride oral solution may cause serious side effects, including:</content> • See <content styleCode="bold">“What is the most important information I should know about methylphenidate hydrochloride oral solution?”</content> • <content styleCode="bold">Painful and prolonged erections (priapism).</content>Priapism has happened in males who take products that contain methylphenidate. <content styleCode="bold">If you or your child develop priapism, get medical help right away.</content> • <content styleCode="bold">Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon).</content>Signs and symptoms may include: o fingers or toes may feel numb, cool, painful o fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes, or if you or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with methylphenidate hydrochloride oral solution. • <content styleCode="bold">Slowing of growth (height and weight) in children.</content>Children should have their height and weight checked often during treatment with methylphenidate hydrochloride oral solution.
nds appearing on fingers or toes during treatment with methylphenidate hydrochloride oral solution. • <content styleCode="bold">Slowing of growth (height and weight) in children.</content>Children should have their height and weight checked often during treatment with methylphenidate hydrochloride oral solution. Methylphenidate hydrochloride oral solution treatment may be stopped if your child is not growing or gaining weight. • <content styleCode="bold">Eye problems (increased pressure in the eye and glaucoma).</content>Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. • <content styleCode="bold">New or worsening tics or worsening Tourette’s syndrome.</content>Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride oral solution </paragraph><paragraph>The most common side effects of methylphenidate hydrochloride oral solution include:</paragraph><paragraph>• increased heart rate • irregular heart beat (palpitations)</paragraph><paragraph>• headache • trouble sleeping • anxiety • sweating • weight loss • decreased appetite • dry mouth • nausea </paragraph><paragraph>• stomach pain</paragraph><paragraph>These are not all the possible side effects of methylphenidate hydrochloride oral solution. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 </paragraph></td></tr><tr><td><content styleCode="bold">How should I store methylphenidate hydrochloride oral solution?</content> • Store methylphenidate hydrochloride oral solution at room temperature between 20° to 25°C (68° to 77°F), with excursions permitted between 15° to 30°C (59° to 86°F). Store methylphenidate hydrochloride oral solution in a safe place, like a locked cabinet. • Protect from light and moisture. • Dispose of remaining, unused, or expired methylphenidate hydrochloride oral solution by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride oral solution with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away methylphenidate hydrochloride oral solution in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. <content styleCode="bold">Keep methylphenidate hydrochloride oral solution and all medicines out of the reach of children.</content></td></tr><tr><td><content styleCode="bold">General information about the safe and effective use of methylphenidate hydrochloride oral solution.</content> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use methylphenidate hydrochloride oral solution for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride oral solution to other people, even if they have the same symptoms. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about methylphenidate hydrochloride oral solution that is written for healthcare professionals.
ed. Do not give methylphenidate hydrochloride oral solution to other people, even if they have the same symptoms. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about methylphenidate hydrochloride oral solution that is written for healthcare professionals. </td></tr><tr><td><content styleCode="bold">What are the ingredients in methylphenidate hydrochloride oral solution?</content> <content styleCode="bold">Active Ingredient:</content>methylphenidate hydrochloride USP <content styleCode="bold">Inactive Ingredients:</content>artificial grape flavor, glycerin, hydrochloric acid, maltitol syrup, propylene glycol, purified water, sodium hydroxide, and sorbitol. Hydrochloric acid may be added to adjust pH. </td></tr></tbody></table>
WARNING: ABUSE AND DEPENDENCE CNS stimulants, including Methylphenidate hydrochloride extended-release tablets, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2 , 9.3 )] . WARNING: ABUSE AND DEPENDANCE See full prescribing information for complete boxed warning. CNS stimulants, including Methylphenidate hydrochloride extended-release tablets, other methylphenidate-containing products, and amphetamine, have a high potential for abuse and dependence ( 5.1 , 9.2 , 9.3 ). Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy ( 5.1 , 9.2 )
1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release tablets are indicated for the treatment of: Attention Deficit Hyperactivity Disorders (ADHD) in pediatric patients 6 years and older and adults Narcolepsy Limitations of Use The use of methylphenidate hydrochloride extended-release tablets are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.7) , Use in Specific Populations (8.4) ] . Methylphenidate hydrochloride extended-release tablet is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorders (ADHD) and Narcolepsy ( 1 ). Limitations of Use The use of methylphenidate hydrochloride extended-release tablets are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.7 , 8.4 ).
2 DOSAGE AND ADMINISTRATION N/A Methylphenidate hydrochloride extended-release tablets (2.2) : May switch to Methylphenidate hydrochloride extended-release tablets when the 8-hour dosage of Methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride tablets. Must be swallowed whole and never crushed or chewed. 2.1 Pretreatment Screening Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants, including Methylphenidate hydrochloride extended-release tablets, assess for the presence of cardiac disease (i.e., perform a careful history including family history of sudden death or ventricular arrhythmia, and physical examination) [see Warnings and Precautions (5.2) ] . Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically reevaluate the need for Methylphenidate hydrochloride extended-release tablets use [see Boxed Warning , Warnings and Precautions (5.1) , Drug Abuse and Dependence (9) ]. 2.2 General Dosing Information Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours. Therefore, Methylphenidate hydrochloride extended-release tablets may be used in place of methylphenidate hydrochloride tablets when the 8-hour dosage of Methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride tablets. Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed. Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of Methylphenidate hydrochloride extended-release tablets, and adjust dosage as needed. 2.3 Dose Reduction and Discontinuation If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue Methylphenidate hydrochloride extended-release tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
3 DOSAGE FORMS AND STRENGTHS 10 mg extended-release tablets, white to off white, round shaped, uncoated, tablets debossed with “FM4” on one side and plain on other side. 20 mg extended-release tablets, white to off white, round shaped, uncoated, tablets debossed with “FM5” on one side and plain on other side. Extended-release Tablets: 10 mg and 20 mg ( 3 )
4 CONTRAINDICATIONS Hypersensitivity to methylphenidate or other components of Methylphenidate hydrochloride extended-release tablets. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [ see Adverse Reactions (6) ]. Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [ see Drug Interactions (7.1) ]. Known hypersensitivity to methylphenidate or other product components of Methylphenidate hydrochloride extended-release tablets. (4) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days (4) .
5 WARNINGS AND PRECAUTIONS N/A Serious Cardiovascular Events: Sudden death has been reported in association with CNS-stimulant treatment at usual doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke, and myocardial infarction have been reported. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm arrhythmias, or coronary artery disease (5.2) . Blood Pressure and Heart Rate Increases: Monitor blood pressure and pulse. Consider the benefits and risk in patients for whom an increase in blood pressure or heart rate would be problematic (5.3) . Psychiatric Adverse Reactions: Use of stimulants may cause psychotic or manic symptoms in patients with no prior history or exacerbation of symptoms in patients with pre-existing psychiatric illness. Evaluate for pre-existing psychotic or bipolar disorder prior to Methylphenidate hydrochloride extended-release tablets use (5.4) . Priapism: Cases of painful and prolonged penile erections, and priapism have been reported with methylphenidate products. Immediate medical attention should be sought if signs or symptoms of prolonged penile erections or priapism are observed (5.5) . Peripheral Vasculopathy, including Raynaud’s Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Careful observation for digital changes is necessary during treatment with ADHD stimulants (5.6) . Long-Term Suppression of Growth in Pediatric Patients: Monitor height and weight at appropriate intervals in pediatric patients (5.7) . 5.1 Potential for Abuse and Dependence CNS stimulants, including Methylphenidate hydrochloride extended-release tablets other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Boxed Warning , Drug Abuse and Dependence (9.2 , 9.3 )]. 5.2 Serious Cardiovascular Reactions Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Methylphenidate hydrochloride extended-release tablets treatment. 5.3 Blood Pressure and Heart Rate Increases CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Preexisting Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed mood episode in patients.
verse Reactions Exacerbation of Preexisting Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing Methylphenidate hydrochloride extended-release tablets. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0 in placebo-treated patients. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including Methylphenidate hydrochloride extended-release tablets used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. 5.7 Long-Term Suppression of Growth in Pediatric Patients Methylphenidate hydrochloride extended-release tablets are not approved for use and are not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4) ] . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants including Methylphenidate hydrochloride extended-release tablets. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse and Dependence [see Boxed Warning , Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2 , 9.3 ) ] Known hypersensitivity to methylphenidate or other ingredients of Methylphenidate hydrochloride extended-release tablets [ see Contraindications (4) ] Hypertensive crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4) , Drug Interactions (7.1) ] Serious Cardiovascular Reactions [see Warnings and Precautions (5.2) ] Blood Pressure and Heart Rate Increases [see Warnings and Precautions (5.3) ] Psychiatric Adverse Reactions [see Warnings and Precautions (5.4) ] Priapism [see Warnings and Precautions (5.5) ] Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions (5.6) ] Long-term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7) ] The following adverse reactions associated with the use of all Methylphenidate hydrochloride extended-release tablets and other methylphenidate products were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Adverse Reactions Reported with Methylphenidate hydrochloride extended-release tablets Infections and Infestations: nasopharyngitis Blood and the Lymphatic System Disorders : leukopenia, thrombocytopenia, anemia Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood Nervous System Disorders: headache, dizziness, tremor, dyskinesia including choreoathetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs Eye Disorders: blurred vision, difficulties in visual accommodation Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris Respiratory, Thoracic and Mediastinal Disorders: cough Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis Investigations: weight loss (adult ADHD patients) Additional Adverse Reactions Reported with Other Methylphenidate-Containing Products The list below shows adverse reactions not listed for Methylphenidate hydrochloride extended-release tablets that have been reported with other methylphenidate-containing products.
ysis Investigations: weight loss (adult ADHD patients) Additional Adverse Reactions Reported with Other Methylphenidate-Containing Products The list below shows adverse reactions not listed for Methylphenidate hydrochloride extended-release tablets that have been reported with other methylphenidate-containing products. Blood and Lymphatic Disorders: pancytopenia Immune System Disorders: hypersensitivity reactions such as auricular swelling, bullous conditions, eruptions, exanthemas Psychiatric Disorders: affect lability, mania, disorientation and libido changes Nervous System Disorders: migraine Eye Disorders: diplopia, mydriasis Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole Vascular Disorders: peripheral coldness, Raynaud's phenomenon Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea Gastrointestinal Disorders: diarrhea, constipation Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption Musculoskeletal, Connective Tissue and bone Disorders: myalgia, muscle twitching Renal and Urinary Disorders: hematuria Reproductive System and Breast Disorders: gynecomastia General Disorders: fatigue, hyperpyrexia Urogenital Disorders : priapism Common adverse reactions: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Granules Pharmaceuticals Inc. at 1-877-770-3138 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7 DRUG INTERACTIONS N/A Antihypertensive drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed (7) Halogenated anesthetics: Avoid use of Methylphenidate hydrochloride extended-release tablets on the day of surgery if halogenated anesthetics will be used (7) Risperidone: The combined use of methylphenidate with risperidone when there is a change in dose of either or both medications may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS (7) . 7.1 Clinically Important Interactions with Methylphenidate hydrochloride extended-release tablets Table 1 presents clinically important drug interactions with Methylphenidate hydrochloride extended-release tablets. Table 1: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Extended-Release Tablets Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including Methylphenidate hydrochloride extended-release tablets can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [ see Contraindications (4) ] . Intervention Concomitant use of Methylphenidate hydrochloride extended-release tablets with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Antihypertensive Drugs Clinical Impact Methylphenidate hydrochloride extended-release tablets may decrease the effectiveness of drugs used to treat hypertension [ see Warnings and Precautions (5.3) ] . Intervention Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Examples Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists Halogenated Anesthetics Clinical Impact Concomitant use of halogenated anesthetics and Methylphenidate hydrochloride extended-release tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of Methylphenidate hydrochloride extended-release tablets in patients being treated with anesthetics on the day of surgery. Examples halothane, isoflurane, enflurane, desflurane, sevoflurane Risperidone The combined use of methylphenidate with risperidone when there is a change in dose of either or both medications may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.
<table border="1" cellpadding="0" cellspacing="0"><tbody><tr><td colspan="2" valign="top"><paragraph><content styleCode="bold">Monoamine Oxidase Inhibitors (MAOI)</content></paragraph></td></tr><tr><td><paragraph><content styleCode="italics">Clinical Impact</content></paragraph></td><td valign="top"><paragraph>Concomitant use of MAOIs and CNS stimulants, including Methylphenidate hydrochloride extended-release tablets can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure <content styleCode="italics">[ <linkHtml href="#L72258ea3-7f43-4f1e-80f0-ce51257ce9f8">see</linkHtml></content><content styleCode="italics"><linkHtml href="#L72258ea3-7f43-4f1e-80f0-ce51257ce9f8">Contraindications (4)</linkHtml>] </content>. </paragraph></td></tr><tr><td><paragraph><content styleCode="italics">Intervention</content></paragraph></td><td valign="top"><paragraph>Concomitant use of Methylphenidate hydrochloride extended-release tablets with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.</paragraph></td></tr><tr><td><paragraph><content styleCode="italics">Examples</content></paragraph></td><td valign="top"><paragraph>selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue</paragraph></td></tr><tr><td colspan="2" valign="top"><paragraph><content styleCode="bold">Antihypertensive Drugs</content></paragraph></td></tr><tr><td><paragraph><content styleCode="italics">Clinical Impact</content></paragraph></td><td valign="top"><paragraph>Methylphenidate hydrochloride extended-release tablets may decrease the effectiveness of drugs used to treat hypertension <content styleCode="italics">[ <linkHtml href="#Lf5d5e1f6-a7ae-4433-8254-f48285fa2c9c">see Warnings and Precautions (5.3)</linkHtml>] </content>.
content></paragraph></td><td valign="top"><paragraph>Methylphenidate hydrochloride extended-release tablets may decrease the effectiveness of drugs used to treat hypertension <content styleCode="italics">[ <linkHtml href="#Lf5d5e1f6-a7ae-4433-8254-f48285fa2c9c">see Warnings and Precautions (5.3)</linkHtml>] </content>. </paragraph></td></tr><tr><td><paragraph><content styleCode="italics">Intervention</content></paragraph></td><td valign="top"><paragraph>Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.</paragraph></td></tr><tr><td><paragraph><content styleCode="italics">Examples</content></paragraph></td><td valign="top"><paragraph>Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists</paragraph></td></tr><tr><td colspan="2" valign="top"><paragraph><content styleCode="bold">Halogenated Anesthetics</content></paragraph></td></tr><tr><td><paragraph><content styleCode="italics">Clinical Impact</content></paragraph></td><td valign="top"><paragraph>Concomitant use of halogenated anesthetics and Methylphenidate hydrochloride extended-release tablets may increase the risk of sudden blood pressure and heart rate increase during surgery.</paragraph></td></tr><tr><td><paragraph><content styleCode="italics">Intervention</content></paragraph></td><td valign="top"><paragraph>Avoid use of Methylphenidate hydrochloride extended-release tablets in patients being treated with anesthetics on the day of surgery.</paragraph></td></tr><tr><td><paragraph><content styleCode="italics">Examples</content></paragraph></td><td valign="top"><paragraph>halothane, isoflurane, enflurane, desflurane, sevoflurane</paragraph></td></tr><tr><td><content styleCode="bold">Risperidone</content></td><td valign="top"/></tr><tr><td><paragraph/></td><td valign="top"><paragraph>The combined use of methylphenidate with risperidone when there is a change in dose of either or both medications may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.</paragraph></td></tr></tbody></table>
8 USE IN SPECIFIC POPULATIONS N/A 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including Methylphenidate hydrochloride extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/ Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy [see Clinical Considerations] . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as Methylphenidate hydrochloride extended-release tablets, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis).
n rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Methylphenidate hydrochloride extended-release tablets and any potential adverse effects on the breastfed infant from Methylphenidate hydrochloride extended-release tablets or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride extended-release tablets have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. The safety and effectiveness of Methylphenidate hydrochloride extended-release tablets for the treatment of ADHD have been established in pediatric patients 6 to 17 years. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including Methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [ see Warnings and Precautions (5.7) ] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis).
ved in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Methylphenidate hydrochloride tablet has not been studied in the geriatric population.
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including Methylphenidate hydrochloride extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/ Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy [see Clinical Considerations] . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as Methylphenidate hydrochloride extended-release tablets, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed.
g/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adolescents on a mg/m 2 basis).
8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride extended-release tablets have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. The safety and effectiveness of Methylphenidate hydrochloride extended-release tablets for the treatment of ADHD have been established in pediatric patients 6 to 17 years. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including Methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [ see Warnings and Precautions (5.7) ] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
9 DRUG ABUSE AND DEPENDENCE N/A 9.1 Controlled Substance Methylphenidate hydrochloride extended-release tablets contain methylphenidate hydrochloride, a Schedule II controlled substance. 9.2 Abuse CNS stimulants, including Methylphenidate hydrochloride extended-release tablets have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving. Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [ see Overdosage (10) ] . To reduce the abuse of CNS stimulants including Methylphenidate hydrochloride extended-release tablets assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [ see How Supplied/Storage and Handling (16) ] , monitor for signs of abuse while on therapy, and reevaluate the need for Methylphenidate hydrochloride extended-release tablets use. 9.3 Dependence Tolerance Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including Methylphenidate hydrochloride extended-release tablets. Dependence Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including Methylphenidate hydrochloride extended-release tablets. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.
9.2 Abuse CNS stimulants, including Methylphenidate hydrochloride extended-release tablets have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving. Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [ see Overdosage (10) ] . To reduce the abuse of CNS stimulants including Methylphenidate hydrochloride extended-release tablets assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [ see How Supplied/Storage and Handling (16) ] , monitor for signs of abuse while on therapy, and reevaluate the need for Methylphenidate hydrochloride extended-release tablets use.
9.3 Dependence Tolerance Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including Methylphenidate hydrochloride extended-release tablets. Dependence Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including Methylphenidate hydrochloride extended-release tablets. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.
10 OVERDOSAGE Human Experience Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperreflexia, muscle twitching, convulsions (which may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, hypotension, tachypnea, mydriasis, dryness of mucous membranes, and rhabdomyolysis. Overdose Management Consult with a Certified Poison Control Center (1-800-222-1222) for the latest recommendations.
11 DESCRIPTION Methylphenidate hydrochloride extended-release tablets, USP contains methylphenidate hydrochloride a CNS stimulant. It is available as extended-release tablets of 10 mg and 20 mg strength for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is: Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77 g/mol. Methylphenidate hydrochloride extended-release tablets, USP contains the following inactive ingredients: hypromellose, microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide and magnesium stearate. FDA approved dissolution test differs from the USP dissolution test. methyl-ER-tabs-str
12 CLINICAL PHARMACOLOGY N/A 12.1 Mechanism of Action Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD and narcolepsy is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking Methylphenidate hydrochloride extended-release tablets. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of Methylphenidate hydrochloride tablets on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethylphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms (ECGs) were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval (CI) was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship. 12.3 Pharmacokinetics Absorption Methylphenidate hydrochloride in the extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the extended-release tablet compared to the Methylphenidate hydrochloride tablet measured by the urinary excretion of Methylphenidate hydrochloride major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49% to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the Methylphenidate hydrochloride tablets and 4.7 hours (1.3 to 8.2 hours) for the Methylphenidate hydrochloride extended-release tablets. An average of 67% of extended-release tablet dose was excreted in children as compared to 86% in adults. Effect of Food After a high-fat meal, both area under the curve (AUC) (by 25%) and C max (by 27%) are higher. Time to C max (T max ) is faster after a high-fat meal (median T max : 2.5 hours) as compared to without food (median T max : 3 hours). Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate. Elimination The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. Metabolism Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). The cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for Methylphenidate hydrochloride extended-release tablets.
n feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). The cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for Methylphenidate hydrochloride extended-release tablets. Studies in Specific Populations Male and Female Patients In a clinical study involving adult subjects who received Methylphenidate hydrochloride extended-release tablets plasma concentrations of Methylphenidate hydrochloride's major metabolite appeared to be greater in females than in males. No gender differences were observed for Methylphenidate hydrochloride plasma concentration in the same subjects. Racial or Ethnic Groups There is insufficient experience with the use of Methylphenidate hydrochloride extended-release to detect ethnic variations in pharmacokinetics. Patients with Renal Impairment Methylphenidate hydrochloride has not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochloride has not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.
12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking Methylphenidate hydrochloride extended-release tablets. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of Methylphenidate hydrochloride tablets on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethylphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms (ECGs) were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval (CI) was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship.
12.3 Pharmacokinetics Absorption Methylphenidate hydrochloride in the extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the extended-release tablet compared to the Methylphenidate hydrochloride tablet measured by the urinary excretion of Methylphenidate hydrochloride major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49% to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the Methylphenidate hydrochloride tablets and 4.7 hours (1.3 to 8.2 hours) for the Methylphenidate hydrochloride extended-release tablets. An average of 67% of extended-release tablet dose was excreted in children as compared to 86% in adults. Effect of Food After a high-fat meal, both area under the curve (AUC) (by 25%) and C max (by 27%) are higher. Time to C max (T max ) is faster after a high-fat meal (median T max : 2.5 hours) as compared to without food (median T max : 3 hours). Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate. Elimination The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. Metabolism Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). The cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for Methylphenidate hydrochloride extended-release tablets. Studies in Specific Populations Male and Female Patients In a clinical study involving adult subjects who received Methylphenidate hydrochloride extended-release tablets plasma concentrations of Methylphenidate hydrochloride's major metabolite appeared to be greater in females than in males. No gender differences were observed for Methylphenidate hydrochloride plasma concentration in the same subjects. Racial or Ethnic Groups There is insufficient experience with the use of Methylphenidate hydrochloride extended-release to detect ethnic variations in pharmacokinetics. Patients with Renal Impairment Methylphenidate hydrochloride has not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochloride has not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.
13 NONCLINICAL TOXICOLOGY N/A 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis.
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis.
16 HOW SUPPLIED/STORAGE AND HANDLING Methylphenidate hydrochloride extended-release tablets, USP are available as follows: 10 mg: White to off white, round shaped, uncoated, tablets debossed with “FM4” on one side and plain on other side. Bottles of 100 tablets NDC 51407-527-01 20 mg: White to off white, round shaped, uncoated, tablets debossed with “FM5” on one side and plain on other side. Bottles of 100 tablets NDC 51407-528-01 NOTE : Methylphenidate hydrochloride extended-release tablets, USP are color-additive free. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure. Disposal Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired Methylphenidate hydrochloride extended-release tablets, USP by a medicine takeback program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix Methylphenidate hydrochloride extended-release tablets, USP with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard Methylphenidate hydrochloride extended-release tablets, USP in the household trash.
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Controlled Substance Status/High Potential for Abuse and Dependence Advise patients that Methylphenidate hydrochloride extended-release tablets are controlled substances, and they can be abused and lead to dependence. Instruct patients that they should not give Methylphenidate hydrochloride extended-release tablets to anyone else. Advise patients to store Methylphenidate hydrochloride extended-release tablets in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired Methylphenidate hydrochloride extended-release tablets by a medicine take-back program if available [see Boxed Warning , Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.1, 9.2, 9.3) , How Supplied/Storage and Handling (16) ] . Serious Cardiovascular Risks Advise patients that there is a potential serious cardiovascular risk including sudden death, myocardial infarction, stroke, and hypertension with Methylphenidate hydrochloride extended-release tablets use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [ see Warnings and Precautions (5.2) ]. Blood Pressure and Heart Rate Increases Instruct patients that Methylphenidate hydrochloride extended-release tablets can cause elevations of their blood pressure and pulse rate [ see Warnings and Precautions (5.3) ] . Psychiatric Risks Advise patients that Methylphenidate hydrochloride extended-release tablets at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [ see Warnings and Precautions (5.4) ]. Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [ see Warnings and Precautions (5.5) ] . Circulation Problems in Fingers and Toes [Peripheral vasculopathy, including Raynaud’s Phenomenon] Instruct patients about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking Methylphenidate hydrochloride extended-release tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [ see Warnings and Precautions (5.6) ] . Suppression of Growth Advise patients that Methylphenidate hydrochloride extended-release tablets may cause slowing of growth and weight loss [ see Warnings and Precautions (5.7) ]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including Methylphenidate hydrochloride extended-release tablets, during pregnancy [see Use in Specific Populations (8.1) ] . The Medication Guide may also be obtained by calling 877-770-3183. Manufactured by: Granules Pharmaceuticals Inc.
gistry that monitors pregnancy outcomes in patients exposed to ADHD medications, including Methylphenidate hydrochloride extended-release tablets, during pregnancy [see Use in Specific Populations (8.1) ] . The Medication Guide may also be obtained by calling 877-770-3183. Manufactured by: Granules Pharmaceuticals Inc. Chantilly, VA 20151 Rev. 03/2026 Marketed by: GSMS, Inc. Camarillo, CA 93012 USA
MEDICATION GUIDE MEDICATION GUIDE Methylphenidate Hydrochloride Extended-Release Tablets (meth" il fen' i date hye" droe klor' ide) What is the most important information I should know about Methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets is a federal controlled substance (CII) because it can be abused or lead to dependence. Keep Methylphenidate hydrochloride extended-release tablets in a safe place to prevent misuse and abuse. Selling or giving away Methylphenidate hydrochloride extended-release tablets may harm others and is against the law. Tell your doctor if you or your child have ever abused or been dependent on alcohol, prescription medicines or street drugs. The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines: 1. Heart-related problems: sudden death in patients who have heart problems or heart defects stroke and heart attack in adults increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting Methylphenidate hydrochloride extended-release tablets. Your doctor should check you or your child’s blood pressure and heart rate regularly during treatment with Methylphenidate hydrochloride extended-release tablets. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking Methylphenidate hydrochloride extended-release tablets. 2. Mental (Psychiatric) problems: All Patients new or worse behavior and thought problems new or worse bipolar illness new or worse aggressive behavior or hostility new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking Methylphenidate hydrochloride extended-release tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. What is Methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablet is a central nervous system (CNS) stimulant prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. Methylphenidate hydrochloride extended-release tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Methylphenidate hydrochloride extended-release tablets are not recommended for use in children under 6 years of age with ADHD. Methylphenidate hydrochloride extended-release tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride extended-release tablets are also used in the treatment of a sleep disorder called narcolepsy. Who should not take Methylphenidate hydrochloride extended-release tablets?
tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride extended-release tablets are also used in the treatment of a sleep disorder called narcolepsy. Who should not take Methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets should not be taken if you or your child: are allergic to methylphenidate hydrochloride, or any of the ingredients in Methylphenidate hydrochloride extended-release tablets. See the end of this Medication Guide for a complete list of ingredients in Methylphenidate hydrochloride extended-release tablets. are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI. Methylphenidate hydrochloride extended-release tablets may not be right for you or your child. Before starting Methylphenidate hydrochloride extended-release tablets tell you or your child’s doctor about all health conditions (or a family history of) including: heart problems, heart defects, high blood pressure mental problems including psychosis, mania, bipolar illness, or depression circulation problems in fingers or toes if you are pregnant or plan to become pregnant. It is not known if Methylphenidate hydrochloride extended-release tablets will harm your unborn baby. There is a pregnancy registry for females who are exposed to ADHD medications, including Methylphenidate hydrochloride extended-release tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to Methylphenidate hydrochloride extended-release tablets and their baby. If you or your child becomes pregnant during treatment with Methylphenidate hydrochloride extended-release tablets talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhdmedications/. if you are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with Methylphenidate hydrochloride extended-release tablets. Tell your doctor about all of the medicines that you or your child takes including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride extended-release tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking Methylphenidate hydrochloride extended-release tablets. Your doctor will decide whether Methylphenidate hydrochloride extended-release tablets can be taken with other medicines. Especially tell your doctor if you or your child takes: anti-depression medicines including MAOIs blood pressure medicines (anti-hypertensive) Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking Methylphenidate hydrochloride extended-release tablets without talking to your doctor first. How should Methylphenidate hydrochloride extended-release tablets be taken? Take Methylphenidate hydrochloride extended-release tablets exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. Take Methylphenidate hydrochloride extended-release tablets 30 to 45 minutes before a meal. The effect of a dose of Methylphenidate hydrochloride extended-release tablets usually lasts about 8 hours. Do not chew or crush Methylphenidate hydrochloride extended-release tablets.
se until it is right for you or your child. Take Methylphenidate hydrochloride extended-release tablets 30 to 45 minutes before a meal. The effect of a dose of Methylphenidate hydrochloride extended-release tablets usually lasts about 8 hours. Do not chew or crush Methylphenidate hydrochloride extended-release tablets. Swallow Methylphenidate hydrochloride extended-release tablets whole with water or other liquids. Tell your doctor if you or your child cannot swallow Methylphenidate hydrochloride extended-release tablets whole. A different medicine may need to be prescribed. From time to time, your doctor may stop Methylphenidate hydrochloride extended-release tablets treatment for a while to check ADHD symptoms. Your doctor may do regular checks of the blood, heart, and blood pressure while taking Methylphenidate hydrochloride extended-release tablets. Children should have their height and weight checked often while taking Methylphenidate hydrochloride extended-release tablets. Methylphenidate hydrochloride extended-release tablets treatment may be stopped if a problem is found during these check-ups. In case of poisoning call your poison control center at 1-800-222-1222 right away or go to the nearest hospital emergency room. What are the possible side effects of Methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets may cause serious side effects, including: What are possible side effects of Methylphenidate hydrochloride extended-release tablets? See “What is the most important information I should know about Methylphenidate hydrochloride extended-release tablets?” for information on reported heart and mental problems. painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately. circulation problems in fingers and toes (Peripheral vasculopathy, including Raynaud’s phenomenon): fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your doctor if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking Methylphenidate hydrochloride extended-release tablets. slowing of growth (height and weight) in children Common side effects include: • fast heart beat • abnormal heartbeat (palpitations) • headache • trouble sleeping • nervousness • sweating a lot • decreased appetite • dry mouth • nausea • stomach pain Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Methylphenidate hydrochloride extended-release tablets? Store Methylphenidate hydrochloride extended-release tablets in a safe place and in a tightly closed container at room temperature between 68°F to 77°F (20°C to 25°C). Protect from moisture. Dispose of remaining, unused, or expired Methylphenidate hydrochloride extended-release tablets by a medicine take-back program at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix Methylphenidate hydrochloride extended-release tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away (discard) Methylphenidate hydrochloride extended-release tablets in the household trash.
d-release tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away (discard) Methylphenidate hydrochloride extended-release tablets in the household trash. Keep Methylphenidate hydrochloride extended-release tablets and all medicines out of the reach of children. General information about the safe and effective use of Methylphenidate hydrochloride extended-release tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or doctor for information about Methylphenidate hydrochloride extended-release tablets that is written for healthcare professionals. Do not use Methylphenidate hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give Methylphenidate hydrochloride extended-release tablets to other people, even if they have the same symptoms. It may harm them and it is against the law. What are the ingredients in Methylphenidate hydrochloride extended-release tablets? Active ingredient: methylphenidate hydrochloride Inactive ingredients: hypromellose, microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide and magnesium stearate. Manufactured by: Granules Pharmaceuticals Inc. Chantilly, VA 20151 Marketed by: GSMS, Inc. Camarillo, CA 93012 USA This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 03/2026 methyl-ER-tabs-cii
<table border="1" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td><paragraph><content styleCode="bold">MEDICATION GUIDE</content></paragraph><paragraph><content styleCode="bold">Methylphenidate Hydrochloride Extended-Release Tablets</content><renderMultiMedia referencedObject="img_398dfbc2-58b6-d3b7-e063-6394a90a4976"/></paragraph><paragraph>(meth" il fen' i date hye" droe klor' ide)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">What is the most important information I should know about</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets?</content></paragraph><paragraph/><paragraph><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets is a federal controlled substance (CII) because it can be abused or lead to dependence. Keep Methylphenidate hydrochloride extended-release tablets in a safe place to prevent misuse and abuse. Selling or giving away Methylphenidate hydrochloride extended-release tablets may harm others and is against the law.</content>Tell your doctor if you or your child have ever abused or been dependent on alcohol, prescription medicines or street drugs. </paragraph><paragraph/><paragraph><content styleCode="bold">The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines:</content></paragraph><paragraph/><paragraph><content styleCode="bold">1. <content styleCode="underline">Heart-related problems:</content></content></paragraph><paragraph/><list listType="unordered"><item><content styleCode="bold">sudden death in patients who have heart problems or heart defects</content></item><item><content styleCode="bold">stroke and heart attack in adults</content></item><item><content styleCode="bold">increased blood pressure and heart rate</content></item></list><paragraph>Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems.</paragraph><paragraph>Your doctor should check you or your child carefully for heart problems before starting Methylphenidate hydrochloride extended-release tablets.</paragraph><paragraph>Your doctor should check you or your child’s blood pressure and heart rate regularly during treatment with Methylphenidate hydrochloride extended-release tablets.</paragraph><paragraph/><paragraph><content styleCode="bold">Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets.</content></paragraph><paragraph/><paragraph><content styleCode="bold">2.
de="bold">Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets.</content></paragraph><paragraph/><paragraph><content styleCode="bold">2. <content styleCode="underline">Mental (Psychiatric) problems:</content></content></paragraph><paragraph><content styleCode="bold">All Patients</content></paragraph><list listType="unordered"><item><content styleCode="bold">new or worse behavior and thought problems</content></item><item><content styleCode="bold">new or worse bipolar illness</content></item><item><content styleCode="bold">new or worse aggressive behavior or hostility</content></item><item><content styleCode="bold">new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms</content></item></list><paragraph>Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.</paragraph><paragraph><content styleCode="bold">Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">What is Methylphenidate hydrochloride extended-release tablets?</content></paragraph><paragraph>Methylphenidate hydrochloride extended-release tablet is a central nervous system (CNS) stimulant prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. Methylphenidate hydrochloride extended-release tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.</paragraph><paragraph/><paragraph/><paragraph>Methylphenidate hydrochloride extended-release tablets are not recommended for use in children under 6 years of age with ADHD.</paragraph><paragraph/><paragraph>Methylphenidate hydrochloride extended-release tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.</paragraph><paragraph>Methylphenidate hydrochloride extended-release tablets are also used in the treatment of a sleep disorder called narcolepsy.</paragraph><paragraph/></td></tr><tr><td><paragraph><content styleCode="bold">Who should not take Methylphenidate hydrochloride extended-release tablets?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets should not be taken if you or your child:</content></paragraph><list listType="unordered"><item>are allergic to methylphenidate hydrochloride, or any of the ingredients in Methylphenidate hydrochloride extended-release tablets. See the end of this Medication Guide for a complete list of ingredients in Methylphenidate hydrochloride extended-release tablets.</item><item>are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.</item></list></td></tr><tr><td><paragraph><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets may not be right for you or your child.
ended-release tablets.</item><item>are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.</item></list></td></tr><tr><td><paragraph><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets may not be right for you or your child. Before starting Methylphenidate hydrochloride extended-release tablets tell you or your child’s doctor about all health conditions (or a family history of) including:</content></paragraph><list listType="unordered"><item>heart problems, heart defects, high blood pressure</item><item>mental problems including psychosis, mania, bipolar illness, or depression</item><item>circulation problems in fingers or toes</item><item>if you are pregnant or plan to become pregnant. It is not known if Methylphenidate hydrochloride extended-release tablets will harm your unborn baby. <list listType="unordered"><item>There is a pregnancy registry for females who are exposed to ADHD medications, including Methylphenidate hydrochloride extended-release tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to Methylphenidate hydrochloride extended-release tablets and their baby. If you or your child becomes pregnant during treatment with Methylphenidate hydrochloride extended-release tablets talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd­medications/.</item><item>if you are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with Methylphenidate hydrochloride extended-release tablets.</item></list></item></list><paragraph><content styleCode="bold">Tell your doctor about all of the medicines that you or your child takes including prescription and over-the-counter medicines, vitamins, and herbal supplements.</content>Methylphenidate hydrochloride extended-release tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking Methylphenidate hydrochloride extended-release tablets. </paragraph><paragraph>Your doctor will decide whether Methylphenidate hydrochloride extended-release tablets can be taken with other medicines.</paragraph><paragraph><content styleCode="bold">Especially tell your doctor if you or your child takes:</content></paragraph><list listType="unordered"><item>anti-depression medicines including MAOIs</item><item>blood pressure medicines (anti-hypertensive)</item></list><paragraph>Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist.</paragraph><paragraph><content styleCode="bold">Do not start any new medicine while taking</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets</content><content styleCode="bold">without talking to your doctor first.</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">How should</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets be taken?</content></paragraph><list listType="unordered"><item>Take Methylphenidate hydrochloride extended-release tablets exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.</item><item>Take Methylphenidate hydrochloride extended-release tablets 30 to 45 minutes before a meal.
taken?</content></paragraph><list listType="unordered"><item>Take Methylphenidate hydrochloride extended-release tablets exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.</item><item>Take Methylphenidate hydrochloride extended-release tablets 30 to 45 minutes before a meal. The effect of a dose of Methylphenidate hydrochloride extended-release tablets usually lasts about 8 hours.</item><item><content styleCode="bold">Do not chew or crush</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets.</content>Swallow Methylphenidate hydrochloride extended-release tablets whole with water or other liquids. Tell your doctor if you or your child cannot swallow Methylphenidate hydrochloride extended-release tablets whole. A different medicine may need to be prescribed. </item><item>From time to time, your doctor may stop Methylphenidate hydrochloride extended-release tablets treatment for a while to check ADHD symptoms.</item><item>Your doctor may do regular checks of the blood, heart, and blood pressure while taking Methylphenidate hydrochloride extended-release tablets.</item><item>Children should have their height and weight checked often while taking Methylphenidate hydrochloride extended-release tablets. Methylphenidate hydrochloride extended-release tablets treatment may be stopped if a problem is found during these check-ups.</item><item><content styleCode="bold">In case of poisoning call your poison control center at 1-800-222-1222 right away or go to the nearest hospital emergency room.</content></item></list></td></tr><tr><td><paragraph><content styleCode="bold">What are the possible side effects of</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets may cause serious side effects, including:</content></paragraph><paragraph><content styleCode="bold">What are possible side effects of</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets?</content></paragraph><list listType="unordered"><item>See <content styleCode="bold">“What is the most important information I should know about</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets?”</content>for information on reported heart and mental problems. </item><item><content styleCode="bold">painful and prolonged erections (priapism)</content>have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately.
art and mental problems. </item><item><content styleCode="bold">painful and prolonged erections (priapism)</content>have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately. </item><item><content styleCode="bold">circulation problems in fingers and toes</content>(Peripheral vasculopathy, including Raynaud’s phenomenon): </item><item>fingers or toes may feel numb, cool, painful</item><item>fingers or toes may change color from pale, to blue, to red</item></list><paragraph>Tell your doctor if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.</paragraph><list listType="unordered"><item><content styleCode="bold">Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets.</content></item><item><content styleCode="bold">slowing of growth (height and weight) in children</content></item></list><paragraph><content styleCode="bold">Common side effects include:</content></paragraph><paragraph>• fast heart beat • abnormal heartbeat (palpitations) • headache • trouble sleeping • nervousness</paragraph><paragraph>• sweating a lot • decreased appetite • dry mouth • nausea • stomach pain</paragraph><paragraph><content styleCode="bold">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">How should I store</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets?</content></paragraph><list listType="unordered"><item>Store Methylphenidate hydrochloride extended-release tablets in a safe place and in a tightly closed container at room temperature between 68°F to 77°F (20°C to 25°C).</item><item>Protect from moisture.</item><item>Dispose of remaining, unused, or expired Methylphenidate hydrochloride extended-release tablets by a medicine take-back program at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix Methylphenidate hydrochloride extended-release tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away (discard) Methylphenidate hydrochloride extended-release tablets in the household trash.</item><item><content styleCode="bold">Keep</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets and all medicines out of the reach of children.</content></item></list></td></tr><tr><td><paragraph><content styleCode="bold">General information about the safe and effective use of</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets.</content></paragraph><paragraph/><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or doctor for information about Methylphenidate hydrochloride extended-release tablets that is written for healthcare professionals. Do not use Methylphenidate hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give Methylphenidate hydrochloride extended-release tablets to other people, even if they have the same symptoms.
hydrochloride extended-release tablets that is written for healthcare professionals. Do not use Methylphenidate hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give Methylphenidate hydrochloride extended-release tablets to other people, even if they have the same symptoms. It may harm them and it is against the law.</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">What are the ingredients in</content><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content>methylphenidate hydrochloride </paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content>hypromellose, microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide and magnesium stearate. </paragraph><paragraph/><paragraph/><paragraph/><paragraph>Manufactured by:</paragraph><paragraph><content styleCode="bold">Granules Pharmaceuticals Inc.</content></paragraph><paragraph>Chantilly, VA 20151</paragraph><paragraph>Marketed by: <content styleCode="bold">GSMS, Inc.</content> Camarillo, CA 93012 USA </paragraph></td></tr></tbody></table>
WARNING: ABUSE AND DEPENDENCE CNS stimulants, including methylphenidate hydrochloride tablets, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)] . WARNING: ABUSE AND DEPENDENCE See full prescribing information for complete boxed warning. CNS stimulants, including m ethylphenidate hydrochloride tablets , other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence (5.1, 9.2, 9.3). Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy (5.1, 9.2)
1. INDICATIONS AND USAGE Methylphenidate hydrochloride tablets are indicated for the treatment of: Attention Deficit Hyperactivity Disorders (ADHD) in pediatric patients 6 years and older and adults Narcolepsy Methylphenidate hydrochloride is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorders (ADHD) and Narcolepsy
2. DOSAGE AND ADMINISTRATION Methylphenidate hydrochloride Tablets, USP (2.2) : Pediatric Patients 6 years and older: Start with 5 mg twice daily (before breakfast and lunch), titrating the dose weekly in 5 to 10 mg increments. Dosages above 60 mg/day are not recommended. Adults: Average daily dosage is 20 to 30 mg, administered 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum total daily dosage is 60 mg. 2.1 Pretreatment Screening Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants, including methylphenidate hydrochloride tablets, assess for the presence of cardiac disease (i.e., perform a careful history including family history of sudden death or ventricular arrhythmia, and physical examination) [see Warnings and Precautions (5.2)] . Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically reevaluate the need for methylphenidate hydrochloride tablets use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)]. 2.2 General Dosing Information Methylphenidate hydrochloride Tablets Pediatric Patients 6 years and Older: Start with 5 mg orally twice daily (before breakfast and lunch). Increase dosage gradually, in increments of 5 to 10 mg weekly. Daily dosage above 60 mg is not recommended. Adults: Average dosage is 20 to 30 mg daily. Administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum total daily dosage is 60 mg. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of methylphenidate hydrochloride tablets, and adjust dosage as needed. 2.3 Dose Reduction and Discontinuation If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue methylphenidate hydrochloride tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
3 DOSAGE FORMS AND STRENGTHS Tablets • 5 mg, Light yellow, round, biconvex, beveled edge tablets de-bossed with ‘T’ on one side and ‘173’ on the other side. • 10 mg, White to off white, round, flat, beveled edge tablets de-bossed with ‘T’ and ‘174’ with a functional score line on one side and plain on the other side. • 20 mg, Light yellow, round, flat, beveled edge tablets de-bossed with ‘T’ and ‘175’ with a functional score line on one side and plain on the other side. • Tablets: 5 mg, 10 mg, and 20 mg (3)
4 CONTRAINDICATIONS Hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride tablets. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions (6.1)]. Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions (7.1)]. Known hypersensitivity to methylphenidate or other product components of methylphenidate hydrochloride tablets (4) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days (4)
5 WARNINGS AND PRECAUTIONS Serious Cardiovascular Events : Sudden death has been reported in association with CNS-stimulant treatment at usual doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke, and myocardial infarction have been reported. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm arrhythmias, or coronary artery disease (5.2). Blood Pressure and Heart Rate Increases : Monitor blood pressure and pulse. Consider the benefits and risk in patients for whom an increase in blood pressure or heart rate would be problematic (5.3) Psychiatric Adverse Reactions : Use of stimulants may cause psychotic or manic symptoms in patients with no prior history or exacerbation of symptoms in patients with preexisting psychiatric illness. Evaluate for preexisting psychotic or bipolar disorder prior to methylphenidate hydrochloride tablets use (5.4). Priapism : Cases of painful and prolonged penile erections, and priapism have been reported with methylphenidate products. Immediate medical attention should be sought if signs or symptoms of prolonged penile erections or priapism are observed (5.5). Peripheral Vasculopathy, including Raynaud’s Phenomenon : Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Careful observation for digital changes is necessary during treatment with ADHD stimulants (5.6). Long-Term Suppression of Growth : Monitor height and weight at appropriate intervals in pediatric patients (5.7). 5.1 Potential for Abuse and Dependence CNS stimulants, including methylphenidate hydrochloride, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Boxed Warning, Drug Abuse and Dependence (9.2, 9.3)]. 5.2 Serious Cardiovascular Reactions Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during methylphenidate hydrochloride treatment. 5.3 Blood Pressure and Heart Rate Increases CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Preexisting Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g. comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).
Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g. comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing methylphenidate hydrochloride. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0 in placebo-treated patients. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including methylphenidate hydrochloride, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. 5.7 Long-Term Suppression of Growth CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants including methylphenidate hydrochloride. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse and Dependence [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3 ) ] Known hypersensitivity to methylphenidate or other ingredients of methylphenidate hydrochloride tablets [see Contraindications (4)] Hypertensive crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4), Drug Interactions (7.1)] Serious Cardiovascular Reactions [see Warnings and Precautions (5.2)] Blood Pressure and Heart Rate Increases [see Warnings and Precautions (5.3)] Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)] Priapism [see Warnings and Precautions (5.5)] Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions (5.6)] Long-term Suppression of Growth [see Warnings and Precautions (5.7)] The following adverse reactions associated with the use of all methylphenidate hydrochloride tablets and other methylphenidate products were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Adverse Reactions Reported with methylphenidate hydrochloride Infections and Infestations: nasopharyngitis Blood and the Lymphatic System Disorders : leukopenia, thrombocytopenia, anemia Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood Nervous System Disorders: headache, dizziness, tremor, dyskinesia including choreoatheetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs Eye Disorders: blurred vision, difficulties in visual accommodation Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris Respiratory, Thoracic and Mediastinal Disorders: cough Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis Investigations: weight loss (adult ADHD patients) Additional Adverse Reactions Reported With Other Methylphenidate-Containing Products The list below shows adverse reactions not listed for methylphenidate hydrochloride that have been reported with other methylphenidate-containing products.
muscle cramps, rhabdomyolysis Investigations: weight loss (adult ADHD patients) Additional Adverse Reactions Reported With Other Methylphenidate-Containing Products The list below shows adverse reactions not listed for methylphenidate hydrochloride that have been reported with other methylphenidate-containing products. Blood and Lymphatic Disorders: pancytopenia Immune System Disorders: hypersensitivity reactions such as auricular swelling, bullous conditions, eruptions, exanthemas Psychiatric Disorders: affect lability, mania, disorientation and libido changes Nervous System Disorders: migraine Eye Disorders: diplopia, mydriasis Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole Vascular Disorders: peripheral coldness, Raynaud's phenomenon Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea Gastrointestinal Disorders: diarrhea, constipation Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption Musculoskeletal, Connective Tissue and bone Disorders: myalgia, muscle twitching Renal and Urinary Disorders: hematuria Reproductive System and Breast Disorders: gynecomastia General Disorders: fatigue, hyperpyrexia Urogenital Disorders : priapism To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Common adverse reactions: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain (6) . To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7 DRUG INTERACTIONS Antihypertensive drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed (7) Halogenated anesthetics: Avoid use of methylphenidate hydrochloride tablets on the day of surgery if halogenated anesthetics will be used (7) 7.1 Clinically Important Interactions with methylphenidate hydrochloride Table 1 presents clinically important drug interactions with methylphenidate hydrochloride tablets Table 1: Clinically Important Drug Interactions with methylphenidate hydrochloride Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4)]. Intervention Concomitant use of methylphenidate hydrochloride with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Antihypertensive Drugs Clinical Impact Methylphenidate hydrochloride may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3)] . Intervention Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Examples Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists Halogenated Anesthetics Clinical Impact Concomitant use of halogenated anesthetics and methylphenidate hydrochloride may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of methylphenidate hydrochloride in patients being treated with anesthetics on the day of surgery. Examples halothane, isoflurane, enflurane, desflurane, sevoflurane
<table border="1" cellspacing="0" cellpadding="0"><tbody><tr><td colspan="2" valign="top"><paragraph/><paragraph><content styleCode="bold">Monoamine Oxidase Inhibitors (MAOI)</content></paragraph><paragraph/></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">Clinical Impact</content></paragraph><paragraph/><paragraph/><paragraph/><paragraph/><paragraph/></td><td valign="top"><paragraph>Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4)].</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">Intervention </content></paragraph></td><td valign="top"><paragraph>Concomitant use of methylphenidate hydrochloride with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated.</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">Examples</content></paragraph><paragraph/></td><td valign="top"><paragraph>selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue</paragraph><paragraph/></td></tr><tr><td colspan="2" valign="top"><paragraph/><paragraph><content styleCode="bold">Antihypertensive Drugs</content></paragraph><paragraph/></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">Clinical Impact</content></paragraph><paragraph/></td><td valign="top"><paragraph>Methylphenidate hydrochloride may decrease the effectiveness of drugs used to treat hypertension <content styleCode="italics">[see Warnings and Precautions (5.3)]</content>. </paragraph><paragraph/></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">Intervention</content></paragraph><paragraph/></td><td valign="top"><paragraph>Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.</paragraph><paragraph/></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">Examples</content></paragraph></td><td valign="top"><paragraph>Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists</paragraph><paragraph/></td></tr><tr><td colspan="2" valign="top"><paragraph/><paragraph><content styleCode="bold">Halogenated Anesthetics</content></paragraph><paragraph/></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">Clinical Impact</content></paragraph></td><td valign="top"><paragraph>Concomitant use of halogenated anesthetics and methylphenidate hydrochloride may increase the risk of sudden blood pressure and heart rate increase during surgery.</paragraph><paragraph/></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">Intervention</content></paragraph></td><td valign="top"><paragraph>Avoid use of methylphenidate hydrochloride in patients being treated with anesthetics on the day of surgery.</paragraph><paragraph/></td></tr><tr><td valign="top"><paragraph><content styleCode="italics">Examples</content></paragraph></td><td valign="top"><paragraph>halothane, isoflurane, enflurane, desflurane, sevoflurane</paragraph><paragraph/></td></tr></tbody></table>
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 ADHD medications, including methylphenidate hydrochloride tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/ Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20% respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride tablets, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed.
g/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride for the treatment of ADHD have been established in pediatric patients 6 to 17 years. The safety and effectiveness of methylphenidate hydrochloride in pediatric patients less than 6 years have not been established. The long-term efficacy of methylphenidate hydrochloride in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7)] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Methylphenidate hydrochloride has not been studied in the geriatric population.
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate hydrochloride tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/ Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20% respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride tablets, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed.
g/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adolescents on a mg/m 2 basis).
8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.
8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride for the treatment of ADHD have been established in pediatric patients 6 to 17 years. The safety and effectiveness of methylphenidate hydrochloride in pediatric patients less than 6 years have not been established. The long-term efficacy of methylphenidate hydrochloride in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7)] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate hydrochloride tablets contain methylphenidate hydrochloride, a Schedule II controlled substance. 9.2 Abuse CNS stimulants, including methylphenidate hydrochloride tablets, have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving. Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [see Overdosage (10)] . To reduce the abuse of CNS stimulants including methylphenidate hydrochloride tablets, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see How Supplied/Storage and Handling (16)] , monitor for signs of abuse while on therapy, and reevaluate the need for methylphenidate hydrochloride tablets use. 9.3 Dependence Tolerance Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including methylphenidate hydrochloride tablets. Dependence Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including methylphenidate hydrochloride tablets. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.
11 DESCRIPTION Methylphenidate hydrochloride tablets, USP is a central nervous system (CNS) stimulant. It is available as tablets of 5 mg, 10 mg, and 20 mg strength for oral administration. Methylphenidate hydrochloride is methyl α- phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate hydrochloride USP is a white to off white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77 g/mol. Methylphenidate hydrochloride tablets, USP contain the following inactive ingredients: compressible sugar, colloidal silicon dioxide, D&C yellow no. 10 (5 mg and 20 mg tablets), lactose monohydrate, magnesium stearate, and microcrystalline cellulose. image description
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate hydrochloride is a CNS stimulant. The mode of therapeutic action in ADHD and narcolepsy is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking methylphenidate hydrochloride tablets. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride on the QT interval was evaluated in a double-blind, placebo and open-label active (moxifloxacin)-controlled study following single doses of dexmethylphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms (ECGs) were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval (CI) was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship. 12.3 Pharmacokinetics Absorption Methylphenidate hydrochloride in the extended release tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the extended-release tablet compared to the methylphenidate hydrochloride tablet, measured by the urinary excretion of methylphenidate hydrochloride major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49% to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the methylphenidate hydrochloride tablets and 4.7 hours (1.3 to 8.2 hours) for the methylphenidate hydrochloride extended-release tablets. An average of 67% of extended-release tablet dose was excreted in children as compared to 86% in adults. Effect of Food After a high-fat meal, both area under the curve (AUC) (by 25 %) and C max (by 27 %) are higher. Time to C max (T max ) is faster after a high-fat meal (median T max : 2.5 hours) as compared to without food (median T max : 3 hours). Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d- methylphenidate and 1.80 ± 0.91 L/kg for 1- methylphenidate. Elimination The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for 1-methylphenidate. Metabolism Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). The cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for methylphenidate hydrochloride extended release tablets.
n feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). The cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for methylphenidate hydrochloride extended release tablets. Studies in Specific Populations Male and Female Patients In a clinical study involving adult subjects who received methylphenidate hydrochloride extended release, plasma concentrations of methylphenidate hydrochloride’s major metabolite appeared to be greater in females than in males. No gender differences were observed for methylphenidate hydrochloride plasma concentration in the same subjects. Racial or Ethnic Groups There is insufficient experience with the use of methylphenidate hydrochloride tablets to detect ethnic variations in pharmacokinetics. Patients with Renal Impairment Methylphenidate hydrochloride tablets have not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochloride tablets have not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis.
16 HOW SUPPLIED/STORAGE AND HANDLING 5 mg Tablets - Light yellow, round, biconvex, beveled edge tablets de-bossed with ‘ T ’ on one side and ‘ 173 ’ on the other side. 10 mg Tablets – White to off white, round, flat, beveled edge tablets de-bossed with ‘ T ’ and ‘ 174 ’ with a functional score line on one side and plain on the other side. NDC 50268-528-15 (10 tablets per card, 5 cards per carton) 20 mg Tablets - Light yellow, round, flat, beveled edge tablets de-bossed with ‘ T ’ and ‘ 175 ’ with a functional score line on one side and plain on the other side. NDC 50268-529-15 (10 tablets per card, 5 cards per carton) Store at 20° to 25°C (68° to 77°F), excursions permitted 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Protect from light. Dispensed in Unit Dose Package. For Institutional Use Only. Disposal Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired methylphenidate hydrochloride tablets by a medicine take-back program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix methylphenidate hydrochloride tablets with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard methylphenidate hydrochloride tablets in the household trash.
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Controlled Substance Status/High Potential for Abuse and Dependence Advise patients that methylphenidate hydrochloride tablets are controlled substances, and they can be abused and lead to dependence. Instruct patients that they should not give methylphenidate hydrochloride tablets to anyone else. Advise patients to store methylphenidate hydrochloride tablets in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired methylphenidate hydrochloride tablets by a medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.1, 9.2, 9.3), How Supplied/Storage and Handling (16)] . Serious Cardiovascular Risks Advise patients that there is a potential serious cardiovascular risk including sudden death, myocardial infarction, stroke, and hypertension with methylphenidate hydrochloride tablets use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)]. Blood Pressure and Heart Rate Increases Instruct patients that methylphenidate hydrochloride tablets can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3)] . Psychiatric Risks Advise patients that methylphenidate hydrochloride tablets at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)]. Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5)] . Circulation Problems in Fingers and Toes [Peripheral vasculopathy, Including Raynaud’s Phenomenon] Instruct patients about the risk of peripheral vasculopathy, including Raynaud’s Phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)] . Suppression of Growth Advise patients that methylphenidate hydrochloride tablets may cause slowing of growth and weight loss [see Warnings and Precautions (5.7)]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including methylphenidate hydrochloride, during pregnancy [see Use in Specific Populations (8.1)] . \Manufactured for: AvKARE Pulaski, TN 38478 Mfg. Rev. 01/20 AV Rev. 07/20 (P) AvPAK
MEDICATION GUIDE MEDICATION GUIDE Methylphenidate hydrochloride tablets, USP CII (meth'' il fen' i date hye'' droe klor' ide) What is the most important information I should know about methylphenidate hydrochloride tablets? Methylphenidate hydrochloride is a federal controlled substance (CII) because it can be abused or lead to dependence. Keep methylphenidate hydrochloride tablets in a safe place to prevent misuse and abuse. Selling or giving away methylphenidate hydrochloride tablets may harm others and is against the law. Tell your doctor if you or your child have abused or been dependent on alcohol, prescription medicines or street drugs. The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines. 1. Heart-related problems : sudden death in patients who have heart problems or heart defects stroke and heart attack in adults increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting methylphenidate hydrochloride tablets. Your doctor should check you or your childs blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride tablets. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride tablets. 2. Mental (Psychiatric) problems : All Patients new or worse behavior and thought problems new or worse bipolar illness new or worse aggressive behavior or hostility new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride tablets , especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. What are methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Methylphenidate hydrochloride tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Methylphenidate hydrochloride tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride tablets are also used in the treatment of a sleep disorder called narcolepsy. It is not known if methylphenidate hydrochloride tablets are safe and effective in children under 6 years of age. Who should not take methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets should not be taken if you or your child: are allergic to methylphenidate hydrochloride, or any of the ingredients in methylphenidate hydrochloride tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride tablets. are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.
hydrochloride, or any of the ingredients in methylphenidate hydrochloride tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride tablets. are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI. Methylphenidate hydrochloride tablets may not be right for you or your child. Before starting methylphenidate hydrochloride tablets, tell your or your child’s doctor about all health conditions (or a family history of) including: heart problems, heart defects, high blood pressure mental problems including psychosis, mania, bipolar illness, or depression circulation problems in fingers or toes if you are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride tablets will harm your unborn baby. There is a pregnancy registry for females who are exposed to ADHD medications, including methylphenidate hydrochloride, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate hydrochloride and their baby. If you or your child becomes pregnant during treatment with methylphenidate hydrochloride, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/. if you are breastfeeding or plan to breastfeed, methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with methylphenidate hydrochloride. Tell your doctor about all of the medicines that you or your child takes including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride tablets. Your doctor will decide whether methylphenidate hydrochloride tablets can be taken with other medicines. Especially tell your doctor if you or your child takes: anti-depression medicines including monoamine oxidase inhibitors (MAOIs) blood pressure medicines (anti-hypertensive) Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. You should not take methylphenidate hydrochloride tablets on the day of your operation if a certain type of anesthetic is used. This is because there is a chance of a sudden rise in blood pressure and heart rate during the operation. Do not start any new medicine while taking methylphenidate hydrochloride tablets without talking to your doctor first. How should methylphenidate hydrochloride tablets be taken? Take methylphenidate hydrochloride tablets exactly as prescribed . Your doctor may adjust the dose until it is right for you or your child. Methylphenidate hydrochloride tablets is usually taken 2 to 3 times a day. Take methylphenidate hydrochloride tablets 30 to 45 minutes before a meal. From time to time, your doctor may stop methylphenidate hydrochloride tablets treatment for a while to check ADHD symptoms. Your doctor may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride tablets. Children should have their height and weight checked often while taking methylphenidate hydrochloride tablets. Methylphenidate hydrochloride tablets treatment may be stopped if a problem is found during these check-ups. In case of poisoning call your poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room. What are the possible side effects of methylphenidate hydrochloride tablets?
lets. Methylphenidate hydrochloride tablets treatment may be stopped if a problem is found during these check-ups. In case of poisoning call your poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room. What are the possible side effects of methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets may cause serious side effects, including: See " What is the most important information I should know about methylphenidate hydrochloride tablets? " for information on reported heart and mental problems. painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately. circulation problems in fingers and toes (Peripheral vasculopathy, including Raynaud's phenomenon): fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your doctor if you or your child have, numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets. slowing of growth (height and weight) in children Common side effects include: fast heart beat sweating a lot nervousness abnormal heartbeat (palpitations) decreased appetite stomach pain head ache dry mouth trouble sleeping nausea Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store methylphenidate hydrochloride tablets? Store methylphenidate hydrochloride tablets in a safe place and in a tightly closed container at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light. Dispose of remaining, unused, or expired methylphenidate hydrochloride tablets by a medicine take-back program at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix methylphenidate hydrochloride tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away (discard) methylphenidate hydrochloride tablets in the household trash. Keep methylphenidate hydrochloride tablets and all medicines out of the reach of children. General information about the safe and effective use of methylphenidate hydrochloride tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or doctor for information about methylphenidate hydrochloride tablets that is written for healthcare professionals. Do not use methylphenidate hydrochloride tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them and it is against the law. What are the ingredients in methylphenidate hydrochloride tablets? Active Ingredient: Methylphenidate HCl. Inactive Ingredients: Methylphenidate hydrochloride tablets, USP contain inactive ingredients: compressible sugar, colloidal silicon dioxide, D&C yellow no. 10 (5 mg and 20 mg tablets), lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Manufactured for: AvKARE Pulaski, TN 38478 Mfg. Rev. 01/20 AV Rev. 07/20 (P) AvPAK For more information and request for additional copies of the Medication Guide, call AvKARE at 1-855-361-3993. This Medication Guide has been approved by the U.S.
, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Manufactured for: AvKARE Pulaski, TN 38478 Mfg. Rev. 01/20 AV Rev. 07/20 (P) AvPAK For more information and request for additional copies of the Medication Guide, call AvKARE at 1-855-361-3993. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev: 01/20
<table border="1" cellpadding="0" cellspacing="0"><tbody><tr><td valign="top"><content styleCode="bold">MEDICATION GUIDE</content><paragraph><content styleCode="bold">Methylphenidate </content><content styleCode="bold">hydrochloride </content><content styleCode="bold">tablets, USP CII</content></paragraph> (meth'' il fen' i date hye'' droe klor' ide) </td></tr><tr><td valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about methylphenidate hydrochloride tablets?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate hydrochloride is a federal controlled substance (CII) because it can be abused or lead to dependence. </content>Keep methylphenidate hydrochloride tablets in a safe place to prevent misuse and abuse. Selling or giving away methylphenidate hydrochloride tablets may harm others and is against the law. </paragraph><paragraph>Tell your doctor if you or your child have abused or been dependent on alcohol, prescription medicines or street drugs.</paragraph><paragraph/><paragraph><content styleCode="bold">The following have been reported with use of methylphenidate hydrochloride</content><content styleCode="bold"> and other stimulant medicines.</content></paragraph><paragraph><content styleCode="bold">1. <content styleCode="underline">Heart-related problems</content></content>: </paragraph><list listType="unordered"><item><content styleCode="bold">sudden death in patients who have heart problems or heart defects</content></item><item><content styleCode="bold">stroke and heart attack in adults</content></item><item><content styleCode="bold">increased blood pressure and heart rate</content></item></list><paragraph>Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems.</paragraph><paragraph>Your doctor should check you or your child carefully for heart problems before starting methylphenidate hydrochloride tablets.</paragraph><paragraph>Your doctor should check you or your childs blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride tablets.</paragraph><paragraph/><paragraph><content styleCode="bold">Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride tablets.</content></paragraph><paragraph/><paragraph><content styleCode="bold">2.
.</paragraph><paragraph/><paragraph><content styleCode="bold">Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride tablets.</content></paragraph><paragraph/><paragraph><content styleCode="bold">2. <content styleCode="underline">Mental (Psychiatric) problems</content></content>: </paragraph><paragraph><content styleCode="bold">All Patients</content></paragraph><list listType="unordered"><item><content styleCode="bold">new or worse behavior and thought problems</content></item><item><content styleCode="bold">new or worse bipolar illness</content></item><item><content styleCode="bold">new or worse aggressive behavior or hostility</content></item><item><content styleCode="bold">new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms</content></item></list><paragraph/><paragraph>Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.</paragraph><paragraph/><paragraph><content styleCode="bold">Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride tablets</content>, <content styleCode="bold"> especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.</content></paragraph><paragraph/></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">What are methylphenidate hydrochloride tablets?</content></paragraph><list listType="unordered"><item>Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant prescription medicine. <content styleCode="bold">It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). </content>Methylphenidate hydrochloride tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. </item><item>Methylphenidate hydrochloride tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.</item><item>Methylphenidate hydrochloride tablets are also used in the treatment of a sleep disorder called narcolepsy.</item></list><paragraph><content styleCode="bold">It is not known if methylphenidate hydrochloride tablets</content><content styleCode="bold"> are safe and effective in children under 6 years of age.</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Who should not take methylphenidate hydrochloride tablets?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate hydrochloride tablets</content><content styleCode="bold"> should not be taken if you or your child:</content></paragraph><list listType="unordered"><item>are allergic to methylphenidate hydrochloride, or any of the ingredients in methylphenidate hydrochloride tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride tablets.</item><item>are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.</item></list></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Methylphenidate hydrochloride tablets</content><content styleCode="bold"> may not be right for you or your child.
em>are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.</item></list></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Methylphenidate hydrochloride tablets</content><content styleCode="bold"> may not be right for you or your child. Before starting methylphenidate hydrochloride tablets, tell your or your child’s doctor about all health conditions (or a family history of) including:</content></paragraph><list listType="unordered"><item>heart problems, heart defects, high blood pressure</item><item>mental problems including psychosis, mania, bipolar illness, or depression</item><item>circulation problems in fingers or toes</item><item>if you are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride tablets will harm your unborn baby. <list listType="unordered"><item>There is a pregnancy registry for females who are exposed to ADHD medications, including methylphenidate hydrochloride, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate hydrochloride and their baby. If you or your child becomes pregnant during treatment with methylphenidate hydrochloride, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/.</item></list></item><item>if you are breastfeeding or plan to breastfeed, methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with methylphenidate hydrochloride.</item></list><paragraph><content styleCode="bold">Tell your doctor about all of the medicines that you or your child takes including prescription and over-the-counter medicines, vitamins, and herbal supplements. </content>Methylphenidate hydrochloride tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride tablets. </paragraph><paragraph>Your doctor will decide whether methylphenidate hydrochloride tablets can be taken with other medicines.</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Especially tell your doctor if you or your child takes:</content></paragraph><list listType="unordered"><item>anti-depression medicines including monoamine oxidase inhibitors (MAOIs)</item><item>blood pressure medicines (anti-hypertensive)</item></list><paragraph>Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist.</paragraph><list listType="unordered"><item>You should not take methylphenidate hydrochloride tablets on the day of your operation if a certain type of anesthetic is used. This is because there is a chance of a sudden rise in blood pressure and heart rate during the operation.</item></list><paragraph><content styleCode="bold">Do not start any new medicine while taking methylphenidate hydrochloride tablets</content><content styleCode="bold"> without talking to your doctor first.</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">How should methylphenidate hydrochloride tablets be taken?</content></paragraph><list listType="unordered"><item>Take methylphenidate hydrochloride tablets exactly as prescribed <content styleCode="bold">. </content>Your doctor may adjust the dose until it is right for you or your child.
graph><content styleCode="bold">How should methylphenidate hydrochloride tablets be taken?</content></paragraph><list listType="unordered"><item>Take methylphenidate hydrochloride tablets exactly as prescribed <content styleCode="bold">. </content>Your doctor may adjust the dose until it is right for you or your child. </item><item>Methylphenidate hydrochloride tablets is usually taken 2 to 3 times a day.</item><item>Take methylphenidate hydrochloride tablets 30 to 45 minutes before a meal.</item><item>From time to time, your doctor may stop methylphenidate hydrochloride tablets treatment for a while to check ADHD symptoms.</item><item>Your doctor may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride tablets.</item><item>Children should have their height and weight checked often while taking methylphenidate hydrochloride tablets. Methylphenidate hydrochloride tablets treatment may be stopped if a problem is found during these check-ups.</item><item><content styleCode="bold">In case of poisoning call your poison control center at 1-800-222-1222 right away, or go to the nearest hospital </content><content styleCode="bold">emergency room.</content></item></list></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">What are the possible side effects of methylphenidate hydrochloride tablets?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate hydrochloride tablets may cause serious side effects, including:</content></paragraph><list listType="unordered"><item>See <content styleCode="bold"> "</content><content styleCode="bold">What is the most important information I should know about methylphenidate hydrochloride tablets?</content><content styleCode="bold">" </content>for information on reported heart and mental problems. </item><item><content styleCode="bold">painful and prolonged erections (priapism) </content>have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately. </item><item><content styleCode="bold">circulation problems in fingers and toes </content>(Peripheral vasculopathy, including Raynaud's phenomenon): <list listType="unordered"><item>fingers or toes may feel numb, cool, painful</item><item>fingers or toes may change color from pale, to blue, to red</item></list></item></list><paragraph>Tell your doctor if you or your child have, numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.</paragraph><list listType="unordered"><item><content styleCode="bold">Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets.</content></item><item><content styleCode="bold">slowing of growth (height and weight) in children</content></item></list><paragraph><content styleCode="bold">Common side effects include:</content></paragraph><paragraph/><list listType="unordered"><item>fast heart beat</item><item>sweating a lot</item><item>nervousness</item><item>abnormal heartbeat (palpitations)</item><item>decreased appetite</item><item>stomach pain</item><item>head ache</item><item>dry mouth</item><item>trouble sleeping</item><item>nausea</item></list><paragraph>Call your doctor for medical advice about side effects.
m><item>sweating a lot</item><item>nervousness</item><item>abnormal heartbeat (palpitations)</item><item>decreased appetite</item><item>stomach pain</item><item>head ache</item><item>dry mouth</item><item>trouble sleeping</item><item>nausea</item></list><paragraph>Call your doctor for medical advice about side effects. <content styleCode="bold">You may report side effects to FDA at 1-800-FDA-1088.</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">How should I store methylphenidate hydrochloride tablets?</content></paragraph><list listType="unordered"><item>Store methylphenidate hydrochloride tablets in a safe place and in a tightly closed container at room temperature between 68°F to 77°F (20°C to 25°C).</item><item>Protect from light.</item><item>Dispose of remaining, unused, or expired methylphenidate hydrochloride tablets by a medicine take-back program at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix methylphenidate hydrochloride tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away (discard) methylphenidate hydrochloride tablets in the household trash.</item><item><content styleCode="bold">Keep methylphenidate hydrochloride tablets and all medicines out of the reach of children.</content></item></list></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of methylphenidate hydrochloride tablets.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or doctor for information about methylphenidate hydrochloride tablets that is written for healthcare professionals. Do not use methylphenidate hydrochloride tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them and it is against the law.</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">What </content><content styleCode="bold">are the ingredients in methylphenidate hydrochloride tablets? </content></paragraph><paragraph><content styleCode="bold">Active </content><content styleCode="bold">Ingredient:</content>Methylphenidate HCl. </paragraph><paragraph><content styleCode="bold">Inactive Ingredients:</content>Methylphenidate hydrochloride tablets, USP contain inactive ingredients: compressible sugar, colloidal silicon dioxide, D&C yellow no. 10 (5 mg and 20 mg tablets), lactose monohydrate, magnesium stearate, and microcrystalline cellulose. </paragraph><paragraph/><paragraph/><paragraph>Manufactured for:</paragraph><paragraph>AvKARE</paragraph><paragraph>Pulaski, TN 38478</paragraph><paragraph/><paragraph>Mfg. Rev. 01/20</paragraph><paragraph>AV Rev. 07/20 (P)</paragraph><paragraph>AvPAK</paragraph><paragraph>For more information and request for additional copies of the Medication Guide, call AvKARE at 1-855-361-3993.</paragraph><paragraph/></td></tr></tbody></table>
WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate hydrochloride chewable tablets has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride chewable tablets, can result in overdose and death ([see Overdosage]), and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride chewable tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout methylphenidate hydrochloride chewable tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction (see Warnings and Precautions and Drug Abuse and Dependence).
DESCRIPTION Methylphenidate hydrochloride chewable tablets are a mild central nervous system (CNS) stimulant, available as 2.5 mg, 5 mg and 10 mg for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate Hydrochloride C 14 H 19 NO 2 • HCl MW = 269.77 Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Each methylphenidate hydrochloride chewable tablet, for oral administration, contains 2.5 mg, 5 mg or 10 mg of methylphenidate hydrochloride USP. In addition, methylphenidate hydrochloride chewable tablets also contain the following inactive ingredients: aspartame, lactose anhydrous, microcrystalline cellulose, guar gum, grape flavor, pregelatinized starch, and stearic acid.
CLINICAL PHARMACOLOGY Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in humans is not completely understood, but methylphenidate presumably activates the brain stem arousal system and cortex to produce its stimulant effect. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. There is neither specific evidence which clearly establishes the mechanism whereby methylphenidate hydrochloride chewable tablets produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. Pharmacokinetics Absorption Methylphenidate hydrochloride chewable tablets are readily absorbed. Following oral administration of methylphenidate hydrochloride chewable tablets, peak plasma methylphenidate concentrations are achieved at about 1 to 2 hours. Methylphenidate hydrochloride chewable tablets have been shown to be bioequivalent to Ritalin ® tablet. The mean C max following a 20 mg dose is approximately 10 ng/mL. Food Effect In a study in adult volunteers investigating the effects of a high-fat meal on the bioavailability of methylphenidate hydrochloride chewable tablets at a dose of 20 mg, the presence of food delayed the peak concentrations by approximately 1 hour (1.5 hours, fasted and 2.4 hours, fed). Overall, a high-fat meal increased the AUC of methylphenidate hydrochloride chewable tablets by about 20%, on average. Through a cross-study comparison, the magnitude of food effect is found to be comparable between the methylphenidate hydrochloride chewable tablets and Ritalin, the immediate release tablet. Metabolism and Excretion In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenylpiperidine acetic acid (PPA, ritalinic acid). The metabolite has little or no pharmacologic activity. After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPA, accounting for approximately 80% of the dose. The pharmacokinetics of the methylphenidate hydrochloride chewable tablets have been studied in healthy adult volunteers. The mean terminal half-life (t ½ ) of methylphenidate following administration of 20 mg methylphenidate hydrochloride chewable tablets (t ½ = 3 hours) is comparable to the mean terminal t ½ following administration of Ritalin (methylphenidate hydrochloride immediate-release tablets) (t ½ = 2.8 hours) in healthy adult volunteers. Special Populations Gender – The effect of gender on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride chewable tablets administration has not been studied. Race – The influence of race on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride chewable tablets administration has not been studied. Age – The pharmacokinetics of methylphenidate after methylphenidate hydrochloride chewable tablets administration have not been studied in pediatrics. Renal Insufficiency There is no experience with the use of methylphenidate hydrochloride chewable tablets in patients with renal insufficiency.
ion has not been studied. Age – The pharmacokinetics of methylphenidate after methylphenidate hydrochloride chewable tablets administration have not been studied in pediatrics. Renal Insufficiency There is no experience with the use of methylphenidate hydrochloride chewable tablets in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride chewable tablets. Hepatic Insufficiency There is no experience with the use of methylphenidate hydrochloride chewable tablets in patients with hepatic insufficiency.
INDICATIONS AND USAGE Attention Deficit Disorders, Narcolepsy Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction. Methylphenidate hydrochloride chewable tablets are indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics. Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms.
CONTRAINDICATIONS Methylphenidate hydrochloride chewable tablets are contraindicated in patients known to be hypersensitive to methylphenidate or other components of the drug. Methylphenidate hydrochloride chewable tablets are contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises may result).
WARNINGS Abuse, Misuse, and Addiction Methylphenidate hydrochloride chewable tablets has a high potential for abuse and misuse. The use of methylphenidate hydrochloride chewable tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate hydrochloride chewable tablets can be diverted for non-medical use into illicit channels or distribution (see DRUG ABUSE and DEPENDENCE). Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride chewable tablets can result in overdose and death (see OVERDOSAGE) , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride chewable tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride chewable tablets to anyone else. Throughout methylphenidate hydrochloride chewable tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who are treated with CNS stimulants at the recommended ADHD dosages. Avoid methylphenidate hydrochloride chewable tablets use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Monitor all patients for potential tachycardia and hypertension. Psychiatric Adverse Reactions Exacerbations of Pre-Existing Psychosis – CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disease – CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms – CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consideration discontinuing methylphenidate hydrochloride chewable tablets. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures.
de chewable tablets. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or discontinuation): Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. Peripheral Vasculopathy, Including Raynaud’s Phenomenon Stimulants, including methylphenidate hydrochloride chewable tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Long-Term Suppression of Growth in Pediatric Patients CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in methylphenidate hydrochloride chewable tablets-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted (see PRECAUTIONS, PEDIATRIC USE). Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate hydrochloride chewable tablets-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment (see Adverse Reactions). Prescribe methylphenidate hydrochloride chewable tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride chewable tablets-treated patients with a history of abnormally increased IOP or open angle glaucoma.
henidate hydrochloride chewable tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride chewable tablets-treated patients with a history of abnormally increased IOP or open angle glaucoma. Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported. Assess the family history and clinically evaluate patients for tics or Tourette’s syndrome before initiating methylphenidate hydrochloride chewable tablets. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome with methylphenidate hydrochloride chewable tablets, and discontinue treatment if clinically appropriate. USE IN CHILDREN LESS THAN SIX YEARS OF AGE Methylphenidate hydrochloride chewable tablets should not be used in children under six years, since safety and efficacy in this age group have not been established.
DRUG ABUSE AND DEPENDENCE Controlled Substance Methylphenidate hydrochloride chewable tablets contains methylphenidate, a Schedule II controlled substance. Abuse Methylphenidate hydrochloride chewable tablets has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction (see Warnings and Precautions). Methylphenidate hydrochloride chewable tablets can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride chewable tablets, can result in overdose and death (see Overdosage), and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Dependence Physical Dependence Methylphenidate hydrochloride chewable tablets may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride chewable tablets include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate hydrochloride chewable tablets may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
PRECAUTIONS General Patients with an element of agitation may react adversely; discontinue therapy if necessary. Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe methylphenidate hydrochloride chewable tablets should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with methylphenidate hydrochloride chewable tablets are usually not indicated. Long-term effects of methylphenidate hydrochloride chewable tablets in children have not been well established. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of methylphenidate hydrochloride chewable tablets, which can lead to overdose and death, and proper disposal of any unused drug (see WARNINGS and PRECAUTIONS, DRUG ABUSE AND DEPENDENCE , OVERDOSAGE ) . Advise patients to store methylphenidate hydrochloride chewable tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride chewable tablets to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with methylphenidate hydrochloride chewable tablets use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease (see WARNINGS). Increased Blood Pressure and Heart Rate Advise patients that methylphenidate hydrochloride chewable tablets can elevate blood pressure and heart rate (see WARNINGS). Psychiatric Adverse Reactions Advise patients that methylphenidate hydrochloride chewable tablets, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania (see WARNINGS). Priapism Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism . Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon] Instruct patients beginning treatment with methylphenidate hydrochloride chewable tablets about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride chewable tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
ivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride chewable tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Suppression of Growth in Pediatric Patients Advise patients, caregivers, and family members that methylphenidate hydrochloride chewable tablets can cause slowing of growth and weight loss (see Warnings). Increased Intraocular Pressure and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with methylphenidate hydrochloride chewable tablets (see Warnings). Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with methylphenidate hydrochloride chewable tablets. Instruct the patients to notify their healthcare provider if emergence or worsening of tics or Tourette’s syndrome occurs (see WARNINGS). Choking – Taking this product without adequate fluid may cause it to swell and block your throat or esophagus and may cause choking. Do not take this product if you have difficulty in swallowing. If you experience chest pain, vomiting, or difficulty in swallowing or breathing after taking this product, seek immediate medical attention. Directions – Take this product (child or adult dose) with at least 8 ounces (a full glass) of water or other fluid. Taking this product without enough liquid may cause choking. See choking warning. Phenylketonurics – Phenylalanine is a component of aspartame. Each 2.5 mg methylphenidate hydrochloride chewable tablet contains 0.35 mg of phenylalanine; each 5 mg methylphenidate hydrochloride chewable tablet contains 0.70 mg of phenylalanine and each 10 mg methylphenidate hydrochloride chewable tablet contains 1.40 mg of phenylalanine. Drug Interactions Monoamine Oxidase Inhibitors (MAOI) Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride chewable tablets can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure (see CONTRAINDICATIONS ). Concomitant use of methylphenidate hydrochloride chewable tablets with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Methylphenidate hydrochloride chewable tablets may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Risperidone Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS. Methylphenidate hydrochloride chewable tablets may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that methylphenidate hydrochloride chewable tablets may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with methylphenidate hydrochloride chewable tablets. Carcinogenesis, Mutagenesis, Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day.
lphenidate hydrochloride chewable tablets. Carcinogenesis, Mutagenesis, Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 2.5 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 4 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. The genotoxic potential of methylphenidate has not been evaluated in an in vivo assay. Usage in Pregnancy Adequate animal reproduction studies to establish safe use of methylphenidate hydrochloride chewable tablet during pregnancy have not been conducted. However, in a recently conducted study, methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 167 times and 78 times the maximum recommended human dose on a mg/kg and a mg/m 2 basis, respectively. In rats, teratogenic effects were not seen when the drug was given in doses of 75 mg/kg/day, which is approximately 62.5 and 13.5 times the maximum recommended human dose on a mg/kg and a mg/m 2 basis, respectively. Therefore, until more information is available, methylphenidate should not be prescribed for women of childbearing age unless, in the opinion of the physician, the potential benefits outweigh the possible risks.
ADVERSE REACTIONS Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy; libido changes; and rhabdomyolysis increased intraocular pressure and glaucoma, motor and verbal tics. There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to severe hepatic injury; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; a few instances of scalp hair loss; serotonin syndrome in combination with serotonergic drugs. Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten year old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also occur.
OVERDOSAGE Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
DOSAGE AND ADMINISTRATION Prior to treating patients with Methylphenidate hydrochloride chewable tablets assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) (see WARNINGS). the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome (see WARNINGS). Dosage should be individualized according to the needs and responses of the patient. Directions – Take this product (child or adult dose) with at least 8 ounces (a full glass) of water or other fluid. Taking this product without enough liquid may cause choking. See choking warning. Adults Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. Children (6 years and over) Methylphenidate hydrochloride chewable tablets should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue methylphenidate hydrochloride chewable tablets. Methylphenidate hydrochloride chewable tablets should be periodically discontinued to assess the patient’s condition. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly. Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.
HOW SUPPLIED Each methylphenidate hydrochloride chewable tablet 10 mg is available as a white to off-white flat round chewable tablets debossed with 'AT' on left side and '262' on the right side of the bisect line and other side plain. NDC: 72162-1306-1: 100 Tablets in a BOTTLE Protect from moisture. Dispense in tight container with child-resistant closure. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504
MEDICATION GUIDE Methylphenidate HCl Chewable Tablet, CII (meth'' il fen' i date hye'' droe klor' ide) Read the Medication Guide that comes with methylphenidate hydrochloride chewable tablets before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your or your child’s treatment with methylphenidate hydrochloride chewable tablets. What is the most important information I should know about methylphenidate hydrochloride chewable tablets? Methylphenidate hydrochloride chewable tablets may cause serious side effects, including: Abuse, misuse, and addiction. Methylphenidate hydrochloride chewable tablets have a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride chewable tablets, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride chewable tablets or when it is used in ways that are not approved, such as snorting or injection. Heart-related problems: Mental (Psychiatric) problems: Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. What Are methylphenidate hydrochloride chewable tablets? Methylphenidate hydrochloride chewable tablets are a central nervous system stimulant prescription medicine. Methylphenidate hydrochloride chewable tablets are tablets that are made to be chewed and swallowed. They are used for the treatment of Attention Deficit and Hyperactivity Disorder (ADHD). Methylphenidate hydrochloride chewable tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Methylphenidate hydrochloride chewable tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride chewable tablets are also used in the treatment of a sleep disorder called narcolepsy. Methylphenidate hydrochloride chewable tablets are a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep methylphenidate hydrochloride chewable tablets in a safe place to protect it from theft. Never give your methylphenidate hydrochloride chewable tablets to anyone else, because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride chewable tablets may harm others, and is against the law. Who should not take methylphenidate hydrochloride chewable tablets? Methylphenidate hydrochloride chewable tablets should not be taken if you or your child: are very anxious, tense, or agitated have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome are taking or have taken within the past 14 days an antidepression medicine called a monoamine oxidase inhibitor or MAOI. are allergic to anything in methylphenidate hydrochloride chewable tablets. See the end of this Medication Guide for a complete list of ingredients.
e a family history of tics or Tourette’s syndrome are taking or have taken within the past 14 days an antidepression medicine called a monoamine oxidase inhibitor or MAOI. are allergic to anything in methylphenidate hydrochloride chewable tablets. See the end of this Medication Guide for a complete list of ingredients. Methylphenidate hydrochloride chewable tablets should not be used in children less than 6 years old because they have not been studied in this age group. Methylphenidate hydrochloride chewable tablets may not be right for you or your child. Before starting methylphenidate hydrochloride chewable tablets tell your or your child’s healthcare provider about all health conditions (or a family history of) including: have heart problems, heart disease, heart defects, or high blood pressure mental problems including psychosis, mania, bipolar illness, or depression tics or Tourette’s syndrome seizures or have had an abnormal brain wave test (EEG) circulation problems in fingers and toes Tell your healthcare provider if you or your child is pregnant, planning to become pregnant, or breastfeeding. Can methylphenidate hydrochloride chewable tablets be taken with other medicines? Tell your healthcare provider about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride chewable tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride chewable tablets. Your healthcare provider will decide whether methylphenidate hydrochloride chewable tablets can be taken with other medicines. Especially tell your healthcare provider if you or your child takes: antidepression medicines including MAOIs seizure medicines blood thinner medicines blood pressure medicines cold or allergy medicines that contain decongestants Know the medicines that you or your child takes. Keep a list of your medicines with you to show your healthcare provider and pharmacist. Do not start any new medicine while taking methylphenidate hydrochloride chewable tablets without talking to your healthcare provider first. How should methylphenidate hydrochloride chewable tablets be taken? Take methylphenidate hydrochloride chewable tablets exactly as prescribed. Your healthcare provider may adjust the dose until it is right for you or your child. Methylphenidate hydrochloride chewable tablets are usually taken 2 to 3 times a day. Take methylphenidate hydrochloride chewable tablets 30 to 45 minutes before a meal. Chew methylphenidate hydrochloride chewable tablets well and swallow with at least 8 ounces (a full glass) of water or other liquid. Methylphenidate hydrochloride chewable tablets can swell and cause choking if enough liquid is not taken with them. Get emergency medical care if you have chest pain, vomiting, or trouble swallowing, or breathing after taking a methylphenidate hydrochloride chewable tablet. From time to time, your healthcare provider may stop methylphenidate hydrochloride chewable tablets treatment for awhile to check ADHD symptoms. Your healthcare provider may do regular checks of the blood, heart, and blood pressure while you are taking methylphenidate hydrochloride chewable tablets. Children should have their height and weight checked often while taking methylphenidate hydrochloride chewable tablets. Methylphenidate hydrochloride chewable tablets treatment may be stopped if a problem is found during these check-ups. If you or your child take too much methylphenidate hydrochloride chewable tablets, call your healthcare provider or Poison Helpline, at 1-800-222-1222 or go to the nearest hospital emergency room right away.
lphenidate hydrochloride chewable tablets treatment may be stopped if a problem is found during these check-ups. If you or your child take too much methylphenidate hydrochloride chewable tablets, call your healthcare provider or Poison Helpline, at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are possible side effects of methylphenidate hydrochloride chewable tablets? See “What is the most important information I should know about methylphenidate hydrochloride chewable tablets?” for information on reported heart and mental problems. Other serious side effects include: Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with methylphenidate hydrochloride chewable tablets. Your healthcare provider may stop your child’s methylphenidate hydrochloride chewable tablets treatment if they are not growing or gaining weight as expected. Seizures, mainly in patients with a history of seizures Painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develop priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a healthcare provider immediately. Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon): fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Tell your healthcare provider if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes or if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride chewable tablets. Eyes problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride chewable tablets. Common side effects include: Talk to your healthcare provider if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store methylphenidate hydrochloride chewable tablets? Store methylphenidate hydrochloride chewable tablets in a safe place at room temperature, at 20° to 25°C (68° to 77°F). [see USP Controlled Room Temperature]. Protect from moisture. Dispose of remaining, unused, or expired methylphenidate hydrochloride chewable tablets by a medicine take back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no takeback program or DEA authorized collector is available, mix methylphenidate hydrochloride chewable tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away methylphenidate hydrochloride chewable tablets in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep methylphenidate hydrochloride chewable tablets and all medicines out of the reach of children. General information about methylphenidate hydrochloride chewable tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
itional information on disposal of unused medicines. Keep methylphenidate hydrochloride chewable tablets and all medicines out of the reach of children. General information about methylphenidate hydrochloride chewable tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use methylphenidate hydrochloride chewable tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride chewable tablets to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about methylphenidate hydrochloride chewable tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about methylphenidate hydrochloride chewable tablets that is written for healthcare professionals. For more information, please contact Camber Pharmaceuticals, Inc. at 1-866-495-8330. What are the ingredients in methylphenidate hydrochloride chewable tablets? CAUTION PHENYLKETONURICS: Methylphenidate hydrochloride chewable tablets contain phenylalanine. Active Ingredient: methylphenidate hydrochloride USP Inactive Ingredients: aspartame, lactose anhydrous, microcrystalline cellulose, guar gum, grape flavor, pregelatinized starch, and stearic acid. Medication Guide available at http://camberpharma.com/medication-guides Manufactured by: Ascent Pharmaceuticals, Inc. Central Islip, NY 11722 Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 09/2023
<table border="1" cellspacing="0" cellpadding="0"><tbody><tr styleCode="First Last"><td valign="top"><paragraph styleCode="CM14 First"><content styleCode="bold"><content>What is the most important information I should know about methylphenidate hydrochloride chewable tablets?</content></content></paragraph><paragraph styleCode="CM19"><content styleCode="bold">Methylphenidate hydrochloride chewable tablets may cause serious side effects, including:</content></paragraph><list listType="unordered"><item><content styleCode="bold">Abuse, misuse, and addiction.</content> Methylphenidate hydrochloride chewable tablets have a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride chewable tablets, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride chewable tablets or when it is used in ways that are not approved, such as snorting or injection.</item></list><renderMultiMedia referencedObject="Lfcb75013-c036-4c65-9991-5de715bd283c"/><list listType="unordered"><item><content styleCode="bold">Heart-related problems:</content></item></list><content styleCode="bold"><renderMultiMedia referencedObject="L9830458f-1dfd-4433-b278-4ccff241714c"/></content><list listType="unordered"><item><content styleCode="bold">Mental (Psychiatric) problems:</content></item></list><paragraph styleCode="CM19"><content styleCode="bold"><renderMultiMedia referencedObject="L84468787-df28-415e-afc7-0d86daa84e49"/></content></paragraph><list listType="unordered"><item><content styleCode="bold">Circulation problems in fingers and toes</content> [Peripheral vasculopathy, including Raynaud’s phenomenon]: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.</item></list><renderMultiMedia referencedObject="L68aa100b-5a62-456a-99cf-b90e5e456b2e"/></td></tr></tbody></table>
n problems in fingers and toes</content> [Peripheral vasculopathy, including Raynaud’s phenomenon]: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.</item></list><renderMultiMedia referencedObject="L68aa100b-5a62-456a-99cf-b90e5e456b2e"/></td></tr></tbody></table> <table border="1" cellspacing="0" cellpadding="0"><tbody><tr styleCode="First Last"><td valign="top"><paragraph styleCode="CM12 First"><content styleCode="bold">Methylphenidate hydrochloride chewable tablets are a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. </content>Keep<content styleCode="bold"> methylphenidate hydrochloride chewable tablets </content>in a safe place to protect it from theft. Never give your <content styleCode="bold">methylphenidate hydrochloride chewable tablets</content> to anyone else, because it may cause death or harm them. Selling or giving away <content styleCode="bold">methylphenidate hydrochloride chewable tablets</content> may harm others, and is against the law.</paragraph></td></tr></tbody></table> <table border="1" cellspacing="0" cellpadding="0"><tbody><tr styleCode="First Last"><td valign="top"><list listType="unordered"><item><content styleCode="bold">Chew methylphenidate hydrochloride chewable tablets well and swallow with at least 8 ounces (a full glass) of water or other liquid. Methylphenidate hydrochloride chewable tablets can swell and cause choking if enough liquid is not taken with them. Get emergency medical care if you have chest pain, vomiting, or trouble swallowing, or breathing after taking a methylphenidate hydrochloride chewable tablet.</content></item></list></td></tr></tbody></table> <table border="1" cellspacing="0" cellpadding="0"><tbody><tr styleCode="First Last"><td valign="top"><paragraph styleCode="CM13 First"><content styleCode="bold">CAUTION PHENYLKETONURICS: </content><content styleCode="bold">Methylphenidate hydrochloride chewable tablets contain phenylalanine. </content></paragraph></td></tr></tbody></table>
WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate hydrochloride extended-release tablets has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with a higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of methylphenidate hydrochloride extended-release tablets and proper disposal of any unused drug. Throughout methylphenidate hydrochloride extended-release tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence ( 9.1 , 9.2 )]. WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. Methylphenidate hydrochloride extended-release tablets has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death ( 5.1 , 9.2 , 10 ): Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of methylphenidate hydrochloride extended-release tablets, and proper disposal of any unused drug. Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
Indications and Usage ( 1 ) 9/2025 Dosage and Administration ( 2.3 , 2.4 ) 2/2026 Warnings and Precautions: Long-Term Suppression of Growth in Pediatric Patients 9/2025 Warnings and Precautions: Removal Seizures and Hematologic Monitoring 2/2026
1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release tablets are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 to 65 years old. Limitations of Use The use of methylphenidate hydrochloride extended-release tablets are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.4 )]. Methylphenidate hydrochloride extended-release tablets are a CNS stimulant indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 to 65 years old. ( 1 ) Limitations of Use The use of methylphenidate hydrochloride extended-release tablets are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.7 , 8.4 ).
2 DOSAGE AND ADMINISTRATION Prior to initiating methylphenidate hydrochloride extended-release tablets treatment assess for ( 2.1 ): the presence of cardiac disease for family history of tics or Tourette’ syndrome and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome Administer once daily in the morning with or without food. Swallow whole with liquids; do not chew, divide, or crush. ( 2.2 ) Recommended dosage in pediatric patients 6 to 17 years of age new to methylphenidate: starting dosage is18 mg once daily. May be increased weekly in 18 mg increments. Maximum dosage for pediatric patients ( 2.3 ): 6 to 12 years: 54 mg once daily 13 to 17 years: 72 mg once daily Recommended dosage in adults (up to 65 years of age) new to methylphenidate: starting dosage is 18 mg or 36 mg once daily. May be increased weekly in 18 mg increments, up to 72 mg once daily. ( 2.3 ) Patients currently using immediate-release methylphenidate: starting methylphenidate hydrochloride extended-release tablets dosage is based on current dosage regimen. ( 2.4 ) 2.1 Pretreatment Screening Prior to treating patients with methylphenidate hydrochloride extended-release tablets, assess: For the presence of cardiac disease (e.g., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions ( 5.2) ]. The family history for tics or Tourette’ syndrome and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome [see Warnings and Precautions ( 5.11 )]. 2.2 Important Administration Instructions Administer methylphenidate hydrochloride extended-release tablets orally once daily in the morning with or without food. Swallow methylphenidate hydrochloride extended-release tablets whole with liquids. Do not split, crush, or chew the extended-release tablets because doing so will compromise the extended-release characteristics of methylphenidate hydrochloride extended-release tablets and may compromise the effectiveness or safety of methylphenidate hydrochloride extended-release tablets. 2.3 Recommended Methylphenidate Hydrochloride Extended-Release Tablets Dosage in Patients New to Methylphenidate See Table 1 for the recommended once-daily dosage of methylphenidate hydrochloride extended-release tablets in patients who were not taking a methylphenidate product. In patients who have not achieved an optimal response at a lower dosage, increase the methylphenidate hydrochloride extended-release tablets dosage in 18 mg increments at weekly intervals. However, if a slower titration is recommended for patients who have not achieved an optimal response taking 18 mg of methylphenidate hydrochloride extended-release tablets once daily, increase their daily dosage to 27 mg once per day. Table 1.
ide extended-release tablets dosage in 18 mg increments at weekly intervals. However, if a slower titration is recommended for patients who have not achieved an optimal response taking 18 mg of methylphenidate hydrochloride extended-release tablets once daily, increase their daily dosage to 27 mg once per day. Table 1. Recommended Methylphenidate Hydrochloride Extended-Release Tablets Dosage in Patients New to Methylphenidate Patient Population Recommended Starting Dosage Dosage Range Pediatric patients 6 to 12 years of age 18 mg once daily 18 mg to 54 mg once daily Pediatric patients 13 to 17 years of age 18 mg once daily 18 mg to 72 mg once daily (not to exceed 2 mg/kg/day) Adults 18 to 65 years of age 18 or 36 mg once daily 18 mg to 72 mg once daily 2.4 Recommended Methylphenidate Hydrochloride Extended-Release Tablets Dosage in Patients Switching from Another Methylphenidate Product See Table 2 for the recommended starting dosage of methylphenidate hydrochloride extended-release tablets in patients switching from an immediate-release methylphenidate product administered twice daily or three times daily (total daily dosage of 10 to 60 mg/day). Table 2. Recommended Starting Dosage in Patients Switching from Another Methylphenidate Product Previous Immediate-release Methylphenidate Daily Dosage Recommended Methylphenidate Hydrochloride Extended-Release Tablets Starting Dosage 5 mg twice daily or three times daily 18 mg every morning 10 mg twice daily or three times daily 36 mg every morning 15 mg twice daily or three times daily 54 mg every morning 20 mg twice daily or three times daily 72 mg every morning* * Only for patients 13-65 years of age. In patients who have not achieved an optimal response at a lower dosage, increase the methylphenidate hydrochloride extended-release tablets dosage in 18 mg increments at weekly intervals. The maximum recommended dosage in pediatric patients 6 to 12 years of age is 54 mg/day, and the maximum recommended dosage in patients 13 to 65 years old is 72 mg/day. 2.5 Dosage Reduction and Discontinuation If paradoxical aggravation of ADHD symptoms or methylphenidate hydrochloride extended-release tablets- associated adverse reactions occur, reduce the methylphenidate hydrochloride extended-release tablets dosage or, if necessary, discontinue methylphenidate hydrochloride extended-release tablets. If ADHD improvement is not observed after appropriate dosage modification over a one-month period, discontinue methylphenidate hydrochloride extended-release tablets.
e the methylphenidate hydrochloride extended-release tablets dosage or, if necessary, discontinue methylphenidate hydrochloride extended-release tablets. If ADHD improvement is not observed after appropriate dosage modification over a one-month period, discontinue methylphenidate hydrochloride extended-release tablets. 2.1 Pretreatment Screening Prior to treating patients with methylphenidate hydrochloride extended-release tablets, assess: For the presence of cardiac disease (e.g., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions ( 5.2) ]. The family history for tics or Tourette’ syndrome and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome [see Warnings and Precautions ( 5.11 )].
3 DOSAGE FORMS AND STRENGTHS Methylphenidate hydrochloride extended-release tablets, USP are available in the following dosage strengths: 18 mg – Each yellow, film-coated, capsule shaped tablet imprinted with the Andrx logo and 725 on one side and plain on the other side contains 18 mg methylphenidate hydrochloride, USP. 27 mg – Each gray, film-coated, capsule shaped tablet imprinted with the Andrx logo and 734 on one side and plain on the other side contains 27 mg methylphenidate hydrochloride, USP. 36 mg – Each white, film-coated, capsule shaped tablet imprinted with the Andrx logo and 726 on one side and plain on the other side contains 36 mg methylphenidate hydrochloride, USP. 54 mg – Each red brown, film-coated, capsule shaped tablet imprinted with the Andrx logo and 727 on one side and plain on the other side contains 54 mg methylphenidate hydrochloride, USP. Extended-release tablets: 18 mg, 27 mg, 36 mg, and 54 mg ( 3 )
4 CONTRAINDICATIONS Methylphenidate hydrochloride extended-release tablets is contraindicated in patients: Known to be hypersensitive to methylphenidate or other components of methylphenidate hydrochloride extended-release tablets. Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been reported in patients treated with methylphenidate hydrochloride extended-release tablets. [see Adverse Reactions ( 6 )] . Receiving concomitant monoamine oxidase inhibitors (MAOIs), and within 14 days following discontinuation of treatment with a MAO inhibitor because of the risk of a hypertensive crisis [see Drug Interactions ( 7 )] . Known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride extended-release tablets ( 4 ) Receiving concomitant monoamine oxidase inhibitors and within 14 days following discontinuation of treatment with a MAO inhibitor ( 4 )
5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease : Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease ( 5.2 ). Increased Blood Pressure and Heart Rate : Monitor blood pressure and pulse ( 5.3 ). Psychiatric Adverse Reactions : Prior to initiating methylphenidate hydrochloride extended-release tablets, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release tablets. ( 5.4 ) Priapism : If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention ( 5.5 ) Peripheral Vasculopathy, including Raynaud’s Phenomenon : Carefully assess for digital changes during methylphenidate hydrochloride extended-release tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy ( 5.6 ) Long-Term Suppression of Growth in Pediatric Patients : Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their methylphenidate hydrochloride extended-release tablets treatment interrupted. ( 5.7 ) Risk of Gastrointestinal (GI) Obstruction in Patients with GI Narrowing : Only use in patients able to swallow the extended-release tablet whole, and should not ordinarily be used in patients with pre-existing severe GI narrowing.( 5.8 ) Acute Angle Closure Glaucoma : Methylphenidate hydrochloride extended-release tablets -treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. ( 5.9 ) Increased Intraocular Pressure (IOP) and Glaucoma : Prescribe methylphenidate hydrochloride extended-release tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma. ( 5.10 ) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome : Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue methylphenidate treatment if clinically appropriate. ( 5.11 ) 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride extended-release tablets has a high potential for abuse and misuse. The use of methylphenidate hydrochloride extended-release tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction [see Drug Abuse and Dependence ( 9.1 , 9.2 )]. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage ( 10 )], and this risk is increased with higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction.
tablets, can result in overdose and death [see Overdosage ( 10 )], and this risk is increased with higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate hydrochloride extended-release tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride extended-release tablets to anyone else. Throughout methylphenidate hydrochloride extended-release tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate hydrochloride extended-release tablets use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute) [see Adverse Reactions ( 6 )] . Some patients may have larger increases. Monitor all methylphenidate hydrochloride extended-release tablets-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Psychosis in Patients with a Psychotic Disorder CNS stimulants, including methylphenidate hydrochloride extended-release tablets, may exacerbate behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants, including methylphenidate hydrochloride extended-release tablets may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating methylphenidate hydrochloride extended-release tablets treatment, screen patients for risk factors for developing a manic episode (e.g., history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms in Patients without a History of a Bipolar or Psychotic Disorder CNS stimulants (including methylphenidate hydrochloride extended-release tablets), at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release tablets. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in adult and pediatric male patients [see Adverse Reactions ( 6 )]. Although priapism was not reported with methylphenidate initiation, priapism occurred in patients treated with methylphenidate after some time, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation).
ts [see Adverse Reactions ( 6 )]. Although priapism was not reported with methylphenidate initiation, priapism occurred in patients treated with methylphenidate after some time, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride extended-release tablets-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including methylphenidate hydrochloride extended-release, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon [see Adverse Reactions ( 6.2 )] . Signs and symptoms of these cases of peripheral vasculopathy were usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms of peripheral vasculopathy generally improved after CNS stimulant dosage reduction or discontinuation. During methylphenidate hydrochloride extended-release tablets treatment, carefully assess for digital changes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride extended-release tablets-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients Methylphenidate hydrochloride extended-release tablets are not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations ( 8.4 )] . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Pediatric patients 7 to 13 years of age who received methylphenidate for 7 days per week for over 14 months to over 36 months had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in methylphenidate hydrochloride extended-release tablets-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 Risk of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing Because the methylphenidate hydrochloride extended-release tablets are nondeformable and do not appreciably change in shape in the gastrointestinal (GI) tract, methylphenidate hydrochloride extended-release tablets should not ordinarily be administered to patients with preexisting severe pathologic or iatrogenic GI narrowing. There have been rare reports of obstructive GI symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable modified-release dosage forms. Methylphenidate hydrochloride extended-release tablets should be used only in patients who are able to swallow the extended-release tablets whole [see Dosage and Administration ( 2.2 )] . 5.9 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate hydrochloride extended-release tablets-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.
rts of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate hydrochloride extended-release tablets-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.10 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions ( 6 )]. Prescribe methylphenidate hydrochloride extended-release tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride extended-release tablets-treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.11 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics [see Adverse Reactions ( 6 )] . Worsening of Tourette’s syndrome has also been reported . Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history for tics or Tourette’ syndrome and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride extended-release tablets-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue methylphenidate hydrochloride extended-release tablets treatment if clinically appropriate.
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2) ] Hypersensitivity Reactions [see Contraindications ( 4 )] Monoamine Oxidase Inhibitors [see Contraindications ( 4 ), Drug Interactions ( 7 )] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions ( 5.2 )] Increased Blood Pressure and Heart Rate [see Warnings and Precautions ( 5.3 )] Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.4 )] Priapism [see Warnings and Precautions ( 5.5 )] Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions ( 5.6 )] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions ( 5.7 )] Risks of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing [see Warnings and Precautions ( 5.8 )] Acute Angle Closure Glaucoma [see Warnings and Precautions ( 5.9 )] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions ( 5.10 )] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.11 )] The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients 6 to 17 years: upper abdominal pain. ( 6.1 ) Adults up to 65 years of age: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 clinical trials of another drug and may not reflect the rates observed in clinical practice. The data below is based on a total of 3,906 patients in clinical studies who received methylphenidate hydrochloride extended-release tablets. Patients aged 6 up to 65 years old with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies [see Table 3] . Table 3. Methylphenidate Hydrochloride Extended-Release Tablets-treated Patients in Double-Blind and Open-Label Clinical Studies Patient Population N Dosage Range Pediatric patients 6 to 12 years of age 2,216 18 to 54 mg once daily Adolescents 502 18 to 72 mg once daily Adults up to 65 years of age 1,188 18 to 108 mg once daily The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients: upper abdominal pain [see Table 4] . Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis [see Table 5] . The most common adverse reactions associated with methylphenidate hydrochloride extended-release tablets discontinuation (≥1%) from the pediatric and adult clinical trials were anxiety, irritability, insomnia, and increased blood pressure. Most Common Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.
ediatric and adult clinical trials were anxiety, irritability, insomnia, and increased blood pressure. Most Common Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations. Adverse Reactions in Pediatric Patients Aged 6 years and Older Table 4 displays adverse reactions reported in 2% or more of methylphenidate hydrochloride extended-release tablets -treated pediatric patients ages 6 and older with ADHD in 4 placebo-controlled, double-blind clinical trials. Table 4: Most Common Adverse Reactions 1 in Pediatric Patients 6 Years of Age and Older with ADHD in 4 Placebo-Controlled, Double-Blind Clinical Trials Methylphenidate Hydrochloride Extended-Release Tablets (n=321) Placebo (n=318) Upper abdominal pain 6% 4% Insomnia 2 3% 1% Nasopharyngitis 3% 2% Vomiting 3% 2% Pyrexia 2% 1% 1 Reported in ≥ 2% of Methylphenidate Hydrochloride Extended-Release Tablets-treated patients 2 Initial insomnia (Methylphenidate Hydrochloride Extended-Release Tablets=0.6%) and insomnia (Methylphenidate Hydrochloride Extended-Release Tablets=2.2%) terms were combined into Insomnia. Adverse Reactions in Adults Table 5 lists the adverse reactions reported in 2% or more of Methylphenidate Hydrochloride Extended-Release Tablets-treated adults with ADHD in 2 placebo-controlled, double-blind clinical trials. Table 5: Most Common Adverse Reactions 1 in Adults with ADHD in 2 Placebo- Controlled, Double-Blind Clinical Trials Methylphenidate Hydrochloride Extended-Release Tablets 2 (n=415) Placebo (n=212) Decreased appetite 25% 7% Headache 22% 16% Dry mouth 14% 4% Nausea 13% 3% Insomnia 12% 6% Anxiety 8% 2% Decreased weight 7% 3% Dizziness 7% 5% Irritability 6% 1% Tachycardia 5% 0% Hyperhidrosis 5% 1% Depressed mood 4% 1% Initial insomnia 4% 3% Restlessness 3% 0% Palpitations 3% 1% Nervousness 3% 1% Tremor 3% 1% Upper respiratory tract infection 2% 1% Agitation 2% 1% Dyspepsia 2% 1% 1 Reported in ≥ 2% of Methylphenidate Hydrochloride Extended-Release Tablets-treated patients 2 Included dosages up to 108 mg/day (1.5 times the maximum recommended dosage). Other Adverse Reactions Observed in Clinical Trials of Methylphenidate Hydrochloride Extended-Release Tablets The following adverse reactions occurred in less than 2% of methylphenidate hydrochloride extended-release tablets-treated patients ages 6 to 65 years of age in the double-blind and open-label clinical ADHD trials.
r Adverse Reactions Observed in Clinical Trials of Methylphenidate Hydrochloride Extended-Release Tablets The following adverse reactions occurred in less than 2% of methylphenidate hydrochloride extended-release tablets-treated patients ages 6 to 65 years of age in the double-blind and open-label clinical ADHD trials. Blood and Lymphatic System Disorders : Leukopenia Cardiac Disorders : Cardiac murmur, Hypertension, Heart rate increased Ear and Labyrinth Disorders : Vertigo Eye Disorders : Accommodation disorder, Dry eye, Vision blurred Gastrointestinal Disorders : Abdominal discomfort/pain, Constipation, Diarrhea, Vomiting General Disorders and Administration Site Conditions : Asthenia, Fatigue, Feeling jittery, Thirst Hepatobiliary Disorders : Hepatic enzymes increased Infections and Infestations : Sinusitis Metabolism and Nutrition Disorders : Anorexia Musculoskeletal and Connective Tissue Disorders: Muscle spasms, Muscle tightness Nervous System Disorders : Lethargy, Paresthesia, Psychomotor hyperactivity, Sedation, Somnolence, Tension headache Psychiatric Disorders : Affect lability, Aggression, Anger, Bruxism, Confusional state, Depression, Hypervigilance, decreased libido, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tension, Tic Reproductive System and Breast Disorders : Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders : Cough, Dyspnea, Oropharyngeal pain Skin and Subcutaneous Tissue Disorders : Rash Vascular Disorders : Hot flush Discontinuation Due to Adverse Reactions In the 2 placebo-controlled studies in adults with ADHD, 25 (6%) methylphenidate hydrochloride extended-release tablets-treated patients and 6 (3%) placebo-treated patients discontinued due to an adverse reaction. In the methylphenidate hydrochloride extended-release tablets group, adverse reactions leading to discontinuation with an incidence of >0.5% were anxiety (1.7%), irritability (1.4%), increased blood pressure (1%), and nervousness (0.7%). In the placebo group, adverse reactions leading to discontinuation with an incidence of >0.5% were increased blood pressure (0.9%) and depressed mood (0.9%). In the 11 open-label studies in patients 6 to 65 years of age with ADHD, 266 (7%) methylphenidate hydrochloride extended-release tablets-treated patients discontinued due to an adverse reaction including insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%). Blood Pressure and Heart Rate Increases In the 1-week treatment, controlled trials in pediatric patients 6 to 12 years of age with ADHD (Studies 1 and 2) [see Clinical Studies ( 14.2 )] , both the methylphenidate hydrochloride extended-release tablets once daily group and the methylphenidate three times daily group increased resting pulse by an average of 2 to 6 beats per minute (bpm) and increased the average systolic and diastolic blood pressure roughly 1 to 4 mm Hg during the day, relative to placebo. In the randomized withdrawal portion of the double-blind, placebo-controlled trial with pediatric patients 13 to 17 years of age with ADHD (Study 4) [see Clinical Studies ( 14.3 )] , mean increases from baseline in resting pulse rate were observed with methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute (bpm), respectively). At the end of four weeks of treatment, mean increases from baseline in blood pressure for methylphenidate hydrochloride extended-release tablets and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively.
double-blind phase (5 and 3 beats/minute (bpm), respectively). At the end of four weeks of treatment, mean increases from baseline in blood pressure for methylphenidate hydrochloride extended-release tablets and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. In the 7-week dose-titration, placebo-controlled study in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (1 4.4 )] , mean changes from baseline in resting pulse rate were 3.6 in methylphenidate hydrochloride extended-release tablets-treated patients and -1.6 for placebo-treated patients after 7 weeks of treatment. Mean changes from baseline in blood pressure after 7 weeks of treatment in methylphenidate hydrochloride extended-release tablets-treated and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions ( 5.3 )] . In the 5-week fixed-dose, placebo-controlled trial in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (14.4)] , dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with methylphenidate hydrochloride extended-release tablets-treated patients and 2.7 bpm with placebo-treated patients at the end of 5 weeks. Mean changes from baseline in standing blood pressure after 5 weeks of treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for methylphenidate hydrochloride extended-release tablets-treated patients and 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of methylphenidate hydrochloride extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency: Blood and Lymphatic System Disorders : Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura Cardiac Disorders : Angina pectoris, Bradycardia, Supraventricular tachycardia, Ventricular extrasystoles Eye Disorders : Diplopia, Increased intraocular pressure, Mydriasis General Disorders and Administration Site Conditions : Chest pain, Drug effect decreased, Hyperpyrexia Hepatobiliary Disorders : Hepatocellular injury, Acute hepatic failure, Blood bilirubin increased Immune System Disorders : Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Exanthemas NEC Investigations : Blood alkaline phosphatase increased, Platelet count decreased, Musculoskeletal and Connective Tissue Disorders : Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System Disorders : Convulsion, Grand mal convulsion, Stroke in pediatric patients, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics Psychiatric Disorders : Disorientation, Hallucination, Mania, Logorrhea Reproductive System and Breast Disorders : Priapism Skin and Subcutaneous Tissue Disorders : Alopecia, Bullous conditions, Erythema, Exfoliative conditions, Pruritus, Urticarias Vascular Disorders : Raynaud’s phenomenon
<table width="848.75px"><caption>Table 3. Methylphenidate Hydrochloride Extended-Release Tablets-treated Patients in Double-Blind and Open-Label Clinical Studies</caption><col/><col/><col/><tbody><tr><td styleCode=" Botrule Toprule"><content styleCode="bold">Patient Population</content> </td><td styleCode=" Botrule Toprule"> <content styleCode="bold">N</content></td><td styleCode=" Botrule Toprule"> <content styleCode="bold">Dosage Range</content></td></tr><tr><td>Pediatric patients 6 to 12 years of age</td><td> 2,216</td><td> 18 to 54 mg once daily</td></tr><tr><td> Adolescents </td><td> 502</td><td> 18 to 72 mg once daily</td></tr><tr><td styleCode=" Botrule"> Adults up to 65 years of age</td><td styleCode=" Botrule"> 1,188</td><td styleCode=" Botrule"> 18 to 108 mg once daily</td></tr></tbody></table>
years of age</td><td> 2,216</td><td> 18 to 54 mg once daily</td></tr><tr><td> Adolescents </td><td> 502</td><td> 18 to 72 mg once daily</td></tr><tr><td styleCode=" Botrule"> Adults up to 65 years of age</td><td styleCode=" Botrule"> 1,188</td><td styleCode=" Botrule"> 18 to 108 mg once daily</td></tr></tbody></table> <table width="1000px" cellspacing="0" cellpadding="5" border="0"><caption>Table 4: Most Common Adverse Reactions<sup>1</sup> in Pediatric Patients 6 Years of Age and Older with ADHD in 4 Placebo-Controlled, Double-Blind Clinical Trials</caption><col width="1px1.5pt1pt1pt"/><col width="3.25in"/><col width="180.9pt"/><tbody><tr><td/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Methylphenidate Hydrochloride Extended-Release Tablets (n=321)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo (n=318)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Upper abdominal pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Insomnia<sup>2</sup></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nasopharyngitis</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>Vomiting</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>Pyrexia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</paragraph></td></tr><tr><td colspan="3"> <sup>1</sup> Reported in ≥ 2% of Methylphenidate Hydrochloride Extended-Release Tablets-treated patients<paragraph><sup> 2</sup> Initial insomnia (Methylphenidate Hydrochloride Extended-Release Tablets=0.6%) and insomnia (Methylphenidate Hydrochloride Extended-Release Tablets=2.2%) terms were combined into Insomnia.</paragraph></td></tr></tbody></table>
thylphenidate Hydrochloride Extended-Release Tablets-treated patients<paragraph><sup> 2</sup> Initial insomnia (Methylphenidate Hydrochloride Extended-Release Tablets=0.6%) and insomnia (Methylphenidate Hydrochloride Extended-Release Tablets=2.2%) terms were combined into Insomnia.</paragraph></td></tr></tbody></table> <table width="1000px" cellspacing="0" cellpadding="5" border="0"><caption>Table 5: Most Common Adverse Reactions<sup>1</sup> in Adults with ADHD in 2 Placebo- Controlled, Double-Blind Clinical Trials</caption><col width="1px1.5pt1px1pt"/><col width="2.75in"/><col width="99.05pt"/><tbody><tr><td/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Methylphenidate Hydrochloride Extended-Release Tablets<sup> 2</sup> (n=415)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo (n=212)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Decreased appetite</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>25%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Headache</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>22%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dry mouth</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Insomnia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12%</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>8%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Decreased weight</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 styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Irritability</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Tachycardia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hyperhidrosis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Depressed mood</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><par
graph>5%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Depressed mood</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><par agraph>1%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Initial insomnia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Restlessness</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>Palpitations</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nervousness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Tremor</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Upper respiratory tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</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>1%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspepsia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><sup>1</sup> Reported in ≥ 2% of Methylphenidate Hydrochloride Extended-Release Tablets-treated patients</paragraph><paragraph><sup>2</sup> Included dosages up to 108 mg/day (1.5 times the maximum recommended dosage).</paragraph></td></tr></tbody></table>
7 DRUG INTERACTIONS Table 6 describes clinically significant drug interactions with methylphenidate hydrochloride extended-release tablets. Table 6: Clinically Significant Drug Interactions Monoamine Oxidase Inhibitors Prevention or Management Concomitant use of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, with MAOIs or within 14 days after discontinuing an MAOI is contraindicated [ see Contraindications (4)]. Mechanism and Clinical Effect(s) Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. Antihypertensive Drugs Prevention or Management Increase monitoring for blood pressure and adjust the dosage of the antihypertensive drug, as needed. Mechanism and Clinical Effect(s) Methylphenidate hydrochloride extended-release tablets may decrease effectiveness of drugs used to treat hypertension [see Warnings and Precautions 5.3]. Halogenated Anesthetics Prevention or Management Avoid use of methylphenidate hydrochloride extended-release tablets in patients being treated with anesthetics on the day of surgery. Mechanism and Clinical Effect(s) Concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. Risperidone Prevention or Management Monitor for signs of extrapyramidal symptoms. Mechanism and Clinical Effect(s) The risk of risperidone-associated extrapyramidal symptoms may increase in patients taking concomitant methylphenidate hydrochloride extended-release tablets when there is a change in the methylphenidate hydrochloride extended-release tablets or risperidone dosage. Antihypertensive drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7 ) See additional clinically significant drug interactions, in the DRUG INTERACTIONS section ( 7 ).
<table cellspacing="0" cellpadding="0" border="0"><caption>Table 6: Clinically Significant Drug Interactions</caption><col width="1px1pt1pt"/><col/><tbody><tr><td colspan="2"><paragraph><content styleCode="bold">Monoamine Oxidase Inhibitors</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Prevention or Management</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, with MAOIs or within 14 days after discontinuing an MAOI is contraindicated [<content styleCode="italics">see Contraindications (4)].</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mechanism and Clinical Effect(s)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can cause hypertensive crisis.
aph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mechanism and Clinical Effect(s)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Antihypertensive Drugs</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Prevention or Management</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Increase monitoring for blood pressure and adjust the dosage of the antihypertensive drug, as needed.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mechanism and Clinical Effect(s)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Methylphenidate hydrochloride extended-release tablets may decrease effectiveness of drugs used to treat hypertension <content styleCode="italics">[see Warnings and Precautions 5.3].</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Halogenated Anesthetics</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Prevention or Management</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Avoid use of methylphenidate hydrochloride extended-release tablets in patients being treated with anesthetics on the day of surgery.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mechanism and Clinical Effect(s)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release tablets may increase the risk of sudden blood pressure and heart rate increase during surgery.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Prevention or Management</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Monitor for signs of extrapyramidal symptoms.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mechanism and Clinical Effect(s)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>The risk of risperidone-associated extrapyramidal symptoms may increase in patients taking concomitant methylphenidate hydrochloride extended-release tablets when there is a change in the methylphenidate hydrochloride extended-release tablets or risperidone dosage.</paragraph></td></tr></tbody></table>
8 USE IN SPECIFIC POPULATIONS Caution should be exercised if administered to nursing mothers ( 8.3 ) Safety and efficacy has not been established in children less than six years old or elderly patients greater than 65 years of age ( 8.4 and 8.5 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD drugs, including methylphenidate hydrochloride extended-release tablets, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/ . Risk Summary Published studies and post-marketing reports on methylphenidate use during pregnancy have inconsistent findings about a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the fetus associated with the use of central nervous system (CNS) stimulants during pregnancy ( see Clinical Considerations) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits throughout organogenesis at doses up to 4 and 16 times, respectively, the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 54 times the MRHD given to adults. A slight decrease in body weight was observed in pregnant rats at the highest dose of 30 mg/kg/day (4 times the MRHD given to adults). In a pre- and postnatal development study in which rats were treated with oral administration of methylphenidate throughout pregnancy and lactation, a decrease in pup body weight, alterations in sensory and neuromotor performance, and deficits in learning and memory were observed in both sexes at the highest dose (4 times the MRHD given to adults on a mg/m 2 basis) (see Data) . The background risk of major birth defects and miscarriage in those with ADHD is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions: CNS stimulants, such as methylphenidate hydrochloride extended-release tablets, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of a therapeutic dosage of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine dependent mothers. Data Animal Data: In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses up to 30 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 54 times the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (16 times the MRHD given to adults on a mg/m 2 basis).
fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 54 times the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (16 times the MRHD given to adults on a mg/m 2 basis). There was no evidence of changes in morphological development in rats, although a reduction in maternal body weight was observed at the highest dose of 30 mg/kg/day (4 times the MRHD of 72 mg/day given to adults (on a mg/m 2 basis). The no effect level for maternal body weight in rats is 5 mg/day (equal to the MRHD for adults on a mg/m 2 basis); and the no effect level for embryo-fetal development is 30 mg/kg/day (4 times the MRHD for adults on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 30 mg/kg/day, decreases in offspring body weight, alterations in sensory and neuromotor performance, and deficits in learning and memory were observed in both sexes at the highest dose (4 times the MRHD of 72 mg/day, given to adults on a mg/m 2 basis). The no effect level for pre- and post-natal development in rats was 12.5 mg/kg/day (2 times the MRHD given to adults on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on breast milk sampling from a small number of methylphenidate-treated lactating women, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted methylphenidate dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant or effects on milk production. Long-term neurodevelopmental effects on infants from CNS stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate and any potential adverse effects on the breastfed child from methylphenidate hydrochloride extended-release tablets or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants of methylphenidate hydrochloride extended-release tablets-treated lactating women for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride extended-release tablets for the treatment of ADHD have been established in pediatric patients 6 years of age and older. The safety and effectiveness of methylphenidate hydrochloride extended-release tablets have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Growth (weight and height) should be monitored in pediatric patients during treatment with CNS stimulants, including methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their methylphenidate hydrochloride extended-release tablets treatment interrupted [see Warnings and Precautions (5.7)] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only.
rupted [see Warnings and Precautions (5.7)] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 54 mg/day given to pediatric patients 6 to 12 years of age on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 54 mg/day given to pediatric patients 6 to 12 years of age on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (9 times the MRHD given to pediatric patients 6 to 12 years of age on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.4 times the MRHD given to pediatric patients 6 to 12 years of age on a mg/m 2 basis). The clinical significance of the long- term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Methylphenidate hydrochloride extended-release tablets are not indicated for use in patients greater than 65 years of age.
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD drugs, including methylphenidate hydrochloride extended-release tablets, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/ . Risk Summary Published studies and post-marketing reports on methylphenidate use during pregnancy have inconsistent findings about a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the fetus associated with the use of central nervous system (CNS) stimulants during pregnancy ( see Clinical Considerations) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits throughout organogenesis at doses up to 4 and 16 times, respectively, the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 54 times the MRHD given to adults. A slight decrease in body weight was observed in pregnant rats at the highest dose of 30 mg/kg/day (4 times the MRHD given to adults). In a pre- and postnatal development study in which rats were treated with oral administration of methylphenidate throughout pregnancy and lactation, a decrease in pup body weight, alterations in sensory and neuromotor performance, and deficits in learning and memory were observed in both sexes at the highest dose (4 times the MRHD given to adults on a mg/m 2 basis) (see Data) . The background risk of major birth defects and miscarriage in those with ADHD is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions: CNS stimulants, such as methylphenidate hydrochloride extended-release tablets, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of a therapeutic dosage of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine dependent mothers. Data Animal Data: In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses up to 30 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 54 times the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (16 times the MRHD given to adults on a mg/m 2 basis). There was no evidence of changes in morphological development in rats, although a reduction in maternal body weight was observed at the highest dose of 30 mg/kg/day (4 times the MRHD of 72 mg/day given to adults (on a mg/m 2 basis).
ment in rabbits was 60 mg/kg/day (16 times the MRHD given to adults on a mg/m 2 basis). There was no evidence of changes in morphological development in rats, although a reduction in maternal body weight was observed at the highest dose of 30 mg/kg/day (4 times the MRHD of 72 mg/day given to adults (on a mg/m 2 basis). The no effect level for maternal body weight in rats is 5 mg/day (equal to the MRHD for adults on a mg/m 2 basis); and the no effect level for embryo-fetal development is 30 mg/kg/day (4 times the MRHD for adults on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 30 mg/kg/day, decreases in offspring body weight, alterations in sensory and neuromotor performance, and deficits in learning and memory were observed in both sexes at the highest dose (4 times the MRHD of 72 mg/day, given to adults on a mg/m 2 basis). The no effect level for pre- and post-natal development in rats was 12.5 mg/kg/day (2 times the MRHD given to adults on a mg/m 2 basis).
8.2 Lactation Risk Summary Limited published literature, based on breast milk sampling from a small number of methylphenidate-treated lactating women, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted methylphenidate dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant or effects on milk production. Long-term neurodevelopmental effects on infants from CNS stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate and any potential adverse effects on the breastfed child from methylphenidate hydrochloride extended-release tablets or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants of methylphenidate hydrochloride extended-release tablets-treated lactating women for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.
8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride extended-release tablets for the treatment of ADHD have been established in pediatric patients 6 years of age and older. The safety and effectiveness of methylphenidate hydrochloride extended-release tablets have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Growth (weight and height) should be monitored in pediatric patients during treatment with CNS stimulants, including methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their methylphenidate hydrochloride extended-release tablets treatment interrupted [see Warnings and Precautions (5.7)] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 54 mg/day given to pediatric patients 6 to 12 years of age on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 54 mg/day given to pediatric patients 6 to 12 years of age on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (9 times the MRHD given to pediatric patients 6 to 12 years of age on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.4 times the MRHD given to pediatric patients 6 to 12 years of age on a mg/m 2 basis). The clinical significance of the long- term behavioral effects observed in rats is unknown.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate hydrochloride extended-release tablets contains methylphenidate, a Schedule II controlled substance. 9.2 Abuse Methylphenidate hydrochloride extended-release tablets has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions ( 5.1) ] . Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Studies of Abuse Potential with Methylphenidate Hydrochloride Extended-Release Tablets In two placebo- and active-controlled, crossover human abuse potential (HAP) studies, the relative abuse potential of single oral doses of methylphenidate hydrochloride extended-release tablets were compared to single oral doses of immediate-release methylphenidate (IR MPH) and placebo in subjects with a history of recreational CNS stimulant use. In these studies, the response for each of the abuse-related subjective measures was defined as the maximum effect within the first 8 hours after treatment administration. When evaluating these results, consider that 22% of the total methylphenidate amount in methylphenidate hydrochloride extended-release tablets (methylphenidate hydrochloride) extended-release tablets is available for immediate release and the remaining 78% is available for extended-release over 24 hours. In the first HAP study (n=40), single dose administration of methylphenidate hydrochloride extended-release tablets 108 mg (1.5 times the maximum recommended adult dose of methylphenidate hydrochloride extended-release tablets), IR MPH 60 mg (2 times the maximum recommended adult dose of IR MPH), or placebo were administered to subjects in a cross-over design. methylphenidate hydrochloride extended-release tablets 108 mg and IR MPH 60 mg produced responses on the subjective measures of Drug Liking and Abuse Potential that were statistically similar, and both were statistically significantly greater than the responses to placebo. However, on subjective measures of Euphoria, methylphenidate hydrochloride extended-release tablets 108 mg produced responses that were statistically less than those produced by IR MPH 60 mg.
buse Potential that were statistically similar, and both were statistically significantly greater than the responses to placebo. However, on subjective measures of Euphoria, methylphenidate hydrochloride extended-release tablets 108 mg produced responses that were statistically less than those produced by IR MPH 60 mg. In the second HAP study (n=49), a single dose of methylphenidate hydrochloride extended-release tablets 108 mg (1.5 times the maximum recommended adult dose of methylphenidate hydrochloride extended-release tablets), methylphenidate hydrochloride extended-release tablets 54 mg (0.75 times the maximum recommended adult dose of methylphenidate hydrochloride extended-release tablets), IR MPH 90 mg (3 times the maximum recommended adult dose of IR MPH), 50 mg (1.7 times the maximum recommended adult dose of IR MPH), or placebo were administered to subjects in a cross- over design. The three active treatments each produced responses on the subjective measure of Drug Liking that were statistically significantly greater than responses to placebo. IR MPH produced greater responses on Drug Liking compared to methylphenidate hydrochloride extended-release tablets when similar doses were compared (50 mg vs. 54 mg, and 90 mg vs. 108 mg, respectively), consistent with the extended-release properties of methylphenidate hydrochloride extended-release tablets. However, there were no significant differences in response between methylphenidate hydrochloride extended-release tablets 108 mg and IR MPH 50 mg on the subjective measures of Drug Liking and Euphoria. The clinical significance of the differences in response between methylphenidate hydrochloride extended-release tablets and IR MPH on subjective measures of abuse potential as reported in these HAP studies is unknown. 9.3 Dependence Physical Dependence Methylphenidate hydrochloride extended-release tablets may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dosage reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride extended-release tablets included dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate hydrochloride extended-release tablets may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
10 OVERDOSAGE 10.1 Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. 10.2 Overdose Management Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of methylphenidate hydrochloride extended-release tablets should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
11 DESCRIPTION Methylphenidate hydrochloride extended-release tablets, USP are a central nervous system (CNS) stimulant. Methylphenidate hydrochloride extended-release tablets, USP are available in four strengths. Each extended-release tablet for oral administration contains 18 mg, 27 mg, 36 mg, or 54 mg of methylphenidate hydrochloride, USP. Chemically, methylphenidate hydrochloride, USP is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride, its molecular formula is C 14 H 19 NO 2 •HCl, and its structural formula is: Methylphenidate hydrochloride, USP is a white, odorless crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Methylphenidate hydrochloride extended-release tablets, USP also contain the following inert ingredients: colloidal silicon dioxide, fumaric acid, hypromellose 2208, hypromellose 2910, lactose monohydrate, magnesium stearate, methacrylic acid copolymer Type A, methacrylic acid copolymer Type B, talc, titanium dioxide, and triethyl citrate. The 18 mg strength also contains iron oxide red, iron oxide yellow, polyethylene glycol 3350, and polyvinyl alcohol. The 27 mg strength also contains FD&C Blue #2/Indigo Carmine Aluminum Lake, iron oxide black, iron oxide yellow, polyethylene glycol 3350, and polyvinyl alcohol. The 36 mg strength also contains triacetin. The 54 mg strength also contains iron oxide red, polyethylene glycol 3350, and polyvinyl alcohol. The imprinting ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. It is possible that methylphenidate hydrochloride extended-release tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized. Meets USP Dissolution Test 11. Structural Formula
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate is a central nervous system (CNS) stimulant. The mode of therapeutic action of methylphenidate in the treatment of ADHD is not known. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of methylphenidate hydrochloride extended-release tablets have not been fully characterized. 12.3 Pharmacokinetics Absorption Following oral administration of methylphenidate hydrochloride extended-release tablets, plasma methylphenidate concentrations reached an initial maximum concentration at about 1 hour, followed by gradual ascending concentrations over the next 5 to 9 hours, after which a gradual decrease begins. Mean times to reach peak plasma concentrations across all doses of methylphenidate hydrochloride extended-release tablets occurred between 6 and 10 hours. Methylphenidate hydrochloride extended-release once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily [ see Figure 1 ]. No clinically significant difference in methylphenidate exposures was observed following the administration of either methylphenidate hydrochloride extended-release tablets once daily and immediate-release methylphenidate three times daily in adults. Figure 1. Mean Methylphenidate Plasma Concentrations Following a Single 18 mg Methylphenidate Hydrochloride Extended-Release Tablets dose and Immediate-release Methylphenidate 5 mg Doses (Three Doses Administered Every 4 Hours) The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of one 18 mg methylphenidate hydrochloride extended-release tablets dose and three 5 mg methylphenidate doses every four hours are summarized in Table 7. Table 7. Methylphenidate Pharmacokinetic Parameters (Mean ± SD) After Methylphenidate Hydrochloride Extended-Release Tablets and Immediate-release Methylphenidate Dosing in Healthy Adults Parameters Methylphenidate Hydrochloride Extended-Release Tablets (18 mg single dose) (n=36) Immediate-release Methylphenidate (Three 5 mg doses every four hours) (n=35) C max (ng/mL) 3.7 ± 1.0 4.2 ± 1.0 T max (h) 6.8 ± 1.8 6.5 ± 1.8 AUC inf (ng•h/mL) 41.8 ± 13.9 38.0 ± 11.0 t 1/2 (h) 3.5 ± 0.4 3.0 ± 0.5 The methylphenidate pharmacokinetics were evaluated in healthy adults following single- and multiple-doses (steady state) of methylphenidate hydrochloride extended-release tablets (up to 144 mg/day (up to 2 times the maximum recommended dose)). The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of methylphenidate hydrochloride extended-release tablets were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. The AUC and t 1/2 following repeated once-daily dosing are similar to those following a single 18 to 144 mg dose of methylphenidate hydrochloride extended-release tablets.
date hydrochloride extended-release tablets were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. The AUC and t 1/2 following repeated once-daily dosing are similar to those following a single 18 to 144 mg dose of methylphenidate hydrochloride extended-release tablets. Dose Proportionality Following administration of methylphenidate hydrochloride extended-release tablets in single doses of 18, 36, and 54 mg/day to healthy adults, C max and AUC (0-inf) of d-methylphenidate were dose proportional, whereas l-methylphenidate C max and AUC (0-inf) increased disproportionately with respect to dose. Following administration of methylphenidate hydrochloride extended-release tablets, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer. In healthy adults, single and multiple doses (once-daily) methylphenidate hydrochloride extended-release tablets doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in C max and AUC inf for total methylphenidate (MPH) and its major metabolite, α-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing. In a multiple-dose study, after patients aged 13 to 16 with ADHD were administered their prescribed methylphenidate hydrochloride extended-release tablets dose (18 to 72 mg/day), mean C max and AUC TAU of d- and total methylphenidate increased proportionally with respect to dose. Food Effects: In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hydrochloride extended-release tablets when administered after a high-fat breakfast. Distribution Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral methylphenidate hydrochloride extended-release tablets administration. The half-life of methylphenidate in adults and adolescents following oral methylphenidate hydrochloride extended-release tablets administration was approximately 3.5 hours. Elimination Metabolism: In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of methylphenidate hydrochloride extended-release tablets once daily as evaluated by metabolism to PPAA was similar to that of immediate-release methylphenidate three times daily. The metabolism of single and repeated once-daily doses of methylphenidate hydrochloride extended-release tablets was similar. Excretion: After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose. Alcohol Effect on Methylphenidate Release in Methylphenidate Hydrochloride Extended-Release Tablets An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate hydrochloride extended-release tablets 18 mg extended-release tablets. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg extended-release tablet strength are considered representative of the other available tablet strengths. Specific Populations Male and Female Patients: In healthy adults, the mean dose-adjusted AUC (0-inf) values for methylphenidate hydrochloride extended-release tablets were 36.7 ng•h/mL in males and 37.1 ng•h/mL in females, with no differences noted between the two groups.
tative of the other available tablet strengths. Specific Populations Male and Female Patients: In healthy adults, the mean dose-adjusted AUC (0-inf) values for methylphenidate hydrochloride extended-release tablets were 36.7 ng•h/mL in males and 37.1 ng•h/mL in females, with no differences noted between the two groups. Ethnic Groups: In adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted AUC (0-inf) was consistent across ethnic groups; however, the sample size was insufficient to detect ethnic variations in pharmacokinetics. Pediatric Patients: Increase in pediatric age was associated with increased apparent oral clearance (CL/F) (58% increase in adolescents compared to younger pediatric patients). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have a lower exposure of total methylphenidate at similar doses. Patients with Renal Impairment There is no pharmacokinetic information on the use of methylphenidate hydrochloride extended-release tablets in patients with renal impairment. Patients with Hepatic Impairment There is no pharmacokinetic information on the use of methylphenidate hydrochloride extended-release tablets in patients with hepatic impairment. new
12.1 Mechanism of Action Methylphenidate is a central nervous system (CNS) stimulant. The mode of therapeutic action of methylphenidate in the treatment of ADHD is not known. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.
12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of methylphenidate hydrochloride extended-release tablets have not been fully characterized.
12.3 Pharmacokinetics Absorption Following oral administration of methylphenidate hydrochloride extended-release tablets, plasma methylphenidate concentrations reached an initial maximum concentration at about 1 hour, followed by gradual ascending concentrations over the next 5 to 9 hours, after which a gradual decrease begins. Mean times to reach peak plasma concentrations across all doses of methylphenidate hydrochloride extended-release tablets occurred between 6 and 10 hours. Methylphenidate hydrochloride extended-release once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily [ see Figure 1 ]. No clinically significant difference in methylphenidate exposures was observed following the administration of either methylphenidate hydrochloride extended-release tablets once daily and immediate-release methylphenidate three times daily in adults. Figure 1. Mean Methylphenidate Plasma Concentrations Following a Single 18 mg Methylphenidate Hydrochloride Extended-Release Tablets dose and Immediate-release Methylphenidate 5 mg Doses (Three Doses Administered Every 4 Hours) The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of one 18 mg methylphenidate hydrochloride extended-release tablets dose and three 5 mg methylphenidate doses every four hours are summarized in Table 7. Table 7. Methylphenidate Pharmacokinetic Parameters (Mean ± SD) After Methylphenidate Hydrochloride Extended-Release Tablets and Immediate-release Methylphenidate Dosing in Healthy Adults Parameters Methylphenidate Hydrochloride Extended-Release Tablets (18 mg single dose) (n=36) Immediate-release Methylphenidate (Three 5 mg doses every four hours) (n=35) C max (ng/mL) 3.7 ± 1.0 4.2 ± 1.0 T max (h) 6.8 ± 1.8 6.5 ± 1.8 AUC inf (ng•h/mL) 41.8 ± 13.9 38.0 ± 11.0 t 1/2 (h) 3.5 ± 0.4 3.0 ± 0.5 The methylphenidate pharmacokinetics were evaluated in healthy adults following single- and multiple-doses (steady state) of methylphenidate hydrochloride extended-release tablets (up to 144 mg/day (up to 2 times the maximum recommended dose)). The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of methylphenidate hydrochloride extended-release tablets were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. The AUC and t 1/2 following repeated once-daily dosing are similar to those following a single 18 to 144 mg dose of methylphenidate hydrochloride extended-release tablets. Dose Proportionality Following administration of methylphenidate hydrochloride extended-release tablets in single doses of 18, 36, and 54 mg/day to healthy adults, C max and AUC (0-inf) of d-methylphenidate were dose proportional, whereas l-methylphenidate C max and AUC (0-inf) increased disproportionately with respect to dose. Following administration of methylphenidate hydrochloride extended-release tablets, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer. In healthy adults, single and multiple doses (once-daily) methylphenidate hydrochloride extended-release tablets doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in C max and AUC inf for total methylphenidate (MPH) and its major metabolite, α-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate.
lphenidate hydrochloride extended-release tablets doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in C max and AUC inf for total methylphenidate (MPH) and its major metabolite, α-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing. In a multiple-dose study, after patients aged 13 to 16 with ADHD were administered their prescribed methylphenidate hydrochloride extended-release tablets dose (18 to 72 mg/day), mean C max and AUC TAU of d- and total methylphenidate increased proportionally with respect to dose. Food Effects: In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hydrochloride extended-release tablets when administered after a high-fat breakfast. Distribution Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral methylphenidate hydrochloride extended-release tablets administration. The half-life of methylphenidate in adults and adolescents following oral methylphenidate hydrochloride extended-release tablets administration was approximately 3.5 hours. Elimination Metabolism: In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of methylphenidate hydrochloride extended-release tablets once daily as evaluated by metabolism to PPAA was similar to that of immediate-release methylphenidate three times daily. The metabolism of single and repeated once-daily doses of methylphenidate hydrochloride extended-release tablets was similar. Excretion: After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose. Alcohol Effect on Methylphenidate Release in Methylphenidate Hydrochloride Extended-Release Tablets An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate hydrochloride extended-release tablets 18 mg extended-release tablets. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg extended-release tablet strength are considered representative of the other available tablet strengths. Specific Populations Male and Female Patients: In healthy adults, the mean dose-adjusted AUC (0-inf) values for methylphenidate hydrochloride extended-release tablets were 36.7 ng•h/mL in males and 37.1 ng•h/mL in females, with no differences noted between the two groups. Ethnic Groups: In adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted AUC (0-inf) was consistent across ethnic groups; however, the sample size was insufficient to detect ethnic variations in pharmacokinetics. Pediatric Patients: Increase in pediatric age was associated with increased apparent oral clearance (CL/F) (58% increase in adolescents compared to younger pediatric patients). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have a lower exposure of total methylphenidate at similar doses. Patients with Renal Impairment There is no pharmacokinetic information on the use of methylphenidate hydrochloride extended-release tablets in patients with renal impairment.
among these populations. This suggests that subjects with higher body weight may have a lower exposure of total methylphenidate at similar doses. Patients with Renal Impairment There is no pharmacokinetic information on the use of methylphenidate hydrochloride extended-release tablets in patients with renal impairment. Patients with Hepatic Impairment There is no pharmacokinetic information on the use of methylphenidate hydrochloride extended-release tablets in patients with hepatic impairment. new
<table width="800pt" cellspacing="0" cellpadding="0"><caption>Table 7. Methylphenidate Pharmacokinetic Parameters (Mean ± SD) After Methylphenidate Hydrochloride Extended-Release Tablets and Immediate-release Methylphenidate Dosing in Healthy Adults</caption><col width="110.5pt"/><col width="162.65pt"/><col width="1.4in"/><tbody><tr><td align="center" styleCode=" Botrule Toprule"><paragraph><content styleCode="bold">Parameters</content></paragraph></td><td align="center" styleCode=" Botrule Toprule"><paragraph><content styleCode="bold">Methylphenidate Hydrochloride Extended-Release Tablets</content></paragraph><paragraph><content styleCode="bold">(18 mg single dose)</content></paragraph><paragraph><content styleCode="bold">(n=36)</content></paragraph></td><td align="center" styleCode=" Botrule Toprule"><paragraph><content styleCode="bold">Immediate-release Methylphenidate (Three 5 mg doses every four hours) (n=35)</content></paragraph></td></tr><tr><td align="center"><paragraph>C<sub>max </sub>(ng/mL)</paragraph></td><td align="center"><paragraph>3.7 ± 1.0</paragraph></td><td align="center"><paragraph>4.2 ± 1.0</paragraph></td></tr><tr><td align="center"><paragraph>T<sub>max </sub>(h)</paragraph></td><td align="center"><paragraph>6.8 ± 1.8</paragraph></td><td align="center"><paragraph>6.5 ± 1.8</paragraph></td></tr><tr><td align="center"><paragraph>AUC<sub>inf </sub>(ng•h/mL)</paragraph></td><td align="center"><paragraph>41.8 ± 13.9</paragraph></td><td align="center"><paragraph>38.0 ± 11.0</paragraph></td></tr><tr><td align="center"><paragraph>t<sub>1/2 </sub>(h)</paragraph></td><td align="center"><paragraph>3.5 ± 0.4</paragraph></td><td align="center"><paragraph>3.0 ± 0.5</paragraph></td></tr></tbody></table>
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the maximum recommended human dose (MRHD) of methylphenidate hydrochloride extended-release tablets given to adults on a mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 6 times the MRHD (adults) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 11 times the MRHD of methylphenidate hydrochloride extended-release tablets given to adults on a mg/m 2 basis.
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the maximum recommended human dose (MRHD) of methylphenidate hydrochloride extended-release tablets given to adults on a mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 6 times the MRHD (adults) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 11 times the MRHD of methylphenidate hydrochloride extended-release tablets given to adults on a mg/m 2 basis.
14 CLINICAL STUDIES 14.1 Overview of Clinical Trials Methylphenidate was demonstrated to be effective in the treatment of ADHD in patients who met the Diagnostic and Statistical Manual 4 th edition (DSM-IV) criteria for ADHD in the following trials: • Three trials in pediatric patients 6 to 12 years old (Studies 1, 2, and 3), • One trial in adolescents (13 to 18 years old), • Two trials in adults (18 to 65 years old). 14.2 Clinical Trials in Pediatric Patients 6 to 12 Years Three double-blind, active- and placebo-controlled trials were conducted in 416 pediatric patients 6 to 12 years of age with ADHD: (1) two single-center, crossover trials (patients received each treatment for one week) (Studies 1 and 2) and (2) a multicenter, 4-week, parallel-group comparison trial (Study 3). In these trials, patients were randomized to receive: • 18 mg, 36 mg, or 54 mg of oral methylphenidate hydrochloride extended-release tablets given once daily, • 5 mg, 10 mg, or 15 mg of oral immediate-release methylphenidate given three times daily (15, 30, or 45 mg total daily dosage) over 12 hours, and • Placebo The primary comparison of interest in all three trials was the methylphenidate hydrochloride extended-release tablets group versus the placebo group. ADHD symptoms were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. A statistically significant reduction in the Inattention/Overactivity subscale (0 to 15) in the methylphenidate hydrochloride extended-release tablets group versus the placebo group was shown in all three trials. The scores for methylphenidate hydrochloride extended-release tablets and placebo for the three trials are presented in Figure 2. Studies 1 and 2 involved a 3-way crossover of 1-week per treatment arm. Study 3 involved 4 weeks of parallel- group treatments with a Last Observation Carried Forward analysis at week 4. Error bars represent the mean plus standard error of the mean. In Studies 1 and 2, symptoms of ADHD including attentiveness were evaluated by schoolteachers using the Swanson, Kotkin, Agler, M-Fynn, and Pelham (SKAMP) laboratory school rating scale. The combined results from these two trials demonstrated statistically significant improvements in attention and behavior in the methylphenidate hydrochloride extended-release tablets group compared to the placebo group. These results were maintained through 12 hours after dosing. Figure 3 presents the schoolteacher SKAMP ratings for the methylphenidate hydrochloride extended-release tablets and placebo groups in Studies 1 and 2. Figure 3. School Teacher SKAMP Ratings (Mean (SEM) of Combined Attention) in Pediatric Patients 6 to 12 Years with ADHD (Studies 1 and 2) 2 3 14.3 Clinical Trials in Pediatric Patients 13 to 17 Years In a randomized-withdrawal, double-blind, multicenter, placebo-controlled trial (Study 4) with 177 pediatric patients 13 to 17 years of age with ADHD, methylphenidate hydrochloride extended-release tablets demonstrated effectiveness with a dosage up to 72 mg/day (1.4 mg/kg/day): Of 220 patients who entered an open 4-week titration phase, 177 patients were titrated to an individualized methylphenidate hydrochloride extended-release tablets dosage (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability.
ho entered an open 4-week titration phase, 177 patients were titrated to an individualized methylphenidate hydrochloride extended-release tablets dosage (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability. Patients who met these criteria were then randomized to receive either their individualized dosage of methylphenidate hydrochloride extended-release tablets (18 - 72 mg/day, n=87) or placebo (n=90) during a two-week double-blind phase. At the end of the double blind phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that the methylphenidate hydrochloride extended-release tablets group was statistically significantly superior to the placebo group. 14.4 Clinical Trials in Adults up to 65 Years Old Two randomized double-blind, placebo-controlled multicenter, parallel-group trials were conducted in 627 adults aged 18 to 65 years with ADHD who received methylphenidate hydrochloride extended-release tablets or placebo once daily: Study 5 was a 7-week, dose-titration trial where patients were randomized to receive methylphenidate hydrochloride extended-release tablets (n=110) or placebo (n=116) once daily. Patients treated with methylphenidate hydrochloride extended-release tablets started at 36 mg/day and had incremental increases of 18 mg/day up to 108 mg/day of methylphenidate hydrochloride extended-release tablets (titration was based on improvement criteria with acceptable tolerability). Study 6 was a 5-week, fixed-dose trial where patients were randomized to receive 18 mg (n=101), 36 mg (n=102), or 72 mg (n=102) of methylphenidate hydrochloride extended-release tablets versus placebo (n=96) once daily. In Study 5, methylphenidate hydrochloride extended-release tablets demonstrated efficacy based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that the methylphenidate hydrochloride extended-release tablets group was statistically significantly superior to the placebo group. In Study 6, all three methylphenidate hydrochloride extended-release tablets dosages were statistically significantly more effective than placebo in improving Conners’ Adult ADHD Rating Scale (CAARS) total scores after five weeks of treatment.
16 HOW SUPPLIED/STORAGE AND HANDLING Methylphenidate hydrochloride extended-release tablets, USP are available as follows: 18 mg – Each yellow, film-coated, capsule shaped tablet imprinted with the Andrx logo and 725 on one side and plain on the other side contains 18 mg methylphenidate hydrochloride, USP. Tablets are supplied in bottles of 100 (NDC 62037-725-01). 27 mg – Each gray, film-coated, capsule shaped tablet imprinted with the Andrx logo and 734 on one side and plain on the other side contains 27 mg methylphenidate hydrochloride, USP. Tablets are supplied in bottles of 100 (NDC 62037-734-01). 36 mg – Each white, film-coated, capsule shaped tablet imprinted with the Andrx logo and 726 on one side and plain on the other side contains 36 mg methylphenidate hydrochloride, USP. Tablets are supplied in bottles of 100 (NDC 62037-726-01). 54 mg – Each red brown, film-coated, capsule shaped tablet imprinted with the Andrx logo and 727 on one side and plain on the other side contains 54 mg methylphenidate hydrochloride, USP. Tablets are supplied in bottles of 100 (NDC 62037-727-01). Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from humidity. Dispense in tight, light-resistant container as defined in USP, with a child-resistant closure (as required).
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of methylphenidate hydrochloride extended-release tablets, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.1 , 9.2 ), Overdosage ( 10 )]. Advise patients to store methylphenidate hydrochloride extended-release tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride extended-release tablets to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with methylphenidate hydrochloride extended-release tablets use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions ( 5.2 )]. Increased Blood Pressure and Heart Rate Advise patients and their caregivers that methylphenidate hydrochloride extended-release tablets can cause elevations in blood pressure and heart rate [see Warnings and Precautions ( 5.3 )]. Psychiatric Risks Advise patients and their caregivers that methylphenidate hydrochloride extended-release tablets, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania [see Warnings and Precautions ( 5.4 )]. Priapism Advise patients, caregivers, and family members of methylphenidate hydrochloride extended-release tablets-treated males of the possibility of priapism. Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions ( 5.5 )] . Peripheral Vasculopathy, including Raynaud’s Phenomenon Instruct patients about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms; to report to their health care provider any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes; to call their health care provider immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride extended-release tablets [see Warnings and Precautions ( 5.6) ] . Long-term Suppression of Growth in Pediatric Patients Advise patients, caregivers, and family members that methylphenidate hydrochloride extended-release tablets may cause slowing of growth and weight loss in pediatric patients [see Warnings and Precautions ( 5.7) ]. Glaucoma and Increased Intraocular Pressure Advise patients that increased intraocular pressure and glaucoma may occur during methylphenidate hydrochloride extended-release tablets treatment [see Warnings and Precautions ( 5.10 )]. Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during methylphenidate hydrochloride extended-release tablets treatment. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions ( 5.11 )].
ts that motor and verbal tics and worsening of Tourette’s Syndrome may occur during methylphenidate hydrochloride extended-release tablets treatment. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions ( 5.11 )]. Administration Instructions Instruct patients to swallow methylphenidate hydrochloride extended-release tablets whole with liquids, and not to split, crush, or chew, the extended-release tablets. Advise patients not to be concerned if they occasionally notice a tablet-appearing substance in their stool. Pregnancy Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to methylphenidate hydrochloride extended-release tablets during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Advise methylphenidate hydrochloride extended-release tablets -treated breastfeeding women to monitor their infants for agitation, poor sleeping patterns, changes in feeding, and reduced weight gain [see Use in Specific Populations ( 8.2 )] . For more information call Teva at 1-888-838-2872. Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. D 4/2026
MEDICATION GUIDE Methylphenidate Hydrochloride (meth" il fen' i date hye" droe klor' ide) Extended-Release Tablets CII What is the most important information I should know about methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets may cause serious side effects, including: Abuse, misuse, and addiction. Methylphenidate hydrochloride extended-release tablets has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride extended-release tablets, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride extended-release tablets or when it is used in ways that are not approved, such as snorting or injection. Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride extended-release tablets and will monitor you or your child during treatment. Methylphenidate hydrochloride extended-release tablets may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. Do not give methylphenidate hydrochloride extended-release tablets to anyone else. See “ What is methylphenidate hydrochloride extended-release tablets?” for more information. Keep methylphenidate hydrochloride extended-release tablets in a safe place and properly dispose of any unused medicine. See “How should I store methylphenidate hydrochloride extended-release tablets?” for more information. Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting treatment with methylphenidate hydrochloride extended-release tablets. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child have any signs of heart problems, such as chest pain, shortness of breath, or fainting during treatment with methylphenidate hydrochloride extended-release tablets. Increased blood pressure and heart rate. Your healthcare provider should check your or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride extended-release tablets. Mental (psychiatric) problems, including: new or worse behavior or thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with methylphenidate hydrochloride extended-release tablets, especially hearing voices, seeing or believing things that are not real, or new manic symptoms.
ipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with methylphenidate hydrochloride extended-release tablets, especially hearing voices, seeing or believing things that are not real, or new manic symptoms. See “What are the possible side effects of methylphenidate hydrochloride extended-release tablets?” for more information about side effects. What are methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets are a central nervous system (CNS) stimulant prescription medicine used for the treatment of attention deficit hyperactivity disorder (ADHD) in people 6 to 65 years of age. Methylphenidate hydrochloride extended-release tablets may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. Methylphenidate hydrochloride extended-release tablets are not recommended for use in children under 6 years of age with ADHD. Methylphenidate hydrochloride extended-release tablets are federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs . Keep methylphenidate hydrochloride extended-release tablets in a safe place to protect it from theft. Never give your methylphenidate hydrochloride extended-release tablets to anyone else because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride extended-release tablets may harm others and is against the law. Who should not take methylphenidate hydrochloride extended-release tablets? Do not take methylphenidate hydrochloride extended-release tablets if you or your child are: allergic to methylphenidate or any of the ingredients in methylphenidate hydrochloride extended-release tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride extended-release tablets. taking, or have stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI) Before taking methylphenidate hydrochloride extended-release tablets, tell your healthcare provider about all of your or your child’s medical conditions, including if you or your child: have heart problems, heart disease, heart defects, or high blood pressure have mental problems including psychosis, mania, bipolar illness, or depression, or have a family history of suicide, bipolar illness, or depression have circulation problems in fingers and toes have had a blockage or narrowing of the intestines have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride extended-release tablets will harm the unborn baby. There is a pregnancy exposure registry for women are exposed to methylphenidate hydrochloride extended-release tablets during pregnancy. The purpose of the registry is to collect information about the health of women exposed to methylphenidate hydrochloride extended-release tablets and their baby. If you or your child becomes pregnant during treatment with methylphenidate hydrochloride extended-release tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/. are breastfeeding or plan to breastfeed. methylphenidate hydrochloride extended-release tablets passes into the breast milk.
talk to your healthcare provider about registering with the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/. are breastfeeding or plan to breastfeed. methylphenidate hydrochloride extended-release tablets passes into the breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate hydrochloride extended-release tablets. If you breastfeed during treatment with methylphenidate hydrochloride extended-release tablets, monitor your baby for agitation, poor sleeping patterns, changes in feeding, and reduced weight gain. Tell your healthcare provider about all of the medicines that you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride extended-release tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with methylphenidate hydrochloride extended-release tablets. Your healthcare provider will decide whether methylphenidate hydrochloride extended-release tablets can be taken with other medicines. Especially tell your healthcare provider if you or your child take: a medicine to treat blood pressure (anti-hypertensive) risperidone Know the medicines that you or your child take. Keep a list of your or your child’s medicines with you to show your healthcare provider and pharmacist when you or your child get a new medicine. Do not start any new medicine during treatment with methylphenidate hydrochloride extended-release tablets without first talking to your healthcare provider. How should I take methylphenidate hydrochloride extended-release tablets? Take methylphenidate hydrochloride extended-release tablets exactly as prescribed by your or your child’s healthcare provider. Your healthcare provider may change the dose or tell you to stop taking methylphenidate hydrochloride extended-release tablets if needed. Take methylphenidate hydrochloride extended-release tablets 1 time each day in the morning with or without food. Swallow methylphenidate hydrochloride extended-release tablets whole with water or other liquids. Do not split, crush, or chew the tablets. Tell your healthcare provider if you or your child cannot swallow methylphenidate hydrochloride extended-release tablets whole. A different medicine will need to be prescribed. Methylphenidate hydrochloride extended-release tablets does not dissolve completely in the body after all the medicine has been released. You or your child may sometimes notice the empty tablet in a bowel movement. This is normal. If you or your child take too much methylphenidate hydrochloride extended-release tablets, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets may cause serious side effects, including: See “What is the most important information I should know about methylphenidate hydrochloride extended-release tablets?” Painful and prolonged erections (priapism). Priapism that may require surgery has happened in males who take products that contain methylphenidate. If you or your child develop priapism, get medical help right away. Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon).
ts?” Painful and prolonged erections (priapism). Priapism that may require surgery has happened in males who take products that contain methylphenidate. If you or your child develop priapism, get medical help right away. Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon). Signs and symptoms may include: fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have any numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes. Call your healthcare provider right away if you or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with methylphenidate hydrochloride extended-release tablets. Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with methylphenidate hydrochloride extended-release tablets. Methylphenidate hydrochloride extended-release tablets treatment may be stopped if your child is not growing or gaining weight as expected. Risk of intestinal blockage in people with narrowed digestive tract (gastrointestinal narrowing). Because the methylphenidate hydrochloride extended-release tablets tablet does not change in shape in the intestines (GI tract), methylphenidate hydrochloride extended-release tablets should not be taken by people with severe intestinal problems (pre-existing severe gastrointestinal narrowing). Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette’s syndrome . Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride extended-release tablets. The most common side effect of methylphenidate hydrochloride extended-release tablets in children 6 to 17 years of age is upper stomach-area (abdominal) pain. The most common side effects of methylphenidate hydrochloride extended-release tablets in adults up to 65 years of age include: decreased appetite headache dry mouth nausea trouble sleeping anxiety dizziness weight loss irritability fast heart beat increased sweating These are not all the possible side effects of methylphenidate hydrochloride extended-release tablets. 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 Teva at 1-888-838-2872. How should I store methylphenidate hydrochloride extended-release tablets? Store methylphenidate hydrochloride extended-release tablets at room temperature between 59° to 86°F (15° to 30°C). Protect from moisture. Store methylphenidate hydrochloride extended-release tablets in a safe place, like a locked cabinet. Dispose of remaining, unused, or expired methylphenidate hydrochloride extended-release tablets by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride extended-release tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away methylphenidate hydrochloride extended-release tablets in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep methylphenidate hydrochloride extended-release tablets and all medicines out of the reach of children.
uch as a sealed plastic bag and throw away methylphenidate hydrochloride extended-release tablets in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep methylphenidate hydrochloride extended-release tablets and all medicines out of the reach of children. General information about the safe and effective use of methylphenidate hydrochloride extended-release tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use methylphenidate hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride extended-release tablets to other people, even if they have the same condition. It may harm them and it is against the law. You can ask your pharmacist or healthcare provider for information about methylphenidate hydrochloride extended-release tablets that is written for health professionals. What are the ingredients in methylphenidate hydrochloride extended-release tablets? Active ingredient: methylphenidate hydrochloride Inactive ingredients: colloidal silicon dioxide, fumaric acid, hypromellose 2208, hypromellose 2910, lactose monohydrate, magnesium stearate, methacrylic acid copolymer Type A, methacrylic acid copolymer Type B, talc, titanium dioxide, and triethyl citrate. The 18 mg strength also contains iron oxide red, iron oxide yellow, polyethylene glycol 3350, and polyvinyl alcohol. The 27 mg strength also contains FD&C Blue #2/Indigo Carmine Aluminum Lake, iron oxide black, iron oxide yellow, polyethylene glycol 3350, and polyvinyl alcohol. The 36 mg strength also contains triacetin. The 54 mg strength also contains iron oxide red, polyethylene glycol 3350, and polyvinyl alcohol. The imprinting ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. Manufactured For: Teva Pharmaceuticals, Parsippany, NJ 07054 This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. D 4/2026
<table width="814.333px"><col/><col/><tbody><tr><td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">MEDICATION GUIDE</content><paragraph><content styleCode="bold">Methylphenidate Hydrochloride </content><content styleCode="bold">(meth" il fen' i date hye" droe klor' ide)</content></paragraph><paragraph><content styleCode="bold"> </content><content styleCode="bold">Extended-Release Tablets CII</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">What is the most important information I should know about methylphenidate hydrochloride extended-release tablets?</content><paragraph><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Abuse, misuse, and addiction.</content> Methylphenidate hydrochloride extended-release tablets has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride extended-release tablets, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride extended-release tablets or when it is used in ways that are not approved, such as snorting or injection.</item></list><list listType="unordered" styleCode="Circle"><item>Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride extended-release tablets and will monitor you or your child during treatment.</item><item>Methylphenidate hydrochloride extended-release tablets may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider.</item><item>Do not give methylphenidate hydrochloride extended-release tablets to anyone else. See “<content styleCode="bold">What is methylphenidate hydrochloride extended-release tablets?”</content> for more information.</item><item>Keep methylphenidate hydrochloride extended-release tablets in a safe place and properly dispose of any unused medicine. See <content styleCode="bold">“How should I store methylphenidate hydrochloride extended-release tablets?”</content> for more information.</item><item>Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs.</item></list><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Risks for people with serious heart disease.</content> Sudden death has happened in people who have heart defects or other serious heart disease.</item></list><paragraph>Your healthcare provider should check you or your child carefully for heart problems before starting treatment with methylphenidate hydrochloride extended-release tablets.
serious heart disease.</content> Sudden death has happened in people who have heart defects or other serious heart disease.</item></list><paragraph>Your healthcare provider should check you or your child carefully for heart problems before starting treatment with methylphenidate hydrochloride extended-release tablets. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects.</paragraph><paragraph><content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child </content>have any signs of heart problems, such as chest pain, shortness of breath, or fainting during treatment with methylphenidate hydrochloride extended-release tablets.</paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Increased blood pressure and heart rate.</content></item></list><paragraph>Your healthcare provider should check your or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride extended-release tablets.</paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Mental (psychiatric) problems, including:</content></item></list><list listType="unordered" styleCode="Circle"><item>new or worse behavior or thought problems</item><item>new or worse bipolar illness</item><item>new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms</item></list><paragraph>Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.</paragraph><paragraph><content styleCode="bold">Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with methylphenidate hydrochloride extended-release tablets, especially hearing voices, seeing or believing things that are not real, or new manic symptoms.</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>See <content styleCode="bold">“What are the possible side effects of methylphenidate hydrochloride extended-release tablets?”</content> for more information about side effects.</paragraph><paragraph><content styleCode="bold">What are methylphenidate hydrochloride extended-release tablets?</content></paragraph><paragraph>Methylphenidate hydrochloride extended-release tablets are a central nervous system (CNS) stimulant prescription medicine used for the treatment of attention deficit hyperactivity disorder (ADHD) in people 6 to 65 years of age. Methylphenidate hydrochloride extended-release tablets may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. </paragraph><paragraph>Methylphenidate hydrochloride extended-release tablets are not recommended for use in children under 6 years of age with ADHD. </paragraph><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets are federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs</content>. Keep methylphenidate hydrochloride extended-release tablets in a safe place to protect it from theft. Never give your methylphenidate hydrochloride extended-release tablets to anyone else because it may cause death or harm them.
that can be a target for people who abuse prescription medicines or street drugs</content>. Keep methylphenidate hydrochloride extended-release tablets in a safe place to protect it from theft. Never give your methylphenidate hydrochloride extended-release tablets to anyone else because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride extended-release tablets may harm others and is against the law.</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Who should not take methylphenidate hydrochloride extended-release tablets?</content> <content styleCode="bold">Do not take methylphenidate hydrochloride extended-release tablets if you or your child are:</content><list listType="unordered" styleCode="Disc"><item>allergic to methylphenidate or any of the ingredients in methylphenidate hydrochloride extended-release tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride extended-release tablets.</item></list><list listType="unordered" styleCode="Disk"><item>taking, or have stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI)</item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">Before taking methylphenidate hydrochloride extended-release tablets, tell your healthcare provider about all of your or your child’s medical conditions, including if you or your child:</content><list listType="unordered" styleCode="Disc"><item>have heart problems, heart disease, heart defects, or high blood pressure</item><item>have mental problems including psychosis, mania, bipolar illness, or depression, or have a family history of suicide, bipolar illness, or depression</item><item>have circulation problems in fingers and toes</item><item>have had a blockage or narrowing of the intestines</item><item>have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness)</item><item>have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome</item><item>are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride extended-release tablets will harm the unborn baby. <list listType="unordered" styleCode="Circle"><item>There is a pregnancy exposure registry for women are exposed to methylphenidate hydrochloride extended-release tablets during pregnancy. The purpose of the registry is to collect information about the health of women exposed to methylphenidate hydrochloride extended-release tablets and their baby. If you or your child becomes pregnant during treatment with methylphenidate hydrochloride extended-release tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/.</item></list></item></list><list listType="unordered" styleCode="Disk"><item>are breastfeeding or plan to breastfeed. methylphenidate hydrochloride extended-release tablets passes into the breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate hydrochloride extended-release tablets.
list listType="unordered" styleCode="Disk"><item>are breastfeeding or plan to breastfeed. methylphenidate hydrochloride extended-release tablets passes into the breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate hydrochloride extended-release tablets. If you breastfeed during treatment with methylphenidate hydrochloride extended-release tablets, monitor your baby for agitation, poor sleeping patterns, changes in feeding, and reduced weight gain.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all of the medicines that you or your child take, </content>including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph><paragraph>Methylphenidate hydrochloride extended-release tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with methylphenidate hydrochloride extended-release tablets. Your healthcare provider will decide whether methylphenidate hydrochloride extended-release tablets can be taken with other medicines.</paragraph><paragraph><content styleCode="bold">Especially tell your healthcare provider if you or your child take:</content></paragraph><list listType="unordered" styleCode="Disc"><item>a medicine to treat blood pressure (anti-hypertensive)</item><item>risperidone</item></list><paragraph>Know the medicines that you or your child take. Keep a list of your or your child’s medicines with you to show your healthcare provider and pharmacist when you or your child get a new medicine.</paragraph><paragraph><content styleCode="bold">Do not start any new medicine during treatment with methylphenidate hydrochloride extended-release tablets without first talking to your healthcare provider.</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">How should I take methylphenidate hydrochloride extended-release tablets?</content><list listType="unordered" styleCode="Disc"><item>Take methylphenidate hydrochloride extended-release tablets exactly as prescribed by your or your child’s healthcare provider.</item><item>Your healthcare provider may change the dose or tell you to stop taking methylphenidate hydrochloride extended-release tablets if needed.</item><item>Take methylphenidate hydrochloride extended-release tablets 1 time each day in the morning with or without food.</item><item>Swallow methylphenidate hydrochloride extended-release tablets whole with water or other liquids. <content styleCode="bold">Do not split, crush, or chew the tablets.</content> Tell your healthcare provider if you or your child cannot swallow methylphenidate hydrochloride extended-release tablets whole. A different medicine will need to be prescribed.</item><item>Methylphenidate hydrochloride extended-release tablets does not dissolve completely in the body after all the medicine has been released. You or your child may sometimes notice the empty tablet in a bowel movement. This is normal.</item><item>If you or your child take too much methylphenidate hydrochloride extended-release tablets, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away.
You or your child may sometimes notice the empty tablet in a bowel movement. This is normal.</item><item>If you or your child take too much methylphenidate hydrochloride extended-release tablets, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. </item></list></td></tr><tr><td colspan="2" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">What are the possible side effects of methylphenidate hydrochloride extended-release tablets?</content><paragraph><content styleCode="bold">Methylphenidate hydrochloride extended-release tablets may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item>See <content styleCode="bold">“What is the most important information I should know about methylphenidate hydrochloride extended-release tablets?”</content></item><item><content styleCode="bold">Painful and prolonged erections (priapism).</content> Priapism that may require surgery has happened in males who take products that contain methylphenidate. <content styleCode="bold">If you or your child develop priapism, get medical help right away.</content></item><item><content styleCode="bold">Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon).</content></item></list><paragraph>Signs and symptoms may include:</paragraph><list listType="unordered" styleCode="Circle"><item>fingers or toes may feel numb, cool, painful</item><item>fingers or toes may change color from pale, to blue, to red</item></list><paragraph>Tell your healthcare provider if you or your child have any numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes.</paragraph><paragraph><content styleCode="bold">Call your healthcare provider right away if you or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with methylphenidate hydrochloride extended-release tablets.</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Slowing of growth (height and weight) in children. </content>Children should have their height and weight checked often during treatment with methylphenidate hydrochloride extended-release tablets. Methylphenidate hydrochloride extended-release tablets treatment may be stopped if your child is not growing or gaining weight as expected.</item><item><content styleCode="bold">Risk of intestinal blockage in people with narrowed digestive tract (gastrointestinal narrowing).</content> Because the methylphenidate hydrochloride extended-release tablets tablet does not change in shape in the intestines (GI tract), methylphenidate hydrochloride extended-release tablets should not be taken by people with severe intestinal problems (pre-existing severe gastrointestinal narrowing).</item><item><content styleCode="bold">Eye problems (increased pressure in the eye and glaucoma). </content>Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness.</item><item><content styleCode="bold">New or worsening tics or worsening Tourette’s syndrome</content>.
eCode="bold">Eye problems (increased pressure in the eye and glaucoma). </content>Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness.</item><item><content styleCode="bold">New or worsening tics or worsening Tourette’s syndrome</content>. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride extended-release tablets.</item></list><paragraph><content styleCode="bold">The most common side effect of methylphenidate hydrochloride extended-release tablets in children 6 to 17 years of age is </content>upper stomach-area (abdominal) pain.</paragraph><paragraph><content styleCode="bold">The most common side effects of methylphenidate hydrochloride extended-release tablets in adults up to 65 years of age include:</content></paragraph></td></tr><tr><td styleCode=" Lrule"> <list listType="unordered" styleCode="Disc"><item>decreased appetite</item><item>headache</item><item>dry mouth</item><item>nausea </item><item>trouble sleeping</item><item>anxiety</item></list></td><td styleCode=" Rrule"><list listType="unordered" styleCode="Disk"><item>dizziness</item><item>weight loss</item><item>irritability</item><item>fast heart beat</item><item>increased sweating</item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Lrule Rrule"> These are not all the possible side effects of methylphenidate hydrochloride extended-release tablets. <paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph> You may also report side effects to Teva at 1-888-838-2872.</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">How should I store methylphenidate hydrochloride extended-release tablets?</content><list listType="unordered" styleCode="Disc"><item>Store methylphenidate hydrochloride extended-release tablets at room temperature between 59° to 86°F (15° to 30°C).</item><item>Protect from moisture.</item><item>Store methylphenidate hydrochloride extended-release tablets in a safe place, like a locked cabinet.</item><item>Dispose of remaining, unused, or expired methylphenidate hydrochloride extended-release tablets by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride extended-release tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away methylphenidate hydrochloride extended-release tablets in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</item></list><content styleCode="bold">Keep methylphenidate hydrochloride extended-release tablets and all medicines out of the reach of children.</content></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">General information about the safe and effective use of methylphenidate hydrochloride extended-release tablets.</content><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use methylphenidate hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride extended-release tablets to other people, even if they have the same condition. It may harm them and it is against the law.
han those listed in a Medication Guide. Do not use methylphenidate hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride extended-release tablets to other people, even if they have the same condition. It may harm them and it is against the law. </paragraph> You can ask your pharmacist or healthcare provider for information about methylphenidate hydrochloride extended-release tablets that is written for health professionals.</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">What are the ingredients in methylphenidate hydrochloride extended-release tablets?</content><paragraph><content styleCode="bold">Active ingredient: </content>methylphenidate hydrochloride</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content> colloidal silicon dioxide, fumaric acid, hypromellose 2208, hypromellose 2910, lactose monohydrate, magnesium stearate, methacrylic acid copolymer Type A, methacrylic acid copolymer Type B, talc, titanium dioxide, and triethyl citrate. The 18 mg strength also contains iron oxide red, iron oxide yellow, polyethylene glycol 3350, and polyvinyl alcohol. The 27 mg strength also contains FD&C Blue #2/Indigo Carmine Aluminum Lake, iron oxide black, iron oxide yellow, polyethylene glycol 3350, and polyvinyl alcohol. The 36 mg strength also contains triacetin. The 54 mg strength also contains iron oxide red, polyethylene glycol 3350, and polyvinyl alcohol. The imprinting ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.</paragraph><paragraph>Manufactured For: <content styleCode="bold">Teva Pharmaceuticals, </content>Parsippany, NJ 07054</paragraph></td></tr></tbody></table>
DESCRIPTION Methylphenidate HCl is a mild central nervous system (CNS) stimulant, available as 2.5 mg, 5 mg and 10 mg chewable tablets for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate Hydrochloride C 14 H 19 NO 2 • HCl MW = 269.77 Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Each methylphenidate hydrochloride chewable tablet, for oral administration, contains 2.5 mg, 5 mg or 10 mg of methylphenidate hydrochloride USP. In addition, methylphenidate hydrochloride chewable tablets also contain the following inactive ingredients: aspartame, lactose anhydrous, microcrystalline cellulose, guar gum, grape flavor, pregelatinized starch, and stearic acid.
CLINICAL PHARMACOLOGY Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in humans is not completely understood, but methylphenidate presumably activates the brain stem arousal system and cortex to produce its stimulant effect. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. There is neither specific evidence which clearly establishes the mechanism whereby methylphenidate hydrochloride chewable tablets produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. Pharmacokinetics Absorption Methylphenidate hydrochloride chewable tablets are readily absorbed. Following oral administration of methylphenidate hydrochloride chewable tablets, peak plasma methylphenidate concentrations are achieved at about 1 to 2 hours. Methylphenidate hydrochloride chewable tablets have been shown to be bioequivalent to Ritalin ® tablet. The mean C max following a 20 mg dose is approximately 10 ng/mL. Food Effect In a study in adult volunteers investigating the effects of a high-fat meal on the bioavailability of methylphenidate hydrochloride chewable tablets at a dose of 20 mg, the presence of food delayed the peak concentrations by approximately 1 hour (1.5 hours, fasted and 2.4 hours, fed). Overall, a high-fat meal increased the AUC of methylphenidate hydrochloride chewable tablets by about 20%, on average. Through a cross-study comparison, the magnitude of food effect is found to be comparable between the methylphenidate hydrochloride chewable tablets and Ritalin ® , the immediate release tablet. Metabolism and Excretion In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenylpiperidine acetic acid (PPA, ritalinic acid). The metabolite has little or no pharmacologic activity. After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPA, accounting for approximately 80% of the dose. The pharmacokinetics of the methylphenidate hydrochloride chewable tablets have been studied in healthy adult volunteers. The mean terminal half-life (t ½ ) of methylphenidate following administration of 20 mg methylphenidate hydrochloride chewable tablets (t ½ = 3 hours) is comparable to the mean terminal t ½ following administration of Ritalin ® (methylphenidate hydrochloride immediate-release tablets) (t ½ = 2.8 hours) in healthy adult volunteers. Special Populations Gender – The effect of gender on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride chewable tablets administration has not been studied. Race – The influence of race on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride chewable tablets administration has not been studied. Age – The pharmacokinetics of methylphenidate after methylphenidate hydrochloride chewable tablets administration have not been studied in pediatrics. Renal Insufficiency There is no experience with the use of methylphenidate hydrochloride chewable tablets in patients with renal insufficiency.
INDICATIONS AND USAGE Attention Deficit Disorders, Narcolepsy Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction. Methylphenidate hydrochloride is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics. Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms.
CONTRAINDICATIONS Marked anxiety, tension, and agitation are contraindications to methylphenidate hydrochloride, since the drug may aggravate these symptoms. Methylphenidate hydrochloride is contraindicated also in patients known to be hypersensitive to the drug, in patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. Methylphenidate hydrochloride is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises may result).
WARNINGS Serious Cardiovascular Events Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents – Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults – Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mmHg) and average heart rate (about 3 to 6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis – Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness – Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms – Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients. Aggression – Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or discontinuation): Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. Peripheral Vasculopathy, Including Raynaud’s Phenomenon Stimulants, including methylphenidate hydrochloride, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
oups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. USE IN CHILDREN LESS THAN SIX YEARS OF AGE Methylphenidate hydrochloride should not be used in children under six years, since safety and efficacy in this age group have not been established. DRUG ABUSE AND DEPENDENCE Methylphenidate hydrochloride should be given cautiously to emotionally unstable patients, such as those with a history of drug dependence or alcoholism, because such patients may increase dosage on their own initiative. Chronically abusive use can lead to marked tolerance and psychic dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during drug withdrawal, since severe depression as well as the effects of chronic overactivity can be unmasked. Long-term follow-up may be required because of the patient’s basic personality disturbances.
<table border="1" cellspacing="0" cellpadding="0"><tbody><tr styleCode="First Last"><td valign="top"><paragraph styleCode="CM12 First"><content styleCode="bold">DRUG ABUSE AND DEPENDENCE </content></paragraph><paragraph styleCode="CM12">Methylphenidate hydrochloride should be given cautiously to emotionally unstable patients, such as those with a history of drug dependence or alcoholism, because such patients may increase dosage on their own initiative.</paragraph><paragraph styleCode="CM12"/><paragraph styleCode="CM12">Chronically abusive use can lead to marked tolerance and psychic dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during drug withdrawal, since severe depression as well as the effects of chronic overactivity can be unmasked. Long-term follow-up may be required because of the patient’s basic personality disturbances.</paragraph></td></tr></tbody></table>
PRECAUTIONS General Patients with an element of agitation may react adversely; discontinue therapy if necessary. Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe methylphenidate hydrochloride should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with methylphenidate hydrochloride is usually not indicated. Long-term effects of methylphenidate hydrochloride in children have not been well established. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for methylphenidate hydrochloride chewable tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Physicians are advised to discuss the following issues with patients for whom they prescribe methylphenidate hydrochloride: Choking – Taking this product without adequate fluid may cause it to swell and block your throat or esophagus and may cause choking. Do not take this product if you have difficulty in swallowing. If you experience chest pain, vomiting, or difficulty in swallowing or breathing after taking this product, seek immediate medical attention. Directions – Take this product (child or adult dose) with at least 8 ounces (a full glass) of water or other fluid. Taking this product without enough liquid may cause choking. See choking warning. Priapism Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism. Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon] Instruct patients beginning treatment with methylphenidate hydrochloride about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Phenylketonurics – Phenylalanine is a component of aspartame.
ruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Phenylketonurics – Phenylalanine is a component of aspartame. Each 2.5 mg methylphenidate hydrochloride chewable tablet contains 0.35 mg of phenylalanine; each 5 mg methylphenidate hydrochloride chewable tablet contains 0.70 mg of phenylalanine and each 10 mg methylphenidate hydrochloride chewable tablet contains 1.40 mg of phenylalanine. Drug Interactions Monoamine Oxidase Inhibitors (MAOI) Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure ( see CONTRAINDICATIONS ). Concomitant use of methylphenidate hydrochloride with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Methylphenidate hydrochloride may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Risperidone Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS. Methylphenidate hydrochloride may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that methylphenidate hydrochloride may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with methylphenidate hydrochloride. Carcinogenesis, Mutagenesis, Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 2.5 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 4 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. The genotoxic potential of methylphenidate has not been evaluated in an in vivo assay. Usage in Pregnancy Adequate animal reproduction studies to establish safe use of methylphenidate hydrochloride chewable tablet during pregnancy have not been conducted.
an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. The genotoxic potential of methylphenidate has not been evaluated in an in vivo assay. Usage in Pregnancy Adequate animal reproduction studies to establish safe use of methylphenidate hydrochloride chewable tablet during pregnancy have not been conducted. However, in a recently conducted study, methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 167 times and 78 times the maximum recommended human dose on a mg/kg and a mg/m 2 basis, respectively. In rats, teratogenic effects were not seen when the drug was given in doses of 75 mg/kg/day, which is approximately 62.5 and 13.5 times the maximum recommended human dose on a mg/kg and a mg/m 2 basis, respectively. Therefore, until more information is available, methylphenidate should not be prescribed for women of childbearing age unless, in the opinion of the physician, the potential benefits outweigh the possible risks.
ADVERSE REACTIONS Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy; libido changes; and rhabdomyolysis. There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to severe hepatic injury; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; a few instances of scalp hair loss; serotonin syndrome in combination with serotonergic drugs. Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten year old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also occur.
OVERDOSAGE Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, dryness of mucous membranes, and rhabdomyolysis. Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a short-acting barbiturate before performing gastric lavage. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate overdosage has not been established.
DOSAGE AND ADMINISTRATION Dosage should be individualized according to the needs and responses of the patient. Directions – Take this product (child or adult dose) with at least 8 ounces (a full glass) of water or other fluid. Taking this product without enough liquid may cause choking. See choking warning. Adults Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. Children (6 years and over) Methylphenidate hydrochloride should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued. Chewable Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. Methylphenidate hydrochloride should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.
HOW SUPPLIED Each methylphenidate hydrochloride chewable tablet 5 mg is available as a white to off-white round beveled edge chewable tablets debossed with ' 261 ' on one side and ' AT ' on the other side. Bottles of 100 NDC 63629-1923-1 Protect from moisture. Dispense in tight container with child-resistant closure. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Ritalin ® is a registered trademark of Novartis Corporation. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504
MEDICATION GUIDE CII Methylphenidate Hydrochloride Chewable Tablets, 2.5 mg, 5 mg, and 10 mg (meth'' il fen' i date hye'' droe klor' ide) Read the Medication Guide that comes with methylphenidate hydrochloride chewable tablets before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child’s treatment with methylphenidate hydrochloride chewable tablets. What is the most important information I should know about methylphenidate hydrochloride chewable tablets? The following have been reported with use of methylphenidate HCl and other stimulant medicines. 1. Heart-related problems : sudden death in patients who have heart problems or heart defects stroke and heart attack in adults increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting methylphenidate hydrochloride chewable tablets. Your doctor should check you or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride chewable tablets. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride chewable tablets. 2. Mental (Psychiatric) problems : All Patients new or worse behavior and thought problems new or worse bipolar illness new or worse aggressive behavior or hostility Children and Teenagers new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride chewable tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. 3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes. Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride. What Are Methylphenidate Hydrochloride Chewable Tablets? Methylphenidate hydrochloride chewable tablets are a central nervous system stimulant prescription medicine. Methylphenidate hydrochloride chewable tablets are tablets that are made to be chewed and swallowed. They are used for the treatment of Attention Deficit and Hyperactivity Disorder (ADHD). Methylphenidate hydrochloride chewable tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Methylphenidate hydrochloride chewable tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride chewable tablets are also used in the treatment of a sleep disorder called narcolepsy.
ness and hyperactivity in patients with ADHD. Methylphenidate hydrochloride chewable tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride chewable tablets are also used in the treatment of a sleep disorder called narcolepsy. Methylphenidate hydrochloride chewable tablets are a federally controlled substance (CII) because they can be abused or lead to dependence. Keep methylphenidate hydrochloride chewable tablets in a safe place to prevent misuse and abuse. Selling or giving away methylphenidate hydrochloride chewable tablets may harm others, and is against the law. Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take methylphenidate hydrochloride chewable tablets? Methylphenidate hydrochloride chewable tablets should not be taken if you or your child: are very anxious, tense, or agitated have an eye problem called glaucoma have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated movements or sounds. are taking or have taken within the past 14 days an antidepression medicine called a monoamine oxidase inhibitor or MAOI. are allergic to anything in methylphenidate hydrochloride chewable tablets. See the end of this Medication Guide for a complete list of ingredients. Methylphenidate hydrochloride chewable tablets should not be used in children less than 6 years old because they have not been studied in this age group. Methylphenidate hydrochloride chewable tablets may not be right for you or your child. Before starting methylphenidate hydrochloride chewable tablets tell your or your child’s doctor about all health conditions (or a family history of) including: heart problems, heart defects, high blood pressure mental problems including psychosis, mania, bipolar illness, or depression tics or Tourette’s syndrome seizures or have had an abnormal brain wave test (EEG) circulation problems in fingers and toes Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding. Can methylphenidate hydrochloride chewable tablets be taken with other medicines? Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride chewable tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride chewable tablets. Your doctor will decide whether methylphenidate hydrochloride chewable tablets can be taken with other medicines. Especially tell your doctor if you or your child takes: antidepression medicines including MAOIs seizure medicines blood thinner medicines blood pressure medicines cold or allergy medicines that contain decongestants Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while taking methylphenidate hydrochloride chewable tablets without talking to your doctor first. How should methylphenidate hydrochloride chewable tablets be taken? Take methylphenidate hydrochloride chewable tablets exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. Methylphenidate hydrochloride chewable tablets are usually taken 2 to 3 times a day. Take methylphenidate hydrochloride chewable tablets 30 to 45 minutes before a meal. Chew methylphenidate hydrochloride chewable tablets well and swallow with at least 8 ounces (a full glass) of water or other liquid.
you or your child. Methylphenidate hydrochloride chewable tablets are usually taken 2 to 3 times a day. Take methylphenidate hydrochloride chewable tablets 30 to 45 minutes before a meal. Chew methylphenidate hydrochloride chewable tablets well and swallow with at least 8 ounces (a full glass) of water or other liquid. Methylphenidate hydrochloride chewable tablets can swell and cause choking if enough liquid is not taken with them. Get emergency medical care if you have chest pain, vomiting, or trouble swallowing, or breathing after taking a methylphenidate hydrochloride chewable tablet. From time to time, your doctor may stop methylphenidate hydrochloride chewable tablets treatment for awhile to check ADHD symptoms. Your doctor may do regular checks of the blood, heart, and blood pressure while you are taking methylphenidate hydrochloride chewable tablets. Children should have their height and weight checked often while taking methylphenidate hydrochloride chewable tablets. Methylphenidate hydrochloride chewable tablets treatment may be stopped if a problem is found during these check-ups. If you or your child takes too much methylphenidate hydrochloride chewable tablets or overdoses, call your doctor or poison control center right away, or get emergency treatment. What are possible side effects of methylphenidate hydrochloride chewable tablets? See “What is the most important information I should know about methylphenidate hydrochloride chewable tablets?” for information on reported heart and mental problems. Other serious side effects include: slowing of growth (height and weight) in children seizures, mainly in patients with a history of seizures eyesight changes or blurred vision Painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develop priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately. Common side effects include: nervousness • stomach ache • decreased appetite trouble sleeping • fast heart beat • dizziness headache • nausea • weight loss Talk to your doctor if you or your child has side effects that are bothersome or do not go away. This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store methylphenidate hydrochloride chewable tablets? Store methylphenidate hydrochloride chewable tablets in a safe place at room temperature, at 20° to 25°C (68° to 77°F). [see USP Controlled Room Temperature]. Protect from moisture. Keep methylphenidate hydrochloride chewable tablets and all medicines out of the reach of children. General information about methylphenidate hydrochloride chewable tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use methylphenidate hydrochloride chewable tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride chewable tablets to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about methylphenidate hydrochloride chewable tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about methylphenidate hydrochloride chewable tablets that was written for healthcare professionals. For more information, please contact Camber Pharmaceuticals, Inc. at 1-866-495-8330. What are the ingredients in methylphenidate hydrochloride chewable tablets? CAUTION PHENYLKETONURICS: Methylphenidate hydrochloride chewable tablets contain phenylalanine.
chewable tablets that was written for healthcare professionals. For more information, please contact Camber Pharmaceuticals, Inc. at 1-866-495-8330. What are the ingredients in methylphenidate hydrochloride chewable tablets? CAUTION PHENYLKETONURICS: Methylphenidate hydrochloride chewable tablets contain phenylalanine. Active Ingredient: methylphenidate hydrochloride USP Inactive Ingredients: aspartame, lactose anhydrous, microcrystalline cellulose, guar gum, grape flavor, pregelatinized starch, and stearic acid. Medication Guide available at http://camberpharma.com/medication-guides This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Ascent Pharmaceuticals, Inc. Central Islip, NY 11722 Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 Rev: 08/21
<table border="1" cellspacing="0" cellpadding="0"><tbody><tr styleCode="First Last"><td valign="top"><paragraph styleCode="CM14 First"><content styleCode="bold">What is the most important information I should know about </content><content styleCode="bold">methylphenidate hydrochloride chewable tablets? </content></paragraph><paragraph styleCode="CM12"><content styleCode="bold">The following have been reported with use of methylphenidate HCl and other stimulant medicines. </content></paragraph><paragraph styleCode="CM19"><content styleCode="bold">1. <content styleCode="underline">Heart-related problems</content>: </content></paragraph><list listType="unordered"><item><content styleCode="bold">sudden death in patients who have heart problems or heart defects </content></item><item><content styleCode="bold">stroke and heart attack in adults </content></item><item><content styleCode="bold">increased blood pressure and heart rate </content></item></list><paragraph styleCode="Default"/><paragraph styleCode="CM16">Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems.</paragraph><paragraph styleCode="CM16">Your doctor should check you or your child carefully for heart problems before starting methylphenidate hydrochloride chewable tablets.</paragraph><paragraph styleCode="CM16">Your doctor should check you or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride chewable tablets.</paragraph><paragraph styleCode="CM16"><content styleCode="bold">Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking </content><content styleCode="bold">methylphenidate hydrochloride chewable tablets. </content></paragraph><paragraph styleCode="CM20"/><paragraph styleCode="CM20"><content styleCode="bold">2. <content styleCode="underline">Mental (Psychiatric) problems</content>: </content></paragraph><paragraph styleCode="CM20"><content styleCode="bold">All Patients </content></paragraph><list listType="unordered"><item><content styleCode="bold">new or worse behavior and thought problems </content></item><item><content styleCode="bold">new or worse bipolar illness </content></item><item><content styleCode="bold">new or worse aggressive behavior or hostility </content></item></list><content styleCode="bold">Children and Teenagers</content> <list listType="unordered"><item><content styleCode="bold">new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms</content></item></list><paragraph styleCode="Default"/><paragraph styleCode="CM16">Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.</paragraph><paragraph styleCode="CM16"><content styleCode="bold">Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking </content><content styleCode="bold">methylphenidate hydrochloride chewable tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. </content></paragraph><paragraph styleCode="CM19"><content styleCode="bold">3.
sening mental symptoms or problems while taking </content><content styleCode="bold">methylphenidate hydrochloride chewable tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. </content></paragraph><paragraph styleCode="CM19"><content styleCode="bold">3. <content styleCode="underline">Circulation problems in fingers and toes </content></content>[Peripheral vasculopathy, including Raynaud’s phenomenon]: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.</paragraph><list listType="unordered"><item>Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes.</item></list><list listType="unordered"><item><content styleCode="bold">Call your doctor right away if you have or your child has any signs of unexplained</content><content styleCode="bold"> wounds appearing on fingers or toes while taking </content><content styleCode="bold">methylphenidate hydrochloride.</content></item></list><paragraph styleCode="Default"/></td></tr></tbody></table> <table border="1" cellspacing="0" cellpadding="0"><tbody><tr styleCode="First Last"><td valign="top"><paragraph styleCode="CM12 First"><content styleCode="bold">Methylphenidate hydrochloride chewable tablets are a federally controlled substance (CII) because they can be abused or lead to dependence. Keep methylphenidate hydrochloride chewable tablets in a safe place to prevent misuse and abuse. Selling or giving away methylphenidate hydrochloride chewable tablets may harm others, and is against the law.</content></paragraph><paragraph styleCode="CM13">Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs.</paragraph></td></tr></tbody></table>
nidate hydrochloride chewable tablets may harm others, and is against the law.</content></paragraph><paragraph styleCode="CM13">Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs.</paragraph></td></tr></tbody></table> <table border="1" cellspacing="0" cellpadding="0"><tbody><tr styleCode="First Last"><td valign="top"><list listType="unordered"><item><content styleCode="bold">Chew </content><content styleCode="bold">methylphenidate hydrochloride chewable tablets well and swallow with at least 8 ounces (a full glass) of water or other liquid. Methylphenidate hydrochloride chewable tablets can swell and cause choking if enough liquid is not taken with them. Get emergency medical care if you have chest pain, vomiting, or trouble swallowing, or breathing after taking a methylphenidate hydrochloride chewable tablet.</content></item></list></td></tr></tbody></table> <table border="1" cellspacing="0" cellpadding="0"><tbody><tr styleCode="First Last"><td valign="top"><paragraph styleCode="CM13 First"><content styleCode="bold">CAUTION PHENYLKETONURICS: </content><content styleCode="bold">Methylphenidate hydrochloride chewable tablets contain phenylalanine. </content></paragraph></td></tr></tbody></table>
WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate hydrochloride oral solution has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride oral solution, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout methylphenidate hydrochloride oral solution treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions ( 5.1 ) and Drug Abuse and Dependence ( 9.2 )] . WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. Methylphenidate hydrochloride oral solution has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride oral solution, can result in overdose and death ( 5.1 , 9.2 , 10 ): Before prescribing methylphenidate hydrochloride oral solution, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
1 INDICATIONS AND USAGE Methylphenidate hydrochloride oral solution is indicated for the treatment of: • Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years of age and older • Narcolepsy Methylphenidate hydrochloride oral solution is a central nervous system (CNS) stimulant indicated for the treatment of: Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years of age and older ( 1 ) Narcolepsy ( 1 )
2 DOSAGE AND ADMINISTRATION Pediatric patients 6 years and older: Starting dose is 5 mg twice daily (before breakfast and lunch); increase the dose 5 mg to 10 mg weekly; daily dosage above 60 mg is not recommended. ( 2.2 ) Adults: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Maximum recommended daily dosage is 60 mg. ( 2 ) 2.1 Pretreatment Screening Prior to treating patients with methylphenidate hydrochloride oral solution, assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions ( 5.2 )] . the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome [see Warnings and Precautions ( 5.10 )] . 2.2 General Dosing Information Pediatric Patients 6 years of Age and Older The recommended starting dosage is 5 mg orally twice daily before breakfast and lunch (preferably 30 to 45 minutes before meals). Increase the dosage gradually, in increments of 5 mg to 10 mg weekly. Daily dosage above 60 mg is not recommended. Adults Administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. The maximum recommended daily dose is 60 mg. The average dosage is 20 to 30 mg daily. For adult patients who are unable to sleep if medication is taken late in the day, administer the last dose before 6 p.m. 2.3 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage, or, if necessary, discontinue methylphenidate hydrochloride oral solution. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue methylphenidate hydrochloride oral solution.
3 DOSAGE FORMS AND STRENGTHS Methylphenidate hydrochloride oral solution is a colorless, grape flavored liquid available in a 500 mL bottle in the following strengths: 5 mg per 5 mL 10 mg per 5 mL Oral solution: 5 mg per 5 mL and 10 mg per 5 mL. ( 3 )
4 CONTRAINDICATIONS Methylphenidate hydrochloride oral solution is contraindicated in patients: with known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride oral solution. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions ( 6 )] . receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions ( 7 )] . Known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride oral solution ( 4 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days ( 4 )
5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. ( 5.2 ) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3 ) Psychiatric Adverse Reactions: Prior to initiating methylphenidate hydrochloride oral solution, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride oral solution. ( 5.4 ) Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention. ( 5.5 ) Peripheral Vasculopathy, Including Raynaud’s Phenomenon: Careful observation for digital changes is necessary during methylphenidate hydrochloride treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.6 ) Long-Term Suppression of Growth in Pediatric Patients: Closely monitor (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.7 ) Acute Angle Closure Glaucoma: Methylphenidate hydrochloride-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. ( 5.8 ) Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe methylphenidate hydrochloride oral solution to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open-angle glaucoma. ( 5.9 ) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating methylphenidate hydrochloride oral solution, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. ( 5.10 ) 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride oral solution has a high potential for abuse and misuse. The use of methylphenidate hydrochloride exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate hydrochloride oral solution can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence ( 9.2 )] . Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride oral solution, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate hydrochloride oral solution in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride oral solution to anyone else.
use, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate hydrochloride oral solution in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride oral solution to anyone else. Throughout methylphenidate hydrochloride treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate hydrochloride use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases. Monitor all methylphenidate hydrochloride-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Pre-Existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Illness CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating methylphenidate hydrochloride treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosages, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride oral solution. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, Including Raynaud’s Phenomenon CNS stimulants, including methylphenidate hydrochloride oral solution, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during methylphenidate hydrochloride treatment.
keting reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during methylphenidate hydrochloride treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication-treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in methylphenidate hydrochloride-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. The safety and effectiveness of methylphenidate hydrochloride oral solution have not been established in pediatric patient less than 6 years of age. 5.8 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate hydrochloride-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.9 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions ( 6.2 )]. Prescribe methylphenidate hydrochloride oral solution to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride-treated patients with a history of abnormally increased IOP or open-angle glaucoma. 5.10 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions ( 6.2 )]. Before initiating methylphenidate hydrochloride oral solution, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Abuse, misuse, and addiction [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] Known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride oral solution [see Contraindications ( 4 )] Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications ( 4 ), Drug Interactions ( 7 )] Risks to patients with serious cardiac disease [see Warnings and Precautions ( 5.2 )] Increased blood pressure and heart rate [see Warnings and Precautions ( 5.3 )] Psychiatric adverse reactions [see Warnings and Precautions ( 5.4 )] Priapism [see Warnings and Precautions ( 5.5 )] Peripheral vasculopathy, including Raynaud’s phenomenon [see Warnings and Precautions ( 5.6 )] Long-term suppression of growth in pediatric patients [see Warnings and Precautions ( 5.7 )] Acute angle closure glaucoma [see Warnings and Precautions ( 5.8 )] Increased intraocular pressure and glaucoma [see Warnings and Precautions ( 5.9 )] Motor and verbal tics, and worsening of Tourette’s syndrome [see Warnings and Precautions ( 5.10 )] The following adverse reactions associated with the use of methylphenidate containing products were identified in clinical studies, postmarketing reports, or literature. Because some of these reactions were 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.
ethylphenidate containing products were identified in clinical studies, postmarketing reports, or literature. Because some of these reactions were 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. Infections and infestations: nasopharyngitis Blood and the lymphatic system disorders: leukopenia, thrombocytopenia, anemia, pancytopenia Immune system disorders: hypersensitivity reactions, including angioedema and anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas Metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients Psychiatric disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, affect lability, mania, disorientation, libido changes Nervous system disorders: headache, dizziness, tremor, dyskinesia including choreoatheetoid movements, drowsiness, convulsions, cerebral arteritis and/or occlusion, serotonin syndrome in combination with serotonergic drugs, migraine, motor and verbal tics Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, mydriasis, increased intraocular pressure Cardiac disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris, sudden cardiac death, myocardial infarction, bradycardia, extrasystole Respiratory, thoracic and mediastinal disorders: cough, pharyngolaryngeal pain, dyspnea Gastrointestinal disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia, diarrhea General disorders: fatigue, hyperpyrexia Hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura angioneurotic edema, erythema, fixed drug eruption Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, rhabdomyolysis, myalgia, muscle twitching Renal and urinary disorders: hematuria Reproductive system and breast disorders: gynecomastia Urogenital disorders: priapism Vascular disorders: peripheral coldness, Raynaud’s phenomenon Investigations: weight loss Common adverse reactions: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS contact Tris Pharma, Inc., at (732) 940 0358 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7.1 ) 7.1 Clinically Important Drug Interactions with Methylphenidate Hydrochloride Oral Solution Table 1 presents clinically important drug interactions with methylphenidate hydrochloride oral solution. Table 1: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Oral Solution Monoamine Oxidase Inhibitors (MAOI) Clinical Impact: Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride oral solution, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications ( 4 )] . Intervention: Concomitant use of methylphenidate hydrochloride oral solution with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical Impact: Methylphenidate hydrochloride oral solution may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions ( 5.3 )] . Intervention: Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical Impact: Concomitant use of halogenated anesthetics and methylphenidate hydrochloride oral solution may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention: Avoid use of methylphenidate hydrochloride oral solution in patients being treated with anesthetics on the day of surgery. Risperidone Clinical Impact: Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Intervention: Monitor for signs of EPS.
<table cellspacing="0" cellpadding="0" border="1"><col width="1pt"/><col/><tbody><tr><td colspan="2"><paragraph>Monoamine Oxidase Inhibitors (MAOI)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride oral solution, can cause hypertensive crisis.
r><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride oral solution, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure <content styleCode="italics">[see Contraindications (</content><content styleCode="italics"><linkHtml href="#LINK_cf0d4f74-036e-4cee-856c-f1616c7f0274">4</linkHtml></content><content styleCode="italics">)]</content>.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of methylphenidate hydrochloride oral solution with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Antihypertensive Drugs</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Methylphenidate hydrochloride oral solution may decrease the effectiveness of drugs used to treat hypertension <content styleCode="italics">[see Warnings and Precautions (</content><content styleCode="italics"><linkHtml href="#LINK_8ee60d7b-2bac-45d4-b0f8-6337633f9058">5.3</linkHtml></content><content styleCode="italics">)]</content>.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Halogenated Anesthetics</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of halogenated anesthetics and methylphenidate hydrochloride oral solution may increase the risk of sudden blood pressure and heart rate increase during surgery.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Avoid use of methylphenidate hydrochloride oral solution in patients being treated with anesthetics on the day of surgery.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule">Risperidone</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode=" Botrule Toprule Lrule Rrule">Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS).</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode=" Botrule Toprule Lrule Rrule">Monitor for signs of EPS. </td></tr></tbody></table>
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 ADHD medications, including methylphenidate hydrochloride oral solution, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations ) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 12 and 19 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adults on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 65 times the MRHD given to adults. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 7 times the MRHD given to adults (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride oral solution, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 65 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (19 times the MRHD given to adults on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (12 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (4 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (7 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed.
n a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (7 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adults on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride oral solution and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride oral solution or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride oral solution for the treatment of ADHD have been established in pediatric patients six years of age and older. The safety and effectiveness of methylphenidate hydrochloride oral solution in pediatric patients under six years of age have not been established. The long-term efficacy of methylphenidate in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride oral solution. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.6 )] . Juvenile Animal Toxicity Data In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats (5 mg/kg/day) is less than the MRHD given to children on a mg/m 2 basis. The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Methylphenidate hydrochloride oral solution has not been studied in the geriatric population.
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate hydrochloride oral solution, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations ) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 12 and 19 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adults on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 65 times the MRHD given to adults. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 7 times the MRHD given to adults (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride oral solution, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 65 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (19 times the MRHD given to adults on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (12 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (4 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (7 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed.
n a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (7 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adults on a mg/m 2 basis).
8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride oral solution and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride oral solution or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.
8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride oral solution for the treatment of ADHD have been established in pediatric patients six years of age and older. The safety and effectiveness of methylphenidate hydrochloride oral solution in pediatric patients under six years of age have not been established. The long-term efficacy of methylphenidate in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride oral solution. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.6 )] . Juvenile Animal Toxicity Data In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats (5 mg/kg/day) is less than the MRHD given to children on a mg/m 2 basis. The clinical significance of the long-term behavioral effects observed in rats is unknown.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate hydrochloride oral solution contains methylphenidate hydrochloride, a Schedule II controlled substance. 9.2 Abuse Methylphenidate hydrochloride oral solution has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )]. Methylphenidate hydrochloride oral solution can be diverted for non medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride oral solution, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses and or unapproved methods of administration, such as snorting or injection. 9.3 Dependence Physical Dependence Methylphenidate hydrochloride oral solution may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate hydrochloride oral solution may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
10 OVERDOSAGE Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
11 DESCRIPTION Methylphenidate hydrochloride oral solution is a CNS stimulant available as 5 mg/5 mL and 10 mg/5 mL strengths for oral administration. Chemically, Methylphenidate hydrochloride is ( d,l racemic) methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is: Methylphenidate hydrochloride, USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Each mL of methylphenidate hydrochloride oral solution 5 mg/5 mL contains 1 mg of methylphenidate hydrochloride, USP. Each mL of methylphenidate hydrochloride oral solution 10 mg/5 mL contains 2 mg of methylphenidate hydrochloride, USP. In addition, methylphenidate hydrochloride oral solution also contains the following inactive ingredients: artificial grape flavor, glycerin, hydrochloric acid, polyethylene glycol 1450, and purified water.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d - and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l - threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in subjects taking methylphenidate hydrochloride oral solution. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride oral solution, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of 40 mg dexmethylphenidate hydrochloride extended-release capsule in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship. 12.3 Pharmacokinetics Absorption Following a single dose administration of 20 mg methylphenidate hydrochloride oral solution and 20 mg tablet of methylphenidate hydrochloride in healthy volunteers under fasted conditions, time to peak plasma concentration (T max ) of methylphenidate was at 1 to 2 hours after dosing, and: The mean peak plasma concentration (C max ) of methylphenidate was 9.1 ng/mL and 9.8 ng/mL, respectively. The mean area under concentration curve (AUC) of methylphenidate was 46.7 hour*ng/mL and 50.0 hour*ng/mL, respectively. Effect of Food Ingestion of a high-fat meal with methylphenidate hydrochloride oral solution increased methylphenidate mean C max and AUC by about 13% and 25%, respectively. Time to C max (T max ) was delayed by approximately 1 hour. Distribution Plasma protein binding is 10% to 33%. The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate. Elimination The mean terminal half-life (t1/2) of methylphenidate was 2.7 hours following administration of 20 mg methylphenidate hydrochloride oral solution. The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. Metabolism Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. Specific Populations Male and Female Patients, Racial Groups, and Age The effect of gender, race, and age on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride oral solution administration have not been studied. Patients with Renal Impairment Methylphenidate hydrochloride oral solution has not been studied in patients with renal impairment.
12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d - and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l - threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in subjects taking methylphenidate hydrochloride oral solution. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride oral solution, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of 40 mg dexmethylphenidate hydrochloride extended-release capsule in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship.
12.3 Pharmacokinetics Absorption Following a single dose administration of 20 mg methylphenidate hydrochloride oral solution and 20 mg tablet of methylphenidate hydrochloride in healthy volunteers under fasted conditions, time to peak plasma concentration (T max ) of methylphenidate was at 1 to 2 hours after dosing, and: The mean peak plasma concentration (C max ) of methylphenidate was 9.1 ng/mL and 9.8 ng/mL, respectively. The mean area under concentration curve (AUC) of methylphenidate was 46.7 hour*ng/mL and 50.0 hour*ng/mL, respectively. Effect of Food Ingestion of a high-fat meal with methylphenidate hydrochloride oral solution increased methylphenidate mean C max and AUC by about 13% and 25%, respectively. Time to C max (T max ) was delayed by approximately 1 hour. Distribution Plasma protein binding is 10% to 33%. The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate. Elimination The mean terminal half-life (t1/2) of methylphenidate was 2.7 hours following administration of 20 mg methylphenidate hydrochloride oral solution. The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. Metabolism Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. Specific Populations Male and Female Patients, Racial Groups, and Age The effect of gender, race, and age on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride oral solution administration have not been studied. Patients with Renal Impairment Methylphenidate hydrochloride oral solution has not been studied in patients with renal impairment. Since renal clearance is not an important route of methylphenidate clearance, renal impairment is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride oral solution. Patients with Hepatic Impairment Methylphenidate hydrochloride oral solution has not been studied in patients with hepatic impairment. Since methylphenidate is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body, hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate hydrochloride oral solution.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 5 times the maximum recommended human dose (MRHD) of 60 mg/kg given to adults on a mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 7 times the MRHD (adults) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 13 times the maximum recommended human dose of 60 mg/day given to adults on a mg/m 2 basis.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 5 times the maximum recommended human dose (MRHD) of 60 mg/kg given to adults on a mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 7 times the MRHD (adults) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 13 times the maximum recommended human dose of 60 mg/day given to adults on a mg/m 2 basis.
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Methylphenidate hydrochloride oral solution 5 mg per 5 mL is a colorless, grape flavored liquid. It is supplied in bottles of 500 mL, NDC 72162-2040-5. Storage and Handling Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in tight container with child-resistant closure. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of methylphenidate hydrochloride oral solution, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 ), Overdosage ( 10 )] . Advise patients to store methylphenidate hydrochloride oral solution in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride oral solution to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with methylphenidate hydrochloride oral solution use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions ( 5.2 )] . Increased Blood Pressure and Heart Rate Instruct patients that methylphenidate hydrochloride oral solution can elevate blood pressure and heart rate [see Warnings and Precautions ( 5.3 )] . Psychiatric Adverse Reactions Advise patients that methylphenidate hydrochloride oral solution, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions ( 5.4 )] . Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions ( 5.5 )] . Circulation Problems in Fingers and Toes (Peripheral Vasculopathy, Including Raynaud’s Phenomenon) Instruct patients about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride oral solution. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions ( 5.6 )] . Long-Term Suppression of Growth in Pediatric Patients Advise patients that methylphenidate hydrochloride oral solution may cause slowing of growth and weight loss in pediatric patients [see Warnings and Precautions ( 5.7 )] . Increased Intraocular Pressure (IOP) and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with methylphenidate hydrochloride oral solution [see Warnings and Precautions ( 5.9 )] . Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s syndrome may occur during treatment with methylphenidate hydrochloride oral solution. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions ( 5.10 )] .
atients that motor and verbal tics and worsening of Tourette’s syndrome may occur during treatment with methylphenidate hydrochloride oral solution. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions ( 5.10 )] . Pregnancy Exposure Registry Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to methylphenidate hydrochloride oral solution during pregnancy [see Use in Specific Populations ( 8.1 )] . Manufactured by: Tris Pharma Inc. Monmouth Junction, NJ 08852 www.trispharma.com LB8477 Rev. 03 12/2023
MEDICATION GUIDE Methylphenidate Hydrochloride Oral Solution CII (METH il FEN i date) 5 mg/5 mL and 10 mg/5 mL Rx only What is the most important information I should know about Methylphenidate Hydrochloride Oral Solution? Methylphenidate Hydrochloride Oral Solution may cause serious side effects, including: Abuse , misuse, and addiction. Methylphenidate Hydrochloride Oral Solution has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of Methylphenidate Hydrochloride Oral Solution, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of Methylphenidate Hydrochloride Oral Solution or when it is used in ways that are not approved, such as snorting or injection. Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with Methylphenidate Hydrochloride Oral Solution and will monitor you or your child during treatment. Methylphenidate Hydrochloride Oral Solution may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. Do not give Methylphenidate Hydrochloride Oral Solution to anyone else. See “What is Methylphenidate Hydrochloride Oral Solution?” for more information. Keep Methylphenidate Hydrochloride Oral Solution in a safe place and properly dispose of any unused medicine. See “How should I store Methylphenidate Hydrochloride Oral Solution?” for more information. Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting treatment with Methylphenidate Hydrochloride Oral Solution. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with Methylphenidate Hydrochloride Oral Solution. Increased blood pressure and heart rate. Your healthcare provider should check your or your child’s blood pressure and heart rate regularly during treatment with Methylphenidate Hydrochloride Oral Solution. Mental (psychiatric) problems, including: new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with Methylphenidate Hydrochloride Oral Solution, especially hearing voices, seeing or believing things that are not real, or new manic symptoms. What is Methylphenidate Hydrochloride Oral Solution? Methylphenidate Hydrochloride Oral Solution is a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older.
y hearing voices, seeing or believing things that are not real, or new manic symptoms. What is Methylphenidate Hydrochloride Oral Solution? Methylphenidate Hydrochloride Oral Solution is a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. Methylphenidate Hydrochloride Oral Solution may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. It is not known if Methylphenidate Hydrochloride Oral Solution is safe and effective for use in children under 6 years of age. Methylphenidate Hydrochloride Oral Solution is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep Methylphenidate Hydrochloride Oral Solution in a safe place to protect it from theft. Never give your Methylphenidate Hydrochloride Oral Solution to anyone else, because it may cause death or harm them. Selling or giving away Methylphenidate Hydrochloride Oral Solution may harm others and is against the law. Do not take Methylphenidate Hydrochloride Oral Solution if you or your child are: allergic to methylphenidate hydrochloride or any of the ingredients in Methylphenidate Hydrochloride Oral Solution. See the end of this Medication Guide for a complete list of ingredients in Methylphenidate Hydrochloride Oral Solution. taking, or have stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI). Before taking Methylphenidate Hydrochloride Oral Solution tell your healthcare provider about all your medical conditions, including if you or your child: have heart problems, heart disease, heart defects, or high blood pressure have mental problems including psychosis, mania, bipolar illness, or depression, or have a family history of suicide, bipolar illness, or depression have circulation problems in fingers and toes have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome are pregnant or plan to become pregnant. It is not known if Methylphenidate Hydrochloride Oral Solution will harm the unborn baby. There is a pregnancy registry for females who are exposed to Methylphenidate Hydrochloride Oral Solution during pregnancy. The purpose of the registry is to collect information about the health of females exposed to Methylphenidate Hydrochloride Oral Solution and their baby. If you or your child becomes pregnant during treatment with Methylphenidate Hydrochloride Oral Solution, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. are breastfeeding or plan to breastfeed. Methylphenidate Hydrochloride Oral Solution passes into breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with Methylphenidate Hydrochloride Oral Solution. Tell your healthcare provider about all the medicines that you take or your child take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate Hydrochloride Oral Solution and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with Methylphenidate Hydrochloride Oral Solution. Your healthcare provider will decide whether Methylphenidate Hydrochloride Oral Solution can be taken with other medicines. Especially tell your healthcare provider if you or your child take a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI).
ith Methylphenidate Hydrochloride Oral Solution. Your healthcare provider will decide whether Methylphenidate Hydrochloride Oral Solution can be taken with other medicines. Especially tell your healthcare provider if you or your child take a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI). Know the medicines that you take or your child take. Keep a list of your medicines with you to show your healthcare provider and pharmacist. Do not start any new medicine during treatment with Methylphenidate Hydrochloride Oral Solution without talking to your healthcare provider first. How should Methylphenidate Hydrochloride Oral Solution be taken? Take Methylphenidate Hydrochloride Oral Solution exactly as prescribed by your healthcare provider. Your healthcare provider may change the dose if needed. Children 6 years of age and older: Take Methylphenidate Hydrochloride Oral Solution by mouth 2 times a day before breakfast and lunch, 30 to 45 minutes before a meal, as prescribed by your healthcare provider. Adults: Take Methylphenidate Hydrochloride Oral Solution by mouth 2 or 3 times a day, 30 to 45 minutes before a meal, as prescribed by your healthcare provider. For adults who have sleep problems when Methylphenidate Hydrochloride Oral Solution is taken late in the day, take your last dose of Methylphenidate Hydrochloride Oral Solution before 6 p.m. If you or your child take too much Methylphenidate Hydrochloride Oral Solution, call your healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of Methylphenidate Hydrochloride Oral Solution? Methylphenidate Hydrochloride Oral Solution may cause serious side effects, including: See “What is the most important information I should know about Methylphenidate Hydrochloride Oral Solution? ” Painful and prolonged erections (priapism). Priapism has happened in males who take products that contain methylphenidate. If you or your child develop priapism, get medical help right away. Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon). Signs and symptoms may include: fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes, or if you or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with Methylphenidate Hydrochloride Oral Solution. Slowing of growth (height and weight) in children . Children should have their height and weight checked often during treatment with Methylphenidate Hydrochloride Oral Solution. Methylphenidate Hydrochloride Oral Solution treatment may be stopped if your child is not growing or gaining weight. Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with Methylphenidate Hydrochloride Oral Solution. The most common side effects of Methylphenidate Hydrochloride Oral Solution include: increased heart rate headache anxiety weight loss dry mouth stomach pain irregular heart beat (palpitations) trouble sleeping sweating decreased appetite nausea These are not all the possible side effects of Methylphenidate Hydrochloride Oral Solution. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
ht loss dry mouth stomach pain irregular heart beat (palpitations) trouble sleeping sweating decreased appetite nausea These are not all the possible side effects of Methylphenidate Hydrochloride Oral Solution. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Methylphenidate Hydrochloride Oral Solution? Store Methylphenidate Hydrochloride Oral Solution at room temperature between 68°F to 77°F (20°C to 25°C). Store Methylphenidate Hydrochloride Oral Solution in a safe place, like a locked cabinet. Protect from light and moisture. Dispose of remaining, unused, or expired Methylphenidate Hydrochloride Oral Solution by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix Methylphenidate Hydrochloride Oral Solution with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away Methylphenidate Hydrochloride Oral Solution in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep Methylphenidate Hydrochloride Oral Solution and all medicines out of the reach of children. General information about the safe and effective use of Methylphenidate Hydrochloride Oral Solution. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Methylphenidate Hydrochloride Oral Solution for a condition for which it was not prescribed. Do not give Methylphenidate Hydrochloride Oral Solution to other people, even if they have the same symptoms. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about Methylphenidate Hydrochloride Oral Solution that is written for healthcare professionals. What are the ingredients in Methylphenidate Hydrochloride Oral Solution? Active Ingredient: methylphenidate hydrochloride, USP Inactive Ingredients: artificial grape flavor, glycerin, hydrochloric acid, polyethylene glycol 1450, and purified water. Manufactured by: Tris Pharma, Inc. Monmouth Junction, NJ 08852 For more information about Methylphenidate Hydrochloride Oral Solution contact Tris Pharma, Inc at 732-940-0358 or go to www.trispharma.com . LB8478 Rev. 03 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2023
<table cellspacing="0" cellpadding="0" border="1"><col width="1pt"/><col/><tbody><tr><td colspan="2"><paragraph><content styleCode="bold">Methylphenidate Hydrochloride Oral Solution CII</content></paragraph><paragraph><content styleCode="bold">(METH il FEN i date)</content></paragraph><paragraph><content styleCode="bold">5 mg/5 mL and 10 mg/5 mL</content></paragraph><paragraph><content styleCode="bold">Rx only</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What is the most important information I should know about Methylphenidate Hydrochloride Oral Solution?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate Hydrochloride Oral Solution may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Abuse<content styleCode="bold">, misuse, and addiction.</content></content> Methylphenidate Hydrochloride Oral Solution has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of Methylphenidate Hydrochloride Oral Solution, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of Methylphenidate Hydrochloride Oral Solution or when it is used in ways that are not approved, such as snorting or injection. <list listType="unordered" styleCode="Circle"><item>Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with Methylphenidate Hydrochloride Oral Solution and will monitor you or your child during treatment.</item><item>Methylphenidate Hydrochloride Oral Solution may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider.</item><item>Do not give Methylphenidate Hydrochloride Oral Solution to anyone else. See <content styleCode="bold">“What is Methylphenidate Hydrochloride Oral Solution?”</content> for more information.</item><item>Keep Methylphenidate Hydrochloride Oral Solution in a safe place and properly dispose of any unused medicine. See <content styleCode="bold">“How should I store Methylphenidate Hydrochloride Oral Solution?”</content> for more information.</item><item>Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs.</item></list></item><item><content styleCode="bold"><content styleCode="bold">Risks for people with serious heart disease. </content></content>Sudden death has happened in people who have heart defects or other serious heart disease. <paragraph>Your healthcare provider should check you or your child carefully for heart problems before starting treatment with Methylphenidate Hydrochloride Oral Solution.
or people with serious heart disease. </content></content>Sudden death has happened in people who have heart defects or other serious heart disease. <paragraph>Your healthcare provider should check you or your child carefully for heart problems before starting treatment with Methylphenidate Hydrochloride Oral Solution. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects.</paragraph><paragraph><content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with Methylphenidate Hydrochloride Oral Solution.</content></paragraph></item><item><content styleCode="bold">Increased blood pressure and heart rate.</content><content styleCode="bold"> </content>Your healthcare provider should check your or your child’s blood pressure and heart rate regularly during treatment with Methylphenidate Hydrochloride Oral Solution.</item><item><content styleCode="bold">Mental (psychiatric) problems, including:</content></item></list><list listType="unordered" styleCode="Circle"><item>new or worse behavior and thought problems</item><item>new or worse bipolar illness</item><item>new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms</item></list><paragraph>Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.</paragraph><paragraph><content styleCode="bold">Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with Methylphenidate Hydrochloride Oral Solution, especially hearing voices, seeing or believing things that are not real, or new manic symptoms.</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What is Methylphenidate Hydrochloride Oral Solution?</content></paragraph><paragraph>Methylphenidate Hydrochloride Oral Solution is a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. Methylphenidate Hydrochloride Oral Solution may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD.</paragraph><paragraph>It is not known if Methylphenidate Hydrochloride Oral Solution is safe and effective for use in children under 6 years of age.</paragraph><paragraph><content styleCode="bold">Methylphenidate Hydrochloride Oral Solution is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs.</content></paragraph><paragraph>Keep Methylphenidate Hydrochloride Oral Solution in a safe place to protect it from theft. Never give your Methylphenidate Hydrochloride Oral Solution to anyone else, because it may cause death or harm them. Selling or giving away Methylphenidate Hydrochloride Oral Solution may harm others and is against the law.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Do not take Methylphenidate Hydrochloride Oral Solution if you or your child are:</content></paragraph><list listType="unordered" styleCode="Disc"><item>allergic to methylphenidate hydrochloride or any of the ingredients in Methylphenidate Hydrochloride Oral Solution.
e Lrule Rrule"><paragraph><content styleCode="bold">Do not take Methylphenidate Hydrochloride Oral Solution if you or your child are:</content></paragraph><list listType="unordered" styleCode="Disc"><item>allergic to methylphenidate hydrochloride or any of the ingredients in Methylphenidate Hydrochloride Oral Solution. See the end of this Medication Guide for a complete list of ingredients in Methylphenidate Hydrochloride Oral Solution.</item><item>taking, or have stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI).</item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Before taking Methylphenidate Hydrochloride Oral Solution tell your healthcare provider about all your medical conditions, including if you or your child:</content></paragraph><list listType="unordered" styleCode="Disc"><item>have heart problems, heart disease, heart defects, or high blood pressure</item><item>have mental problems including psychosis, mania, bipolar illness, or depression, or have a family history of suicide, bipolar illness, or depression</item></list><list listType="unordered" styleCode="Disc"><item>have circulation problems in fingers and toes </item><item>have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness)</item><item>have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome</item></list><list listType="unordered" styleCode="Disc"><item>are pregnant or plan to become pregnant. It is not known if Methylphenidate Hydrochloride Oral Solution will harm the unborn baby. <list listType="unordered" styleCode="Circle"><item>There is a pregnancy registry for females who are exposed to Methylphenidate Hydrochloride Oral Solution during pregnancy. The purpose of the registry is to collect information about the health of females exposed to Methylphenidate Hydrochloride Oral Solution and their baby. If you or your child becomes pregnant during treatment with Methylphenidate Hydrochloride Oral Solution, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.</item></list></item></list><list listType="unordered" styleCode="Disc"><item>are breastfeeding or plan to breastfeed. Methylphenidate Hydrochloride Oral Solution passes into breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with Methylphenidate Hydrochloride Oral Solution.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines that you take or your child take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph><paragraph>Methylphenidate Hydrochloride Oral Solution and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with Methylphenidate Hydrochloride Oral Solution. Your healthcare provider will decide whether Methylphenidate Hydrochloride Oral Solution can be taken with other medicines.</paragraph><paragraph><content styleCode="bold">Especially tell your healthcare provider if you or your child take </content>a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI).</paragraph><paragraph>Know the medicines that you take or your child take. Keep a list of your medicines with you to show your healthcare provider and pharmacist.
Especially tell your healthcare provider if you or your child take </content>a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI).</paragraph><paragraph>Know the medicines that you take or your child take. Keep a list of your medicines with you to show your healthcare provider and pharmacist. <content styleCode="bold">Do not start any new medicine during treatment with Methylphenidate Hydrochloride Oral Solution without talking to your healthcare provider first.</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How should Methylphenidate Hydrochloride Oral Solution be taken?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Take Methylphenidate Hydrochloride Oral Solution exactly as prescribed by your healthcare provider.</item><item>Your healthcare provider may change the dose if needed.</item></list><list listType="unordered" styleCode="Disk"><item><content styleCode="bold">Children 6 years of age and older:</content></item></list><list listType="unordered" styleCode="Circle"><item>Take Methylphenidate Hydrochloride Oral Solution by mouth 2 times a day before breakfast and lunch, 30 to 45 minutes before a meal, as prescribed by your healthcare provider. </item></list><list listType="unordered" styleCode="Disk"><item><content styleCode="bold">Adults:</content><list listType="unordered" styleCode="Circle"><item>Take Methylphenidate Hydrochloride Oral Solution by mouth 2 or 3 times a day, 30 to 45 minutes before a meal, as prescribed by your healthcare provider.</item><item>For adults who have sleep problems when Methylphenidate Hydrochloride Oral Solution is taken late in the day, take your last dose of Methylphenidate Hydrochloride Oral Solution before 6 p.m.</item></list></item></list><list listType="unordered" styleCode="Disc"><item>If you or your child take too much Methylphenidate Hydrochloride Oral Solution, call your healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away.</item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the possible side effects of Methylphenidate Hydrochloride Oral Solution?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate Hydrochloride Oral Solution may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item>See <content styleCode="bold">“What is the most important information I should know about Methylphenidate Hydrochloride Oral Solution?</content>”</item><item><content styleCode="bold">Painful and prolonged erections (priapism).</content> Priapism has happened in males who take products that contain methylphenidate. <content styleCode="bold">If you or your child develop priapism, get medical help right away.</content></item><item><content styleCode="bold">Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon).</content> Signs and symptoms may include: <list listType="unordered" styleCode="Circle"><item>fingers or toes may feel numb, cool, painful</item><item>fingers or toes may change color from pale, to blue, to red</item></list><paragraph>Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes, or if you or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with Methylphenidate Hydrochloride Oral Solution.</paragraph></item><item><content styleCode="bold">Slowing of growth (height and weight) in children</content>.
r sensitivity to temperature in the fingers or toes, or if you or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with Methylphenidate Hydrochloride Oral Solution.</paragraph></item><item><content styleCode="bold">Slowing of growth (height and weight) in children</content>. Children should have their height and weight checked often during treatment with Methylphenidate Hydrochloride Oral Solution. Methylphenidate Hydrochloride Oral Solution treatment may be stopped if your child is not growing or gaining weight. </item><item><content styleCode="bold">Eye problems (increased pressure in the eye and glaucoma). </content>Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness.</item><item><content styleCode="bold">New or worsening tics or worsening Tourette’s syndrome. </content>Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with Methylphenidate Hydrochloride Oral Solution.</item></list><paragraph><content styleCode="bold">The most common side effects of Methylphenidate Hydrochloride Oral Solution include:</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>increased heart rate</item><item>headache</item><item>anxiety</item><item>weight loss</item><item>dry mouth</item><item>stomach pain</item></list></td><td styleCode=" Botrule Toprule Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>irregular heart beat (palpitations)</item><item>trouble sleeping</item><item>sweating</item><item>decreased appetite</item><item>nausea</item></list></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>These are not all the possible side effects of Methylphenidate Hydrochloride Oral Solution.</paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How should I store Methylphenidate Hydrochloride Oral Solution?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Store Methylphenidate Hydrochloride Oral Solution at room temperature between 68°F to 77°F (20°C to 25°C). <paragraph>Store Methylphenidate Hydrochloride Oral Solution in a safe place, like a locked cabinet.</paragraph></item><item>Protect from light and moisture.</item><item>Dispose of remaining, unused, or expired Methylphenidate Hydrochloride Oral Solution by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix Methylphenidate Hydrochloride Oral Solution with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away Methylphenidate Hydrochloride Oral Solution in the household trash.
lphenidate Hydrochloride Oral Solution with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away Methylphenidate Hydrochloride Oral Solution in the household trash. Visit <linkHtml href="https://www.fda.gov/drugs/ensuring-safe-use-medicine/safe-disposal-medicines">www.fda.gov/drugdisposal</linkHtml> for additional information on disposal of unused medicines.</item></list><paragraph><content styleCode="bold">Keep Methylphenidate Hydrochloride Oral Solution and all medicines out of the reach of children.</content></paragraph><paragraph><content styleCode="bold">General information about the safe and effective use of Methylphenidate Hydrochloride Oral Solution.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Methylphenidate Hydrochloride Oral Solution for a condition for which it was not prescribed. Do not give Methylphenidate Hydrochloride Oral Solution to other people, even if they have the same symptoms. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about Methylphenidate Hydrochloride Oral Solution that is written for healthcare professionals.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the ingredients in Methylphenidate Hydrochloride Oral Solution?</content></paragraph><paragraph><content styleCode="bold">Active Ingredient:</content> methylphenidate hydrochloride, USP</paragraph><paragraph><content styleCode="bold">Inactive Ingredients: </content>artificial grape flavor, glycerin, hydrochloric acid, polyethylene glycol 1450, and purified water.</paragraph><paragraph>Manufactured by:</paragraph><paragraph><content styleCode="bold">Tris Pharma, Inc.</content></paragraph><paragraph>Monmouth Junction, NJ 08852</paragraph><paragraph>For more information about Methylphenidate Hydrochloride Oral Solution contact Tris Pharma, Inc at 732-940-0358 or go to <linkHtml href="#www.trispharma.com">www.trispharma.com</linkHtml>.</paragraph><paragraph>LB8478</paragraph><paragraph>Rev. 03</paragraph></td></tr></tbody></table>
HOW SUPPLIED Each methylphenidate hydrochloride chewable tablet 2.5 mg is available as a white to off-white round beveled edge chewable tablets debossed with ' 260 ' on one side and ' AT ' on the other side. Bottles of 100 NDC 63629-1921-1 Protect from moisture. Dispense in tight container with child-resistant closure. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Ritalin ® is a registered trademark of Novartis Corporation. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504
WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate hydrochloride has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout methylphenidate hydrochloride treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2) ] . WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. Methylphenidate hydrochloride has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride , can result in overdose and death (5.1 , 9.2 , 10) : Before prescribing methylphenidate hydrochloride , assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
1 INDICATIONS AND USAGE Methylphenidate hydrochloride tablets are indicated for the treatment of: Attention Deficit Hyperactivity Disorders (ADHD) in pediatric patients 6 years and older and adults Narcolepsy Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorders (ADHD) and Narcolepsy ( 1 ).
2 DOSAGE AND ADMINISTRATION Pediatric Patients 6 Years and Older: Start with 5 mg twice daily (before breakfast and lunch), titrating the dose weekly in 5 mg to 10 mg increments. Dosages above 60 mg/day are not recommended (2.2) . Adults: Average daily dosage is 20 mg to 30 mg, administered 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum total daily dosage is 60 mg (2.2) . 2.1 Pre-treatment Screening Prior to treating patients with methylphenidate hydrochloride tablets, assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2) ] . the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating methylphenidate hydrochloride tablets [see Warnings and Precautions (5.10) ] . 2.2 General Dosing Information Pediatric Patients 6 years and Older: Start with 5 mg orally twice daily (before breakfast and lunch). Increase dosage gradually, in increments of 5 mg to 10 mg weekly. Daily dosage above 60 mg is not recommended. Adults: Average dosage is 20 mg to 30 mg daily. Administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum total daily dosage is 60 mg. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. 2.3 Dosage Reduction and Discontinuation If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue methylphenidate hydrochloride tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
3 DOSAGE FORMS AND STRENGTHS Tablets Methylphenidate hydrochloride tablets USP, 5 mg are light orange to orange, round compressed tablets, debossed cor on one side and 237 on the other side. Methylphenidate hydrochloride tablets USP, 10 mg are light orange to orange, round compressed tablets, debossed cor above bisect and 238 below the bisect on one side and plain on the other side. Methylphenidate hydrochloride tablets USP, 20 mg are light orange to orange, round compressed tablets, debossed cor over 239 on one side and bisect on the other side. Tablets: 5 mg, 10 mg, 20 mg ( 3 ).
4 CONTRAINDICATIONS Hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride tablets. Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been reported in patients treated with methylphenidate [see Adverse Reactions ( 6.1 )]. Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions ( 7.1 )]. Known hypersensitivity to methylphenidate or other product components of methylphenidate hydrochloride tablets ( 4 ). Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days ( 4 ).
5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease (5.2) . Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse (5.3) . Psychiatric Adverse Reactions: Prior to initiating methylphenidate hydrochloride, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride (5.4) . Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention (5.5) . Peripheral Vasculopathy, Including Raynaud’s Phenomenon: Careful observation for digital changes is necessary during methylphenidate hydrochloride treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy (5.6) . Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted (5.7) . Acute Angle Closure Glaucoma: Methylphenidate hydrochloride-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist (5.8) . Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe methylphenidate hydrochloride to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma (5.9) . Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating methylphenidate hydrochloride, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate (5.10) . 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride have a high potential for abuse and misuse. The use of methylphenidate hydrochloride exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate hydrochloride can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2) ] . Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate hydrochloride in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride to anyone else. Throughout methylphenidate hydrochloride treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
ydrochloride in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride to anyone else. Throughout methylphenidate hydrochloride treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who are treated with CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate hydrochloride use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase approximately 2 mmHg to 4 mmHg) and heart rate (mean increase approximately 3 bpm to 6 bpm). Some patients may have larger increases. Monitor all methylphenidate hydrochloride-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Pre-existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating methylphenidate hydrochloride treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism has also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, Including Raynaud’s Phenomenon CNS stimulants, including methylphenidate hydrochloride, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during methylphenidate hydrochloride treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride-treated patients who develop signs or symptoms of peripheral vasculopathy.
ontinuation of the CNS stimulant. Careful observation for digital changes is necessary during methylphenidate hydrochloride treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in methylphenidate hydrochloride-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate hydrochloride-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.9 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2) ] . Prescribe methylphenidate hydrochloride to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride-treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.10 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2) ] . Before initiating methylphenidate hydrochloride, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning , Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] Known hypersensitivity to methylphenidate or other ingredients of methylphenidate hydrochloride tablets [see Contraindications ( 4 )] Hypertensive crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions ( 5.2 )] Increased Blood Pressure and Heart Rate [see Warnings and Precautions ( 5.3 )] Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.4 )] Priapism [see Warnings and Precautions ( 5.5 )] Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions ( 5.6 )] Long-term Suppression of Growth in Pediatric Patients [see Warnings and Precautions ( 5.7 )] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.8) ] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.9) ] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.10) ] The following adverse reactions associated with the use of methylphenidate hydrochloride tablets and other methylphenidate products were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
ablets and other methylphenidate products were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Adverse Reactions Reported with Methylphenidate Hydrochloride Infections and Infestations: nasopharyngitis Blood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemia Immune System Disorders: hypersensitivity reactions, including angioedema, and anaphylaxis Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, depression Nervous System Disorders: headache, dizziness, tremor, dyskinesia, including choreoatheetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs Eye Disorders: blurred vision, difficulties in visual accommodation Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris Respiratory, Thoracic, and Mediastinal Disorders: cough Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis, trismus Investigations: weight loss (adult ADHD patients) Vascular Disorders: peripheral coldness, Raynaud's phenomenon Additional Adverse Reactions Reported with Other Methylphenidate-Containing Products The list below shows adverse reactions not listed for methylphenidate hydrochloride tablets, that have been reported with other methylphenidate-containing products. Blood and Lymphatic Disorders: pancytopenia Immune System Disorders: hypersensitivity reactions, such as auricular swelling, bullous conditions, eruptions, exanthemas Psychiatric Disorders: affect lability, mania, disorientation, and libido changes Nervous System Disorders: migraine, motor and verbal tics Eye Disorders: diplopia, increased intraocular pressure, mydriasis Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea Gastrointestinal Disorders: diarrhea, constipation Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption Musculoskeletal, Connective Tissue, and Bone Disorders: myalgia, muscle twitching Renal and Urinary Disorders: hematuria Reproductive System and Breast Disorders: gynecomastia General Disorders: fatigue, hyperpyrexia Urogenital Disorders: priapism Common adverse reactions: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7.1 ). 7.1 Clinically Important Drug Interactions with Methylphenidate Hydrochloride Table 1 presents clinically important drug interactions with methylphenidate hydrochloride. Table 1: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications ( 4 )] . Intervention Concomitant use of methylphenidate hydrochloride with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical Impact Methylphenidate hydrochloride may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions ( 5.3 )] . Intervention Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical Impact Concomitant use of halogenated anesthetics and methylphenidate hydrochloride may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of methylphenidate hydrochloride in patients being treated with anesthetics on the day of surgery. Risperidone Clinical Impact Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS) Intervention Monitor for signs of EPS
<table width="100%" cellspacing="0" cellpadding="0" border="1"><col width="17pt"/><col/><tbody><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Monoamine Oxidase Inhibitors (MAOI)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride can cause hypertensive crisis.
ragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure <content styleCode="italics">[see Contraindications (<linkHtml href="#LINK_7600ad47-5a2d-4055-b6a8-9334addd62c5">4</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of methylphenidate hydrochloride with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Antihypertensive Drugs</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Methylphenidate hydrochloride may decrease the effectiveness of drugs used to treat hypertension <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#LINK_ee01e211-af26-45f2-b0b3-029dced0f0bb">5.3</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Halogenated Anesthetics</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of halogenated anesthetics and methylphenidate hydrochloride may increase the risk of sudden blood pressure and heart rate increase during surgery.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Avoid use of methylphenidate hydrochloride in patients being treated with anesthetics on the day of surgery.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">Risperidone</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">Monitor for signs of EPS</td></tr></tbody></table>
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 ADHD medications, including methylphenidate hydrochloride, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/ . Risk Summary Published studies and post-marketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed.
g/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (approximately 2 times the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride for the treatment of ADHD have been established in pediatric patients aged 6 to 17 years. The safety and effectiveness of methylphenidate hydrochloride in pediatric patients aged less than 6 years have not been established. The long-term efficacy of methylphenidate in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.7 )] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Methylphenidate hydrochloride has not been studied in the geriatric population.
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate hydrochloride, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/ . Risk Summary Published studies and post-marketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed.
g/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (approximately 2 times the MRHD given to adolescents on a mg/m 2 basis).
8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.
8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride for the treatment of ADHD have been established in pediatric patients aged 6 to 17 years. The safety and effectiveness of methylphenidate hydrochloride in pediatric patients aged less than 6 years have not been established. The long-term efficacy of methylphenidate in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.7 )] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate hydrochloride tablets contain methylphenidate hydrochloride, a Schedule II controlled substance. 9.2 Abuse Methylphenidate hydrochloride has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1) ] . Methylphenidate hydrochloride can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate hydrochloride may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. 9.3 Dependence Physical Dependence Methylphenidate hydrochloride may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate hydrochloride may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
11 DESCRIPTION Methylphenidate hydrochloride tablets, USP contains methylphenidate hydrochloride USP, a CNS stimulant. It is available as tablets of 5 mg, 10 mg and 20 mg strengths for oral administration. Methylphenidate hydrochloride, USP is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is: Methylphenidate hydrochloride, USP is a white to off-white powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77 g/mol. Methylphenidate hydrochloride tablets, USP contain the following inactive ingredients: Lactose monohydrate, microcrystalline cellulose, stearic acid and FD&C Yellow No. 6 Aluminum Lake.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD and narcolepsy is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking methylphenidate hydrochloride tablets. The effect of dexmethylphenidate, the pharmacologically active d -enantiomer of methylphenidate hydrochloride tablet, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethlyphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms (ECGs) were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval (CI) was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship. 12.3 Pharmacokinetics Absorption The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the methylphenidate hydrochloride. Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l -methylphenidate. Elimination The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l -methylphenidate. Metabolism Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). Studies in Specific Populations Male and Female Patients No gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults are expected. Racial or Ethnic Groups There is insufficient experience with the use of methylphenidate hydrochloride tablets to detect ethnic variations in pharmacokinetics. Patients with Renal Impairment Methylphenidate hydrochloride tablets have not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochloride tablets have not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.
12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking methylphenidate hydrochloride tablets. The effect of dexmethylphenidate, the pharmacologically active d -enantiomer of methylphenidate hydrochloride tablet, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethlyphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms (ECGs) were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval (CI) was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship.
12.3 Pharmacokinetics Absorption The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the methylphenidate hydrochloride. Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l -methylphenidate. Elimination The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l -methylphenidate. Metabolism Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). Studies in Specific Populations Male and Female Patients No gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults are expected. Racial or Ethnic Groups There is insufficient experience with the use of methylphenidate hydrochloride tablets to detect ethnic variations in pharmacokinetics. Patients with Renal Impairment Methylphenidate hydrochloride tablets have not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochloride tablets have not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 mg/kg/day to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis.
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 mg/kg/day to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis.
16 HOW SUPPLIED/STORAGE AND HANDLING Methylphenidate Hydrochloride Tablets USP, 20 mg are supplied as light orange to orange, round compressed tablets, debossed cor over 239 on one side and bisect on the other side. They are available as follows: Bottles of 100: NDC 72162-2087-1 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Dispense in tight, light-resistant container (USP). Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) . Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of methylphenidate hydrochloride, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2) , Overdosage (10) ] . Advise patients to store methylphenidate hydrochloride in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patient with serious cardiac disease, including sudden death, with methylphenidate hydrochloride use. Instruct patients to contact a healthcare provider immediately if they develop symptoms, such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2) ]. Increased Blood Pressure and Heart Rate Instruct patients that methylphenidate hydrochloride can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3) ] . Psychiatric Adverse Reactions Advise patients that methylphenidate hydrochloride, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4) ]. Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5) ] . Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon] Instruct patients about the risk of peripheral vasculopathy, including Raynaud’s Phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6) ] . Long-Term Suppression of Growth in Pediatric Patients Advise patients that methylphenidate hydrochloride may cause slowing of growth and weight loss [see Warnings and Precautions (5.7) ]. Increased Intraocular Pressure (IOP) and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with methylphenidate hydrochloride [see Warnings and Precautions (5.9) ] . Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with methylphenidate hydrochloride. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions (5.10) ] . Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including methylphenidate hydrochloride, during pregnancy [see Use in Specific Populations (8.1) ] .
ourette’s syndrome occurs [see Warnings and Precautions (5.10) ] . Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including methylphenidate hydrochloride, during pregnancy [see Use in Specific Populations (8.1) ] . Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 11-2023-04 Dispense with Medication Guide available at: documents.amneal.com/mg/methylphenidate-hcl-tablets.pdf
MEDICATION GUIDE Methylphenidate Hydrochloride (meth" il fen' i date hye" droe klor' ide) Tablets, for oral use, CII What is the most important information I should know about methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets may cause serious side effects, including: Abuse, misuse, and addiction. Methylphenidate hydrochloride tablets have a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride tablets, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride tablets or when it is used in ways that are not approved, such as snorting or injection. Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride tablets and will monitor you or your child during treatment. Methylphenidate hydrochloride tablets may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. Do not give methylphenidate hydrochloride tablets to anyone else. See “What is methylphenidate hydrochloride tablets?” for more information. Keep methylphenidate hydrochloride tablets in a safe place and properly dispose of any unused medicine. See “How should I store methylphenidate hydrochloride tablets?” for more information. Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting methylphenidate hydrochloride tablets. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child has any signs of heart problems, such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride tablets. Increased blood pressure and heart rate. Your healthcare provider should check you or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride tablets. Mental (psychiatric) problems: All Patients new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. What are methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant prescription medicine. It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).
ring things that are not real, believing things that are not real, or are suspicious. What are methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant prescription medicine. It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Methylphenidate hydrochloride tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Methylphenidate hydrochloride tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride tablets are also used in the treatment of a sleep disorder called narcolepsy. It is not known if methylphenidate hydrochloride tablets are safe and effective in children under 6 years of age. Methylphenidate hydrochloride tablets are a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep methylphenidate hydrochloride tablets in a safe place to protect it from theft. Never give your methylphenidate hydrochloride tablets to anyone else, because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride tablets may harm others and is against the law. Who should not take methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets should not be taken if you or your child: are allergic to methylphenidate hydrochloride, or any of the ingredients in methylphenidate hydrochloride tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride tablets. are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor (MAOI). Methylphenidate hydrochloride tablets may not be right for you or your child. Before starting methylphenidate hydrochloride tablets tell your or your child’s healthcare provider about all health conditions (or a family history of), including: heart problems, heart disease, heart defects, or high blood pressure mental problems, including psychosis, mania, bipolar illness, or depression circulation problems in fingers or toes have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome. if you are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride tablets will harm your unborn baby. There is a pregnancy registry for females who are exposed to ADHD medications, including methylphenidate hydrochloride tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate hydrochloride tablets and their baby. If you or your child becomes pregnant during treatment with methylphenidate hydrochloride tablets, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/. if you are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with methylphenidate hydrochloride. Tell your healthcare provider about all of the medicines that you or your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride tablets and some medicines may interact with each other and cause serious side effects.
ylphenidate hydrochloride. Tell your healthcare provider about all of the medicines that you or your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride tablets. Your healthcare provider will decide whether methylphenidate hydrochloride tablets can be taken with other medicines. Especially tell your healthcare provider if you or your child takes: anti-depression medicines, including monoamine oxidase inhibitors (MAOIs) blood pressure medicines (anti-hypertensive) Know the medicines that you or your child takes. Keep a list of your medicines with you to show your healthcare provider and pharmacist. You should not take methylphenidate hydrochloride tablets on the day of your operation if a certain type of anesthetic is used. This is because there is a chance of a sudden rise in blood pressure and heart rate during the operation. Do not start any new medicine while taking methylphenidate hydrochloride tablets without talking to your healthcare provider first. How should methylphenidate hydrochloride tablets be taken? Take methylphenidate hydrochloride tablets exactly as prescribed . Your healthcare provider may adjust the dose until it is right for you or your child. Methylphenidate hydrochloride tablet is usually taken 2 to 3 times a day. Take methylphenidate hydrochloride tablet 30 to 45 minutes before a meal. Your healthcare provider may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride tablets. Children should have their height and weight checked often while taking methylphenidate hydrochloride tablets. If you or your child take too many methylphenidate hydrochloride tablets, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets may cause serious side effects, including: see “What is the most important information I should know about methylphenidate hydrochloride tablets?” for information on reported heart and mental problems. painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a healthcare provider immediately. circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon): fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have, numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your healthcare provider right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets. Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with methylphenidate hydrochloride tablets. Methylphenidate hydrochloride tablets treatment may be stopped if your child is not growing or gaining weight. Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette’s syndrome.
lets treatment may be stopped if your child is not growing or gaining weight. Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride tablets. Common side effects include: fast heart beat abnormal heartbeat (palpitations) headache trouble sleeping nervousness sweating a lot decreased appetite dry mouth nausea stomach pain Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store methylphenidate hydrochloride tablets? Store methylphenidate hydrochloride tablets in a safe place and in a tightly closed container at room temperature between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). Protect from light. Dispose of remaining, unused, or expired methylphenidate hydrochloride tablets by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and throw away methylphenidate hydrochloride tablets in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep methylphenidate hydrochloride tablets and all medicines out of the reach of children. General information about the safe and effective use of methylphenidate hydrochloride tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about methylphenidate hydrochloride tablets that is written for healthcare professionals. Do not use methylphenidate hydrochloride tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them and it is against the law. What are the ingredients in methylphenidate hydrochloride tablets ? Active ingredient: methylphenidate hydrochloride, USP Inactive ingredients: Lactose monohydrate, microcrystalline cellulose, stearic acid and FD&C Yellow No. 6 Aluminum Lake For more information call, 1-877-835-5472. This Medication Guide has been approved by the U.S. Food and Drug Administration. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 11-2023-04 Dispense with Medication Guide available at: documents.amneal.com/mg/methylphenidate-hcl-tablets.pdf
<table><colgroup><col/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center"><paragraph><content styleCode="bold">Methylphenidate Hydrochloride</content><content styleCode="bold">(meth" il fen' i date hye" droe klor' ide)</content><content styleCode="bold"><content styleCode="bold">Tablets, for oral use, CII</content></content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">What is the most important information I should know about methylphenidate hydrochloride tablets?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate hydrochloride tablets may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Abuse, misuse, and addiction.</content> Methylphenidate hydrochloride tablets have a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride tablets, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride tablets or when it is used in ways that are not approved, such as snorting or injection.</item></list><list listType="unordered" styleCode="Circle"><item>Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride tablets and will monitor you or your child during treatment.</item><item>Methylphenidate hydrochloride tablets may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider.</item><item>Do not give methylphenidate hydrochloride tablets to anyone else. See <content styleCode="bold">“What is </content><content styleCode="bold">methylphenidate hydrochloride tablets?”</content> for more information.</item><item>Keep methylphenidate hydrochloride tablets in a safe place and properly dispose of any unused medicine.
idate hydrochloride tablets to anyone else. See <content styleCode="bold">“What is </content><content styleCode="bold">methylphenidate hydrochloride tablets?”</content> for more information.</item><item>Keep methylphenidate hydrochloride tablets in a safe place and properly dispose of any unused medicine. See <content styleCode="bold">“How should I store </content><content styleCode="bold">methylphenidate hydrochloride tablets?”</content> for more information.</item><item>Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs.<list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Risks for people with serious heart disease.</content> Sudden death has happened in people who have heart defects or other serious heart disease.</item></list></item></list><paragraph>Your healthcare provider should check you or your child carefully for heart problems before starting methylphenidate hydrochloride tablets.</paragraph><paragraph>Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects.</paragraph><paragraph><content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child has any signs of heart problems, such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride tablets.</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Increased blood pressure and heart rate.</content><paragraph>Your healthcare provider should check you or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride tablets.</paragraph></item><item><content styleCode="bold">Mental (psychiatric) problems:</content></item></list><paragraph><content styleCode="bold">All Patients</content></paragraph><list listType="unordered" styleCode="Circle"><item>new or worse behavior and thought problems</item><item>new or worse bipolar illness</item><item>new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms</item></list><paragraph>Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.</paragraph><paragraph><content styleCode="bold">Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">What are methylphenidate hydrochloride tablets?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant prescription medicine. <content styleCode="bold">It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).
thylphenidate hydrochloride tablets?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant prescription medicine. <content styleCode="bold">It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). </content>Methylphenidate hydrochloride tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.</item><item>Methylphenidate hydrochloride tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.</item><item>Methylphenidate hydrochloride tablets are also used in the treatment of a sleep disorder called narcolepsy.</item></list><paragraph><content styleCode="bold">It is not known if methylphenidate hydrochloride tablets are safe and effective in children under 6 years of age.</content></paragraph><paragraph><content styleCode="bold">Methylphenidate hydrochloride tablets are a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs.</content> Keep methylphenidate hydrochloride tablets in a safe place to protect it from theft. Never give your methylphenidate hydrochloride tablets to anyone else, because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride tablets may harm others and is against the law.</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">Who should not take methylphenidate hydrochloride tablets?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate hydrochloride tablets should not be taken if you or your child:</content></paragraph><list listType="unordered" styleCode="Disc"><item>are allergic to methylphenidate hydrochloride, or any of the ingredients in methylphenidate hydrochloride tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride tablets.</item><item>are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor (MAOI).</item></list></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">Methylphenidate hydrochloride tablets may not be right for you or your child. Before starting methylphenidate hydrochloride tablets tell your or your child’s healthcare provider about all health conditions (or a family history of), including:</content></paragraph><list listType="unordered" styleCode="Disc"><item>heart problems, heart disease, heart defects, or high blood pressure</item><item>mental problems, including psychosis, mania, bipolar illness, or depression</item><item>circulation problems in fingers or toes</item></list><list listType="unordered" styleCode="Disc"><item>have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness)</item><item>have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome.</item></list><list listType="unordered" styleCode="Disc"><item>if you are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride tablets will harm your unborn baby.</item></list><list listType="unordered" styleCode="Circle"><item>There is a pregnancy registry for females who are exposed to ADHD medications, including methylphenidate hydrochloride tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate hydrochloride tablets and their baby.
d" styleCode="Circle"><item>There is a pregnancy registry for females who are exposed to ADHD medications, including methylphenidate hydrochloride tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate hydrochloride tablets and their baby. If you or your child becomes pregnant during treatment with methylphenidate hydrochloride tablets, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/.<list listType="unordered" styleCode="Disc"><item>if you are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with methylphenidate hydrochloride.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all of the medicines that you or your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. </content>Methylphenidate hydrochloride tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride tablets.</paragraph><paragraph>Your healthcare provider will decide whether methylphenidate hydrochloride tablets can be taken with other medicines.</paragraph><paragraph><content styleCode="bold">Especially tell your healthcare provider if you or your child takes:</content></paragraph><list listType="unordered" styleCode="Disc"><item>anti-depression medicines, including monoamine oxidase inhibitors (MAOIs)</item><item>blood pressure medicines (anti-hypertensive)</item></list><paragraph>Know the medicines that you or your child takes. Keep a list of your medicines with you to show your healthcare provider and pharmacist.</paragraph><list listType="unordered" styleCode="Disc"><item>You should not take methylphenidate hydrochloride tablets on the day of your operation if a certain type of anesthetic is used. This is because there is a chance of a sudden rise in blood pressure and heart rate during the operation.</item></list></item></list><paragraph><content styleCode="bold">Do not start any new medicine while taking methylphenidate hydrochloride tablets without talking to your healthcare provider first.</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">How should methylphenidate hydrochloride tablets be taken?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Take methylphenidate hydrochloride tablets exactly as prescribed<content styleCode="bold">.
aph></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">How should methylphenidate hydrochloride tablets be taken?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Take methylphenidate hydrochloride tablets exactly as prescribed<content styleCode="bold">. </content>Your healthcare provider may adjust the dose until it is right for you or your child.</item><item>Methylphenidate hydrochloride tablet is usually taken 2 to 3 times a day.</item><item>Take methylphenidate hydrochloride tablet 30 to 45 minutes before a meal.</item><item>Your healthcare provider may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride tablets.</item><item>Children should have their height and weight checked often while taking methylphenidate hydrochloride tablets.</item></list><paragraph>If you or your child take too many methylphenidate hydrochloride tablets, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away.</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">What are the possible side effects of methylphenidate hydrochloride tablets?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate hydrochloride tablets may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item>see <content styleCode="bold">“What is the most important information I should know about methylphenidate hydrochloride tablets?” </content>for information on reported heart and mental problems.</item><item><content styleCode="bold">painful and prolonged erections (priapism) </content>have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a healthcare provider immediately.</item><item><content styleCode="bold">circulation problems in fingers and toes </content>(peripheral vasculopathy, including Raynaud’s phenomenon):</item></list><list listType="unordered" styleCode="Circle"><item>fingers or toes may feel numb, cool, painful</item><item>fingers or toes may change color from pale, to blue, to red<paragraph>Tell your healthcare provider if you or your child have, numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.</paragraph><paragraph><content styleCode="bold">Call your healthcare provider right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets.</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Slowing of growth (height and weight) in children. </content>Children should have their height and weight checked often during treatment with methylphenidate hydrochloride tablets.
ing methylphenidate hydrochloride tablets.</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Slowing of growth (height and weight) in children. </content>Children should have their height and weight checked often during treatment with methylphenidate hydrochloride tablets. Methylphenidate hydrochloride tablets treatment may be stopped if your child is not growing or gaining weight.</item></list></item></list><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Eye problems (increased pressure in the eye and glaucoma).</content> Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness.</item><item><content styleCode="bold">New or worsening tics or worsening Tourette’s syndrome.</content> Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride tablets.</item></list><paragraph><content styleCode="bold">Common side effects include:</content></paragraph><list listType="unordered" styleCode="Disk"><item>fast heart beat</item><item>abnormal heartbeat (palpitations)</item><item>headache</item><item>trouble sleeping</item><item>nervousness</item><item>sweating a lot</item><item>decreased appetite</item><item>dry mouth</item><item>nausea</item><item>stomach pain</item></list><paragraph>Call your doctor for medical advice about side effects. <content styleCode="bold">You may report side effects to FDA at 1-800-FDA-1088.</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">How should I store methylphenidate hydrochloride tablets?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Store methylphenidate hydrochloride tablets in a safe place and in a tightly closed container at room temperature between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).</item><item>Protect from light.</item><item>Dispose of remaining, unused, or expired methylphenidate hydrochloride tablets by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and throw away methylphenidate hydrochloride tablets in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</item><item><content styleCode="bold">Keep methylphenidate hydrochloride tablets </content><content styleCode="bold">and all medicines out of the reach of children.</content></item></list></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">General information about the safe and effective use of methylphenidate hydrochloride tablets.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about methylphenidate hydrochloride tablets that is written for healthcare professionals. Do not use methylphenidate hydrochloride tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride tablets to other people, even if they have the same symptoms that you have.
or information about methylphenidate hydrochloride tablets that is written for healthcare professionals. Do not use methylphenidate hydrochloride tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them and it is against the law.</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">What are the ingredients in </content><content styleCode="bold">methylphenidate hydrochloride tablets</content><content styleCode="bold">?</content></paragraph><paragraph><content styleCode="bold">Active ingredient: </content>methylphenidate hydrochloride, USP</paragraph><paragraph><content styleCode="bold">Inactive ingredients: </content>Lactose monohydrate, microcrystalline cellulose, stearic acid and FD&C Yellow No. 6 Aluminum Lake</paragraph><paragraph>For more information call, 1-877-835-5472.</paragraph><paragraph>This Medication Guide has been approved by the U.S. Food and Drug Administration.</paragraph><paragraph>Distributed by: <content styleCode="bold">Amneal Pharmaceuticals LLC</content>Bridgewater, NJ 08807</paragraph><paragraph>Rev. 11-2023-04</paragraph></td></tr><tr><td><paragraph>Dispense with Medication Guide available at: documents.amneal.com/mg/methylphenidate-hcl-tablets.pdf</paragraph></td></tr></tbody></table>
WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate hydrochloride tablets has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride tablets, can result in overdose and death [ see Overdosage (10) ], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout methylphenidate hydrochloride tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [ see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2) ]. See full prescribing information for complete boxed warning. Methylphenidate hydrochloride tablets have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride tablets, can result in overdose and death (5.1, 9.2, 10): Before prescribing methylphenidate hydrochloride tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
1 INDICATIONS AND USAGE Methylphenidate hydrochloride tablets are indicated for the treatment of: Attention Deficit Hyperactivity Disorders (ADHD) in pediatric patients 6 years and older and adults Narcolepsy Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorders (ADHD) and Narcolepsy (1).
2 DOSAGE AND ADMINISTRATION Methylphenidate Hydrochloride Tablets (2.2) : Pediatric Patients 6 Years and Older: Start with 5 mg twice daily (before breakfast and lunch), titrating the dose weekly in 5- to 10-mg increments. Dosages above 60 mg/day are not recommended. Adults: Average daily dosage is 20 mg to 30 mg, administered 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum total daily dosage is 60 mg (2.2) . 2.1 Pretreatment Screening Prior to treating patients with methylphenidate hydrochloride tablets, assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2) ]. the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating methylphenidate hydrochloride tablets [see Warnings and Precautions (5.10) ]. 2.2 General Dosing Information Methylphenidate Hydrochloride Tablets Pediatric Patients 6 years and Older: Start with 5 mg orally twice daily (before breakfast and lunch). Increase dosage gradually, in increments of 5- to 10-mg weekly. Daily dosage above 60 mg is not recommended. Adults: Average dosage is 20 to 30 mg daily. Administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum total daily dosage is 60 mg. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m. 2.3 Dosage Reduction and Discontinuation If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue methylphenidate hydrochloride tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
3 DOSAGE FORMS AND STRENGTHS Methylphenidate Hydrochloride Tablets, USP 5 mg, light purple, round-shaped, flat faced, beveled edge, uncoated tablets, debossed with "228" on one side and S5 on the other side. 10 mg, light green, round-shaped, flat faced, beveled edge, uncoated tablets, debossed with "229" on one side and S and 10 on either side of the score line on the other side. 20 mg, light peach, round-shaped, flat faced, beveled edge, uncoated tablets, debossed with "230" on one side and S and 20 on either side of the score line on the other side. Tablets: 5 mg, 10 mg, and 20 mg (3)
4 CONTRAINDICATIONS Hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride tablets. Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been reported in patients treated with methylphenidate [ see Adverse Reactions (6.1) ]. Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [ see Drug Interactions (7.1) ]. Known hypersensitivity to methylphenidate or other product components of methylphenidate hydrochloride tablets (4) . Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days (4) .
5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease : Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease (5.2). Increased Blood Pressure and Heart Rate : Monitor blood pressure and pulse (5.3). Psychiatric Adverse Reactions : Prior to initiating methylphenidate hydrochloride tablets, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride tablets (5.4). Priapism : If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention (5.5). Peripheral Vasculopathy, Including Raynaud’s Phenomenon : Careful observation for digital changes is necessary during methylphenidate hydrochloride tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy (5.6). Long-Term Suppression of Growth in Pediatric Patients : Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted (5.7). Acute Angle Closure Glaucoma: Methylphenidate hydrochloride tablets -treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist (5.8). Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe methylphenidate hydrochloride tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma (5.9). Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating methylphenidate hydrochloride tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate (5.10). 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride tablets have a high potential for abuse and misuse. The use of methylphenidate hydrochloride tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate hydrochloride tablets can be diverted for nonmedical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2) ]. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride tablets, can result in overdose and death [see Overdosage (10)] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate hydrochloride tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride tablets to anyone else.
risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate hydrochloride tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride tablets to anyone else. Throughout methylphenidate hydrochloride tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who are treated with CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate hydrochloride tablets use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute). Some patients may have larger increases. Monitor all methylphenidate hydrochloride tablets-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Pre-existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating methylphenidate hydrochloride tablets treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple shortterm, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride tablets. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride tablets-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, Including Raynaud’s Phenomenon CNS stimulants, including methylphenidate hydrochloride tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant.
reakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during methylphenidate hydrochloride tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride tablets-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in methylphenidate hydrochloride tablets-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate hydrochloride tablets-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.9 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2)]. Prescribe methylphenidate hydrochloride tablets and methylphenidate hydrochloride sustained-release tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride tablets-treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.10 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6) ]. Before initiating methylphenidate hydrochloride tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride tablets-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1) , Drug Abuse and Dependence ( 9.2, 9.3 ) ] Known hypersensitivity to methylphenidate or other ingredients of methylphenidate hydrochloride tablets [see Contraindications (4) ] Hypertensive crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4) , Drug Interactions (7.1) ] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2) ] Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3) ] Psychiatric Adverse Reactions [see Warnings and Precautions (5.4) ] Priapism [see Warnings and Precautions (5.5) ] Peripheral Vasculopathy, Including Raynaud’s Phenomenon [see Warnings and Precautions (5.6) ] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7) ] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.8) ] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.9) ] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.10) ] The following adverse reactions associated with the use of methylphenidate hydrochloride tablets, and other methylphenidate products were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Adverse Reactions Reported with Methylphenidate Hydrochloride Tablets Infections and Infestations: nasopharyngitis Blood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemia Immune System Disorders: hypersensitivity reactions, including angioedema, and anaphylaxis Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, depression Nervous System Disorders: headache, dizziness, tremor, dyskinesia, including choreoatheetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs Eye Disorders: blurred vision, difficulties in visual accommodation Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris Respiratory, Thoracic, and Mediastinal Disorders: cough Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis, trismus Investigations: weight loss (adult ADHD patients) Additional Adverse Reactions Reported with Other Methylphenidate-Containing Products The list below shows adverse reactions not listed for methylphenidate hydrochloride tablets that have been reported with other methylphenidate-containing products.
abdomyolysis, trismus Investigations: weight loss (adult ADHD patients) Additional Adverse Reactions Reported with Other Methylphenidate-Containing Products The list below shows adverse reactions not listed for methylphenidate hydrochloride tablets that have been reported with other methylphenidate-containing products. Blood and Lymphatic Disorders: pancytopenia Immune System Disorders: hypersensitivity reactions, such as auricular swelling, bullous conditions, eruptions, exanthemas Psychiatric Disorders: affect lability, mania, disorientation, and libido changes Nervous System Disorders: migraine, motor and verbal tics Eye Disorders: diplopia, increased intraocular pressure, mydriasis Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole Vascular Disorders: peripheral coldness, Raynaud's phenomenon Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea Gastrointestinal Disorders: diarrhea, constipation Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption Musculoskeletal, Connective Tissue, and Bone Disorders: myalgia, muscle twitching Renal and Urinary Disorders: hematuria Reproductive System and Breast Disorders: gynecomastia General Disorders: fatigue, hyperpyrexia Urogenital Disorders : priapism Common adverse reactions: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain (6) . To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7 DRUG INTERACTIONS Antihypertensive Drugs : Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7.1 ). 7.1 Clinically Important Drug Interactions with Methylphenidate Hydrochloride Tablets Table 1 presents clinically important drug interactions with methylphenidate hydrochloride tablets Table 1: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Tablets Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride tablets can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [ see Contraindications (4) ] . Intervention Concomitant use of methylphenidate hydrochloride tablets with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical Impact Methylphenidate hydrochloride tablets may decrease the effectiveness of drugs used to treat hypertension [ see Warnings and Precautions (5.3) ] . Intervention Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical Impact Concomitant use of halogenated anesthetics and methylphenidate hydrochloride tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of methylphenidate hydrochloride tablets in patients being treated with anesthetics on the day of surgery. Risperidone Clinical Impact Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS) Intervention Monitor for signs of EPS
<table width="100%"> <col width="27%"/> <col width="73%"/> <tbody> <tr> <td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Monoamine Oxidase Inhibitors (MAOI)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride tablets can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure <content styleCode="italics">[ <linkHtml href="#ID_ef182656-42ed-4746-95e0-45c25aa7257c">see Contraindications (4)</linkHtml>] </content>. </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Intervention</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Concomitant use of methylphenidate hydrochloride tablets with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Antihypertensive Drugs</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Methylphenidate hydrochloride tablets may decrease the effectiveness of drugs used to treat hypertension <content styleCode="italics">[ <linkHtml href="#ID_db3567b8-aff3-4a2e-ae64-6ad200992c2d">see Warnings and Precautions (5.3)</linkHtml>] </content>.
d styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Methylphenidate hydrochloride tablets may decrease the effectiveness of drugs used to treat hypertension <content styleCode="italics">[ <linkHtml href="#ID_db3567b8-aff3-4a2e-ae64-6ad200992c2d">see Warnings and Precautions (5.3)</linkHtml>] </content>. </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Intervention</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Halogenated Anesthetics</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Concomitant use of halogenated anesthetics and methylphenidate hydrochloride tablets may increase the risk of sudden blood pressure and heart rate increase during surgery.</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Intervention</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Avoid use of methylphenidate hydrochloride tablets in patients being treated with anesthetics on the day of surgery.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Risperidone</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">Clinical Impact</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="italics">Intervention</content> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Monitor for signs of EPS</paragraph> </td> </tr> </tbody> </table>
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 ADHD medications, including methylphenidate hydrochloride tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/ . Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations). No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride tablets, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed.
g/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (approximately 2 times the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride tablets and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride tablets or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride tablets for the treatment of ADHD have been established in pediatric patients aged 6 to 17 years. The safety and effectiveness of methylphenidate hydrochloride tablets in pediatric patients aged less than 6 years have not been established. The long-term efficacy of methylphenidate in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [ see Warnings and Precautions (5.7) ] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 timesthe MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Methylphenidate hydrochloride tablets have not been studied in the geriatric population.
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate hydrochloride tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/ . Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations). No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride tablets, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed.
8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride tablets for the treatment of ADHD have been established in pediatric patients aged 6 to 17 years. The safety and effectiveness of methylphenidate hydrochloride tablets in pediatric patients aged less than 6 years have not been established. The long-term efficacy of methylphenidate in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [ see Warnings and Precautions (5.7) ] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 timesthe MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate hydrochloride tablets contain methylphenidate hydrochloride, a Schedule II controlled substance. 9.2 Abuse Methylphenidate hydrochloride tablets has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1) ]. Methylphenidate hydrochloride tablets can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate hydrochloride may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride tablets, can result in overdose and death [see Overdosage (10) ], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. 9.3 Dependence Physical Dependence Methylphenidate hydrochloride tablets may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride tablets include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate hydrochloride tablets may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
9.2 Abuse Methylphenidate hydrochloride tablets has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1) ]. Methylphenidate hydrochloride tablets can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate hydrochloride may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride tablets, can result in overdose and death [see Overdosage (10) ], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
9.3 Dependence Physical Dependence Methylphenidate hydrochloride tablets may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride tablets include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate hydrochloride tablets may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
11 DESCRIPTION Methylphenidate hydrochloride tablets contain methylphenidate hydrochloride, USP a CNS stimulant. It is available as tablets of 5 mg, 10 mg, and 20 mg strengths for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is: Methylphenidate hydrochloride, USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77 g/mol. Each tablet contains 5 mg, 10 mg, or 20 mg of methylphenidate hydrochloride, USP. Inactive ingredients include: lactose monohydrate, magnesium stearate, polyethylene glycol 8000, and talc. In addition, the 5 mg tablet contains FD&C blue No. 2 aluminum lake and FD&C red No. 40 aluminum lake, the 10 mg tablet contains FD&C blue No. 2 aluminum lake and D&C yellow No. 10 aluminum lake and the 20 mg tablet contains FD&C yellow No. 6 aluminum lake.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate hydrochloride is a CNS stimulant. The mode of therapeutic action in ADHD and narcolepsy is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking methylphenidate hydrochloride tablets. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride tablets, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethlyphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship. 12.3 Pharmacokinetics Absorption The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the methylphenidate hydrochloride tablets. Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d -methylphenidate and 1.80 ± 0.91 L/kg for l -methylphenidate. Elimination The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. Metabolism Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). Studies in Specific Populations Male and Female Patients No gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults are expected. Racial or Ethnic Groups There is insufficient experience with the use of methylphenidate hydrochloride tablets to detect ethnic variations in pharmacokinetics. Patients with Renal Impairment Methylphenidate hydrochloride tablets have not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochloride tablets have not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.
12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking methylphenidate hydrochloride tablets. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride tablets, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethlyphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship.
12.3 Pharmacokinetics Absorption The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the methylphenidate hydrochloride tablets. Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d -methylphenidate and 1.80 ± 0.91 L/kg for l -methylphenidate. Elimination The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. Metabolism Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). Studies in Specific Populations Male and Female Patients No gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults are expected. Racial or Ethnic Groups There is insufficient experience with the use of methylphenidate hydrochloride tablets to detect ethnic variations in pharmacokinetics. Patients with Renal Impairment Methylphenidate hydrochloride tablets have not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochloride tablets have not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis.
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis.
16 HOW SUPPLIED/STORAGE AND HANDLING Methylphenidate Hydrochloride Tablets, USP 5 mg are ight purple, round-shaped, flat faced, beveled edge, uncoated tablets, debossed with "228" on one side and S5 on the other side. NDC: 72162-1636-1: 100 Tablets in a BOTTLE Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F). [See USP controlled room temperature]. Protect from light. Dispense in tight, light-resistant container (USP) with a child-resistant closure. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of methylphenidate hydrochloride tablets, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2) , Overdosage (10) ]. Advise patients to store methylphenidate hydrochloride tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride tablets to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patient with serious cardiac disease, including sudden death, with methylphenidate hydrochloride tablets use. Instruct patients to contact a healthcare provider immediately if they develop symptoms, such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2) ]. Increased Blood Pressure and Heart Rate Instruct patients that methylphenidate hydrochloride tablets can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3) ]. Psychiatric Adverse Reactions Advise patients that methylphenidate hydrochloride tablets, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4) ]. Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5) ]. Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon] Instruct patients about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6) ]. Long-Term Suppression of Growth in Pediatric Patients Advise patients that methylphenidate hydrochloride tablets may cause slowing of growth and weight loss [see Warnings and Precautions (5.7) ]. Increased Intraocular Pressure (IOP) and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with methylphenidate hydrochloride tablets [see Warnings and Precautions (5.9) ]. Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with methylphenidate hydrochloride tablets. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions (5.10) ].
Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with methylphenidate hydrochloride tablets. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions (5.10) ]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including methylphenidate hydrochloride tablets, during pregnancy [see Use in Specific Populations (8.1) ]. Dispense with Medication Guide available at: www.sunpharma.com/usa/products. Manufactured by: Ohm Laboratories Inc. New Brunswick, NJ 08901 Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 5249227 Rev. 03/2024
MEDICATION GUIDE Dispense with Medication Guide available at: www.sunpharma.com/usa/products Methylphenidate Hydrochloride Tablets USP, for oral use, CII (meth" ǝl-fen 'i-dāt) Rx Only What is the most important information I should know about methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets may cause serious side effects, including: Abuse, misuse, and addiction. Methylphenidate hydrochloride tablets has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride tablets, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride tablets or when it is used in ways that are not approved, such as snorting or injection. Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride tablets and will monitor you or your child during treatment. Methylphenidate hydrochloride tablets may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. Do not give methylphenidate hydrochloride tablets to anyone else. See “ What is methylphenidate hydrochloride tablets? ” for more information. Keep methylphenidate hydrochloride tablets in a safe place and properly dispose of any unused medicine. See “ How should I store methylphenidate hydrochloride tablets? ” for more information. Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting methylphenidate hydrochloride tablets Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child has any signs of heart problems, such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride tablets. Increased blood pressure and heart rate. Your healthcare provider should check you or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride tablets. Mental (psychiatric) problems: All Patients new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. What are methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant prescription medicine. It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).
ring things that are not real, believing things that are not real, or are suspicious. What are methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant prescription medicine. It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Methylphenidate hydrochloride tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Methylphenidate hydrochloride tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride tablets are also used in the treatment of a sleep disorder called narcolepsy. It is not known if methylphenidate hydrochloride tablets are safe and effective in children under 6 years of age. Methylphenidate hydrochloride tablets is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep methylphenidate hydrochloride tablets in a safe place to protect it from theft. Never give your methylphenidate hydrochloride tablets to anyone else, because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride tablets may harm others and is against the law. Who should not take methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets should not be taken if you or your child: are allergic to methylphenidate hydrochloride, or any of the ingredients in methylphenidate hydrochloride tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride tablets. are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor (MAOI). Methylphenidate hydrochloride tablets may not be right for you or your child. Before starting methylphenidate hydrochloride tablets, tell your or your child’s healthcare provider about all health conditions (or a family history of), including: heart problems, heart disease, heart defects, high blood pressure mental problems, including psychosis, mania, bipolar illness, or depression circulation problems in fingers or toes have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome. if you are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride tablets will harm your unborn baby. There is a pregnancy registry for females who are exposed to ADHD medications, including methylphenidate hydrochloride tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate hydrochloride tablets and their baby. If you or your child becomes pregnant during treatment with methylphenidate hydrochloride tablets, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/. if you are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with methylphenidate hydrochloride tablets. Tell your healthcare provider about all of the medicines that you or your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride tablets and some medicines may interact with each other and cause serious side effects.
ate hydrochloride tablets. Tell your healthcare provider about all of the medicines that you or your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride tablets. Your healthcare provider will decide whether methylphenidate hydrochloride tablets can be taken with other medicines. Especially tell your healthcare provider if you or your child takes: anti-depression medicines, including MAOIs blood pressure medicines (anti-hypertensive) Know the medicines that you or your child takes. Keep a list of your medicines with you to show your healthcare provider and pharmacist. You should not take methylphenidate hydrochloride tablets on the day of your operation if a certain type of anesthetic is used. This is because there is a chance of a sudden rise in blood pressure and heart rate during the operation. Do not start any new medicine while taking methylphenidate hydrochloride tablets without talking to your healthcare provider first. How should methylphenidate hydrochloride tablets be taken? Take methylphenidate hydrochloride tablets exactly as prescribed. Your healthcare provider may adjust the dose until it is right for you or your child. Methylphenidate hydrochloride tablets are usually taken 2 to 3 times a day. Take methylphenidate hydrochloride tablets 30 to 45 minutes before a meal. Your healthcare provider may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride tablets. Children should have their height and weight checked often while taking methylphenidate hydrochloride tablets. If you or your child take too much methylphenidate hydrochloride tablets, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of methylphenidate hydrochloride tablets? Methylphenidate hydrochloride tablets may cause serious side effects, including: see “What is the most important information I should know about methylphenidate hydrochloride tablets?” for information on reported heart and mental problems. painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a healthcare provider immediately. circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon): fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have, numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your healthcare provider right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets. Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with methylphenidate hydrochloride tablets. Methylphenidate hydrochloride tablets treatment may be stopped if your child is not growing or gaining weight. Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette’s syndrome.
lets treatment may be stopped if your child is not growing or gaining weight. Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride tablets. Common side effects include: fast heart beat • abnormal heartbeat (palpitations) headache • trouble sleeping nervousness • sweating a lot decreased appetite • dry mouth nausea • stomach pain Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store methylphenidate hydrochloride tablets? Store methylphenidate hydrochloride tablets in a safe place and in a tightly closed container at room temperature between 68°F to 77°F (20°C to 25°C). Protect from light. Dispose of remaining, unused, or expired methylphenidate hydrochloride tablets by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and throw away methylphenidate hydrochloride tablets in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep methylphenidate hydrochloride tablets and all medicines out of the reach of children. General information about the safe and effective use of methylphenidate hydrochloride tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about methylphenidate hydrochloride tablets that is written for healthcare professionals. Do not use methylphenidate hydrochloride tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them and it is against the law. What are the ingredients in methylphenidate hydrochloride tablets? Active ingredient: methylphenidate HCl Inactive ingredients: lactose monohydrate, magnesium stearate, polyethylene glycol 8000, and talc. In addition, the 5 mg tablet contains FD&C blue No. 2 aluminum lake and FD&C red No. 40 aluminum lake, the 10 mg tablet contains FD&C blue No. 2 aluminum lake and D&C yellow No. 10 aluminum lake and the 20 mg tablet contains FD&C yellow No. 6 aluminum lake. Manufactured by: Ohm Laboratories Inc. New Brunswick, NJ 08901 Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. 03/2024
<table width="98.04%"> <col width="100%"/> <tbody> <tr> <td styleCode="Botrule Lrule Rrule Toprule" valign="top"> <paragraph> <content styleCode="bold">Methylphenidate Hydrochloride Tablets USP, for oral use, CII</content> </paragraph> <paragraph>(meth" ǝl-fen 'i-dāt)</paragraph> <paragraph> <content styleCode="bold">Rx Only</content> </paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph> <content styleCode="bold">What is the most important information I should know about methylphenidate hydrochloride tablets?</content> </paragraph> <paragraph> <content styleCode="bold">Methylphenidate hydrochloride tablets</content> <content styleCode="bold">may cause serious side effects, including:</content> </paragraph> <paragraph/> <list listType="unordered"> <item> <content styleCode="bold">Abuse, misuse, and addiction.</content>Methylphenidate hydrochloride tablets has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride tablets, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride tablets or when it is used in ways that are not approved, such as snorting or injection. </item> <item>Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride tablets and will monitor you or your child during treatment.</item> <item>Methylphenidate hydrochloride tablets may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider.</item> <item>Do not give methylphenidate hydrochloride tablets to anyone else. See “ <content styleCode="bold">What is methylphenidate hydrochloride tablets?</content>” for more information. </item> <item>Keep methylphenidate hydrochloride tablets in a safe place and properly dispose of any unused medicine. See “ <content styleCode="bold">How should I store methylphenidate hydrochloride tablets?</content>” for more information. </item> <item>Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs.</item> <item> <content styleCode="bold">Risks for people with serious heart disease.</content>Sudden death has happened in people who have heart defects or other serious heart disease.
l your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs.</item> <item> <content styleCode="bold">Risks for people with serious heart disease.</content>Sudden death has happened in people who have heart defects or other serious heart disease. </item> </list> <paragraph/> <paragraph>Your healthcare provider should check you or your child carefully for heart problems before starting methylphenidate hydrochloride tablets</paragraph> <paragraph/> <paragraph>Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects.</paragraph> <paragraph/> <paragraph> <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child has any signs of heart problems, such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride tablets.</content> </paragraph> <paragraph/> <list listType="unordered"> <item> <content styleCode="bold">Increased blood pressure and heart rate.</content> </item> </list> <paragraph>Your healthcare provider should check you or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride tablets.</paragraph> <paragraph/> <list listType="unordered"> <item> <content styleCode="bold">Mental (psychiatric) problems:</content> </item> </list> <paragraph> <content styleCode="bold">All Patients</content> </paragraph> <list listType="unordered"> <item>new or worse behavior and thought problems</item> <item>new or worse bipolar illness</item> <item>new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms</item> </list> <paragraph/> <paragraph>Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.</paragraph> <paragraph/> <paragraph> <content styleCode="bold">Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.</content> </paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph> <content styleCode="bold">What are methylphenidate hydrochloride tablets?</content> </paragraph> <list listType="unordered"> <item>Methylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant prescription medicine. <content styleCode="bold">It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).</content>Methylphenidate hydrochloride tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. </item> <item>Methylphenidate hydrochloride tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.</item> <item>Methylphenidate hydrochloride tablets are also used in the treatment of a sleep disorder called narcolepsy.</item> <item> <paragraph> <content styleCode="bold">It is not known if methylphenidate hydrochloride tablets are safe and effective in children under 6 years of age.</content> </paragraph> <paragraph> <content styleCode="bold">Methylphenidate hydrochloride tablets is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs.</content>Keep methylphenidate hydrochloride tablets in a safe place to protect it from theft.
h> <content styleCode="bold">Methylphenidate hydrochloride tablets is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs.</content>Keep methylphenidate hydrochloride tablets in a safe place to protect it from theft. </paragraph> <paragraph/>Never give your methylphenidate hydrochloride tablets to anyone else, because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride tablets may harm others and is against the law. </item> </list> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph> <content styleCode="bold">Who should not take methylphenidate hydrochloride tablets?</content> </paragraph> <list listType="unordered"> <item> <content styleCode="bold">Methylphenidate hydrochloride tablets should not be taken if you or your child:</content> </item> </list> <list listType="unordered"> <item>are allergic to methylphenidate hydrochloride, or any of the ingredients in methylphenidate hydrochloride tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride tablets.</item> <item>are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor (MAOI).</item> </list> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph> <content styleCode="bold">Methylphenidate hydrochloride tablets may not be right for you or your child. Before starting methylphenidate hydrochloride tablets, tell your or your child’s healthcare provider about all health conditions (or a family history of), including:</content> </paragraph> <list listType="unordered"> <item>heart problems, heart disease, heart defects, high blood pressure</item> <item>mental problems, including psychosis, mania, bipolar illness, or depression</item> <item>circulation problems in fingers or toes</item> <item>have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness)</item> <item>have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome.</item> <item>if you are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride tablets will harm your unborn baby.</item> <item>There is a pregnancy registry for females who are exposed to ADHD medications, including methylphenidate hydrochloride tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate hydrochloride tablets and their baby. If you or your child becomes pregnant during treatment with methylphenidate hydrochloride tablets, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/.</item> <item>if you are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with methylphenidate hydrochloride tablets.</item> </list> <paragraph> <content styleCode="bold">Tell your healthcare provider about all of the medicines that you or your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</content>Methylphenidate hydrochloride tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride tablets.
rescription and over-the-counter medicines, vitamins, and herbal supplements.</content>Methylphenidate hydrochloride tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride tablets. </paragraph> <paragraph>Your healthcare provider will decide whether methylphenidate hydrochloride tablets can be taken with other medicines.</paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph> <content styleCode="bold">Especially tell your healthcare provider if you or your child takes:</content> </paragraph> <list listType="unordered"> <item>anti-depression medicines, including MAOIs</item> <item>blood pressure medicines (anti-hypertensive)</item> <item>Know the medicines that you or your child takes. Keep a list of your medicines with you to show your healthcare provider and pharmacist.</item> <item>You should not take methylphenidate hydrochloride tablets on the day of your operation if a certain type of anesthetic is used. This is because there is a chance of a sudden rise in blood pressure and heart rate during the operation.</item> </list> <paragraph> <content styleCode="bold">Do not start any new medicine while taking methylphenidate hydrochloride tablets without talking to your healthcare provider first.</content> </paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph> <content styleCode="bold">How should methylphenidate hydrochloride tablets be taken?</content> </paragraph> <list listType="unordered"> <item>Take methylphenidate hydrochloride tablets exactly as prescribed. Your healthcare provider may adjust the dose until it is right for you or your child.</item> <item>Methylphenidate hydrochloride tablets are usually taken 2 to 3 times a day.</item> <item>Take methylphenidate hydrochloride tablets 30 to 45 minutes before a meal.</item> <item>Your healthcare provider may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride tablets.</item> </list>Children should have their height and weight checked often while taking methylphenidate hydrochloride tablets. If you or your child take too much methylphenidate hydrochloride tablets, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph> <content styleCode="bold">What are the possible side effects of methylphenidate hydrochloride tablets?</content> </paragraph> <paragraph> <content styleCode="bold">Methylphenidate hydrochloride tablets may cause serious side effects, including:</content> </paragraph> <list listType="unordered"> <item>see <content styleCode="bold">“What is the most important information I should know about methylphenidate hydrochloride tablets?”</content>for information on reported heart and mental problems. </item> <item> <content styleCode="bold">painful and prolonged erections (priapism)</content>have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a healthcare provider immediately.
problems. </item> <item> <content styleCode="bold">painful and prolonged erections (priapism)</content>have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a healthcare provider immediately. </item> <item> <content styleCode="bold">circulation problems in fingers and toes</content>(peripheral vasculopathy, including Raynaud’s phenomenon): </item> </list> <list listType="unordered" styleCode="Circle"> <item>fingers or toes may feel numb, cool, painful</item> <item>fingers or toes may change color from pale, to blue, to red</item> </list> <paragraph>Tell your healthcare provider if you or your child have, numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.</paragraph> <paragraph> <content styleCode="bold">Call your healthcare provider right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets.</content> </paragraph> <list listType="unordered"> <item> <content styleCode="bold">Slowing of growth (height and weight) in children.</content>Children should have their height and weight checked often during treatment with methylphenidate hydrochloride tablets. Methylphenidate hydrochloride tablets treatment may be stopped if your child is not growing or gaining weight. </item> <item> <content styleCode="bold">Eye problems (increased pressure in the eye and glaucoma).</content>Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. </item> <item> <content styleCode="bold">New or worsening tics or worsening Tourette’s syndrome.</content>Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride tablets. </item> </list> <paragraph> <content styleCode="bold">Common side effects include:</content> </paragraph> <list listType="unordered"> <item>fast heart beat • abnormal heartbeat (palpitations)</item> <item>headache • trouble sleeping</item> <item>nervousness • sweating a lot</item> <item>decreased appetite • dry mouth</item> <item>nausea • stomach pain</item> </list> <paragraph>Call your doctor for medical advice about side effects. <content styleCode="bold">You may report side effects to FDA at 1-800-FDA-1088.</content> </paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph> <content styleCode="bold">How should I store methylphenidate hydrochloride tablets?</content> </paragraph> <list listType="unordered"> <item>Store methylphenidate hydrochloride tablets in a safe place and in a tightly closed container at room temperature between 68°F to 77°F (20°C to 25°C).</item> <item>Protect from light.</item> <item>Dispose of remaining, unused, or expired methylphenidate hydrochloride tablets by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and throw away methylphenidate hydrochloride tablets in the household trash.
, mix methylphenidate hydrochloride tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and throw away methylphenidate hydrochloride tablets in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</item> <item> <content styleCode="bold">Keep methylphenidate hydrochloride tablets and all medicines out of the reach of children.</content> </item> </list> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph> <content styleCode="bold">General information about the safe and effective use of methylphenidate hydrochloride tablets.</content> </paragraph> <paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about methylphenidate hydrochloride tablets that is written for healthcare professionals. Do not use methylphenidate hydrochloride tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them and it is against the law.</paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph> <content styleCode="bold">What are the ingredients in methylphenidate hydrochloride tablets?</content> </paragraph> <paragraph> <content styleCode="bold">Active ingredient:</content>methylphenidate HCl </paragraph> <paragraph> <content styleCode="bold">Inactive ingredients:</content>lactose monohydrate, magnesium stearate, polyethylene glycol 8000, and talc. In addition, the 5 mg tablet contains FD&C blue No. 2 aluminum lake and FD&C red No. 40 aluminum lake, the 10 mg tablet contains FD&C blue No. 2 aluminum lake and D&C yellow No. 10 aluminum lake and the 20 mg tablet contains FD&C yellow No. 6 aluminum lake. </paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" valign="top"> <paragraph>Manufactured by:</paragraph> <paragraph>Ohm Laboratories Inc.</paragraph> <paragraph>New Brunswick, NJ 08901</paragraph> <paragraph>Distributed by:</paragraph> <paragraph>Sun Pharmaceutical Industries, Inc.</paragraph> <paragraph>Cranbury, NJ 08512</paragraph> </td> </tr> </tbody> </table>
WARNING: ABUSE, MISUSE, AND ADDICTION APTENSIO XR has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including APTENSIO XR, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing APTENSIO XR, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout APTENSIO XR treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2) ] . WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. Aptensio XR has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including APTENSIO XR, can result in overdose and death ( 5.1 , 9.2 , 10 ): Before prescribing APTENSIO XR, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout treatment, reassess each patient's risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
<table width="100%"><col width="85%" align="left" valign="top"/><col width="15%" align="left" valign="top"/><tbody><tr><td>Indications and Usage (<linkHtml href="#S1">1</linkHtml>)</td><td>09/2025</td></tr><tr><td>Warnings and Precautions (<linkHtml href="#S5.7">5.7</linkHtml>)</td><td>09/2025</td></tr></tbody></table>
1 INDICATIONS AND USAGE APTENSIO XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD ) in patients 6 years and older [see Clinical Studies (14) ]. APTENSIO XR is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older. ( 1 ) Limitations of Use : The use of Aptensio XR is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage. ( 5.7 , 8.4 ) Limitations of Use The use of Aptensio XR is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions(e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.7) , Use in Specific Populations (8.4) ].
2 DOSAGE AND ADMINISTRATION Recommended starting dose for patients 6 years and older: 10 mg once daily with or without food in the morning. Dosage may be increased weekly in increments of 10 mg per day. Daily dosage above 60 mg is not recommended. ( 2.1 ) Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce. ( 2.1 ) 2.1 Pretreatment Screening Prior to treating patients with APTENSIO XR, assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions 5.2 ]. the family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome before initiating APTENSIO XR [see Warnings and Precautions (5.10) ] . 2.2 Recommended Dosage The recommended starting dose of APTENSIO XR in patients 6 years and older is 10 mg once daily orally in the morning with or without food. Advise patients to establish a routine pattern with regard to meals. The dose should be individualized according to the needs and response of the patient. The dose may be titrated weekly in increments of 10 mg. Daily doses above 60 mg have not been studied and are not recommended. 2.3 Administration Instructions APTENSIO XR may be taken whole or the capsule may be opened and the entire contents sprinkled onto applesauce. If the patient is using the sprinkled administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day. 2.4 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur; the dosage should be reduced, or, if necessary, discontinue APTENSIO XR. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue APTENSIO XR.
3 DOSAGE FORMS AND STRENGTHS 10 mg Extended-Release Capsules – light turquoise blue cap/white body (imprinted with "APTENSIO XR" on cap and "10 mg" on the body) 15 mg Extended-Release Capsules – orange cap/white body (imprinted with "APTENSIO XR" on cap and "15 mg" on the body) 20 mg Extended-Release Capsules – yellow cap/white body (imprinted with "APTENSIO XR" on cap and "20 mg" on the body) 30 mg Extended-Release Capsules – blue violet cap/white body (imprinted with "APTENSIO XR" on cap and "30 mg" on the body) 40 mg Extended-Release Capsules – pink cap/white body (imprinted with "APTENSIO XR" on cap and "40 mg" on the body) 50 mg Extended-Release Capsules – green cap/white body (imprinted with "APTENSIO XR" on cap and "50 mg" on the body) 60 mg Extended-Release Capsules – gray cap/white body (imprinted with "APTENSIO XR" on cap and "60 mg" on the body) Extended-release capsules: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg of methylphenidate hydrochloride, which is equivalent to 8.6 mg, 13.0 mg, 17.3 mg, 25.9 mg, 34.6 mg, 43.2 mg, and 51.9 mg of methylphenidate free base, respectively, per capsule. ( 3 )
4 CONTRAINDICATIONS Hypersensitivity to methylphenidate or other components of the product. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate products [see Adverse Reactions (6.1) ]. Concomitant treatment with monoamine oxidase inhibitors, and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor, because of the risk of hypertensive crisis [see Drug Interactions (7.1) ] . Known hypersensitivity to methylphenidate or product components. ( 4 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. ( 4 )
5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. ( 5.2 ) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3 ) Psychiatric Adverse Reactions: Prior to initiating APTENSIO XR, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing APTENSIO XR. ( 5.4 ) Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention. ( 5.5 ) Peripheral Vasculopathy, including Raynaud's Phenomenon: Careful observation for digital changes is necessary during APTENSION XR treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.6 ) Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.7 ) Acute Angle Closure Glaucoma: APTENSIO XR-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. ( 5.8 ) Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe APTENSIO XR to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma. ( 5.9 ) Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Before initiating APTENSIO XR, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue treatment if clinically appropriate. ( 5.10 ) 5.1 Abuse, Misuse, and Addiction APTENSIO XR has a high potential for abuse and misuse. The use of APTENSIO XR exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. APTENSIO XR can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2) ]. Misuse and abuse of CNS stimulants, including APTENSIO XR, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing APTENSIO XR, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store APTENSIO XR in a safe place, preferably locked, and instruct patients to not give APTENSIO XR to anyone else. Throughout APTENSIO XR treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage.
diction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid APTENSIO XR use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases. Monitor all APTENSIO XR-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Pre-Existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating APTENSIO XR treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing APTENSIO XR. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use, in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occured during methylphenidate withdrawal (drug holidays or during discontinuation). APTENSIO XR patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, including Raynaud's Phenomenon CNS stimulants, including APTENSIO XR, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during APTENSIO XR treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for APTENSIO XR-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients APTENSIO XR is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4) ] . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.
vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients APTENSIO XR is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4) ] . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in APTENSIO XR-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, APTENSIO XR-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.9 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2) ] . Prescribe APTENSIO XR to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor APTENSIO XR-treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.10 Motor and Verbal Tics, and Worsening of Tourette's Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported [see Adverse Reactions (6.2) ] . Before initiating APTENSIO XR, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor APTENSIO XR-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue treatment if clinically appropriate.
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning , Warnings and Precautions (5.1) , and Drug Abuse and Dependence (9.2 , 9.3) ] Hypersensitivity to Methylphenidate [see Contraindications (4) ] Hypertensive Crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1) ] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2) ] Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3) ] Psychiatric Adverse Reactions [see Warnings and Precautions (5.4) ] Priapism [see Warnings and Precautions (5.5) ] Peripheral Vasculopathy, including Raynaud's Phenomenon [see Warnings and Precautions (5.6) ] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7) ] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.8) ] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.9) ] Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.10) ] The most common adverse reactions in double-blind clinical trials (> 5% and twice the rate of placebo) in pediatric patients 6 to 17 years were abdominal pain, decreased appetite, headache and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rhodes Pharmaceuticals at (1-888-827-0616); or 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 clinical practice. Adverse Reactions in Studies with Other Methylphenidate Products in Children, Adolescents, and Adults with ADHD Commonly reported (≥2% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: decreased appetite, decreased weight, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, increased blood pressure, increased heart rate, tachycardia, palpitations, hyperhidrosis, and pyrexia. Adverse Reactions in Studies with APTENSIO XR in Pediatric Patients with ADHD The safety data in this section is based on data from two one-week controlled clinical studies of APTENSIO XR in pediatric patients with ADHD, one in children ages 6 to 12 years (RP-BP-EF001, hereafter "Study 1"), and one in children and adolescents ages 6 to 17 years (RP-BP-EF002, hereafter "Study 2"). Two APTENSIO XR clinical studies evaluated a total of 256 patients with ADHD. Two hundred and forty-three (243) patients participated in the double-blind phase of these two clinical studies. Study 1 was a randomized, double-blind, single center, placebo-controlled, flexible-dose, cross-over study to evaluate the time of onset, duration of efficacy, tolerability and safety of APTENSIO XR 15 mg, 20 mg, 30 mg, or 40 mg administered for one week in 26 pediatric patients aged 6 to 12 years who met DSM-IV criteria for ADHD [see Clinical Studies (14) ] . Most Common Adverse Reactions (incidence of ≥ 5% and at a rate at least twice placebo): abdominal pain, pyrexia and headache.
lity and safety of APTENSIO XR 15 mg, 20 mg, 30 mg, or 40 mg administered for one week in 26 pediatric patients aged 6 to 12 years who met DSM-IV criteria for ADHD [see Clinical Studies (14) ] . Most Common Adverse Reactions (incidence of ≥ 5% and at a rate at least twice placebo): abdominal pain, pyrexia and headache. Adverse Reactions Leading to Discontinuation: No subjects discontinued due to adverse reactions during the double-blind phase of this study. Study 2 was a randomized, double-blind, multicenter, placebo-controlled, parallel group, fixed-dose study of 10 mg, 15 mg, 20 mg, and 40 mg of APTENSIO XR administered for one week in 221 pediatric patients (6 to 17 years of age) who met DSM-IV criteria for ADHD [see Clinical Studies (14) ] . Most Common Adverse Reactions (incidence of ≥ 5% and at a rate of at least twice placebo): abdominal pain, decreased appetite, headache and insomnia. Adverse Reactions Leading to Discontinuation: Two patients (4.4%) in the APTENSIO XR 40 mg group discontinued due to insomnia, nausea and rapid heart rate, respectively during the double-blind phase of the study. Table 1: Common Adverse Reactions Occurring in ≥ 2% of Pediatric Patients (6 to 17 years of age) with ADHD Taking APTENSIO XR and at a Rate Greater than Placebo (Study 2) System Organ Class Adverse Reaction Aptensio XR (n=183) Placebo (n=47) Nervous System Disorders Headache 10.9% 8.5% Insomnia 9.8% 2.1% Dizziness 2.2% 2.1% Gastrointestinal Disorders Abdominal pain upper 8.2% 0% Nausea 3.8% 2.1% Vomiting 3.8% 0% Metabolism and Nutritional Decreased Appetite 4.9% 0% 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of methylphenidate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are as follows: Blood and Lymphatic System Disorders : Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura Cardiac Disorders : Angina pectoris, Bradycardia, Extrasystole, Supraventricular tachycardia, Ventricular extrasystole Eye Disorders : Diplopia, Increased intraocular pressure, Mydriasis, Visual impairment General Disorders : Chest pain, Chest discomfort, Hyperpyrexia Immune System Disorders : Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthems NEC Investigations : Alkaline phosphatase increased, Bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal, severe hepatic injury Musculoskeletal, Connective Tissue and Bone Disorders : Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System : Convulsion, Grand mal convulsion, Dyskinesia, serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics Psychiatric Disorders : Disorientation, Libido changes Skin and Subcutaneous Tissue Disorders : Alopecia, Erythema
<table width="60%"><caption>Table 1: Common Adverse Reactions Occurring in ≥ 2% of Pediatric Patients (6 to 17 years of age) with ADHD Taking APTENSIO XR and at a Rate Greater than Placebo (Study 2) </caption><col width="50%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule">System Organ Class Adverse Reaction</th><th styleCode="Rrule">Aptensio XR (n=183)</th><th styleCode="Rrule">Placebo (n=47)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous System Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">10.9%</td><td styleCode="Rrule">8.5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Insomnia</td><td styleCode="Rrule">9.8%</td><td styleCode="Rrule">2.1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness</td><td styleCode="Rrule">2.2%</td><td styleCode="Rrule">2.1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain upper</td><td styleCode="Rrule">8.2%</td><td styleCode="Rrule">0%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">3.8%</td><td styleCode="Rrule">2.1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">3.8%</td><td styleCode="Rrule">0%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Metabolism and Nutritional</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Decreased Appetite</td><td styleCode="Rrule">4.9%</td><td styleCode="Rrule">0%</td></tr></tbody></table>
7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7 ) 7.1 Clinically Important Interactions with APTENSIO XR Monoamine Oxidase Inhibitors (MAOIs) Do not administer APTENSIO XR concomitantly or within 14 days after discontinuing MAOI treatment. Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4) ]. Antihypertensive Drugs Aptensio XR may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed [see Warnings and Precautions (5.3) ] . Halogenated Anesthetics Concomitant use of halogenated anesthetics and APTENSIO XR may increase the risk of sudden blood pressure and heart rate increase during surgery. Avoid use of APTENSIO XR in patients being treated with anesthetics on the day of surgery. Risperidone Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.
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 APTENSIO XR during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. Risk Summary Limited published studies report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at the highest dose of 60 mg/kg/day (6 times the MRHD given to adolescents) [see Data ]. The background risk of major birth defects and miscarriage for the indicated population are unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Clinical Considerations Fetal/Neonatal adverse reactions CNS stimulants, such as APTENSIO XR, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (1.5 times the MRHD given to adolescents on a mg/m 2 basis).
weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (1.5 times the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on breast milk sampling from five mothers, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. However, long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for APTENSIO XR and any potential adverse effects on the breastfed infant from APTENSIO XR or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of APTENSIO XR have not been established in pediatric patients below the age of 6 years. Safety and efficacy of APTENSIO XR were evaluated in a multicenter, placebo-controlled, double-blind, parallel group study in 119 children 4 to <6 years of age with ADHD followed by a 12-month open-label extension in 44 of these children. In these studies, patients experienced high rates of adverse reactions, most notably weight loss. Comparing weights prior to initiation of APTENSIO XR (in the safety and efficacy study) to weights after 12 months of treatment (in the open-label extension), 20 of 39 patients with data (50%) had lost enough weight to decrease 10 or more percentiles on a Centers for Disease Control growth chart for weight. In addition, systemic drug exposures in patients 4 to <6 years of age were higher than those observed in older children and adolescents at the same dose (2 to 3 fold higher C max and AUC). Therefore, the benefits of APTENSIO XR do not outweigh the risks in pediatric patients 4 to <6 years of age. The safety and effectiveness of APTENSIO XR have been established in pediatric patients ages 6 to 17 years in two adequate and well-controlled clinical trials [see Clinical Studies (14) ] . Long Term Suppression of Growth Growth should be monitored during treatment with stimulants, including APTENSIO XR. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7) ] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 6 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on a mg/m 2 basis. In the study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10).
recommended human dose (MRHD) of 60 mg/day given to children on a mg/m 2 basis. In the study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). When these animals were tested as adults (postnatal weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Clinical trials of APTENSIO XR did not include any patients aged 65 years and over. In general, dose selection for an elderly patient start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to APTENSIO XR during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. Risk Summary Limited published studies report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at the highest dose of 60 mg/kg/day (6 times the MRHD given to adolescents) [see Data ]. The background risk of major birth defects and miscarriage for the indicated population are unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Clinical Considerations Fetal/Neonatal adverse reactions CNS stimulants, such as APTENSIO XR, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (1.5 times the MRHD given to adolescents on a mg/m 2 basis).
8.4 Pediatric Use The safety and effectiveness of APTENSIO XR have not been established in pediatric patients below the age of 6 years. Safety and efficacy of APTENSIO XR were evaluated in a multicenter, placebo-controlled, double-blind, parallel group study in 119 children 4 to <6 years of age with ADHD followed by a 12-month open-label extension in 44 of these children. In these studies, patients experienced high rates of adverse reactions, most notably weight loss. Comparing weights prior to initiation of APTENSIO XR (in the safety and efficacy study) to weights after 12 months of treatment (in the open-label extension), 20 of 39 patients with data (50%) had lost enough weight to decrease 10 or more percentiles on a Centers for Disease Control growth chart for weight. In addition, systemic drug exposures in patients 4 to <6 years of age were higher than those observed in older children and adolescents at the same dose (2 to 3 fold higher C max and AUC). Therefore, the benefits of APTENSIO XR do not outweigh the risks in pediatric patients 4 to <6 years of age. The safety and effectiveness of APTENSIO XR have been established in pediatric patients ages 6 to 17 years in two adequate and well-controlled clinical trials [see Clinical Studies (14) ] . Long Term Suppression of Growth Growth should be monitored during treatment with stimulants, including APTENSIO XR. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7) ] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 6 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on a mg/m 2 basis. In the study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). When these animals were tested as adults (postnatal weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
8.5 Geriatric Use Clinical trials of APTENSIO XR did not include any patients aged 65 years and over. In general, dose selection for an elderly patient start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance APTENSIO XR contains methylphenidate, a Schedule II controlled substance. 9.2 Abuse APTENSIO XR has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1) ] . APTENSIO XR can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including APTENSIO XR, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. 9.3 Dependence Physical Dependence APTENSIO XR may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including APTENSIO XR include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance APTENSIO XR may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
9.2 Abuse APTENSIO XR has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1) ] . APTENSIO XR can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including APTENSIO XR, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
9.3 Dependence Physical Dependence APTENSIO XR may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including APTENSIO XR include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance APTENSIO XR may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
10 OVERDOSAGE Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of APTENSIO XR should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
11 DESCRIPTION APTENSIO XR contains methylphenidate hydrochloride, a central nervous system (CNS) stimulant. APTENSIO XR capsules contain multi layered beads, which are composed of an immediate-release layer which contains approximately 40% of the methylphenidate dose, and a controlled release layer which contains approximately 60% of the methylphenidate dose. APTENSIO XR is available in seven capsule strengths. Each extended-release capsule for once-a-day oral administration contains 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, or 60 mg of methylphenidate HCl USP, which is equivalent to 8.6 mg, 13.0 mg, 17.3 mg, 25.9 mg, 34.6 mg, 43.2 mg, or 51.9 mg of methylphenidate free base, respectively. Chemically, methylphenidate HCl is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride. Its molecular formula is C 14 H 19 NO 2 ∙HCl. Its structural formula is: Methylphenidate hydrochloride USP is a white to off-white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Inactive Ingredients: ammonio methacrylate copolymer, type B; colloidal silicon dioxide (added if necessary); gelatin; hypromelloses; methacrylic acid copolymer, type C; polyethylene glycol; sugar spheres; talc; titanium oxide; and triethyl citrate. Each strength capsule also contains colorant ingredients in the capsule shell as follows: 10 mg: FD&C Blue No. 1 15 mg: D&C Red No. 28, D&C Yellow No. 10, FD&C Red No. 40 20 mg: D&C Red No. 33, D&C Yellow No. 10 30 mg: FD&C Blue No. 1, FD&C Red No. 3 40 mg: D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40 50 mg: D&C Yellow No. 10, FD&C Green No. 3 60 mg: Black Iron Oxide Chemical Structure
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l- isomers. The d- isomer is more pharmacologically active than the l- isomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. 12.3 Pharmacokinetics Absorption Following oral administration of APTENSIO XR in adults, plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 2 hours, followed by gradual descending concentrations over the next 4 to 6 hours, after which a gradual increase begins, reaching a second peak at approximately 8 hours (Figure 1). The relative bioavailability of APTENSIO XR given once daily as compared to a methylphenidate immediate-release oral product given three times daily in adults is comparable. The relative bioavailability is 102%. The pharmacokinetic profiles and parameters of methylphenidate are similar when APTENSIO XR is administered either as a whole capsule or sprinkled onto applesauce in subjects under fasting conditions (see Table 2 and Figure 1 ). Table 2: The Single Dose Pharmacokinetics of d,l-Methylphenidate d,l (racemic) methylphenidate HCl ER Capsule and Sprinkle following an Oral Dose of 80 mg APTENSIO XR under Fasted Conditions in Healthy Adults Pharmacokinetic Parameters Capsule Sprinkle C max C max , AUC (0-t) AUC (0-inf) presented as mean ± SD (ng/mL) 23.47 ± 11.4 21.78 ± 9.5 AUC (0-t) (ng.hr/mL) 262.7 ± 135 262.9 ± 128 AUC (0-inf ) (ng.hr/mL) 258.1 ± 94.2 258.0 ± 84.4 T max (hr) data presented as median (range) 2.0 2.0 Half-life (hr) 5.09 5.43 Relative bioavailability 102% 101% Figure 1: Mean d,l -Methylphenidate Plasma Concentration-Time Profiles following 80 mg Administered as Capsule and Sprinkle Dose in Healthy Adults Figure 1 Metabolism and Excretion In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has little or no pharmacologic activity. After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose. Food Effects Administration of APTENSIO XR with high fat meal showed a decreased or diminished second peak. A high-fat meal also increased the average C max of methylphenidate by about 28% and the AUC by about 19%. In the clinical trials of APTENSIO XR, it was administered without regard to meals. Alcohol Effect At an alcohol concentration up to 40%, there was 96% release of methylphenidate from APTENSIO XR 80 mg capsule within two hours. The results with the 80 mg capsule are considered to be representative of the other available capsules strengths. Studies in Specific Populations Gender There is insufficient experience with the use of APTENSIO XR to detect gender variations in pharmacokinetics. Race There is insufficient experience with the use of APTENSIO XR to detect ethnic variations in pharmacokinetics. Age The pharmacokinetics of methylphenidate after APTENSIO XR administration was studied in pediatric patients with ADHD between 6 and 12 years of age.
O XR to detect gender variations in pharmacokinetics. Race There is insufficient experience with the use of APTENSIO XR to detect ethnic variations in pharmacokinetics. Age The pharmacokinetics of methylphenidate after APTENSIO XR administration was studied in pediatric patients with ADHD between 6 and 12 years of age. Following administration of APTENSIO XR, the bi-phasic plasma methylphenidate concentration profile was qualitatively similar in healthy adult volunteers and pediatric patients with ADHD. The bi-phasic profile in both groups is characterized by an early peak due to rapid absorption of the immediate-release component followed by a delayed, secondary peak due to the controlled-release component of APTENSIO XR. Renal Insufficiency There is no experience with the use of APTENSIO XR in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid metabolite. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of APTENSIO XR. Hepatic Insufficiency There is no experience with the use of APTENSIO XR in patients with hepatic insufficiency.
12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l- isomers. The d- isomer is more pharmacologically active than the l- isomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.
12.3 Pharmacokinetics Absorption Following oral administration of APTENSIO XR in adults, plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 2 hours, followed by gradual descending concentrations over the next 4 to 6 hours, after which a gradual increase begins, reaching a second peak at approximately 8 hours (Figure 1). The relative bioavailability of APTENSIO XR given once daily as compared to a methylphenidate immediate-release oral product given three times daily in adults is comparable. The relative bioavailability is 102%. The pharmacokinetic profiles and parameters of methylphenidate are similar when APTENSIO XR is administered either as a whole capsule or sprinkled onto applesauce in subjects under fasting conditions (see Table 2 and Figure 1 ). Table 2: The Single Dose Pharmacokinetics of d,l-Methylphenidate d,l (racemic) methylphenidate HCl ER Capsule and Sprinkle following an Oral Dose of 80 mg APTENSIO XR under Fasted Conditions in Healthy Adults Pharmacokinetic Parameters Capsule Sprinkle C max C max , AUC (0-t) AUC (0-inf) presented as mean ± SD (ng/mL) 23.47 ± 11.4 21.78 ± 9.5 AUC (0-t) (ng.hr/mL) 262.7 ± 135 262.9 ± 128 AUC (0-inf ) (ng.hr/mL) 258.1 ± 94.2 258.0 ± 84.4 T max (hr) data presented as median (range) 2.0 2.0 Half-life (hr) 5.09 5.43 Relative bioavailability 102% 101% Figure 1: Mean d,l -Methylphenidate Plasma Concentration-Time Profiles following 80 mg Administered as Capsule and Sprinkle Dose in Healthy Adults Figure 1 Metabolism and Excretion In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has little or no pharmacologic activity. After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose. Food Effects Administration of APTENSIO XR with high fat meal showed a decreased or diminished second peak. A high-fat meal also increased the average C max of methylphenidate by about 28% and the AUC by about 19%. In the clinical trials of APTENSIO XR, it was administered without regard to meals. Alcohol Effect At an alcohol concentration up to 40%, there was 96% release of methylphenidate from APTENSIO XR 80 mg capsule within two hours. The results with the 80 mg capsule are considered to be representative of the other available capsules strengths. Studies in Specific Populations Gender There is insufficient experience with the use of APTENSIO XR to detect gender variations in pharmacokinetics. Race There is insufficient experience with the use of APTENSIO XR to detect ethnic variations in pharmacokinetics. Age The pharmacokinetics of methylphenidate after APTENSIO XR administration was studied in pediatric patients with ADHD between 6 and 12 years of age. Following administration of APTENSIO XR, the bi-phasic plasma methylphenidate concentration profile was qualitatively similar in healthy adult volunteers and pediatric patients with ADHD. The bi-phasic profile in both groups is characterized by an early peak due to rapid absorption of the immediate-release component followed by a delayed, secondary peak due to the controlled-release component of APTENSIO XR. Renal Insufficiency There is no experience with the use of APTENSIO XR in patients with renal insufficiency.
c profile in both groups is characterized by an early peak due to rapid absorption of the immediate-release component followed by a delayed, secondary peak due to the controlled-release component of APTENSIO XR. Renal Insufficiency There is no experience with the use of APTENSIO XR in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid metabolite. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of APTENSIO XR. Hepatic Insufficiency There is no experience with the use of APTENSIO XR in patients with hepatic insufficiency.
<table width="50%" ID="Tb2"><caption>Table 2: The Single Dose Pharmacokinetics of d,l-Methylphenidate<footnote ID="foot21"><content styleCode="italics">d,l</content> (racemic) methylphenidate HCl</footnote> ER Capsule and Sprinkle following an Oral Dose of 80 mg APTENSIO XR under Fasted Conditions in Healthy Adults</caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="middle"/><col width="33%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" align="center" valign="top">Pharmacokinetic Parameters</th><th styleCode="Rrule" valign="top">Capsule</th><th styleCode="Rrule" valign="top">Sprinkle</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">C<sub>max</sub><footnote ID="foot22">C<sub>max</sub>, AUC <sub>(0-t)</sub> AUC <sub>(0-inf)</sub> presented as mean ± SD</footnote> (ng/mL)</content></td><td styleCode="Rrule"><content styleCode="bold">23.47 ± 11.4</content></td><td styleCode="Rrule"><content styleCode="bold">21.78 ± 9.5</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">AUC<sub>(0-t)</sub><footnoteRef IDREF="foot22"/> (ng.hr/mL)</content></td><td styleCode="Rrule"><content styleCode="bold">262.7 ± 135</content></td><td styleCode="Rrule"><content styleCode="bold">262.9 ± 128</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">AUC<sub>(0-inf )</sub><footnoteRef IDREF="foot22"/> (ng.hr/mL)</content></td><td styleCode="Rrule"><content styleCode="bold">258.1 ± 94.2</content></td><td styleCode="Rrule"><content styleCode="bold">258.0 ± 84.4</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">T<sub>max</sub> (hr) </content><footnote ID="foot23">data presented as median (range) </footnote></td><td styleCode="Rrule"><content styleCode="bold">2.0</content></td><td styleCode="Rrule"><content styleCode="bold">2.0</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Half-life (hr)</content></td><td styleCode="Rrule"><content styleCode="bold">5.09</content></td><td styleCode="Rrule"><content styleCode="bold">5.43</content></td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Relative bioavailability</content></td><td styleCode="Rrule"><content styleCode="bold">102%</content></td><td styleCode="Rrule"><content styleCode="bold">101%</content></td></tr></tbody></table>
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on a mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on a mg/m 2 basis.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on a mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on a mg/m 2 basis.
14 CLINICAL STUDIES The efficacy of APTENSIO XR for the treatment of ADHD was established in a randomized, double-blind, single center, placebo-controlled, flexible-dose, cross-over trial in pediatric patients aged 6 to 12 years and a second randomized, double-blind, multicenter, placebo-controlled, fixed–dose trial in pediatric patients 6 to 17 years. Pediatric Patients A randomized, double-blind, placebo-controlled, flexible-dose, cross-over, analog classroom study (Study 1) was conducted in pediatric patients ages 6 to 12 years (N=26) who met DSM-IV-TR criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes. Following a 2 to 4 week open-label dose optimization phase in which patients received flexible-dose APTENSIO XR 15 mg, 20 mg, 30 mg, or 40 mg administered once daily in the morning, patients were randomly assigned to APTENSIO XR (dose from open-label phase) or placebo. After 1-week of treatment, patients were evaluated over a period of 12 hours. Subsequently, patients were given the opposite treatment for 1-week and returned for the second evaluation. Patients could then enter an open-label extension phase for up to 21 months. Efficacy assessments were conducted at 1, 2, 3, 4.5, 6, 7.5, 9, 10.5 and 12 hours post-dose using the Swanson, Kotkin, Agler, M. Flynn, and Pelham Total score (SKAMP). The primary efficacy endpoint was the average SKAMP Total Score, comparing APTENSIO XR to placebo. SKAMP is a validated 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting. The SKAMP Total Scores were statistically significantly better (lower) for APTENSIO XR than for placebo at the test day average and at all time points (1, 2, 3, 4.5, 6, 7.5, 9, 10.5 and 12 hours) post-dosing (see Figure 2 ). Figure 2: Absolute SKAMP- Total Score after treatment with APTENSIO XR or Placebo (Study 1). A randomized, double-blind, multicenter, placebo-controlled, parallel-group, fixed-dose study (Study 2) was conducted in pediatric patients age 6 to 17 years (N=230) who met DSM-IV-TR criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes. The ADHD-RS-IV is an 18-item questionnaire with a score range of 0 to 54 points that measures the core symptoms of ADHD and includes both hyperactive/impulsive and inattentive subscales. Patients were randomized to a daily morning dose of APTENSIO XR 10 mg, 15 mg, 20 mg, or 40 mg, or placebo for 1 week. An 11-week open label phase followed the double-blind phase. Patients could then enter another open-label phase for up to 21 months. The primary efficacy endpoint was the mean decrease from baseline to the end of Week 1 in the ADHD-RS-IV Total Score. Each of the four APTENSIO XR doses (10 mg, 15 mg, 20 mg, and 40 mg/day) was compared to placebo at the end of week 1. For both the 20 mg/day and the 40 mg/day doses, APTENSIO XR was superior to placebo in reduction of the ADHD-RS-IV Total Score, but not for the 10 mg/day or the 15 mg/day doses. A total of 221 patients completed the 1-week double-blind phase. Among those, 200 (90.5%) completed the 11-week open label phase and 173 (86.5%) patients continued into the 21-month open-label extension phase.
erior to placebo in reduction of the ADHD-RS-IV Total Score, but not for the 10 mg/day or the 15 mg/day doses. A total of 221 patients completed the 1-week double-blind phase. Among those, 200 (90.5%) completed the 11-week open label phase and 173 (86.5%) patients continued into the 21-month open-label extension phase. Table 3: Summary of Parallel-Group Study Study Number Treatment Group Primary Efficacy Measure: ADHD-RS-IV Total Score Mean Baseline Score (SD) LS Mean Reduction from Baseline (SE) Placebo-subtracted Difference Difference (placebo minus drug) in least-squares mean change from baseline. Positive numbers indicate reduction (improvement). (95% CI) Note: SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons. Study 2 (Pediatric) APTENSIO XR 10 mg/day 37.6 (8.32) 9.1 (1.40) 3.7 (-0.31, 7.66) APTENSIO XR 15 mg/day 38.0 (8.64) 10.3 (1.59) 4.9 (0.63, 9.07) APTENSIO XR 20 mg/day Doses that are demonstrated to be effective. 36.2 (8.46) 11.4 (1.49) 6.0 (1.92, 10.02) APTENSIO XR 40 mg/day 35.6 (9.16) 12.8 (1.49) 7.4 (3.38, 11.45) Placebo 33.4 (11.01) 5.4 (1.48) -- Figure 2
<table width="75%"><caption>Table 3: Summary of Parallel-Group Study</caption><col width="15%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th>Study Number</th><th valign="middle">Treatment Group</th><th styleCode="Botrule" colspan="3" valign="middle">Primary Efficacy Measure: ADHD-RS-IV Total Score</th></tr><tr><th/><th/><th>Mean Baseline Score (SD)</th><th>LS Mean Reduction from Baseline (SE)</th><th>Placebo-subtracted Difference<footnote ID="foot31">Difference (placebo minus drug) in least-squares mean change from baseline. Positive numbers indicate reduction (improvement).</footnote> (95% CI)</th></tr></thead><tfoot><tr><td colspan="5" align="left">Note: SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons.</td></tr></tfoot><tbody><tr><td rowspan="4" valign="top">Study 2 (Pediatric)</td><td>APTENSIO XR 10 mg/day</td><td>37.6 (8.32)</td><td>9.1 (1.40)</td><td>3.7 (-0.31, 7.66)</td></tr><tr><td>APTENSIO XR 15 mg/day</td><td align="center">38.0 (8.64)</td><td>10.3 (1.59)</td><td>4.9 (0.63, 9.07)</td></tr><tr><td>APTENSIO XR 20 mg/day<footnote ID="foot32">Doses that are demonstrated to be effective.</footnote></td><td align="center">36.2 (8.46)</td><td>11.4 (1.49)</td><td>6.0 (1.92, 10.02)</td></tr><tr><td>APTENSIO XR 40 mg/day<footnoteRef IDREF="foot32"/></td><td align="center">35.6 (9.16)</td><td>12.8 (1.49)</td><td>7.4 (3.38, 11.45)</td></tr><tr><td/><td>Placebo</td><td>33.4 (11.01)</td><td>5.4 (1.48)</td><td>--</td></tr></tbody></table>
16 HOW SUPPLIED/STORAGE AND HANDLING APTENSIO XR (methylphenidate hydrochloride extended-release) capsules are available as follows: 10 mg Capsules – light turquoise blue cap/white body, (imprinted with "APTENSIO XR" on cap and "10 mg" on the body) Bottles of 90 NDC 42858-401-45 15 mg Capsules – orange cap/white body, (imprinted with "APTENSIO XR" on cap and "15 mg" on the body) Bottles of 90 NDC 42858-402-45 20 mg Capsules – yellow cap/white body, (imprinted with "APTENSIO XR" on cap and "20 mg" on the body) Bottles of 90 NDC 42858-403-45 30 mg Capsules – blue violet cap/white body, (imprinted with "APTENSIO XR" on cap and "30 mg" on the body) Bottles of 90 NDC 42858-404-45 40 mg Capsules – pink cap/white body, (imprinted with "APTENSIO XR" on cap and "40 mg" on the body) Bottles of 90 NDC 42858-405-45 50 mg Capsules – green cap/white body, (imprinted with "APTENSIO XR" on cap and "50 mg" on the body) Bottles of 90 NDC 42858-406-45 60 mg Capsules – gray cap/white body, (imprinted with "APTENSIO XR" on cap and "60 mg" on the body) Bottles of 90 NDC 42858-407-45 Storage and Handling APTENSIO XR (methylphenidate hydrochloride extended-release) capsules should be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in tight container (USP).
<table width="60%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="right" valign="top"/><tbody><tr><td>Bottles of 90</td><td>NDC 42858-401-45</td></tr></tbody></table> <table width="60%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="right" valign="top"/><tbody><tr><td>Bottles of 90</td><td>NDC 42858-402-45</td></tr></tbody></table> <table width="60%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="right" valign="top"/><tbody><tr><td>Bottles of 90</td><td>NDC 42858-403-45</td></tr></tbody></table> <table width="60%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="right" valign="top"/><tbody><tr><td>Bottles of 90</td><td>NDC 42858-404-45</td></tr></tbody></table> <table width="60%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="right" valign="top"/><tbody><tr><td>Bottles of 90</td><td>NDC 42858-405-45</td></tr></tbody></table> <table width="60%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="right" valign="top"/><tbody><tr><td>Bottles of 90</td><td>NDC 42858-406-45</td></tr></tbody></table> <table width="60%" styleCode="Noautorules"><col width="50%" align="left" valign="top"/><col width="50%" align="right" valign="top"/><tbody><tr><td>Bottles of 90</td><td>NDC 42858-407-45</td></tr></tbody></table>
Storage and Handling APTENSIO XR (methylphenidate hydrochloride extended-release) capsules should be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in tight container (USP).
17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of APTENSIO XR, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2) , Overdosage (10) ] . Advise patients to store APTENSIO XR in a safe place, preferably locked, and instruct patients to not give APTENSIO XR to anyone else. Dosage and Administration Instructions Advise patients that APTENSIO XR can be taken with or without food and that they should establish a routine pattern of taking APTENSIO XR with regard to meals. For patients who take APTENSIO XR sprinkled over applesauce, the contents of the entire capsule should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. When initiating treatment with APTENSIO XR, provide dosage escalation and administration instructions [see Dosage and Administration (2.2) ]. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patient with serious cardiac disease, including sudden death, with APTENSIO XR use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2) ]. Increased Blood Pressure and Heart Rate Instruct patients that APTENSIO XR can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3) ] . Psychiatric Adverse Reactions Advise patients that APTENSIO XR, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4) ]. Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5) ]. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud's phenomenon] Instruct patients beginning treatment with APTENSIO XR about the risk of peripheral vasculopathy, including Raynaud's Phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking APTENSIO XR. Further clinical evaluation (e.g. rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6) ]. Long-Term Suppression of Growth in Pediatric Patients Advise patients that APTENSIO XR may cause slowing of growth and weight loss [see Warnings and Precautions (5.7) ]. Increased Intraocular Pressure (IOP) and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with APTENSIO XR [see Warnings and Precautions (5.9) ]. Motor and Verbal Tics, and Worsening of Tourette's Syndrome Advise patients that motor and verbal tics and worsening of Tourette's syndrome may occur during treatment with APTENSIO XR.
) and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with APTENSIO XR [see Warnings and Precautions (5.9) ]. Motor and Verbal Tics, and Worsening of Tourette's Syndrome Advise patients that motor and verbal tics and worsening of Tourette's syndrome may occur during treatment with APTENSIO XR. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette's syndrome occurs [see Warnings and Precautions (5.10) ]. Alcohol Effect Advise patients to avoid alcohol while taking APTENSIO XR. Consumption of alcohol while taking APTENSIO XR may result in a more rapid release of the dose of methylphenidate [see Clinical Pharmacology (12.3) ] . Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to APTENSIO XR during pregnancy [see Use in Specific Populations (8.1) ] .
Marketed by: Rhodes Pharmaceuticals Wilson, NC 27893 Manufactured by: Purdue Pharma L.P. Stamford, CT 06901 APTENSIO XR ® is a trademark of Rhodes Pharmaceuticals. This product is covered by US patents including US Patents No. 6,419,960, 7,083,808, 7,247,318, 8,580,310, 9,066,869 and 9,801,823. xxxxxx-0x
MEDICATION GUIDE APTENSIO XR ® (App-ten-see-o) (methylphenidate hydrochloride extended-release) capsules, CII This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 09/2025 What is the most important information I should know about APTENSIO XR? APTENSIO XR may cause serious side effects, including: Abuse, misuse, and addiction. APTENSIO XR has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of APTENSIO XR, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of APTENSIO XR or when it is used in ways that are not approved, such as snorting or injection. Your healthcare provider should check you or your child's risk for abuse, misuse, and addiction before starting treatment with APTENSIO XR and will monitor you or your child during treatment. APTENSIO XR may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. Do not give APTENSIO XR to anyone else. See " What is APTENSIO XR? " for more information. Keep APTENSIO XR in a safe place and properly dispose of any unused medicine. See " How should I store APTENSIO XR? " for more information. Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting treatment with APTENSIO XR. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Your healthcare provider should check you or your child's blood pressure and heart rate regularly during treatment with APTENSIO XR. Call your healthcare provider or go the nearest hospital emergency room right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with APTENSIO XR. Increased blood pressure and heart rate. Your healthcare provider should check your or your child's blood pressure and heart rate regularly during treatment with APTENSIO XR. Mental (psychiatric) problems, including: new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with APTENSIO XR, especially hearing voices, seeing or believing things that are not real, or new manic symptoms. What is APTENSIO XR? APTENSIO XR is a central nervous system (CNS) stimulant prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. APTENSIO XR may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. APTENSIO XR is not recommended for use in children under 6 years of age.
stimulant prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. APTENSIO XR may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. APTENSIO XR is not recommended for use in children under 6 years of age. APTENSIO XR is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep APTENSIO XR in a safe place to protect it from theft. Never give your APTENSIO XR to anyone else, because it may cause death or harm them. Selling or giving away APTENSIO XR may harm others and is against the law. Do not take APTENSIO XR if you or your child are: allergic to methylphenidate hydrochloride or any of the ingredients in APTENSIO XR. See the end of this Medication Guide for a complete list of ingredients in APTENSIO XR. taking or have stopped taking within the past 14 days a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI). Before taking APTENSIO XR tell your healthcare provider about all medical conditions, including if you or your child: have heart problems, heart disease, heart defects, or high blood pressure have mental problems including psychosis, mania, bipolar illness, or depression, or have a family history of suicide, bipolar illness, or depression have circulation problems in fingers and toes have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) have or had repeated movements or sounds (tics) or Tourette's syndrome, or have a family history of tics or Tourette's syndrome are pregnant or plan to become pregnant. It is not known if APTENSIO XR will harm your unborn baby. There is a pregnancy registry for females who are exposed to APTENSIO XR during pregnancy. The purpose of the registry is to collect information about the health of females exposed to APTENSIO XR and their baby. If you or your child becomes pregnant during treatment with APTENSIO XR, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. are breastfeeding or plan to breastfeed. APTENSIO XR passes into breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with APTENSIO XR. Tell your healthcare provider about all the medicines that you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. APTENSIO XR and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with APTENSIO XR. Your healthcare provider will decide whether APTENSIO XR can be taken with other medicines. Especially tell your healthcare provider if you or your child take a medicine used to treat depression called monoamine oxidase inhibitor (MAOI). Know the medicines that you or your child take. Keep a list of the medicines with you to show your healthcare provider and pharmacist. Do not start any new medicine during treatment with APTENSIO XR without talking to your healthcare provider first. How should APTENSIO XR be taken? Take APTENSIO XR exactly as prescribed by your healthcare provider. Your healthcare provider may change the dose if needed. Take APTENSIO XR by mouth 1 time each day in the morning. APTENSIO XR can be taken with or without food but take it the same way each time. Swallow APTENSIO XR capsules whole, or if APTENSIO XR capsules cannot be swallowed whole, the capsules may be opened and sprinkled onto a tablespoonful of applesauce. Make sure to sprinkle all the medicine onto the applesauce.
he morning. APTENSIO XR can be taken with or without food but take it the same way each time. Swallow APTENSIO XR capsules whole, or if APTENSIO XR capsules cannot be swallowed whole, the capsules may be opened and sprinkled onto a tablespoonful of applesauce. Make sure to sprinkle all the medicine onto the applesauce. The APTENSIO XR dose should not be divided. swallow all the applesauce and medicine mixture without chewing right away or within 10 minutes do not chew the applesauce and medicine mixture do not store applesauce and medicine mixture If a dose of APTENSIO XR is missed, do not take the dose later in the day or take an extra dose to make up for the missed dose, wait until the next morning to take the next scheduled dose. If you or your child take too much APTENSIO XR, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What should be avoided during treatment with APTENSIO XR? Avoid drinking alcohol during treatment with APTENSIO XR. This may cause a faster release of the APTENSIO XR medicine. What are possible side effects of APTENSIO XR? APTENSIO XR may cause serious side effects, including: See " What is the most important information I should know about APTENSIO XR? " Painful and prolonged erections (priapism). Priapism has happened in males who take products that contain methylphenidate. If you or your child develop priapism, get medical help right away. Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud's phenomenon). Signs and symptoms may include: fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you have or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your healthcare provider right away if you have or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with APTENSIO XR. Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with APTENSIO XR. APTENSIO XR treatment may be stopped if your child is not growing or gaining weight. Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette's syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette's syndrome during treatment with APTENSIO XR. The most common side effects of APTENSIO XR in children 6 to 17 years of age include stomach pain, decreased appetite, headache, trouble sleeping. These are not all the possible side effects of APTENSIO 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 Rhodes Pharmaceuticals at 1-888-827-0616. How should I store APTENSIO XR? Store APTENSIO XR at room temperature between 68°F to 77°F (20°C to 25°C). Store APTENSIO XR in a safe place, like a locked cabinet. Protect from moisture. Dispose of remaining, unused, or expired APTENSIO XR by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix APTENSIO XR with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away APTENSIO XR in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.
nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away APTENSIO XR in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep APTENSIO XR and all medicines out of the reach of children. General information about the safe and effective use of APTENSIO XR. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use APTENSIO XR for a condition for which it was not prescribed. Do not give APTENSIO XR to other people, even if they have the same symptoms. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about APTENSIO XR that is written for healthcare professionals. What are the ingredients in APTENSIO XR? Active Ingredient: methylphenidate hydrochloride Inactive Ingredients: ammonio methacrylate copolymer, type B; colloidal silicon dioxide (added if necessary); gelatin; hypromelloses; methacrylic acid copolymer, type C; polyethylene glycol; sugar spheres; talc; titanium oxide; and triethyl citrate. Manufactured by: Purdue Pharma L.P., Stamford, CT 06901 For more information, call Rhodes Pharmaceuticals (the distributor for APTENSIO XR) at 1-888-827-0616.
<table width="100%"><col width="82%" align="left" valign="top"/><col width="18%" align="left" valign="top"/><thead><tr><th align="center" colspan="2" styleCode="Lrule Rrule">MEDICATION GUIDE APTENSIO XR<sup>®</sup> (App-ten-see-o) (methylphenidate hydrochloride extended-release) capsules, CII</th></tr></thead><tfoot><tr><td align="left" valign="top">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="left" valign="top">Revised: 09/2025</td></tr></tfoot><tbody><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><paragraph ID="important"><content styleCode="bold">What is the most important information I should know about APTENSIO XR? APTENSIO XR may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Abuse, misuse, and addiction.</content> APTENSIO XR has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of APTENSIO XR, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of APTENSIO XR or when it is used in ways that are not approved, such as snorting or injection. <list listType="unordered" styleCode="circle"><item>Your healthcare provider should check you or your child's risk for abuse, misuse, and addiction before starting treatment with APTENSIO XR and will monitor you or your child during treatment.</item><item>APTENSIO XR may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider.</item><item>Do not give APTENSIO XR to anyone else. See "<content styleCode="bold"><linkHtml href="#whatis">What is APTENSIO XR?</linkHtml></content>" for more information.</item><item>Keep APTENSIO XR in a safe place and properly dispose of any unused medicine. See <content styleCode="bold">"<linkHtml href="#howshould">How should I store APTENSIO XR?</linkHtml></content>" for more information.</item><item>Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs.</item></list></item><item><content styleCode="bold">Risks for people with serious heart disease.</content> Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting treatment with APTENSIO XR. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Your healthcare provider should check you or your child's blood pressure and heart rate regularly during treatment with APTENSIO XR.
carefully for heart problems before starting treatment with APTENSIO XR. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Your healthcare provider should check you or your child's blood pressure and heart rate regularly during treatment with APTENSIO XR. <content styleCode="bold">Call your healthcare provider or go the nearest hospital emergency room right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with APTENSIO XR.</content></item><item><content styleCode="bold">Increased blood pressure and heart rate.</content> Your healthcare provider should check your or your child's blood pressure and heart rate regularly during treatment with APTENSIO XR.</item><item><content styleCode="bold">Mental (psychiatric) problems, including:</content><list listType="unordered" styleCode="circle"><item>new or worse behavior and thought problems</item><item>new or worse bipolar illness</item><item>new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms</item></list>Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. <content styleCode="bold">Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with APTENSIO XR, especially hearing voices, seeing or believing things that are not real, or new manic symptoms.</content></item></list></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><paragraph ID="whatis"><content styleCode="bold">What is APTENSIO XR?</content></paragraph> APTENSIO XR is a central nervous system (CNS) stimulant prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. APTENSIO XR may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. <list listType="unordered" styleCode="disc"><item><content styleCode="bold">APTENSIO XR is not recommended for use in children under 6 years of age.</content></item></list><content styleCode="bold">APTENSIO XR is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs.</content> Keep APTENSIO XR in a safe place to protect it from theft. Never give your APTENSIO XR to anyone else, because it may cause death or harm them. Selling or giving away APTENSIO XR may harm others and is against the law. </td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Do not take APTENSIO XR if you or your child are:</content><list listType="unordered" styleCode="disc"><item>allergic to methylphenidate hydrochloride or any of the ingredients in APTENSIO XR.
ers and is against the law. </td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Do not take APTENSIO XR if you or your child are:</content><list listType="unordered" styleCode="disc"><item>allergic to methylphenidate hydrochloride or any of the ingredients in APTENSIO XR. See the end of this Medication Guide for a complete list of ingredients in APTENSIO XR.</item><item>taking or have stopped taking within the past 14 days a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI).</item></list></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Before taking APTENSIO XR tell your healthcare provider about all medical conditions, including if you or your child:</content><list listType="unordered" styleCode="disc"><item>have heart problems, heart disease, heart defects, or high blood pressure</item><item>have mental problems including psychosis, mania, bipolar illness, or depression, or have a family history of suicide, bipolar illness, or depression</item><item>have circulation problems in fingers and toes</item><item>have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness)</item><item>have or had repeated movements or sounds (tics) or Tourette's syndrome, or have a family history of tics or Tourette's syndrome</item><item>are pregnant or plan to become pregnant. It is not known if APTENSIO XR will harm your unborn baby. <list listType="unordered" styleCode="circle"><item>There is a pregnancy registry for females who are exposed to APTENSIO XR during pregnancy. The purpose of the registry is to collect information about the health of females exposed to APTENSIO XR and their baby. If you or your child becomes pregnant during treatment with APTENSIO XR, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.</item></list></item><item>are breastfeeding or plan to breastfeed. APTENSIO XR passes into breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with APTENSIO XR.</item></list><content styleCode="bold">Tell your healthcare provider about all the medicines that you or your child take,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements. APTENSIO XR and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with APTENSIO XR. Your healthcare provider will decide whether APTENSIO XR can be taken with other medicines. <content styleCode="bold">Especially tell your healthcare provider if you or your child take</content> a medicine used to treat depression called monoamine oxidase inhibitor (MAOI). Know the medicines that you or your child take. Keep a list of the medicines with you to show your healthcare provider and pharmacist.
es. <content styleCode="bold">Especially tell your healthcare provider if you or your child take</content> a medicine used to treat depression called monoamine oxidase inhibitor (MAOI). Know the medicines that you or your child take. Keep a list of the medicines with you to show your healthcare provider and pharmacist. <content styleCode="bold">Do not start any new medicine during treatment with APTENSIO XR without talking to your healthcare provider first.</content></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">How should APTENSIO XR be taken?</content><list listType="unordered" styleCode="disc"><item>Take APTENSIO XR exactly as prescribed by your healthcare provider.</item><item>Your healthcare provider may change the dose if needed.</item><item>Take APTENSIO XR by mouth 1 time each day in the morning.</item><item>APTENSIO XR can be taken with or without food but take it the same way each time.</item><item>Swallow APTENSIO XR capsules whole, or if APTENSIO XR capsules cannot be swallowed whole, the capsules may be opened and sprinkled onto a tablespoonful of applesauce. Make sure to sprinkle all the medicine onto the applesauce. The APTENSIO XR dose should not be divided. <list listType="unordered" styleCode="circle"><item>swallow all the applesauce and medicine mixture without chewing right away or within 10 minutes</item><item><content styleCode="bold">do not</content> chew the applesauce and medicine mixture</item><item><content styleCode="bold">do not</content> store applesauce and medicine mixture</item></list></item><item>If a dose of APTENSIO XR is missed, do not take the dose later in the day or take an extra dose to make up for the missed dose, wait until the next morning to take the next scheduled dose.</item></list> If you or your child take too much APTENSIO XR, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. </td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">What should be avoided during treatment with APTENSIO XR?</content> Avoid drinking alcohol during treatment with APTENSIO XR. This may cause a faster release of the APTENSIO XR medicine.</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">What are possible side effects of APTENSIO XR? APTENSIO XR may cause serious side effects, including:</content> See <content styleCode="bold">"<linkHtml href="#important">What is the most important information I should know about APTENSIO XR?</linkHtml>"</content><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Painful and prolonged erections (priapism).</content> Priapism has happened in males who take products that contain methylphenidate. <content styleCode="bold">If you or your child develop priapism, get medical help right away.</content></item><item><content styleCode="bold">Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud's phenomenon).</content> Signs and symptoms may include:<list listType="unordered" styleCode="circle"><item>fingers or toes may feel numb, cool, painful</item><item>fingers or toes may change color from pale, to blue, to red</item></list> Tell your healthcare provider if you have or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.
pe="unordered" styleCode="circle"><item>fingers or toes may feel numb, cool, painful</item><item>fingers or toes may change color from pale, to blue, to red</item></list> Tell your healthcare provider if you have or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. <content styleCode="bold">Call your healthcare provider right away if you have or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with APTENSIO XR.</content></item><item><content styleCode="bold">Slowing of growth (height and weight) in children.</content> Children should have their height and weight checked often during treatment with APTENSIO XR. APTENSIO XR treatment may be stopped if your child is not growing or gaining weight.</item><item><content styleCode="bold">Eye problems (increased pressure in the eye and glaucoma).</content> Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness.</item><item><content styleCode="bold">New or worsening tics or worsening Tourette's syndrome.</content> Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette's syndrome during treatment with APTENSIO XR.</item></list><content styleCode="bold">The most common side effects of APTENSIO XR in children 6 to 17 years of age include</content> stomach pain, decreased appetite, headache, trouble sleeping. These are not all the possible side effects of APTENSIO 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 Rhodes Pharmaceuticals at 1-888-827-0616.</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><paragraph ID="howshould"><content styleCode="bold">How should I store APTENSIO XR?</content></paragraph><list listType="unordered" styleCode="disc"><item>Store APTENSIO XR at room temperature between 68°F to 77°F (20°C to 25°C).</item><item>Store APTENSIO XR in a safe place, like a locked cabinet. Protect from moisture.</item><item>Dispose of remaining, unused, or expired APTENSIO XR by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix APTENSIO XR with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away APTENSIO XR in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</item></list><content styleCode="bold">Keep APTENSIO XR and all medicines out of the reach of children.</content></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">General information about the safe and effective use of APTENSIO XR.</content> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use APTENSIO XR for a condition for which it was not prescribed. Do not give APTENSIO XR to other people, even if they have the same symptoms. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about APTENSIO XR that is written for healthcare professionals.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">What are the ingredients in APTENSIO XR?
y have the same symptoms. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about APTENSIO XR that is written for healthcare professionals.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">What are the ingredients in APTENSIO XR? Active Ingredient:</content> methylphenidate hydrochloride <content styleCode="bold">Inactive Ingredients:</content> ammonio methacrylate copolymer, type B; colloidal silicon dioxide (added if necessary); gelatin; hypromelloses; methacrylic acid copolymer, type C; polyethylene glycol; sugar spheres; talc; titanium oxide; and triethyl citrate. <content styleCode="bold">Manufactured by:</content> Purdue Pharma L.P., Stamford, CT 06901 For more information, call Rhodes Pharmaceuticals (the distributor for APTENSIO XR) at 1-888-827-0616.</td></tr></tbody></table>
WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate hydrochloride extended-release capsules have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release capsules, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release capsules, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout methylphenidate hydrochloride extended-release capsules treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2) ] . WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. Methylphenidate hydrochloride extended-release capsules have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release capsules, can result in overdose and death ( 5.1 , 9.2 , 10 ). Before prescribing methylphenidate hydrochloride extended-release capsules, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), in pediatric patients 6 to 12 years of age [see Clinical Studies (14) ] . Limitations of Use The use of methylphenidate hydrochloride extended-release capsules is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.7) , Use in Specific Populations (8.4) ] . Methylphenidate hydrochloride extended-release capsule is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 12 years of age ( 1 ). Limitations of Use The use of methylphenidate hydrochloride extended-release capsules are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.7 , 8.4 ).
2 DOSAGE AND ADMINISTRATION N/A Administer orally once daily in the morning (2.2) . Capsules may be swallowed whole or opened and the entire contents sprinkled on applesauce (2.2) . Should not be crushed, chewed, or divided ( 2.2 ). Patients new to methylphenidate: Start at 20 mg daily, titrating the dose weekly in 10-mg increments. Doses above 60 mg daily are not recommended (2.3) . For patients currently using methylphenidate hydrochloride tablets: Dosage is based on current dose regimen (2.4) . If switching from other methylphenidate products, discontinue treatment and titrate with methylphenidate hydrochloride extended-release capsules (2.4) . 2.1 Pretreatment Screening Prior to treating patients with methylphenidate hydrochloride extended-release capsules, assess: • for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2) ] . • the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating methylphenidate hydrochloride extended-release capsules [see Warnings and Precautions (5.10) ] . 2.2 General Dosing Information The recommended starting dose for methylphenidate hydrochloride extended-release capsule is 20 mg once daily. Increase dosage gradually, in increments of 10 mg weekly. Daily dosage above 60 mg is not recommended. When a lower initial dose is appropriate, patients may begin treatment with 10 mg. Administer methylphenidate hydrochloride extended-release capsules orally once daily in the morning. Methylphenidate hydrochloride extended-release capsules may be swallowed as whole capsules or may be administered by sprinkling the capsule contents on a small amount of applesauce ( see specific instructions below ). Methylphenidate hydrochloride extended-release capsules and/or their contents should not be crushed, chewed, or divided. The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. 2.3 Patients Currently Using Methylphenidate Hydrochloride Tablets The recommended dose of methylphenidate hydrochloride extended-release capsules for patients currently taking methylphenidate hydrochloride tablets twice daily is provided below in Table 1. Table 1: Recommended Dose Conversion from Methylphenidate Hydrochloride Tablets Previous Methylphenidate Hydrochloride Tablets dose Recommended Methylphenidate Hydrochloride Extended-Release Capsules dose 5 mg methylphenidate hydrochloride tablets twice daily 10 mg once daily 10 mg methylphenidate hydrochloride tablets twice daily 20 mg once daily 15 mg methylphenidate hydrochloride tablets twice daily 30 mg once daily 20 mg methylphenidate hydrochloride tablets twice daily 40 mg once daily 30 mg methylphenidate hydrochloride tablets twice daily 60 mg once daily 2.4 Switching from Other Methylphenidate Products If switching from other methylphenidate products, discontinue that treatment, and titrate with methylphenidate hydrochloride extended-release capsules using the titration schedule.
40 mg once daily 30 mg methylphenidate hydrochloride tablets twice daily 60 mg once daily 2.4 Switching from Other Methylphenidate Products If switching from other methylphenidate products, discontinue that treatment, and titrate with methylphenidate hydrochloride extended-release capsules using the titration schedule. Do not substitute for other methylphenidate products on a milligram-per-milligram basis, because different methylphenidate base compositions and differing pharmacokinetic profiles [see Description (11) , Clinical Pharmacology (12.3) ] . Clinical judgment should be used when selecting the starting dose. Daily dosage above 60 mg is not recommended. 2.5 Dosage Reduction and Discontinuation If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue methylphenidate hydrochloride extended-release capsules. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
3 DOSAGE FORMS AND STRENGTHS 10 mg Hard gelatin capsules, yellow opaque cap printed with “G 10mg” and white opaque body printed with “012” contains white to off-white pellets. 20 mg Hard gelatin capsules, white opaque cap printed with “G 20mg” and white opaque body printed with “013” contains white to off-white pellets. 30 mg Hard gelatin capsules, yellow opaque cap printed with “G 30mg” and yellow opaque body printed with “014” contains white to off-white pellets. 40 mg Hard gelatin capsules, yellow opaque cap printed with “G 40mg” and yellow opaque body printed with “015” contains white to off-white pellets. 60 mg Hard gelatin capsules, yellow opaque cap printed with “G 60mg” and yellow opaque body printed with “016” contains white to off-white pellets. Extended-release capsules: 10 mg, 20 mg, 30 mg, 40 mg and 60 mg ( 3 ).
4 CONTRAINDICATIONS Hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride extended-release capsules. Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been reported in patients treated with methylphenidate [see Adverse Reactions (6.1)]. Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [ see Drug Interactions (7.1)]. Known hypersensitivity to methylphenidate or product components (4) . Concurrent treatment with a monoamine oxidase inhibitor (MAOI) or use of an MAOI within the preceding 14 days ( 4 ).
5 WARNINGS AND PRECAUTIONS N/A Risks to Patients with Serious Cardiac Disease : Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac rhythm arrhythmias, coronary artery disease, or other serious cardiac disease ( 5.2 ). Increased Blood Pressure and Heart Rate : Monitor blood pressure and pulse ( 5.3 ). Psychiatric Adverse Reactions : Prior to initiating methylphenidate hydrochloride extended-release capsules, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release capsules ( 5.4 ). Priapism : If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention ( 5.5 ). Peripheral Vasculopathy, including Raynaud’s Phenomenon : Careful observation for digital changes is necessary during methylphenidate hydrochloride extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy ( 5.6 ). Long-Term Suppression of Growth in Pediatric Patients : Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted ( 5.7 ). Acute Angle Closure Glaucoma : Methylphenidate hydrochloride extended-release capsules-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist ( 5.8 ). Increased Intraocular Pressure (IOP) and Glaucoma : Prescribe methylphenidate hydrochloride extended-release capsules to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of abnormally increased IOP or open angle glaucoma ( 5.9 ). Motor and Verbal Tics, and Worsening of Tourette’s Syndrome : Before initiating methylphenidate hydrochloride extended-release capsules, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate ( 5.10 ). 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride extended-release capsules have a high potential for abuse and misuse. The use of methylphenidate hydrochloride extended-release capsules exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate hydrochloride extended-release capsules can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2) ] . Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release capsules, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release capsules, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug.
with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release capsules, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate hydrochloride extended-release capsules in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride extended-release capsules to anyone else. Throughout methylphenidate hydrochloride extended-release capsules treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who are treated with CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate hydrochloride extended-release capsules use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute). Some patients may have larger increases. Monitor all methylphenidate hydrochloride extended-release capsules-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Preexisting Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating methylphenidate hydrochloride extended-release capsules treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release capsules. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride extended-release capsules-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, Including Raynaud’s Phenomenon CNS stimulants, including methylphenidate hydrochloride extended-release capsules, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown.
omenon CNS stimulants, including methylphenidate hydrochloride extended-release capsules, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon were observed in post-marketing reports and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or the CNS stimulant. Careful observation for digital changes is necessary during methylphenidate hydrochloride extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride extended-release capsules-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients Methylphenidate hydrochloride extended-release capsules are not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)]. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in methylphenidate hydrochloride extended-release capsules-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate hydrochloride extended-release capsules-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.9 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2) ] . Prescribe methylphenidate hydrochloride extended-release capsules to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride extended-release capsules-treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.10 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2) ] . Before initiating methylphenidate hydrochloride extended-release capsules, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride extended-release capsules-treated patients for the emergence or worsening of tics or Tourette’s syndrome and discontinue treatment if clinically appropriate.
nded-release capsules, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride extended-release capsules-treated patients for the emergence or worsening of tics or Tourette’s syndrome and discontinue treatment if clinically appropriate. 5.11 Risk of Allergic Reactions Due to Tartrazine This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning , Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2 , 9.3) ] Known hypersensitivity to methylphenidate or other ingredients of methylphenidate hydrochloride extended-release capsules [see Contraindications (4) ] Hypertensive crisis when used concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) , Drug Interactions (7.1) ] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2) ] Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3) ] Psychiatric Adverse Reactions [see Warnings and Precautions (5.4) ] Priapism [see Warnings and Precautions (5.5) ] Peripheral Vasculopathy, Including Raynaud’s Phenomenon [see Warnings and Precautions (5.6) ] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7) ] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.8) ] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.9) ] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.10) ] Most common adverse reactions (greater than 5% during incidence) were headache, insomnia, upper abdominal pain, decreased appetite, and anorexia (6) . To report SUSPECTED ADVERSE REACTIONS, contact Granules Pharmaceuticals Inc., at 1-877-770-3183 or 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. The clinical program for methylphenidate hydrochloride extended-release capsules consisted of 6 studies: 2 controlled clinical studies conducted in children with ADHD aged 6 to 12 years and 4 clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received methylphenidate hydrochloride extended-release capsules in doses of 10 to 40 mg per day. Safety of methylphenidate hydrochloride extended-release capsules was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight. A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of methylphenidate hydrochloride extended-release capsules in children with ADHD aged 6 to 12 years. All subjects received methylphenidate hydrochloride extended-release capsules for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the 2-week double-blind treatment phase of this study, patients received either placebo or methylphenidate hydrochloride extended-release capsules at their individually-titrated dose (range, 10 mg to 40 mg). Adverse reactions with an incidence greater than 5% during the initial 4-week single-blind methylphenidate hydrochloride extended-release capsules titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia.
at their individually-titrated dose (range, 10 mg to 40 mg). Adverse reactions with an incidence greater than 5% during the initial 4-week single-blind methylphenidate hydrochloride extended-release capsules titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia. Adverse reactions with an incidence greater than 2% among methylphenidate hydrochloride extended-release capsules-treated subjects, during the 2-week double-blind phase of the clinical study, are shown in Table 2. Table 2: Adverse Reactions in Greater Than 2% Methylphenidate Hydrochloride Extended-Release Capsules-Treated Subjects in the 2-Week Double-Blind Phase Preferred Term Methylphenidate Hydrochloride Extended-Release Capsules N = 65 N (%) Placebo N = 71 N (%) Anorexia 2 (3.1) 0 (0) Insomnia 2 (3.1) 0 (0) Adverse Reactions Associated with Discontinuation of Treatment In the 2-week double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, one methylphenidate hydrochloride extended-release capsules-treated subject (1/65, 1.5%) discontinued due to an adverse event (depressed mood). In the single-blind titration period of this study, subjects received methylphenidate hydrochloride extended-release capsules for up to 4 weeks. During this period a total of 6 subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (2 patients), hypomania, anxiety, depressed mood, fatigue, migraine, and lethargy. 6.2 Postmarketing Experience The following adverse reactions have been identified during the post approval use of methylphenidate products. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
nce The following adverse reactions have been identified during the post approval use of methylphenidate products. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Adverse Reactions Reported with Methylphenidate Hydrochloride Tablets and Methylphenidate Hydrochloride Extended-Release Capsules Infections and Infestations: nasopharyngitis Blood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemia Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in children Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, depression Nervous System Disorders: headache, dizziness, tremor, dyskinesia, including choreoathetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs Eye Disorders: blurred vision, difficulties in visual accommodation Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris Respiratory, Thoracic, and Mediastinal Disorders: cough Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis, trismus Investigations: weight loss (adult ADHD patients) Vascular Disorders: peripheral coldness, Raynaud’s phenomenon Adverse Reactions Reported with Other Methylphenidate-Containing Products The list below shows adverse reactions not listed with methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release capsules, formulations that have been reported with other methylphenidate-containing products. Blood and Lymphatic Disorders: pancytopenia Immune System Disorders: hypersensitivity reactions, such as auricular swelling, bullous conditions, eruptions, exanthemas Psychiatric Disorders: affect lability, mania, disorientation, libido changes Nervous System Disorders: migraine, motor and verbal tics Eye Disorders: diplopia, increased intraocular pressure, mydriasis Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea Gastrointestinal Disorders: diarrhea, constipation Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption Musculoskeletal, Connective Tissue, and Bone Disorders: myalgia, muscle twitching Renal and Urinary Disorders: hematuria Reproductive System and Breast Disorders: gynecomastia General Disorders: fatigue, hyperpyrexia Urogenital Disorders: priapism
<table border="0" cellpadding="0" cellspacing="0" width="644.252"><colgroup><col width="31.3480594549959%"/><col width="34.3208092485549%"/><col width="34.3311312964492%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Preferred Term</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Methylphenidate Hydrochloride Extended-Release Capsules</content> <content styleCode="bold">N = 65</content> <content styleCode="bold">N (%)</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">N = 71</content> <content styleCode="bold">N (%)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Anorexia</td><td align="center" styleCode="Rrule" valign="top">2 (3.1)</td><td align="center" styleCode="Rrule" valign="top">0 (0)</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Insomnia</td><td align="center" styleCode="Rrule" valign="top">2 (3.1)</td><td styleCode="Rrule" valign="top">0 (0)</td></tr></tbody></table>
7 DRUG INTERACTIONS Antihypertensive Drugs : Monitor blood pressure and heart. Adjust dosage of antihypertensive drug as needed (7.1) . 7.1 Clinically Important Drug Interactions with Methylphenidate Hydrochloride Extended-Release Capsules Table 3 presents clinically important drug interactions with methylphenidate hydrochloride extended-release capsules Table 3: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOI) Clinical impact Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride extended-release capsules, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4) ] . Intervention Concomitant use of methylphenidate hydrochloride extended-release capsules with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical impact Methylphenidate hydrochloride extended-release capsules may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3) ] . Intervention Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical impact Concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release capsules may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of methylphenidate hydrochloride extended-release capsules in patients being treated with anesthetics on the day of surgery. Risperidone Clinical impact Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS) Intervention Monitor for signs of EPS
<table border="1" width="701px"><tbody><tr><td colspan="2"><content styleCode="bold">Monoamine Oxidase Inhibitors (MAOI)</content></td></tr><tr><td><content styleCode="italics">Clinical impact</content></td><td>Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride extended-release capsules, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure <content styleCode="italics">[see <linkHtml href="#Section_4">Contraindications (4)</linkHtml>] </content>. </td></tr><tr><td><content styleCode="italics">Intervention</content></td><td>Concomitant use of methylphenidate hydrochloride extended-release capsules with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.</td></tr><tr><td colspan="2"><content styleCode="bold">Antihypertensive Drugs</content></td></tr><tr><td><content styleCode="italics">Clinical impact</content></td><td>Methylphenidate hydrochloride extended-release capsules may decrease the effectiveness of drugs used to treat hypertension <content styleCode="italics">[see <linkHtml href="#Section_5.3">Warnings and Precautions (5.3)</linkHtml>] </content>. </td></tr><tr><td><content styleCode="italics">Intervention</content></td><td>Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.</td></tr><tr><td colspan="2"><content styleCode="bold">Halogenated Anesthetics</content></td></tr><tr><td><content styleCode="italics">Clinical impact</content></td><td>Concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release capsules may increase the risk of sudden blood pressure and heart rate increase during surgery.</td></tr><tr><td><content styleCode="italics">Intervention</content></td><td>Avoid use of methylphenidate hydrochloride extended-release capsules in patients being treated with anesthetics on the day of surgery.</td></tr><tr><td colspan="2"><content styleCode="bold">Risperidone</content></td></tr><tr><td><content styleCode="italics">Clinical impact</content></td><td>Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS)</td></tr><tr><td><content styleCode="italics">Intervention</content></td><td>Monitor for signs of EPS</td></tr></tbody></table>
8 USE IN SPECIFIC POPULATIONS N/A 8.1 Pregnancy Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy ( see Clinical Considerations ). No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth-weight-infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and post-natal development in rats was 15 mg/kg/day (approximately 2 times the MRHD given to adolescents on a mg/m 2 basis).
was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and post-natal development in rats was 15 mg/kg/day (approximately 2 times the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride extended-release capsules and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride extended-release capsules or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride extended-release capsules have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. The safety and effectiveness of methylphenidate hydrochloride extended-release capsules for the treatment of ADHD have been established in pediatric patients aged 6 to 12 years. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride extended-release capsules. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7) ] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Methylphenidate hydrochloride extended-release capsules has not been studied in the geriatric population.
8.1 Pregnancy Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy ( see Clinical Considerations ). No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth-weight-infants have been reported in amphetamine-dependent mothers. Data Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and post-natal development in rats was 15 mg/kg/day (approximately 2 times the MRHD given to adolescents on a mg/m 2 basis).
8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride extended-release capsules and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride extended-release capsules or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.
8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride extended-release capsules have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. The safety and effectiveness of methylphenidate hydrochloride extended-release capsules for the treatment of ADHD have been established in pediatric patients aged 6 to 12 years. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride extended-release capsules. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7) ] . Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate hydrochloride extended-release capsules contains methylphenidate hydrochloride, a Schedule II controlled substance. 9.2 Abuse Methylphenidate hydrochloride extended-release capsules have a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1) ] . Methylphenidate hydrochloride extended-release capsules can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate hydrochloride may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release capsules, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. 9.3 Dependence Physical Dependence Methylphenidate hydrochloride extended-release capsules may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride extended-release capsules include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate hydrochloride extended-release capsules may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
9.2 Abuse Methylphenidate hydrochloride extended-release capsules have a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1) ] . Methylphenidate hydrochloride extended-release capsules can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate hydrochloride may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release capsules, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
9.3 Dependence Physical Dependence Methylphenidate hydrochloride extended-release capsules may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride extended-release capsules include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate hydrochloride extended-release capsules may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
10 OVERDOSAGE Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of methylphenidate hydrochloride extended-release capsules should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
11 DESCRIPTION Methylphenidate hydrochloride extended-release capsules contains methylphenidate hydrochloride, a CNS stimulant. Methylphenidate hydrochloride extended-release capsules is an extended-release formulation of methylphenidate for oral administration with a bi-modal release profile. Each bead-filled methylphenidate hydrochloride extended-release capsule contains half the dose as immediate-release beads and half as enteric-coated beads, thus providing an immediate release of methylphenidate and a second delayed release of methylphenidate. The active substance in methylphenidate hydrochloride extended-release capsules is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77 g/mol. Inactive ingredients: Acetyltributyl citrate, cellaburate, corn starch, gelatin, hypromellose acetate succinate, polyethylene glycol, sucrose, talc, and titanium dioxide. The 10 mg, 30 mg, 40 mg, and 60 mg capsules contain FD & C Yellow #6. The 10 mg, 30 mg, and 60 mg capsules also contain FD&C Yellow #5. The 40 mg and 60 mg capsules contain D&C Yellow #10. In addition, capsule printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac glaze. methylphenidate-struct.jpg
12 CLINICAL PHARMACOLOGY N/A 12.1 Mechanism of Action Methylphenidate hydrochloride is a CNS stimulant. The mode of therapeutic action in ADHD is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking methylphenidate hydrochloride extended-release capsules. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethylphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident-exposure response relationship. 12.3 Pharmacokinetics Methylphenidate hydrochloride extended-release capsules produces a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately 4 hours apart) when administered orally to children diagnosed with ADHD and healthy adults. No accumulation of methylphenidate is expected following multiple once daily oral dosing with methylphenidate hydrochloride extended-release capsules, however, there is a slight upward trend in the methylphenidate area under the curve and peak plasma concentrations (C max1 and C max2 ) after oral administration of methylphenidate hydrochloride extended-release capsules 20 mg and 40 mg capsules to adults. Absorption The absolute oral bioavailability of methylphenidate in children was 22% ± 8% for d-methylphenidate and 5% ± 3% for l-methylphenidate. The relative bioavailability of methylphenidate hydrochloride extended-release capsules given once daily is comparable to the same total dose of methylphenidate hydrochloride tablets given in 2 doses 4 hours apart in both children and adults. The initial rate of absorption for methylphenidate hydrochloride extended-release capsules is similar to that of methylphenidate hydrochloride tablets as shown by the similar rate parameters between the 2 formulations, i.e., initial lag time (T lag ), first peak concentration (C max1 ), and time to the first peak (T max1 ), which is reached in 1 to 3 hours. The mean time to the interpeak minimum (T minip ), and time to the second peak (T max2 ) are also similar for methylphenidate hydrochloride extended-release capsules given once daily and methylphenidate hydrochloride tablets given in 2 doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for methylphenidate hydrochloride extended-release capsules.
e second peak (T max2 ) are also similar for methylphenidate hydrochloride extended-release capsules given once daily and methylphenidate hydrochloride tablets given in 2 doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for methylphenidate hydrochloride extended-release capsules. Methylphenidate hydrochloride extended-release capsules given once daily exhibits a lower second peak concentration (C max2 ), higher interpeak minimum concentrations (C minip ), and less peak and trough fluctuations than methylphenidate hydrochloride tablets given in 2 doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1 and Table 4). Figure 1: Mean Plasma Concentration Time-profile of Methylphenidate After a Single Dose of Methylphenidate Hydrochloride Extended-Release Capsules, 40 mg and Methylphenidate Hydrochloride Tablets, 20 mg Given in Two Doses 4 Hours Apart Table 4: Mean ± SD and Range of Pharmacokinetic Parameters of Methylphenidate After a Single Dose of Methylphenidate Hydrochloride Extended-Release Capsules and Methylphenidate Hydrochloride Tablets Given in Two Doses 4 Hours Apart a N = 15. Population Children Adult Males Formulation D ose N Methylphenidate Hydrochloride Tablets 10 mg & 10 mg 21 Methylphenidate Hydrochloride Extended-Release Capsules 20 mg 18 Methylphenidate Hydrochloride Tablets 10 mg & 10 mg 9 Methylphenidate Hydrochloride Extended-Release Capsules 20 mg 8 T lag (h) 0.24 ± 0.44 0 to 1 0.28 ± 0.46 0 to 1 1 ± 0.5 0.7 to 1.3 0.7 ± 0.2 0.3 to 1 T max1 (h) 1.8 ± 0.6 1 to 3 2 ± 0.8 1 to 3 1.9 ± 0.4 1.3 to 2.7 2 ± 0.9 1.3 to 4 C max1 (ng/mL) 10.2 ± 4.2 4.2 to 20.2 10.3 ± 5.1 5.5 to 26.6 4.3 ± 2.3 1.8 to 7.5 5.3 ± 0.9 3.8 to 6.9 T minip (h) 4 ± 0.2 4 to 5 4.5 ± 1.2 2 to 6 3.8 ± 0.4 3.3 to 4.3 3.6 ± 0.6 2.7 to 4.3 C minip (ng/mL) 5.8 ± 2.7 3.1 to 14.4 6.1 ± 4.1 2.9 to 21 1.2 ± 1.4 0 to 3.7 3 ± 0.8 1.7 to 4 T max2 (h) 5.6 ± 0.7 5 to 8 6.6 ± 1.5 5 to 11 5.9 ± 0.5 5 to 6.5 5.5 ± 0.8 4.3 to 6.5 C max2 (ng/mL) 15.3 ± 7 6.2 to 32.8 10.2 ± 5.9 4.5 to 31.1 5.3 ± 1.4 3.6 to 7.2 6.2 ± 1.6 3.9 to 8.3 AUC (0-∞) (ng/mL x h-1) 102.4 ± 54.6 40.5 to 261.6 86.6 ± 64 a 43.3 to 301.44 37.8 ± 21.9 14.3 to 85.3 45.8 ± 10 34 to 61.6 t 1/2 (h) 2.5 ± 0.8 1.8 to 5.3 2.4 ± 0.7 a 1.5 to 4 3.5 ± 1.9 1.3 to 7.7 3.3 ± 0.4 3 to 4.2 Effect of Food Administration times relative to meals and meal composition may need to be individually titrated. When methylphenidate hydrochloride extended-release capsules were administered with a high fat breakfast to adults, methylphenidate hydrochloride extended-release capsules had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. The first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined. There were no differences in the pharmacokinetics of methylphenidate hydrochloride extended-release capsules when administered with applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food. Effect of Alcohol An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate hydrochloride extended-release capsules 40 mg capsule dosage form. At an alcohol concentration of 40% there was a 98% release of methylphenidate in the first hour. The results with the 40 mg capsule are considered to be representative of the other available capsule strengths. Distribution Binding to plasma proteins is low (10% to 33%).
ended-release capsules 40 mg capsule dosage form. At an alcohol concentration of 40% there was a 98% release of methylphenidate in the first hour. The results with the 40 mg capsule are considered to be representative of the other available capsule strengths. Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.8 ± 0.91 L/kg for l-methylphenidate. Elimination The systemic clearance is 0.4 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. In studies with methylphenidate hydrochloride extended-release capsules and methylphenidate hydrochloride tablets in adults, methylphenidate from methylphenidate hydrochloride tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range, 1.3 to 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 to 5 hours. The rapid half-life in both children and adults may result in un-measurable concentrations between the morning and mid-day doses with methylphenidate hydrochloride tablets. No accumulation of methylphenidate is expected following multiple once a day oral dosing with methylphenidate hydrochloride extended-release capsules. The half-life of ritalinic acid is about 3 to 4 hours. Metabolism The absolute oral bioavailability of methylphenidate in children was 22% ± 8% for d-methylphenidate and 5% ± 3% for l-methylphenidate, suggesting pronounced presystemic metabolism. Biotransformation of methylphenidate by the carboxylesterase CES1A1 is rapid and extensive leading to the main, de-esterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. Therapeutic activity is principally due to the parent compound. Excretion After oral administration of an immediate release formulation of methylphenidate, 78% to 97% of the dose is excreted in the urine and 1% to 3% in the feces in the form of metabolites within 48 to 96 hours. Only small quantities (less than 1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60% to 86%), the remainder being accounted for by minor metabolite. Studies in Specific Populations Male and Female Patients There were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered methylphenidate hydrochloride extended-release capsules. Racial or Ethnic Groups There is insufficient experience with the use of methylphenidate hydrochloride extended-release capsules to detect ethnic variations in pharmacokinetics. Pediatric Patients The pharmacokinetics of methylphenidate hydrochloride extended-release capsules was examined in 18 children with ADHD between 7 and 12 years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. After a 20-mg dose of methylphenidate hydrochloride extended-release capsules, concentrations in children were approximately twice the concentrations observed in 18- to 35-year-old adults. This higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age. Patients with Renal Impairment Methylphenidate hydrochloride extended-release capsules has not been studied in renally-impaired patients.
higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age. Patients with Renal Impairment Methylphenidate hydrochloride extended-release capsules has not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochloride extended-release capsules has not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. methylphenidate-fig-1.jpg
12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology A formal QT study has not been conducted in patients taking methylphenidate hydrochloride extended-release capsules. The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethylphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident-exposure response relationship.
12.3 Pharmacokinetics Methylphenidate hydrochloride extended-release capsules produces a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately 4 hours apart) when administered orally to children diagnosed with ADHD and healthy adults. No accumulation of methylphenidate is expected following multiple once daily oral dosing with methylphenidate hydrochloride extended-release capsules, however, there is a slight upward trend in the methylphenidate area under the curve and peak plasma concentrations (C max1 and C max2 ) after oral administration of methylphenidate hydrochloride extended-release capsules 20 mg and 40 mg capsules to adults. Absorption The absolute oral bioavailability of methylphenidate in children was 22% ± 8% for d-methylphenidate and 5% ± 3% for l-methylphenidate. The relative bioavailability of methylphenidate hydrochloride extended-release capsules given once daily is comparable to the same total dose of methylphenidate hydrochloride tablets given in 2 doses 4 hours apart in both children and adults. The initial rate of absorption for methylphenidate hydrochloride extended-release capsules is similar to that of methylphenidate hydrochloride tablets as shown by the similar rate parameters between the 2 formulations, i.e., initial lag time (T lag ), first peak concentration (C max1 ), and time to the first peak (T max1 ), which is reached in 1 to 3 hours. The mean time to the interpeak minimum (T minip ), and time to the second peak (T max2 ) are also similar for methylphenidate hydrochloride extended-release capsules given once daily and methylphenidate hydrochloride tablets given in 2 doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for methylphenidate hydrochloride extended-release capsules. Methylphenidate hydrochloride extended-release capsules given once daily exhibits a lower second peak concentration (C max2 ), higher interpeak minimum concentrations (C minip ), and less peak and trough fluctuations than methylphenidate hydrochloride tablets given in 2 doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1 and Table 4). Figure 1: Mean Plasma Concentration Time-profile of Methylphenidate After a Single Dose of Methylphenidate Hydrochloride Extended-Release Capsules, 40 mg and Methylphenidate Hydrochloride Tablets, 20 mg Given in Two Doses 4 Hours Apart Table 4: Mean ± SD and Range of Pharmacokinetic Parameters of Methylphenidate After a Single Dose of Methylphenidate Hydrochloride Extended-Release Capsules and Methylphenidate Hydrochloride Tablets Given in Two Doses 4 Hours Apart a N = 15.
Methylphenidate Hydrochloride Tablets, 20 mg Given in Two Doses 4 Hours Apart Table 4: Mean ± SD and Range of Pharmacokinetic Parameters of Methylphenidate After a Single Dose of Methylphenidate Hydrochloride Extended-Release Capsules and Methylphenidate Hydrochloride Tablets Given in Two Doses 4 Hours Apart a N = 15. Population Children Adult Males Formulation D ose N Methylphenidate Hydrochloride Tablets 10 mg & 10 mg 21 Methylphenidate Hydrochloride Extended-Release Capsules 20 mg 18 Methylphenidate Hydrochloride Tablets 10 mg & 10 mg 9 Methylphenidate Hydrochloride Extended-Release Capsules 20 mg 8 T lag (h) 0.24 ± 0.44 0 to 1 0.28 ± 0.46 0 to 1 1 ± 0.5 0.7 to 1.3 0.7 ± 0.2 0.3 to 1 T max1 (h) 1.8 ± 0.6 1 to 3 2 ± 0.8 1 to 3 1.9 ± 0.4 1.3 to 2.7 2 ± 0.9 1.3 to 4 C max1 (ng/mL) 10.2 ± 4.2 4.2 to 20.2 10.3 ± 5.1 5.5 to 26.6 4.3 ± 2.3 1.8 to 7.5 5.3 ± 0.9 3.8 to 6.9 T minip (h) 4 ± 0.2 4 to 5 4.5 ± 1.2 2 to 6 3.8 ± 0.4 3.3 to 4.3 3.6 ± 0.6 2.7 to 4.3 C minip (ng/mL) 5.8 ± 2.7 3.1 to 14.4 6.1 ± 4.1 2.9 to 21 1.2 ± 1.4 0 to 3.7 3 ± 0.8 1.7 to 4 T max2 (h) 5.6 ± 0.7 5 to 8 6.6 ± 1.5 5 to 11 5.9 ± 0.5 5 to 6.5 5.5 ± 0.8 4.3 to 6.5 C max2 (ng/mL) 15.3 ± 7 6.2 to 32.8 10.2 ± 5.9 4.5 to 31.1 5.3 ± 1.4 3.6 to 7.2 6.2 ± 1.6 3.9 to 8.3 AUC (0-∞) (ng/mL x h-1) 102.4 ± 54.6 40.5 to 261.6 86.6 ± 64 a 43.3 to 301.44 37.8 ± 21.9 14.3 to 85.3 45.8 ± 10 34 to 61.6 t 1/2 (h) 2.5 ± 0.8 1.8 to 5.3 2.4 ± 0.7 a 1.5 to 4 3.5 ± 1.9 1.3 to 7.7 3.3 ± 0.4 3 to 4.2 Effect of Food Administration times relative to meals and meal composition may need to be individually titrated. When methylphenidate hydrochloride extended-release capsules were administered with a high fat breakfast to adults, methylphenidate hydrochloride extended-release capsules had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. The first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined. There were no differences in the pharmacokinetics of methylphenidate hydrochloride extended-release capsules when administered with applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food. Effect of Alcohol An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate hydrochloride extended-release capsules 40 mg capsule dosage form. At an alcohol concentration of 40% there was a 98% release of methylphenidate in the first hour. The results with the 40 mg capsule are considered to be representative of the other available capsule strengths. Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.8 ± 0.91 L/kg for l-methylphenidate. Elimination The systemic clearance is 0.4 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. In studies with methylphenidate hydrochloride extended-release capsules and methylphenidate hydrochloride tablets in adults, methylphenidate from methylphenidate hydrochloride tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range, 1.3 to 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 to 5 hours. The rapid half-life in both children and adults may result in un-measurable concentrations between the morning and mid-day doses with methylphenidate hydrochloride tablets.
alf-life of about 3.5 hours, (range, 1.3 to 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 to 5 hours. The rapid half-life in both children and adults may result in un-measurable concentrations between the morning and mid-day doses with methylphenidate hydrochloride tablets. No accumulation of methylphenidate is expected following multiple once a day oral dosing with methylphenidate hydrochloride extended-release capsules. The half-life of ritalinic acid is about 3 to 4 hours. Metabolism The absolute oral bioavailability of methylphenidate in children was 22% ± 8% for d-methylphenidate and 5% ± 3% for l-methylphenidate, suggesting pronounced presystemic metabolism. Biotransformation of methylphenidate by the carboxylesterase CES1A1 is rapid and extensive leading to the main, de-esterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. Therapeutic activity is principally due to the parent compound. Excretion After oral administration of an immediate release formulation of methylphenidate, 78% to 97% of the dose is excreted in the urine and 1% to 3% in the feces in the form of metabolites within 48 to 96 hours. Only small quantities (less than 1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60% to 86%), the remainder being accounted for by minor metabolite. Studies in Specific Populations Male and Female Patients There were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered methylphenidate hydrochloride extended-release capsules. Racial or Ethnic Groups There is insufficient experience with the use of methylphenidate hydrochloride extended-release capsules to detect ethnic variations in pharmacokinetics. Pediatric Patients The pharmacokinetics of methylphenidate hydrochloride extended-release capsules was examined in 18 children with ADHD between 7 and 12 years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. After a 20-mg dose of methylphenidate hydrochloride extended-release capsules, concentrations in children were approximately twice the concentrations observed in 18- to 35-year-old adults. This higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age. Patients with Renal Impairment Methylphenidate hydrochloride extended-release capsules has not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Patients with Hepatic Impairment Methylphenidate hydrochloride extended-release capsules has not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. methylphenidate-fig-1.jpg
<table border="0" cellpadding="0" cellspacing="0" width="829.92"><colgroup><col width="17.3076923076923%"/><col width="20.1923076923077%"/><col width="20.5128205128205%"/><col width="20.9935897435897%"/><col width="20.9935897435897%"/></colgroup><tfoot><tr><td colspan="5"><sup>a</sup>N = 15.
<table border="0" cellpadding="0" cellspacing="0" width="829.92"><colgroup><col width="17.3076923076923%"/><col width="20.1923076923077%"/><col width="20.5128205128205%"/><col width="20.9935897435897%"/><col width="20.9935897435897%"/></colgroup><tfoot><tr><td colspan="5"><sup>a</sup>N = 15. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Population</content></td><td align="center" colspan="2" styleCode="Rrule" valign="top"><content styleCode="bold">Children</content></td><td align="center" colspan="2" styleCode="Rrule" valign="top"><content styleCode="bold">Adult Males</content></td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Formulation D</content><content styleCode="bold">ose</content> <content styleCode="bold">N</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Methylphenidate Hydrochloride Tablets</content> <content styleCode="bold">10 mg & 10 mg</content> <content styleCode="bold">21</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Methylphenidate Hydrochloride Extended-Release Capsules</content> <content styleCode="bold">20 mg </content> <content styleCode="bold">18</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Methylphenidate Hydrochloride Tablets </content> <content styleCode="bold">10 mg & 10 mg</content> <content styleCode="bold">9</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Methylphenidate Hydrochloride Extended-Release Capsules</content> <content styleCode="bold">20 mg </content> <content styleCode="bold">8</content></td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">T </content><sub>lag</sub> (h) </td><td align="center" styleCode="Rrule" valign="top">0.24 ± 0.44 0 to 1 </td><td align="center" styleCode="Rrule" valign="top">0.28 ± 0.46 0 to 1 </td><td align="center" styleCode="Rrule" valign="top">1 ± 0.5 0.7 to 1.3 </td><td align="center" styleCode="Rrule" valign="top">0.7 ± 0.2 0.3 to 1 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">T </content><sub>max1</sub> (h) </td><td align="center" styleCode="Rrule" valign="top">1.8 ± 0.6 1 to 3 </td><td align="center" styleCode="Rrule" valign="top">2 ± 0.8 1 to 3 </td><td align="center" styleCode="Rrule" valign="top">1.9 ± 0.4 1.3 to 2.7 </td><td align="center" styleCode="Rrule" valign="top">2 ± 0.9 1.3 to 4 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">C <sub>max1</sub></content> (ng/mL) </td><td align="center" styleCode="Rrule" valign="top">10.2 ± 4.2 4.2 to 20.2 </td><td align="center" styleCode="Rrule" valign="top">10.3 ± 5.1 5.5 to 26.6 </td><td align="center" styleCode="Rrule" valign="top">4.3 ± 2.3 1.8 to 7.5 </td><td align="center" styleCode="Rrule" valign="top">5.3 ± 0.9 3.8 to 6.9 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">T </content><sub>minip</sub> (h) </td><td align="center" styleCode="Rrule" valign="top">4 ± 0.2 4 to 5 </td><td align="center" styleCode="Rrule" valign="top">4.5 ± 1.2 2 to 6 </td><td align="center" styleCode="Rrule" valign="top">3.8 ± 0.4 3.3 to 4.3 </td><td align="center" styleCode="Rrule" valign="top">3.6 ± 0.6 2.7 to 4.3 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">C</content><sub>minip</sub> (ng
1.2 2 to 6 </td><td align="center" styleCode="Rrule" valign="top">3.8 ± 0.4 3.3 to 4.3 </td><td align="center" styleCode="Rrule" valign="top">3.6 ± 0.6 2.7 to 4.3 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">C</content><sub>minip</sub> (ng /mL) </td><td align="center" styleCode="Rrule" valign="top">5.8 ± 2.7 3.1 to 14.4 </td><td align="center" styleCode="Rrule" valign="top">6.1 ± 4.1 2.9 to 21 </td><td align="center" styleCode="Rrule" valign="top">1.2 ± 1.4 0 to 3.7 </td><td align="center" styleCode="Rrule" valign="top">3 ± 0.8 1.7 to 4 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">T </content><sub>max2</sub> (h) </td><td align="center" styleCode="Rrule" valign="top">5.6 ± 0.7 5 to 8 </td><td align="center" styleCode="Rrule" valign="top">6.6 ± 1.5 5 to 11 </td><td align="center" styleCode="Rrule" valign="top">5.9 ± 0.5 5 to 6.5 </td><td align="center" styleCode="Rrule" valign="top">5.5 ± 0.8 4.3 to 6.5 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">C</content><sub>max2</sub> (ng/mL) </td><td align="center" styleCode="Rrule" valign="top">15.3 ± 7 6.2 to 32.8 </td><td align="center" styleCode="Rrule" valign="top">10.2 ± 5.9 4.5 to 31.1 </td><td align="center" styleCode="Rrule" valign="top">5.3 ± 1.4 3.6 to 7.2 </td><td align="center" styleCode="Rrule" valign="top">6.2 ± 1.6 3.9 to 8.3 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">AUC</content><sub>(0-∞)</sub> (ng/mL x h-1) </td><td align="center" styleCode="Rrule" valign="top">102.4 ± 54.6 40.5 to 261.6 </td><td align="center" styleCode="Rrule" valign="top">86.6 ± 64 <sup>a</sup> 43.3 to 301.44 </td><td align="center" styleCode="Rrule" valign="top">37.8 ± 21.9 14.3 to 85.3 </td><td align="center" styleCode="Rrule" valign="top">45.8 ± 10 34 to 61.6 </td></tr><tr><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">t</content><sub>1/2 </sub>(h) </td><td align="center" styleCode="Rrule" valign="top">2.5 ± 0.8 1.8 to 5.3 </td><td align="center" styleCode="Rrule" valign="top">2.4 ± 0.7 <sup>a</sup> 1.5 to 4 </td><td align="center" styleCode="Rrule" valign="top">3.5 ± 1.9 1.3 to 7.7 </td><td align="center" styleCode="Rrule" valign="top">3.3 ± 0.4 3 to 4.2 </td></tr></tbody></table>
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10 times the maximum recommended dose of 60 mg/day given to adolescents on a mg/m 2 basis.
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on a mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 10 times the maximum recommended dose of 60 mg/day given to adolescents on a mg/m 2 basis.
14 CLINICAL STUDIES N/A 14.1 Children and Adolescents Methylphenidate hydrochloride extended-release capsules was evaluated in a randomized, double-blind, placebo-controlled, parallel group clinical study in which 134 children, ages 6 to 12 years, with DSM-IV diagnoses of ADHD received a single morning dose of methylphenidate hydrochloride extended-release capsules in the range of 10 to 40 mg/day, or placebo, for up to 2 weeks. The doses used were the optimal doses established in a previous individual dose titration phase. In that titration phase, 53 of 164 patients (32%) started on a daily dose of 10 mg and 111 of 164 patients (68%) started on a daily dose of 20 mg or higher. The patient’s regular schoolteacher completed the Conners ADHD/DSM-IV Scale for Teachers (CADS-T) at baseline and the end of each week. The CADS-T assesses symptoms of hyperactivity and inattention. The change from baseline of the (CADS-T) scores during the last week of treatment was analyzed as the primary efficacy parameter. Patients treated with methylphenidate hydrochloride extended-release capsules showed a statistically significant improvement in symptom scores from baseline [Mean (final score - baseline) = -10.7 points] over patients who received placebo [Mean (final score - baseline) = +2.8 points]. The lower the final score on the CADS-T scale from baseline, the less severe the disease is. This demonstrates that a single morning dose of methylphenidate hydrochloride extended-release capsules exerts a treatment effect in ADHD. Figure 2: CADS-T Total Subscale - Mean Change from Baseline* methylphenidate-fig-2.jpg
16 HOW SUPPLIED/STORAGE AND HANDLING Methylphenidate hydrochloride extended-release capsules are supplied as: 10 mg: Hard gelatin capsules, yellow opaque cap printed with “G 10mg” and white opaque body printed with “012” contains white to off-white pellets. Bottles of 100 NDC 70010-012-01 20 mg: Hard gelatin capsules, white opaque cap printed with “G 20mg” and white opaque body printed with “013” contains white to off-white pellets. Bottles of 100 NDC 70010-013-01 30 mg: Hard gelatin capsules, yellow opaque cap printed with “G 30mg” and yellow opaque body printed with “014” contains white to off-white pellets. Bottles of 100 NDC 70010-014-01 40 mg: Hard gelatin capsules, yellow opaque cap printed with “G 40mg” and yellow opaque body printed with “015” contains white to off-white pellets. Bottles of 100 NDC 70010-015-01 60 mg: Hard gelatin capsules, yellow opaque cap printed with “G 60mg” and yellow opaque body printed with “016” contains white to off-white pellets. Bottles of 30 NDC 70010-016-03 Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature] Dispense in a tight container as defined in the USP with a child-resistant closure.
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of methylphenidate hydrochloride extended-release capsules, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2) , Overdosage (10) ] . Advise patients to store methylphenidate hydrochloride extended-release capsules in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride extended-release capsules to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with methylphenidate hydrochloride extended-release capsules use. Instruct patients to contact a healthcare provider immediately if they develop symptoms, such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2) ] . Increased Blood Pressure and Heart Rate Instruct patients that methylphenidate hydrochloride extended-release capsules can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3) ] . Psychiatric Adverse Reactions Advise patients that methylphenidate hydrochloride extended-release capsules, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4) ]. Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5) ] . Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon] Instruct patients beginning treatment with methylphenidate hydrochloride extended-release capsules about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride extended-release capsules. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6) ] . Long Term Suppression of Growth in Pediatric Patients Advise patients that methylphenidate hydrochloride extended-release capsules may cause slowing of growth and weight loss [see Warnings and Precautions (5.7) ]. Increased Intraocular Pressure (IOP) and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with methylphenidate hydrochloride extended-release capsules [see Warnings and Precautions (5.9) ] . Motor and Verbal Tics and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with methylphenidate hydrochloride extended-release capsules.
hylphenidate hydrochloride extended-release capsules [see Warnings and Precautions (5.9) ] . Motor and Verbal Tics and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with methylphenidate hydrochloride extended-release capsules. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions (5.10) ] . Alcohol Effect Advise patients to avoid alcohol while taking methylphenidate hydrochloride extended-release capsules. Consumption of alcohol while taking methylphenidate hydrochloride extended-release capsules may result in a more rapid release of the dose of methylphenidate [see Clinical Pharmacology (12.3) ]. Manufactured by: Granules Pharmaceuticals Inc., Chantilly, VA 20151 Revised: 10/2025
SPL MEDGUIDE SECTION MEDICATION GUIDE Methylphenidate Hydrochloride Extended-Release Capsules for oral use, CII (METH-il-FEN-i-date HYE-droe-KLOR-ide) What is the most important information I should know about methylphenidate hydrochloride extended-release capsules? Methylphenidate hydrochloride extended-release capsules may cause serious side effects, including: Abuse, misuse, and addiction. Methylphenidate hydrochloride extended-release capsules have a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride extended-release capsules, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride extended-release capsules or when it is used in ways that are not approved, such as snorting or injection. • Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride extended-release capsules and will monitor you or your child during treatment. • Methylphenidate hydrochloride extended-release capsules may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. • Do not give methylphenidate hydrochloride extended-release capsules to anyone else. See “What are methylphenidate hydrochloride extended-release capsules?” for more information. • Keep methylphenidate hydrochloride extended-release capsules in a safe place and properly dispose of any unused medicine. See “How should I store methylphenidate hydrochloride extended-release capsules?” for more information. • Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting methylphenidate hydrochloride extended-release capsules. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child has any signs of heart problems, such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride extended-release capsules. Increased blood pressure and heart rate. Your healthcare provider should check you or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride extended-release capsules. Mental (psychiatric) problems: All Patients new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride extended-release capsules , especially seeing or hearing things that are not real, believing things that are not real, or are suspicious .
llness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride extended-release capsules , especially seeing or hearing things that are not real, believing things that are not real, or are suspicious . What are methylphenidate hydrochloride extended-release capsules ? Methylphenidate hydrochloride extended-release capsules are a central nervous system (CNS) stimulant prescription medicine. It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Methylphenidate hydrochloride extended-release capsules may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Methylphenidate hydrochloride extended-release capsules should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride extended-release capsules are not recommended for use in children under 6 years of age with ADHD. Methylphenidate hydrochloride extended-release capsule is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep methylphenidate hydrochloride extended-release capsules in a safe place to protect it from theft. Never give your methylphenidate hydrochloride extended-release capsules to anyone else because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride extended-release capsules may harm others and is against the law. Who should not take methylphenidate hydrochloride extended-release capsules? Methylphenidate hydrochloride extended-release capsules should not be taken if you or your child: are allergic to methylphenidate hydrochloride, or any of the ingredients in methylphenidate hydrochloride extended-release capsules. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride extended-release capsules. are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor (MAOI). Methylphenidate hydrochloride extended-release capsules may not be right for you or your child. Before starting methylphenidate hydrochloride extended-release capsules, tell your or your child’s healthcare provider about all health conditions (or a family history of), including: heart problems, heart disease, heart defects, or high blood pressure mental problems, including psychosis, mania, bipolar illness, or depression circulation problems in fingers or toes have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome. if you are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride extended-release capsules will harm your unborn baby. if you are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate hydrochloride extended-release capsules. Tell your healthcare provider about all of the medicines that you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride extended-release capsules and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride extended-release capsules.
unter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride extended-release capsules and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride extended-release capsules. Your healthcare provider will decide whether methylphenidate hydrochloride extended-release capsules can be taken with other medicines. Especially tell your healthcare provider if you or your child takes: anti-depression medicines, including MAOIs blood pressure medicines (anti-hypertensive) risperidone Know the medicines that you or your child takes. Keep a list of your medicines with you to show your healthcare provider and pharmacist. You should not take methylphenidate hydrochloride extended-release capsules on the day of your operation if a certain type of anesthetic is used. This is because there is a chance of a sudden rise in blood pressure and heart rate during the operation. Do not start any new medicine while taking methylphenidate hydrochloride extended-release capsules without talking to your healthcare provider first. How should methylphenidate hydrochloride extended-release capsules be taken? Take methylphenidate hydrochloride extended-release capsules exactly as prescribed. Your healthcare provider may adjust the dose until it is right for you or your child. Take methylphenidate hydrochloride extended-release capsules once a day in the morning. Methylphenidate hydrochloride extended-release capsules are an extended-release capsule. Do not chew or crush methylphenidate hydrochloride extended-release capsules or the medicine inside the capsule. Swallow methylphenidate hydrochloride extended-release capsules whole with water or other liquids. If you cannot swallow the capsule whole, open it and sprinkle the medicine over a spoonful of applesauce. Swallow the applesauce and medicine mixture without chewing. Follow with a drink of water or other liquid. You should avoid drinking alcohol during treatment with methylphenidate hydrochloride extended-release capsules. This may cause a faster release of methylphenidate hydrochloride extended-release capsules. Your healthcare provider may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride extended-release capsules. Children should have their height and weight checked often while taking methylphenidate hydrochloride extended-release capsules. If you or your child take too much methylphenidate hydrochloride extended-release capsules, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are possible side effects of methylphenidate hydrochloride extended-release capsules? see " What is the most important information I should know about methylphenidate hydrochloride extended-release capsules?" for information on reported heart and mental problems. painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a healthcare provider immediately. circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud's phenomenon): o fingers or toes may feel numb, cool, painful o fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your healthcare provider right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride extended-release capsules .
er if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your healthcare provider right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride extended-release capsules . Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with methylphenidate hydrochloride extended-release capsules. Methylphenidate hydrochloride extended-release capsules treatment may be stopped if your child is not growing or gaining weight. Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride extended-release capsules. Common side effects include: fast heartbeat sweating a lot abnormal heartbeat (palpitations) decreased appetite trouble sleeping nausea nervousness stomach pain Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088. How should I store methylphenidate hydrochloride extended-release capsules? Store methylphenidate hydrochloride extended-release capsules in a safe place and in a tightly closed container at room temperature, 68°F to 77°F (20°C to 25°C). Protect from moisture. Dispose of remaining, unused, or expired methylphenidate hydrochloride extended-release capsules by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride extended-release capsules with an undesirable, nontoxic substance, such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and throw away methylphenidate hydrochloride extended-release capsules in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep methylphenidate hydrochloride extended-release capsules and all medicines out of the reach of children. General information about the safe and effective use of methylphenidate hydrochloride extended-release capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about methylphenidate hydrochloride extended-release capsules that is written for healthcare professionals. Do not use methylphenidate hydrochloride extended-release capsules for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride extended-release capsules to other people, even if they have the same symptoms. It may harm them and it is against the law. What are the ingredients in methylphenidate hydrochloride extended-release capsules? Active ingredient: methylphenidate HCl Inactive ingredients: Acetyltributyl citrate, cellaburate, corn starch, gelatin, hypromellose acetate succinate, polyethylene glycol, sucrose, talc, and titanium dioxide. The 10 mg, 30 mg, 40 mg, and 60 mg capsules contain FD & C Yellow #6. The 10 mg, 30 mg, and 60 mg capsules also contain FD&C Yellow #5. The 40 mg and 60 mg capsules contain D&C Yellow #10. In addition, capsule printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac glaze. Methylphenidate Hydrochloride Extended-Release Capsules contain FD&C Yellow #5 (tartrazine).
, 30 mg, and 60 mg capsules also contain FD&C Yellow #5. The 40 mg and 60 mg capsules contain D&C Yellow #10. In addition, capsule printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac glaze. Methylphenidate Hydrochloride Extended-Release Capsules contain FD&C Yellow #5 (tartrazine). Manufactured by: Granules Pharmaceuticals Inc., Chantilly, VA 20151 For more information, call 1-877-770-3183. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 10/2025
<table border="1" cellpadding="0" cellspacing="0" width="663.404"><colgroup><col width="100%"/></colgroup><tbody><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about methylphenidate hydrochloride extended-release capsules?</content> <content styleCode="bold">Methylphenidate hydrochloride extended-release capsules may cause serious side effects, including: </content></paragraph><list listType="unordered"><item><content styleCode="bold">Abuse, misuse, and addiction.</content> Methylphenidate hydrochloride extended-release capsules have a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride extended-release capsules, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride extended-release capsules or when it is used in ways that are not approved, such as snorting or injection. </item></list><paragraph>• Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride extended-release capsules and will monitor you or your child during treatment. • Methylphenidate hydrochloride extended-release capsules may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. • Do not give methylphenidate hydrochloride extended-release capsules to anyone else. See <content styleCode="bold">“What are methylphenidate hydrochloride extended-release capsules?”</content> for more information. • Keep methylphenidate hydrochloride extended-release capsules in a safe place and properly dispose of any unused medicine. See <content styleCode="bold"> “How should I store methylphenidate hydrochloride extended-release capsules?”</content> for more information. • Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. </paragraph><paragraph/><paragraph/><list listType="unordered"><item><content styleCode="bold">Risks for people with serious heart disease.</content> Sudden death has happened in people who have heart defects or other serious heart disease.
r abused or been dependent on alcohol, prescription medicines, or street drugs. </paragraph><paragraph/><paragraph/><list listType="unordered"><item><content styleCode="bold">Risks for people with serious heart disease.</content> Sudden death has happened in people who have heart defects or other serious heart disease. </item></list><paragraph/><paragraph>Your healthcare provider should check you or your child carefully for heart problems before starting methylphenidate hydrochloride extended-release capsules.</paragraph><paragraph/><paragraph>Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects.</paragraph><paragraph/><paragraph><content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child has any signs of heart problems, such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride extended-release capsules.</content></paragraph><paragraph/><paragraph/><list listType="unordered"><item><content styleCode="bold">Increased blood pressure and heart rate.</content></item></list><paragraph>Your healthcare provider should check you or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride extended-release capsules.</paragraph><list listType="unordered"><item><content styleCode="bold">Mental (psychiatric) problems:</content></item></list><paragraph><content styleCode="bold">All Patients</content></paragraph><list listType="unordered"><item>new or worse behavior and thought problems</item><item>new or worse bipolar illness</item><item>new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms</item></list><paragraph/><paragraph/><paragraph>Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.</paragraph><paragraph/><paragraph/><paragraph><content styleCode="bold">Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems while taking </content><content styleCode="bold">methylphenidate hydrochloride extended-release capsules</content><content styleCode="bold">, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious</content><content styleCode="bold">.</content></paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><paragraph><content styleCode="bold">What are </content><content styleCode="bold">methylphenidate hydrochloride extended-release capsules</content><content styleCode="bold">?</content></paragraph><paragraph>Methylphenidate hydrochloride extended-release capsules are a central nervous system (CNS) stimulant prescription medicine. <content styleCode="bold">It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).</content> Methylphenidate hydrochloride extended-release capsules may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. </paragraph><paragraph> Methylphenidate hydrochloride extended-release capsules should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. </paragraph><paragraph> Methylphenidate hydrochloride extended-release capsules are not recommended for use in children under 6 years of age with ADHD.
> Methylphenidate hydrochloride extended-release capsules should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. </paragraph><paragraph> Methylphenidate hydrochloride extended-release capsules are not recommended for use in children under 6 years of age with ADHD. </paragraph><paragraph/><paragraph><content styleCode="bold">Methylphenidate hydrochloride extended-release capsule is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs.</content> Keep methylphenidate hydrochloride extended-release capsules in a safe place to protect it from theft. Never give your methylphenidate hydrochloride extended-release capsules to anyone else because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride extended-release capsules may harm others and is against the law. </paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Who should not take methylphenidate hydrochloride extended-release capsules?</content> <content styleCode="bold">Methylphenidate hydrochloride extended-release capsules should not be taken if you or your child:</content><list listType="unordered"><item>are allergic to methylphenidate hydrochloride, or any of the ingredients in methylphenidate hydrochloride extended-release capsules. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride extended-release capsules.</item><item>are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor (MAOI).</item></list></td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Methylphenidate hydrochloride extended-release capsules may not be right for you or your child. Before starting methylphenidate hydrochloride extended-release capsules, tell your or your child’s healthcare provider about all health conditions (or a family history of), including:</content><list listType="unordered"><item>heart problems, heart disease, heart defects, or high blood pressure</item><item>mental problems, including psychosis, mania, bipolar illness, or depression</item><item>circulation problems in fingers or toes</item><item>have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness)</item><item>have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome.</item><item>if you are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride extended-release capsules will harm your unborn baby.</item><item>if you are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate hydrochloride extended-release capsules.</item></list><paragraph> <content styleCode="bold">Tell your healthcare provider about all of the medicines that you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. </content>Methylphenidate hydrochloride extended-release capsules and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride extended-release capsules. </paragraph><paragraph> Your healthcare provider will decide whether methylphenidate hydrochloride extended-release capsules can be taken with other medicines.
ause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking methylphenidate hydrochloride extended-release capsules. </paragraph><paragraph> Your healthcare provider will decide whether methylphenidate hydrochloride extended-release capsules can be taken with other medicines. </paragraph><paragraph/><paragraph><content styleCode="bold">Especially tell your healthcare provider if you or your child takes:</content></paragraph><list listType="unordered"><item>anti-depression medicines, including MAOIs</item><item>blood pressure medicines (anti-hypertensive)</item><item>risperidone</item></list><paragraph>Know the medicines that you or your child takes. Keep a list of your medicines with you to show your healthcare provider and pharmacist.</paragraph><paragraph/><list listType="unordered"><item>You should not take methylphenidate hydrochloride extended-release capsules on the day of your operation if a certain type of anesthetic is used. This is because there is a chance of a sudden rise in blood pressure and heart rate during the operation.</item></list><paragraph> <content styleCode="bold">Do not start any new medicine while taking </content><content styleCode="bold">methylphenidate hydrochloride extended-release </content><content styleCode="bold">capsules</content><content styleCode="bold"> without talking to your healthcare provider first.</content></paragraph></td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">How should methylphenidate hydrochloride extended-release capsules be taken?</content><list listType="unordered"><item>Take methylphenidate hydrochloride extended-release capsules exactly as prescribed. Your healthcare provider may adjust the dose until it is right for you or your child.</item><item>Take methylphenidate hydrochloride extended-release capsules once a day in the morning. Methylphenidate hydrochloride extended-release capsules are an extended-release capsule.</item><item><content styleCode="bold">Do not chew or crush methylphenidate hydrochloride extended-release capsules or the medicine inside the capsule. </content>Swallow methylphenidate hydrochloride extended-release capsules whole with water or other liquids. </item><item>If you cannot swallow the capsule whole, open it and sprinkle the medicine over a spoonful of applesauce. Swallow the applesauce and medicine mixture without chewing. Follow with a drink of water or other liquid.</item><item>You should avoid drinking alcohol during treatment with methylphenidate hydrochloride extended-release capsules. This may cause a faster release of methylphenidate hydrochloride extended-release capsules.</item></list><paragraph/><paragraph>Your healthcare provider may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride extended-release capsules. Children should have their height and weight checked often while taking methylphenidate hydrochloride extended-release capsules. If you or your child take too much methylphenidate hydrochloride extended-release capsules, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away.</paragraph></td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">What are possible side effects of methylphenidate hydrochloride extended-release capsules?</content><list listType="unordered"><item>see " <content styleCode="bold">What is the most important information I should know about methylphenidate hydrochloride extended-release capsules?" </content>for information on reported heart and mental problems.
thylphenidate hydrochloride extended-release capsules?</content><list listType="unordered"><item>see " <content styleCode="bold">What is the most important information I should know about methylphenidate hydrochloride extended-release capsules?" </content>for information on reported heart and mental problems. </item><item><content styleCode="bold">painful and prolonged erections (priapism) </content>have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a healthcare provider immediately. </item><item><content styleCode="bold">circulation problems in fingers and toes </content>(peripheral vasculopathy, including Raynaud's phenomenon): </item></list><paragraph>o fingers or toes may feel numb, cool, painful o fingers or toes may change color from pale, to blue, to red </paragraph><paragraph/><paragraph>Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.</paragraph><paragraph><content styleCode="bold">Call your healthcare provider right away if you have or your child has any signs of unexplained wounds </content><content styleCode="bold">appearing on fingers or toes while taking </content><content styleCode="bold">methylphenidate hydrochloride extended-release capsules</content><content styleCode="bold">.</content></paragraph><list listType="unordered"><item><content styleCode="bold">Slowing of growth (height and weight) in children.</content> Children should have their height and weight checked often during treatment with methylphenidate hydrochloride extended-release capsules. Methylphenidate hydrochloride extended-release capsules treatment may be stopped if your child is not growing or gaining weight. </item><item><content styleCode="bold">Eye problems (increased pressure in the eye and glaucoma).</content> Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. </item><item><content styleCode="bold">New or worsening tics or worsening Tourette’s syndrome.</content> Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride extended-release capsules. </item><item>Common side effects include:</item><item>fast heartbeat</item><item>sweating a lot</item><item>abnormal heartbeat (palpitations)</item><item>decreased appetite</item><item>trouble sleeping</item><item>nausea</item><item>nervousness</item><item>stomach pain</item></list> <content styleCode="bold">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088.</content></td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">How should I store methylphenidate hydrochloride extended-release capsules?</content><list listType="unordered"><item>Store methylphenidate hydrochloride extended-release capsules in a safe place and in a tightly closed container at room temperature, 68°F to 77°F (20°C to 25°C).</item><item>Protect from moisture.</item><item>Dispose of remaining, unused, or expired methylphenidate hydrochloride extended-release capsules by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride extended-release capsules with an undesirable, nontoxic substance, such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets.
rcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride extended-release capsules with an undesirable, nontoxic substance, such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and throw away methylphenidate hydrochloride extended-release capsules in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</item><item><content styleCode="bold">Keep methylphenidate hydrochloride extended-release capsules and all medicines out of the reach of children.</content></item></list></td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">General information about the safe and effective use of methylphenidate hydrochloride extended-release capsules</content> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about methylphenidate hydrochloride extended-release capsules that is written for healthcare professionals. Do not use methylphenidate hydrochloride extended-release capsules for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride extended-release capsules to other people, even if they have the same symptoms. It may harm them and it is against the law. </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top"><paragraph><content styleCode="bold">What are the ingredients in methylphenidate hydrochloride extended-release capsules?</content> <content styleCode="bold">Active ingredient: </content>methylphenidate HCl </paragraph><paragraph> <content styleCode="bold">Inactive ingredients: </content>Acetyltributyl citrate, cellaburate, corn starch, gelatin, hypromellose acetate succinate, polyethylene glycol, sucrose, talc, and titanium dioxide. The 10 mg, 30 mg, 40 mg, and 60 mg capsules contain FD & C Yellow #6. The 10 mg, 30 mg, and 60 mg capsules also contain FD&C Yellow #5. The 40 mg and 60 mg capsules contain D&C Yellow #10. In addition, capsule printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac glaze. Methylphenidate Hydrochloride Extended-Release Capsules contain FD&C Yellow #5 (tartrazine). </paragraph><paragraph/><paragraph/><paragraph/><paragraph/><paragraph/><paragraph/><paragraph/><paragraph>Manufactured by:</paragraph><paragraph><content styleCode="bold">Granules Pharmaceuticals Inc.,</content> Chantilly, VA 20151 For more information, call 1-877-770-3183. </paragraph></td></tr></tbody></table>
ABUSE, MISUSE, AND ADDICTION WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate HCl extended-release capsules have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate HCl extended-release capsules, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate HCl extended-release capsules, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout methylphenidate HCl extended-release capsules treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions ( 5.1 ) and Drug Abuse and Dependence ( 9.2 )] . WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. Methylphenidate HCl extended-release capsules have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate HCl extended-release capsules, can result in overdose and death ( 5.1 , 9.2 , 10 ): Before prescribing methylphenidate HCl extended-release capsules, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
<table><col/><col/><tbody><tr><td>Indications and Usage (<linkHtml href="#LINK_e6c3a5a7-6f79-4ab3-b792-d68964df7ccc">1</linkHtml>)</td><td align="right">09/2025</td></tr><tr><td>Warnings and Precautions (<linkHtml href="#LINK_a56d0bce-5a61-4fc2-a0d4-1f04459f445c">5.7</linkHtml>)</td><td align="right">09/2025</td></tr></tbody></table>
1 INDICATIONS AND USAGE Methylphenidate HCl extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 15 years of age. Limitations of Use The use of methylphenidate HCl extended-release capsules is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.7), Use in Specific Populations (8.4)] . Methylphenidate HCl extended-release capsules are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 15 years of age. ( 1 ) Limitations of Use The use of methylphenidate HCl extended-release capsules is not recommended in pediatric patients younger than 6 years of age because they had higher exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage. ( 5.7 , 8.4 )
2 DOSAGE AND ADMINISTRATION Take orally once daily in the morning, before breakfast Swallow whole with the aid of liquids, or sprinkle contents onto a small amount of applesauce and give immediately Do not crush or chew the capsule or capsule contents ( 2.1 ) Recommended starting dose is 20 mg once daily. Dosage may be increased 10-20 mg at weekly intervals; do not exceed 60 mg per day ( 2.2 ) 2.1 Pretreatment Screening Prior to treating patients with methylphenidate HCl extended-release capsules, assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions ( 5.10 )] . the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating methylphenidate HCl extended-release capsules [see Warnings and Precautions ( 5.10 )] . 2.2 Dosage Recommendations The recommended starting dose of methylphenidate HCl extended-release capsules is 20 mg once daily. Dosage may be adjusted in weekly 10 mg to 20 mg increments to the maximum recommended dose of 60 mg per day. Dosage should be individualized according to the needs and responses of the patient. 2.3 Administration Instructions Administer methylphenidate HCl extended-release capsules orally once daily in the morning, before breakfast. Swallow the capsule whole with the aid of liquids. Alternatively, open the capsule and sprinkle the contents onto a small amount (tablespoon) of applesauce and administer immediately. Do not store for future use. Drink fluids following the intake of the sprinkled capsule contents with applesauce. The capsules and the capsule contents must not be crushed or chewed. 2.4 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage or, if necessary, discontinue methylphenidate HCl extended-release capsules. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue methylphenidate HCl extended-release capsules.
3 DOSAGE FORMS AND STRENGTHS Methylphenidate HCl extended-release capsules are available in the following dosage strengths (see Table 1): Table 1: Strengths and Identifying Characteristics of Methylphenidate HCl Extended-Release Capsules Strength Capsule Color (cap/body) Imprinting on Capsule Cap Imprinting on Capsule Body 10 mg dark green/white “M” in a box over “1810” in white letters “10 mg” in black letters 20 mg medium blue/white “M” in a box over “1820” in white letters “20 mg” in black letters 30 mg maroon/white “M” in a box over “1830” in white letters “30 mg” in black letters 40 mg yellow ivory/white “M” in a box over “1840” in black letters “40 mg” in black letters 50 mg purple/white “M” in a box over “1850” in white letters “50 mg” in black letters 60 mg white/white “M” in a box over “1860” in black letters “60 mg” in black letters Extended-release capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg ( 3 )
<table><caption>Table 1: Strengths and Identifying Characteristics of Methylphenidate HCl Extended-Release Capsules</caption><col width="58.5pt"/><col width="1.5in"/><col width="162.8pt"/><col width="168.55pt"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Capsule Color</content></paragraph><paragraph><content styleCode="bold">(cap/body)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Imprinting on Capsule Cap</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Imprinting on Capsule Body</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>dark green/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1810” in white letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“10 mg” in black letters</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>medium blue/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1820” in white letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“20 mg” in black letters</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>30 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>maroon/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1830” in white letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“30 mg” in black letters</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>40 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>yellow ivory/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1840” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“40 mg” in black letters</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>50 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>purple/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1850” in white letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“50 mg” in black letters</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>60 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>white/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1860” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“60 mg” in black letters</paragraph></td></tr></tbody></table>
4 CONTRAINDICATIONS Methylphenidate HCl extended-release capsules are contraindicated in patients with: Known hypersensitivity to methylphenidate or other component of methylphenidate HCl extended-release capsules. Angioedema has been reported in patients treated with methylphenidate HCl extended-release capsules. Anaphylactic reactions have been reported in patients treated with other methylphenidate products [see Adverse Reactions ( 6 )] . Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crisis [see Drug Interactions ( 7 )] . Methylphenidate HCl extended-release capsules contain sucrose. Therefore, patients with hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicine. Known hypersensitivity to methylphenidate or other components of methylphenidate HCl extended-release capsules ( 4 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days ( 4 ) Use in patients with patients with hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency ( 4 )
5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. ( 5.2 ) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3 ) Psychiatric Adverse Reactions: Prior to initiating methylphenidate HCl extended-release capsules, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate HCl extended-release capsules. ( 5.4 ) Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention. ( 5.5 ) Peripheral Vasculopathy, including Raynaud’s Phenomenon: Careful observation for digital changes is necessary during methylphenidate HCl extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.6 ) Long-Term Suppression of Growth in Pediatric Patients : Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.7 ) Acute Angle Closure Glaucoma: Methylphenidate HCl extended-release capsules-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. ( 5.8 ) Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe methylphenidate HCl extended-release capsules to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open-angle glaucoma. ( 5.9 ) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating methylphenidate HCl extended-release capsules, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. ( 5.10 ) 5.1 Abuse, Misuse, and Addiction Methylphenidate HCl extended-release capsules have a high potential for abuse and misuse. The use of methylphenidate HCl extended-release capsules exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate HCl extended-release capsules can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence ( 9.2 )] . Misuse and abuse of CNS stimulants, including methylphenidate HCl extended-release capsules, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate HCl extended-release capsules, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate HCl extended-release capsules in a safe place, preferably locked, and instruct patients to not give methylphenidate HCl extended-release capsules to anyone else.
misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate HCl extended-release capsules in a safe place, preferably locked, and instruct patients to not give methylphenidate HCl extended-release capsules to anyone else. Throughout methylphenidate HCl extended-release capsules treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended dosage. Avoid methylphenidate HCl extended-release capsules use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac problems. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases. Monitor all methylphenidate HCl extended-release capsules-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Pre-Existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating methylphenidate HCl extended-release capsules treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosages, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNC stimulant-treated patients, compared to 0% of placebo-treated patients If such symptoms occur, consider discontinuing methylphenidate HCl extended-release capsules. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate HCl extended-release capsules-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including methylphenidate HCl extended-release capsules, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction in or discontinuation of the CNS stimulant.
down. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction in or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during methylphenidate HCl extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate HCl extended-release capsules-treated patients who develop signs of symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients Methylphenidate HCl extended-release capsules are not approved for use and are not recommended in pediatric patients below 6 years of age [see Use in Specific Population ( 8.4 )] . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate- or nonmedication-treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated children over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate treatment for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in methylphenidate HCl extended-release capsules-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate HCl extended-release capsules-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.9 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions ( 6.2 )] . Prescribe methylphenidate HCl extended-release capsules to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate HCl extended-release capsules-treated patients with a history of abnormally increased IOP or open-angle glaucoma. 5.10 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions ( 6.2 )] . Before initiating methylphenidate HCl extended-release capsules, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate HCl extended-release capsules-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] Hypersensitivity to Methylphenidate and Other Component of Methylphenidate HCl Extended-Release Capsules [see Contraindications ( 4 )] Hypertensive Crisis when Used Concomitantly with MAOIs [see Contraindications ( 4 ) and Drug Interactions ( 7 )] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions ( 5.2 )] Increased Blood Pressure and Heart Rate [see Warnings and Precautions ( 5.3 )] Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.4 )] Priapism [see Warnings and Precautions ( 5.5 )] Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions ( 5.6 )] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions ( 5.7 )] Acute Angle Closure Glaucoma [see Warnings and Precautions ( 5.8 )] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions ( 5.9 )] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.10 )] The most common adverse reactions (≥ 5% and twice the rate of placebo) were anorexia and insomnia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt at 1-800-778-7898 or 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. Clinical trials experience with methylphenidate HCl extended-release capsules included 188 pediatric patients 6 to 15 years old with ADHD exposed to methylphenidate HCl extended-release capsules. Patients received methylphenidate HCl extended-release capsules 20 mg, 40 mg, and/or 60 mg per day. The 188 patients were evaluated in the following studies: Study 1, a 3-week placebo-controlled clinical study consisting of a total of 314 pediatric patients (ages 6 to 15 years; methylphenidate HCl extended-release capsules n=155); Study 2, a placebo-controlled, crossover clinical study consisting of 25 pediatric patients (ages 7 to 12 years); and Study 3, an uncontrolled clinical study consisting of 8 pediatric patients (ages 6 to 10 years). Adverse Reactions Leading to Discontinuation of Treatment In the 3-week placebo-controlled, parallel-group trial, two methylphenidate HCl extended-release capsules-treated patients (1%) and no placebo-treated patients discontinued due to an adverse reaction (rash and pruritus; and headache, abdominal pain, and dizziness, respectively). Most Common Adverse Reactions The most common adverse reactions that occurred in 5% or more of patients treated with methylphenidate HCl extended-release capsules in a pool of Studies 1, 2 and 3 (ages 6 to 15 years) where the incidence in patients treated with methylphenidate HCl extended-release capsules was at least twice the incidence in placebo-treated patients were anorexia and insomnia.
ed in 5% or more of patients treated with methylphenidate HCl extended-release capsules in a pool of Studies 1, 2 and 3 (ages 6 to 15 years) where the incidence in patients treated with methylphenidate HCl extended-release capsules was at least twice the incidence in placebo-treated patients were anorexia and insomnia. Adverse reactions that occurred in ≥5% of patients treated with methylphenidate HCl extended-release capsules and greater than placebo in pooled Studies 1, 2, and 3 are presented in Table 2: Table 2: Adverse Reactions (≥5% and Greater than Placebo) in Pediatric Patients Ages 6 to 15 Years Receiving Methylphenidate HCl Extended-Release Capsules in Pooled Three to Four Week Trials Body System Preferred Term Methylphenidate HCl Extended-Release Capsules (n=188) % Placebo (n=190) % General Headache 12 8 Abdominal Pain (stomachache) 7 4 Digestive System Anorexia 9 2 Nervous System Insomnia 5 2 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of methylphenidate HCl extended-release capsules and other methylphenidate HCl products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
identified during postmarketing use of methylphenidate HCl extended-release capsules and other methylphenidate HCl products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse Reactions with Methylphenidate HCl Extended-Release Capsules Blood and the lymphatic system disorders: thrombocytopenia Cardiac disorders: cardiac arrest, sudden death Immune system disorders: angioedema Musculoskeletal and connective tissue disorders: rhabdomyolysis Psychiatric disorders: abnormal behavior, aggression, anxiety, irritability, obsessive-compulsive disorder, suicidal behavior (including completed suicide), libido changes, serotonin syndrome in combination with serotonergic drugs Nervous system disorders : migraine, reversible ischemic neurological deficit, bruxism Skin and subcutaneous tissue disorders: fixed drug eruption Vascular disorders: peripheral coldness, Raynaud’s phenomenon Adverse Reactions with Other Methylphenidate HCl Products Blood and the lymphatic system disorders: leukopenia, anemia, pancytopenia Cardiac disorders: palpitations, increased blood pressure, tachycardia, angina pectoris, cardiac arrhythmia, myocardial infarction, bradycardia, extrasystole Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, increased intraocular pressure, mydriasis Gastrointestinal disorders: nausea, abdominal pain, dry mouth, vomiting, dyspepsia, diarrhea, constipation General disorders: fatigue, hyperpyrexia Hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Immune system disorders : hypersensitivity, including anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas Infections and infestations: nasopharyngitis Metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, myalgia, muscle twitching Nervous system disorders : nervousness, dizziness, headache, dyskinesia, including choreoatheetoid movements, drowsiness, tremor, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs, motor and verbal tics Psychiatric disorders: depressed mood, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), affect liability, mania, disorientation Renal and urinary disorders: hematuria Reproductive system and breast disorders: gynecomastia Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, dyspnea, cough Skin and subcutaneous tissue disorders: scalp hair loss, hyperhidrosis, angioneurotic edema, erythema, exfoliative dermatitis, thrombocytopenic purpura, urticaria, erythema multiforme rash Urogenital disorders: priapism Vascular disorders: isolated cases of cerebral arteritis and/or occlusion
<table><caption>Table 2: Adverse Reactions (≥5% and Greater than Placebo) in Pediatric Patients Ages 6 to 15 Years Receiving Methylphenidate HCl Extended-Release Capsules in Pooled Three to Four Week Trials</caption><col width="25.04%"/><col width="33.4%"/><col width="29.2%"/><col width="12.34%"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Body System</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Preferred Term</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Methylphenidate HCl Extended-Release Capsules</content></paragraph><paragraph><content styleCode="bold">(n=188)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo (n=190)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">General</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Headache</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal Pain (stomachache)</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 styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Digestive System</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anorexia</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 styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td><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>2</paragraph></td></tr></tbody></table>
7 DRUG INTERACTIONS Table 3 presents clinically important drug interactions with methylphenidate HCl extended-release capsules. Table 3: Clinically Important Drug Interactions with Methylphenidate HCl Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOI) Clinical Impact: Concomitant use of MAOIs and CNS stimulants, including methylphenidate HCl extended-release capsules, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications ( 4 )] . Intervention: Concomitant use of methylphenidate HCl extended-release capsules with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical Impact: Methylphenidate HCl extended-release capsules may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions ( 5.3 )] . Intervention: Adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical Impact: Concomitant use of halogenated anesthetics and methylphenidate HCl extended-release capsules may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention: Monitor blood pressure and avoid use of methylphenidate HCl extended-release capsules in patients being treated with anesthetics on the day of surgery. Risperidone Clinical Impact: Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Intervention: Monitor for signs of EPS. Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7 )
<table><caption>Table 3: Clinically Important Drug Interactions with Methylphenidate HCl Extended-Release Capsules</caption><col/><col/><tbody><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Monoamine Oxidase Inhibitors (MAOI)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of MAOIs and CNS stimulants, including methylphenidate HCl extended-release capsules, can cause hypertensive crisis.
<tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of MAOIs and CNS stimulants, including methylphenidate HCl extended-release capsules, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure <content styleCode="italics">[see Contraindications (<linkHtml href="#LINK_b876c62c-d7ca-40b6-b673-6763b7ed5360">4</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of methylphenidate HCl extended-release capsules with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Antihypertensive Drugs</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Methylphenidate HCl extended-release capsules may decrease the effectiveness of drugs used to treat hypertension <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#LINK_7d953611-edcf-4ef0-92e6-dc1be7bf7cba">5.3</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Adjust the dosage of the antihypertensive drug as needed.</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">Halogenated Anesthetics</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Concomitant use of halogenated anesthetics and methylphenidate HCl extended-release capsules may increase the risk of sudden blood pressure and heart rate increase during surgery.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">Monitor blood pressure and avoid use of methylphenidate HCl extended-release capsules in patients being treated with anesthetics on the day of surgery.</td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS).</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Monitor for signs of EPS.</paragraph></td></tr></tbody></table>
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate HCl extended-release capsules, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 53 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and postnatal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate HCl extended-release capsules, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed.
n a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate HCl extended-release capsules and any potential adverse effects on the breastfed infant from methylphenidate HCl extended-release capsules or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of methylphenidate HCl extended-release capsules have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. The safety and effectiveness of methylphenidate HCl extended-release capsules for the treatment of ADHD have been established in pediatric patients 6 to 15 years of age. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate HCl extended-release capsules. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.6 )] . Juvenile Animal Toxicity Data In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the MRHD on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use Methylphenidate HCl extended-release capsules have not been studied in patients over the age of 65 years.
8.1 Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate HCl extended-release capsules, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 53 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and postnatal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate HCl extended-release capsules, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Animal Data In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed.
n a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adolescents on a mg/m 2 basis).
8.4 Pediatric Use The safety and effectiveness of methylphenidate HCl extended-release capsules have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. The safety and effectiveness of methylphenidate HCl extended-release capsules for the treatment of ADHD have been established in pediatric patients 6 to 15 years of age. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate HCl extended-release capsules. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.6 )] . Juvenile Animal Toxicity Data In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the MRHD on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Methylphenidate HCl extended-release capsules contain methylphenidate hydrochloride, a Schedule II controlled substance. 9.2 Abuse Methylphenidate HCl extended-release capsules have a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )] . Methylphenidate HCl extended-release capsules can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate HCl extended-release capsules, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. 9.3 Dependence Physical Dependence Methylphenidate HCl extended-release capsules may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including methylphenidate HCl extended-release capsules include dysphoric mood; depression; fatigue; vivid; unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate HCl extended-release capsules may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
9.2 Abuse Methylphenidate HCl extended-release capsules have a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )] . Methylphenidate HCl extended-release capsules can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including methylphenidate HCl extended-release capsules, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
9.3 Dependence Physical Dependence Methylphenidate HCl extended-release capsules may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including methylphenidate HCl extended-release capsules include dysphoric mood; depression; fatigue; vivid; unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate HCl extended-release capsules may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
10 OVERDOSAGE Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of methylphenidate HCl extended-release capsules should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
11 DESCRIPTION Methylphenidate HCl extended-release capsules contain methylphenidate hydrochloride, a CNS stimulant. The extended-release capsules comprise both immediate-release (IR) and extended-release (ER) beads such that 30% of the dose is provided by the IR component and 70% of the dose is provided by the ER component. Methylphenidate HCl extended-release capsules are available in six capsule strengths containing 10 mg (3 mg IR; 7 mg ER), 20 mg (6 mg IR; 14 mg ER), 30 mg (9 mg IR; 21 mg ER), 40 mg (12 mg IR; 28 mg ER), 50 mg (15 mg IR; 35 mg ER), or 60 mg (18 mg IR; 42 mg ER) of methylphenidate hydrochloride for oral administration. Chemically, methylphenidate HCl is d , l (racemic)- threo -methyl α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C 14 H 19 NO 2 •HCl. Its structural formula is: Methylphenidate HCl USP is a white, odorless, crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Methylphenidate HCl extended-release capsules also contain the following inactive ingredients: Sugar Spheres, Ethylcellulose, Oleic Acid, Medium-Chain Triglycerides, Titanium Dioxide, Gelatin, Shellac, Propylene Glycol, Hypromellose, Polyethylene Glycol, and Black Iron Oxide. The individual capsules contain the following color agents: 10 mg capsules: FD&C Blue No. 2, Yellow Iron Oxide, Sodium Hydroxide, Povidone 20 mg capsules: FD&C Blue No. 2, Sodium Hydroxide, Povidone 30 mg capsules: FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, Sodium Hydroxide, Povidone 40 mg capsules: Yellow Iron Oxide 50 mg capsules: FD&C Blue No. 2, Red Iron Oxide, Sodium Hydroxide, Povidone Chemical Structure
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. 12.3 Pharmacokinetics Following one week of once-daily doses of 20 mg or 40 mg methylphenidate HCl extended-release capsules to children aged 7 to 12 years old with ADHD, C max and AUC of methylphenidate were approximately proportional to the administered doses. Absorption Following administration of methylphenidate HCl extended-release capsules in children aged 7 to 12 years old with ADHD, the plasma concentration time profile of methylphenidate showed two phases of drug release with a sharp, initial slope similar to a methylphenidate immediate-release tablet (median T max1 about 1.5 hours post dose), and a second rising portion approximately three hours later (median T max2 about 4.5 hours post dose)*, followed by a gradual decline (Figure 1). The means for C max and area under the curve (AUC) following a dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at 0 and 4 hours. *25-30% of the subjects had only one observed peak (C max ) concentration of methylphenidate. Figure 1: Comparison of Immediate Release (IR) and Methylphenidate HCl Extended-Release Capsules Formulations After Repeated Doses of Methylphenidate HCl in Pediatric Patients 7 to 12 Years of Age with ADHD Effect of Food Ingestion of a high-fat meal with methylphenidate HCl extended-release capsules increased the mean C max and AUC of methylphenidate by about 30% and 17%, respectively. The presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay) [see Dosage and Administration ( 2.1 )] . The bioavailability (C max and AUC) of methylphenidate was unaffected by sprinkling the methylphenidate HCl extended-release capsule contents on applesauce as compared to the intact capsule. Effect of Alcohol At an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. The results with the 60 mg capsule are considered to be representative of the other available capsule strengths [see Drug Interactions ( 7 )] . Distribution Plasma protein binding is 10% to 33%. The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate. Elimination The mean terminal half-life (t½) of methylphenidate following administration of methylphenidate HCl extended-release capsules (t½=6.8 hours) is longer than the mean terminal t½ following administration of methylphenidate hydrochloride immediate-release tablets (t½=2.9 hours) and methylphenidate hydrochloride extended-release tablets (t½=3.4 hours) in healthy adult volunteers. Metabolism In vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes. Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.
lets (t½=3.4 hours) in healthy adult volunteers. Metabolism In vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes. Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. Specific Populations Male and Female Patients The pharmacokinetics of methylphenidate after a single dose of methylphenidate HCl extended-release capsules were similar between adult men and women. Racial or Ethnic Groups The influence of race on the pharmacokinetics of methylphenidate after methylphenidate HCl extended-release capsules administration has not been studied. Pediatric Patients The pharmacokinetics of methylphenidate after methylphenidate HCl extended-release capsules administration has not been studied in children less than 6 years of age. Patients with Renal Impairment Methylphenidate HCl extended-release capsules have not been studied in patients with renal insufficiency. Since renal clearance is not an important route of methylphenidate clearance, and the major metabolite (ritalinic acid), has little or no pharmacologic activity, renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate HCl extended-release capsules. Patients with Hepatic Impairment Methylphenidate HCl extended-release capsules have not been studied in patients with hepatic insufficiency. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. Drug Interaction Studies In vitro studies showed that methylphenidate did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations. Figure 1
12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.
12.3 Pharmacokinetics Following one week of once-daily doses of 20 mg or 40 mg methylphenidate HCl extended-release capsules to children aged 7 to 12 years old with ADHD, C max and AUC of methylphenidate were approximately proportional to the administered doses. Absorption Following administration of methylphenidate HCl extended-release capsules in children aged 7 to 12 years old with ADHD, the plasma concentration time profile of methylphenidate showed two phases of drug release with a sharp, initial slope similar to a methylphenidate immediate-release tablet (median T max1 about 1.5 hours post dose), and a second rising portion approximately three hours later (median T max2 about 4.5 hours post dose)*, followed by a gradual decline (Figure 1). The means for C max and area under the curve (AUC) following a dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at 0 and 4 hours. *25-30% of the subjects had only one observed peak (C max ) concentration of methylphenidate. Figure 1: Comparison of Immediate Release (IR) and Methylphenidate HCl Extended-Release Capsules Formulations After Repeated Doses of Methylphenidate HCl in Pediatric Patients 7 to 12 Years of Age with ADHD Effect of Food Ingestion of a high-fat meal with methylphenidate HCl extended-release capsules increased the mean C max and AUC of methylphenidate by about 30% and 17%, respectively. The presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay) [see Dosage and Administration ( 2.1 )] . The bioavailability (C max and AUC) of methylphenidate was unaffected by sprinkling the methylphenidate HCl extended-release capsule contents on applesauce as compared to the intact capsule. Effect of Alcohol At an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. The results with the 60 mg capsule are considered to be representative of the other available capsule strengths [see Drug Interactions ( 7 )] . Distribution Plasma protein binding is 10% to 33%. The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate. Elimination The mean terminal half-life (t½) of methylphenidate following administration of methylphenidate HCl extended-release capsules (t½=6.8 hours) is longer than the mean terminal t½ following administration of methylphenidate hydrochloride immediate-release tablets (t½=2.9 hours) and methylphenidate hydrochloride extended-release tablets (t½=3.4 hours) in healthy adult volunteers. Metabolism In vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes. Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. Specific Populations Male and Female Patients The pharmacokinetics of methylphenidate after a single dose of methylphenidate HCl extended-release capsules were similar between adult men and women.
ivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose. Specific Populations Male and Female Patients The pharmacokinetics of methylphenidate after a single dose of methylphenidate HCl extended-release capsules were similar between adult men and women. Racial or Ethnic Groups The influence of race on the pharmacokinetics of methylphenidate after methylphenidate HCl extended-release capsules administration has not been studied. Pediatric Patients The pharmacokinetics of methylphenidate after methylphenidate HCl extended-release capsules administration has not been studied in children less than 6 years of age. Patients with Renal Impairment Methylphenidate HCl extended-release capsules have not been studied in patients with renal insufficiency. Since renal clearance is not an important route of methylphenidate clearance, and the major metabolite (ritalinic acid), has little or no pharmacologic activity, renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate HCl extended-release capsules. Patients with Hepatic Impairment Methylphenidate HCl extended-release capsules have not been studied in patients with hepatic insufficiency. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. Drug Interaction Studies In vitro studies showed that methylphenidate did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations. Figure 1
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg per day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on a mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg per day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg per day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on a mg/m 2 basis.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg per day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on a mg/m 2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m 2 basis. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg per day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg per day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on a mg/m 2 basis.
14 CLINICAL STUDIES Methylphenidate HCl extended-release capsules were evaluated in a double-blind, parallel-group, placebo-controlled trial in which 321 untreated or previously treated pediatric patients with a DSM-IV diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), 6 to 15 years of age, received a single morning dose for up to 3 weeks. Patients were required to have the combined or predominantly hyperactive-impulsive subtype of ADHD; patients with the predominantly inattentive subtype were excluded. Patients randomized to the methylphenidate HCl extended-release capsules group received 20 mg daily for the first week. Their dosage could be increased weekly to a maximum of 60 mg by the third week, depending on individual response to treatment. The patient’s regular school teacher completed the teachers’ version of the Conners’ Global Index Scale (TCGIS), a scale for assessing ADHD symptoms, in the morning and again in the afternoon on three alternate days of each treatment week. The primary efficacy endpoint was determined by the average of the total scores for the 10-item TCGIS completed by the classroom teacher in the morning and again in the afternoon on the three observation days during the last week of double-blind therapy. Patients treated with methylphenidate HCl extended-release capsules showed a statistically significant improvement in symptom scores from baseline over patients who received placebo (See Figure 2). Separate analyses of TCGIS scores in the morning and afternoon revealed superiority in improvement with methylphenidate HCl extended-release capsules over placebo during both time periods (See Figure 3). Figure 2: Least Squares Mean Change from Baseline in TCGIS Total Score in Pediatric Patients 6 to 15 years of Age with ADHD Figure 3: Least Squares Mean Change from Baseline in TCGIS Total Score in Pediatric Patients 6 to 15 years of Age with ADHD: Morning (AM) and Afternoon (PM) * FIGURES 2 & 3 : Last observation carried forward analysis at week 3. Error bars represent the standard error of the mean. Figure 2 Figure 3
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Methylphenidate HCl extended-release capsules are available in six strengths (see Table 4): Table 4: Strengths, Identifying Characteristics, and Packaging Configurations of Methylphenidate HCl Extended-Release Capsules Strength Capsule Color (cap/body) Imprinting on Capsule Cap Imprinting on Capsule Body Capsules per Bottle NDC Number 10 mg dark green/white “M” in a box over “1810” in white letters “10 mg” in black letters 100 NDC 0406-1810-01 20 mg medium blue/white “M” in a box over “1820” in white letters “20 mg” in black letters 100 NDC 0406-1820-01 30 mg maroon/white “M” in a box over “1830” in white letters “30 mg” in black letters 100 NDC 0406-1830-01 40 mg yellow ivory/white “M” in a box over “1840” in black letters “40 mg” in black letters 100 NDC 0406-1840-01 50 mg purple/white “M” in a box over “1850” in white letters “50 mg” in black letters 100 NDC 0406-1850-01 60 mg white/white “M” in a box over “1860” in black letters “60 mg” in black letters 100 NDC 0406-1860-01 Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
<table><caption>Table 4: Strengths, Identifying Characteristics, and Packaging Configurations of Methylphenidate HCl Extended-Release Capsules</caption><col width="46.1pt"/><col width="84.4pt"/><col width="103.5pt"/><col width="112.5pt"/><col width="58.5pt"/><col width="92.85pt"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Capsule Color</content></paragraph><paragraph><content styleCode="bold">(cap/body)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Imprinting on Capsule Cap</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Imprinting on Capsule Body</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"><content styleCode="underline">Capsules per Bottle</content></content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"><content styleCode="underline">NDC Number</content></content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>dark green/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1810” in white letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“10 mg” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>100</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>NDC 0406-1810-01</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>medium blue/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1820” in white letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“20 mg” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>100</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>NDC 0406-1820-01</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>30 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>maroon/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1830” in white letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“30 mg” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>100</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>NDC 0406-1830-01</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>40 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>yellow ivory/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1840” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“40 mg” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>100</paragraph></td><td styleCode="
oprule Lrule Rrule"><paragraph>“M” in a box over “1840” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“40 mg” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>100</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>NDC 0406-1840-01</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>50 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>purple/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1850” in white letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“50 mg” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>100</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>NDC 0406-1850-01</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>60 mg</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>white/white</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“M” in a box over “1860” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>“60 mg” in black letters</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>100</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>NDC 0406-1860-01</paragraph></td></tr></tbody></table>
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of methylphenidate HCl extended-release capsules, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions ( 5.1 )], Drug Abuse and Dependence ( 9.2 ), Overdosage ( 10 )] . Advise patients to store methylphenidate HCl extended-release capsules in a safe place, preferably locked, and instruct patients to not give methylphenidate HCl extended-release capsules to anyone else. Administration Instructions Instruct patients and their caregivers that the methylphenidate HCl extended-release capsules and the capsule contents must not be crushed or chewed. Instruct patients that the capsule may be swallowed whole, or alternatively, the capsule may be opened and the capsule contents sprinkled onto a small amount (tablespoon) of applesauce and given immediately, and not stored for future use [see Dosage and Administration ( 2.3 )] . Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with methylphenidate HCl extended-release capsules use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions ( 5.2 )] . Increased Blood Pressure and Heart Rate Instruct patients and their caregivers that methylphenidate HCl extended-release capsules can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions ( 5.3 )] . Psychiatric Adverse Reactions Advise patients and their caregivers that methylphenidate HCl extended-release capsules, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania [see Warnings and Precautions ( 5.4 )] . Priapism Advise patients and their caregivers of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions ( 5.5 )] . Circulation Problems in Fingers and Toes (peripheral vasculopathy, including Raynaud’s phenomenon) Instruct patients about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions ( 5.6 )] . Long-Term Suppression of Growth in Pediatric Patients Advise patients and their caregivers that methylphenidate HCl extended-release capsules can cause slowing of growth and weight loss [see Warnings and Precautions ( 5.7 )] . Increased Intraocular Pressure (IOP) and Glaucoma Advise patients what IOP and glaucoma may occur during treatment with methylphenidate HCl extended-release capsules [see Warnings and Precautions ( 5.9 )] .
Cl extended-release capsules can cause slowing of growth and weight loss [see Warnings and Precautions ( 5.7 )] . Increased Intraocular Pressure (IOP) and Glaucoma Advise patients what IOP and glaucoma may occur during treatment with methylphenidate HCl extended-release capsules [see Warnings and Precautions ( 5.9 )] . Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s syndrome may occur during treatment with methylphenidate HCl extended-release capsules. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions ( 5.10 )] . Pregnancy Registry Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to methylphenidate HCl extended-release capsules during pregnancy [see Use in Specific Populations ( 8.1 )] . Alcohol Use Advise patients to avoid alcohol while taking methylphenidate HCl extended-release capsules. Consumption of alcohol while taking methylphenidate HCl extended-release capsules may result in a more rapid release of the dose of methylphenidate [see Drug Interactions ( 7 )] . Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. © 2025 Mallinckrodt. Manufactured by: SpecGx LLC Webster Groves, MO 63119 USA Mallinckrodt™ Pharmaceuticals
An electronic copy of this medication guide can be obtained from www.mallinckrodt.com/Medguide/L20M54.pdf or by calling 1-800-778-7898 for alternate delivery options. MEDICATION GUIDE Methylphenidate HCl Extended-Release Capsules, CII (METH il FEN i date) What is the most important information I should know about methylphenidate HCl extended-release capsules? Methylphenidate HCl extended-release capsules may cause serious side effects, including: Abuse, misuse, and addiction. Methylphenidate HCl extended-release capsules have a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate HCl extended-release capsules, other methylphenidate-containing medicines, and amphetamine-containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate HCl extended-release capsules or when they are used in ways that are not approved, such as snorting or injection. Your healthcare provider should check your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate HCl extended-release capsules and will monitor your child during treatment. Methylphenidate HCl extended-release capsules may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. Do not give methylphenidate HCl extended-release capsules to anyone else. See “What is methylphenidate HCl extended-release capsules?” for more information. Keep methylphenidate HCl extended-release capsules in a safe place and properly dispose of any unused medicine. See “How should I store methylphenidate HCl extended-release capsules?” for more information. Tell your healthcare provider if your child has ever abused or been dependent on alcohol, prescription medicines, or street drugs. Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check your child carefully for heart problems before starting treatment with methylphenidate HCl extended-release capsules. Tell your healthcare provider if your child has any heart problems, heart disease, or heart defects. Call your healthcare provider or go to the nearest hospital emergency room right away if your child has any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with methylphenidate HCl extended-release capsules. Increased blood pressure and heart rate. Your healthcare provider should check your child’s blood pressure and heart rate regularly during treatment with methylphenidate HCl extended-release capsules. Mental (psychiatric) problems, including: new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems your child has, or about a family history of, suicide, bipolar illness, or depression. Call your healthcare provider right away if your child has any new or worsening mental symptoms or problems during treatment with methylphenidate HCl extended-release capsules, especially hearing voices, seeing or believing things that are not real, or new manic symptoms. What are methylphenidate HCl extended-release capsules?
r healthcare provider right away if your child has any new or worsening mental symptoms or problems during treatment with methylphenidate HCl extended-release capsules, especially hearing voices, seeing or believing things that are not real, or new manic symptoms. What are methylphenidate HCl extended-release capsules? Methylphenidate HCl extended-release capsules are a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 to 15 years of age. Methylphenidate HCl extended-release capsules may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. Methylphenidate HCl extended-release capsules are not recommended for use in children under 6 years of age with ADHD. Methylphenidate HCl extended-release capsules are a federally controlled substance (CII) because they contain methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep methylphenidate HCl extended-release capsules in a safe place to protect them from theft. Never give your methylphenidate HCl extended-release capsules to anyone else, because they may cause death or harm them. Selling or giving away methylphenidate HCl extended-release capsules may harm others and is against the law. Who should not take methylphenidate HCl extended-release capsules? Your child should not take methylphenidate HCl extended-release capsules if your child: is allergic to methylphenidate hydrochloride or any of the ingredients in methylphenidate HCl extended-release capsules. See the end of this Medication Guide for a complete list of ingredients in methylphenidate HCl extended-release capsules. has a rare inherited problem with the breaking down, absorbing, and processing of certain types of sugar in the body. Methylphenidate HCl extended-release capsules contain a type of sugar called sucrose. is taking, or has stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI). Before starting methylphenidate HCl extended-release capsules tell your healthcare provider about all your child’s medical conditions, including: if your child: has heart problems, heart disease, heart defects, or high blood pressure has mental problems including psychosis, mania, bipolar illness, or depression or has a family history of suicide, bipolar illness, or depression has circulation problems in fingers and toes have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome is pregnant or plan to become pregnant. It is not known if methylphenidate HCl extended-release capsules will harm the unborn baby. There is a pregnancy registry for females who are exposed to methylphenidate HCl extended-release capsules during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate HCl extended-release capsules and their baby. If you or your child becomes pregnant during treatment with methylphenidate HCl extended-release capsules, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. is breastfeeding or plan to breastfeed. Methylphenidate HCl passes into breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate HCl extended-release capsules. Tell your healthcare provider about all the medicines that your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
nto breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate HCl extended-release capsules. Tell your healthcare provider about all the medicines that your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate HCl extended-release capsules and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with methylphenidate HCl extended-release capsules. Your healthcare provider will decide whether methylphenidate HCl extended-release capsules can be taken with other medicines. Especially tell your healthcare provider if your child takes a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI). Know the medicines that your child takes. Keep a list of the medicines with you to show your healthcare provider and pharmacist. Your child should not start taking any new medicines during treatment with methylphenidate HCl extended-release capsules without talking to your healthcare provider first. How should methylphenidate HCl extended-release capsules be taken? Take methylphenidate HCl extended-release capsules exactly as prescribed by your healthcare provider. Your healthcare provider may change the dose if needed. Take methylphenidate HCl extended-release capsules 1 time each day in the morning before breakfast. Swallow methylphenidate HCl extended-release capsules whole with water or other liquids. If methylphenidate HCl extended-release capsules cannot be swallowed whole, the capsule may be opened and the contents sprinkled onto a tablespoonful of applesauce. Follow with a drink of water or other liquid. Do not chew the applesauce and medicine mixture. Swallow all the applesauce and medicine mixture right away. Do not store the applesauce and medicine mixture. If your child takes too many methylphenidate HCl extended-release capsules, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What should be avoided during treatment with methylphenidate HCl extended-release capsules? Avoid drinking alcohol during treatment with methylphenidate HCl extended-release capsules. This may cause a faster release of the methylphenidate HCl extended-release capsules medicine. What are the possible side effects of methylphenidate HCl extended-release capsules? Methylphenidate HCl extended-release capsules may cause serious side effects, including: See “ What is the most important information I should know about methylphenidate HCl extended-release capsules? ” Painful and prolonged erections (priapism). Priapism has happened in males who take products that contain methylphenidate. If your child develops priapism, get medical help right away. Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon). Signs and symptoms may include: fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if your child has numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your healthcare provider right away if your child has any signs of unexplained wounds appearing on the fingers or toes during treatment with methylphenidate HCl extended-release capsules. Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with methylphenidate HCl extended-release capsules. Methylphenidate HCl extended-release capsules treatment may be stopped if your child is not growing or gaining weight. Eye problems (increased pressure in the eye and glaucoma).
) in children. Children should have their height and weight checked often during treatment with methylphenidate HCl extended-release capsules. Methylphenidate HCl extended-release capsules treatment may be stopped if your child is not growing or gaining weight. Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate HCl extended-release capsules. The most common side effects of methylphenidate HCl extended-release capsules include anorexia and trouble sleeping. These are not all the possible side effects of methylphenidate HCl extended-release capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store methylphenidate HCl extended-release capsules? Store methylphenidate HCl extended-release capsules at room temperature between 68°F to 77°F (20°C to 25°C). Store methylphenidate HCl extended-release capsules in a safe place, like a locked cabinet. Protect from light and moisture. Dispose of remaining, unused, or expired methylphenidate HCl extended-release capsules by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate HCl extended-release capsules with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away methylphenidate HCl extended-release capsules in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep methylphenidate HCl extended-release capsules and all medicines out of the reach of children. General information about the safe and effective use of methylphenidate HCl extended-release capsules. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use methylphenidate HCl extended-release capsules for a condition for which they were not prescribed. Do not give methylphenidate HCl extended-release capsules to other people, even if they have the same symptoms. They may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about methylphenidate HCl extended-release capsules that was written for healthcare professionals. What are the ingredients in methylphenidate HCl extended-release capsules? Active Ingredient: methylphenidate hydrochloride Inactive Ingredients: Sugar Spheres, Ethylcellulose, Oleic Acid, Medium-Chain Triglycerides, Titanium Dioxide, Gelatin, Shellac, Propylene Glycol, Hypromellose, Polyethylene Glycol, and Black Iron Oxide. The individual capsules contain the following coloring agents: 10 mg capsules: FD&C Blue No. 2, Yellow Iron Oxide, Sodium Hydroxide, Povidone 20 mg capsules: FD&C Blue No. 2, Sodium Hydroxide, Povidone 30 mg capsules: FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, Sodium Hydroxide, Povidone 40 mg capsules: Yellow Iron Oxide 50 mg capsules: FD&C Blue No. 2, Red Iron Oxide, Sodium Hydroxide, Povidone Manufactured by: SpecGx LLC Webster Groves, MO 63119 USA Mallinckrodt™ For more information about methylphenidate HCl extended-release capsules call 1-800-778-7898. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 09/2025 L20M54
<table><col/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> </content><content styleCode="bold">MEDICATION GUIDE</content></paragraph><paragraph><content styleCode="bold"> Methylphenidate HCl Extended-Release Capsules, CII (METH il FEN i date)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What is the most important information I should know about methylphenidate HCl extended-release capsules?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate HCl extended-release capsules may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disk"><item><content styleCode="bold"><content styleCode="bold">Abuse, misuse, and addiction. </content></content>Methylphenidate HCl extended-release capsules have a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate HCl extended-release capsules, other methylphenidate-containing medicines, and amphetamine-containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate HCl extended-release capsules or when they are used in ways that are not approved, such as snorting or injection. <list listType="unordered" styleCode="Circle"><item>Your healthcare provider should check your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate HCl extended-release capsules and will monitor your child during treatment.</item><item>Methylphenidate HCl extended-release capsules may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider.</item><item>Do not give methylphenidate HCl extended-release capsules to anyone else. See <content styleCode="bold">“What is methylphenidate HCl extended-release capsules?”</content> for more information.</item></list></item></list><paragraph>Keep methylphenidate HCl extended-release capsules in a safe place and properly dispose of any unused medicine. See <content styleCode="bold">“How should I store methylphenidate HCl extended-release capsules?”</content> for more information. Tell your healthcare provider if your child has ever abused or been dependent on alcohol, prescription medicines, or street drugs.</paragraph><list listType="unordered" styleCode="Disk"><item><paragraph><content styleCode="bold">Risks for people with serious heart disease. </content>Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check your child carefully for heart problems before starting treatment with methylphenidate HCl extended-release capsules. Tell your healthcare provider if your child has any heart problems, heart disease, or heart defects.
n people who have heart defects or other serious heart disease. Your healthcare provider should check your child carefully for heart problems before starting treatment with methylphenidate HCl extended-release capsules. Tell your healthcare provider if your child has any heart problems, heart disease, or heart defects. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if your child has any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with methylphenidate HCl extended-release capsules.</content></paragraph></item><item><paragraph><content styleCode="bold">Increased blood pressure and heart rate.</content> Your healthcare provider should check your child’s blood pressure and heart rate regularly during treatment with methylphenidate HCl extended-release capsules.</paragraph></item><item><content styleCode="bold">Mental (psychiatric) problems, including:</content></item><item><list listType="unordered" styleCode="Circle"><item>new or worse behavior and thought problems</item><item>new or worse bipolar illness</item><item>new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms</item></list><paragraph>Tell your healthcare provider about any mental problems your child has, or about a family history of, suicide, bipolar illness, or depression.</paragraph><paragraph><content styleCode="bold"><content styleCode="bold"><content styleCode="bold"><content styleCode="bold"><content styleCode="bold"><content styleCode="bold"><content styleCode="bold"><content styleCode="bold"><content styleCode="bold"><content styleCode="bold"><content styleCode="bold"><content styleCode="bold">Call your healthcare provider right away if your child has any new or worsening mental symptoms or problems during treatment with methylphenidate HCl extended-release capsules, especially hearing voices, seeing or believing things that are not real, or new manic symptoms. </content></content></content></content></content></content></content></content></content></content></content></content></paragraph></item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are methylphenidate HCl extended-release capsules?</content></paragraph><paragraph>Methylphenidate HCl extended-release capsules are a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 to 15 years of age. Methylphenidate HCl extended-release capsules may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD.</paragraph><paragraph>Methylphenidate HCl extended-release capsules are not recommended for use in children under 6 years of age with ADHD.</paragraph><paragraph><content styleCode="bold">Methylphenidate HCl extended-release capsules are a federally controlled substance (CII) because <content styleCode="bold">they contain </content>methylphenidate that can be a target for people who abuse prescription medicines or street drugs.</content></paragraph><paragraph>Keep methylphenidate HCl extended-release capsules in a safe place to protect them from theft. Never give your methylphenidate HCl extended-release capsules to anyone else, because they may cause death or harm them.
be a target for people who abuse prescription medicines or street drugs.</content></paragraph><paragraph>Keep methylphenidate HCl extended-release capsules in a safe place to protect them from theft. Never give your methylphenidate HCl extended-release capsules to anyone else, because they may cause death or harm them. Selling or giving away methylphenidate HCl extended-release capsules may harm others and is against the law.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Who should not take methylphenidate HCl extended-release capsules?</content></paragraph><paragraph><content styleCode="bold">Your child should not take methylphenidate HCl extended-release capsules if your child:</content></paragraph><list listType="unordered" styleCode="Disk"><item>is allergic to methylphenidate hydrochloride or any of the ingredients in methylphenidate HCl extended-release capsules. See the end of this Medication Guide for a complete list of ingredients in methylphenidate HCl extended-release capsules.</item><item>has a rare inherited problem with the breaking down, absorbing, and processing of certain types of sugar in the body. Methylphenidate HCl extended-release capsules contain a type of sugar called sucrose.</item><item>is taking, or has stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI).</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Before starting methylphenidate HCl extended-release capsules tell your healthcare provider about all your child’s medical conditions, including: if your child:</content></paragraph><list listType="unordered" styleCode="Disk"><item>has heart problems, heart disease, heart defects, or high blood pressure</item><item>has mental problems including psychosis, mania, bipolar illness, or depression or has a family history of suicide, bipolar illness, or depression</item><item>has circulation problems in fingers and toes</item><item>have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness)</item><item>have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome</item><item>is pregnant or plan to become pregnant. It is not known if methylphenidate HCl extended-release capsules will harm the unborn baby. <list listType="unordered" styleCode="Circle"><item>There is a pregnancy registry for females who are exposed to methylphenidate HCl extended-release capsules during pregnancy. The purpose of the registry is to collect information about the health of females exposed to methylphenidate HCl extended-release capsules and their baby. If you or your child becomes pregnant during treatment with methylphenidate HCl extended-release capsules, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.</item></list></item><item>is breastfeeding or plan to breastfeed. Methylphenidate HCl passes into breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate HCl extended-release capsules.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines that your child takes,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate HCl extended-release capsules and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with methylphenidate HCl extended-release capsules.
over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate HCl extended-release capsules and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with methylphenidate HCl extended-release capsules. Your healthcare provider will decide whether methylphenidate HCl extended-release capsules can be taken with other medicines.</paragraph><paragraph><content styleCode="bold">Especially tell your healthcare provider if your child takes</content> a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI).</paragraph><paragraph>Know the medicines that your child takes. Keep a list of the medicines with you to show your healthcare provider and pharmacist. <content styleCode="bold">Your child should not start taking any new medicines during treatment with methylphenidate HCl extended-release capsules without talking to your healthcare provider first.</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How should methylphenidate HCl extended-release capsules be taken?</content></paragraph><list listType="unordered" styleCode="Disk"><item>Take methylphenidate HCl extended-release capsules exactly as prescribed by your healthcare provider.</item><item>Your healthcare provider may change the dose if needed.</item><item>Take methylphenidate HCl extended-release capsules 1 time each day in the morning before breakfast.</item><item>Swallow methylphenidate HCl extended-release capsules whole with water or other liquids. If methylphenidate HCl extended-release capsules cannot be swallowed whole, the capsule may be opened and the contents sprinkled onto a tablespoonful of applesauce. <list listType="unordered" styleCode="Circle"><item>Follow with a drink of water or other liquid.</item><item><content styleCode="bold">Do not</content> chew the applesauce and medicine mixture.</item><item>Swallow all the applesauce and medicine mixture right away. <content styleCode="bold">Do not</content> store the applesauce and medicine mixture.</item></list></item></list><paragraph><content styleCode="bold">If your child takes too many methylphenidate HCl extended-release capsules, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away.</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">What should be avoided during treatment with methylphenidate HCl extended-release capsules?</content> Avoid drinking alcohol during treatment with methylphenidate HCl extended-release capsules. This may cause a faster release of the methylphenidate HCl extended-release capsules medicine.</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the possible side effects of methylphenidate HCl extended-release capsules?</content></paragraph><paragraph><content styleCode="bold">Methylphenidate HCl extended-release capsules may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disk"><item>See “<content styleCode="bold">What is the most important information I should know about methylphenidate HCl extended-release capsules?</content>”</item><item><content styleCode="bold">Painful and prolonged erections (priapism).</content> Priapism has happened in males who take products that contain methylphenidate. <content styleCode="bold">If your child develops priapism, get medical help right away.</content></item><item><content styleCode="bold">Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon).
riapism has happened in males who take products that contain methylphenidate. <content styleCode="bold">If your child develops priapism, get medical help right away.</content></item><item><content styleCode="bold">Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon). </content>Signs and symptoms may include: <list listType="unordered" styleCode="Circle"><item>fingers or toes may feel numb, cool, painful</item><item>fingers or toes may change color from pale, to blue, to red</item></list></item></list><paragraph>Tell your healthcare provider if your child has numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.</paragraph><paragraph><content styleCode="bold">Call your healthcare provider right away</content> if your child has any signs of unexplained wounds appearing on the fingers or toes during treatment with methylphenidate HCl extended-release capsules.</paragraph><list listType="unordered" styleCode="Disk"><item><content styleCode="bold">Slowing of growth (height and weight) in children.</content> Children should have their height and weight checked often during treatment with methylphenidate HCl extended-release capsules. Methylphenidate HCl extended-release capsules treatment may be stopped if your child is not growing or gaining weight.</item><item><content styleCode="bold">Eye problems (increased pressure in the eye and glaucoma).</content> Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness.</item><item><content styleCode="bold">New or worsening tics or worsening Tourette’s syndrome.</content> Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate HCl extended-release capsules.</item></list><paragraph><content styleCode="bold">The most common side effects of methylphenidate HCl extended-release capsules include</content> anorexia and trouble sleeping.</paragraph><paragraph>These are not all the possible side effects of methylphenidate HCl extended-release capsules.</paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How should I store methylphenidate HCl extended-release capsules?</content></paragraph><list listType="unordered" styleCode="Disk"><item>Store methylphenidate HCl extended-release capsules at room temperature between 68°F to 77°F (20°C to 25°C).</item><item>Store methylphenidate HCl extended-release capsules in a safe place, like a locked cabinet. Protect from light and moisture.</item><item>Dispose of remaining, unused, or expired methylphenidate HCl extended-release capsules by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate HCl extended-release capsules with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away methylphenidate HCl extended-release capsules in the household trash.
nidate HCl extended-release capsules with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away methylphenidate HCl extended-release capsules in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</item></list><paragraph><content styleCode="bold">Keep methylphenidate HCl extended-release capsules and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">General information about the safe and effective use of methylphenidate HCl extended-release capsules.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use methylphenidate HCl extended-release capsules for a condition for which they were not prescribed. Do not give methylphenidate HCl extended-release capsules to other people, even if they have the same symptoms. They may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about methylphenidate HCl extended-release capsules that was written for healthcare professionals.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the ingredients in methylphenidate HCl extended-release capsules?</content></paragraph><paragraph><content styleCode="bold">Active Ingredient:</content> methylphenidate hydrochloride</paragraph><paragraph><content styleCode="bold">Inactive Ingredients:</content> Sugar Spheres, Ethylcellulose, Oleic Acid, Medium-Chain Triglycerides, Titanium Dioxide, Gelatin, Shellac, Propylene Glycol, Hypromellose, Polyethylene Glycol, and Black Iron Oxide.</paragraph><paragraph>The individual capsules contain the following coloring agents: 10 mg capsules: FD&C Blue No. 2, Yellow Iron Oxide, Sodium Hydroxide, Povidone 20 mg capsules: FD&C Blue No. 2, Sodium Hydroxide, Povidone 30 mg capsules: FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, Sodium Hydroxide, Povidone 40 mg capsules: Yellow Iron Oxide 50 mg capsules: FD&C Blue No. 2, Red Iron Oxide, Sodium Hydroxide, Povidone </paragraph><paragraph>Manufactured by: SpecGx LLC Webster Groves, MO 63119 USA</paragraph><paragraph><content styleCode="bold">Mallinckrodt™</content></paragraph><paragraph><content styleCode="bold">For more information about methylphenidate HCl extended-release capsules call 1-800-778-7898.</content></paragraph></td></tr></tbody></table>
WARNING: ABUSE, MISUSE, AND ADDICTION WARNING: ABUSE, MISUSE, AND ADDICTION Methylphenidate hydrochloride extended-release tablets have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage (10)] , and this risk is increased with a higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of methylphenidate hydrochloride extended-release tablets, and proper disposal of any unused drug. Throughout methylphenidate hydrochloride extended-release tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.1, 9.2)] WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. Methylphenidate hydrochloride extended-release tablets have a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death (5.1, 9.2, 10): Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of methylphenidate hydrochloride extended-release tablets, and proper disposal of any unused drug. Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
Indications and Usage (1) 9/2025 Dosage and Administration (2.3, 2.4) 2/2026 Warnings and Precautions: Long-Term Suppression of Growth in Pediatric Patients 9/2025 Warnings and Precautions: Removal Seizures and Hematologic Monitoring 2/2026
1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release tablets are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 to 65 years old. Limitations of Use The use of methylphenidate hydrochloride extended-release tablets are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.7) and Use in Specific Populations (8.4)]. Methylphenidate hydrochloride extended-release tablets are a CNS stimulant indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 to 65 years old. (1) Limitations of Use The use of methylphenidate hydrochloride extended-release tablets are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage (5.7, 8.4).
2 DOSAGE AND ADMINISTRATION Prior to initiating methylphenidate hydrochloride extended-release tablets treatment assess for (2.1): o the presence of cardiac disease o for family history of tics or Tourette’ syndrome and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome Administer once daily in the morning with or without food. Swallow whole with liquids; do not chew, divide, or crush. (2.2) Recommended dosage in pediatric patients 6 to 17 years of age new to methylphenidate hydrochloride extended-release tablets: starting dosage is18 mg once daily. May be increased weekly in 18 mg increments. Maximum dosage for pediatric patients (2.3): o 6 to 12 years: 54 mg once daily o 13 to 17 years: 72 mg once daily Recommended dosage in adults (up to 65 years of age) new to methylphenidate hydrochloride extended-release tablets: starting dosage is 18 mg or 36 mg once daily. May be increased weekly in 18 mg increments, up to 72 mg once daily. (2.3) Patients currently using immediate-release methylphenidate: starting methylphenidate hydrochloride extended-release tablets dosage is based on current dosage regimen. (2.4) 2.1 Pretreatment Screening Prior to treating patients with methylphenidate hydrochloride extended-release tablets, assess: For the presence of cardiac disease (e.g., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)]. The family history for tics or Tourette’ syndrome and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome [see Warnings and Precautions (5.11)]. 2.2 Important Administration Instructions Administer methylphenidate hydrochloride extended-release tablets orally once daily in the morning with or without food. Swallow methylphenidate hydrochloride extended-release tablets whole with liquids. Do not split, crush, or chew the extended-release tablets because doing so will compromise the extended-release characteristics of methylphenidate hydrochloride extended-release tablets and may compromise the effectiveness or safety of methylphenidate hydrochloride extended-release tablets. 2.3 Recommended Methylphenidate Hydrochloride Extended-Release Tablets Dosage in Patients New to Methylphenidate See Table 1 for the recommended once-daily dosage of methylphenidate hydrochloride extended-release tablets in patients who were not taking a methylphenidate product. In patients who have not achieved an optimal response at a lower dosage, increase the methylphenidate hydrochloride extended-release tablets dosage in 18 mg increments at weekly intervals. However, if a slower titration is recommended for patients who have not achieved an optimal response taking 18 mg of methylphenidate hydrochloride extended-release tablets once daily, increase their daily dosage to 27 mg once per day.
ydrochloride extended-release tablets dosage in 18 mg increments at weekly intervals. However, if a slower titration is recommended for patients who have not achieved an optimal response taking 18 mg of methylphenidate hydrochloride extended-release tablets once daily, increase their daily dosage to 27 mg once per day. Table 1: Recommended Methylphenidate Hydrochloride Extended-Release Tablets Dosage in Patients New to Methylphenidate Patient Population Recommended Starting Dose Dosage Range Pediatric patients 6 to 12 years of age 18 mg once daily 18 mg to 54 mg once daily Pediatric patients 13 to 17 years of age 18 mg once daily 18 mg to 54 mg once daily not to exceed 2 mg/kg/day Adults 18 to 65 years of age 18 or 36 mg once daily 18 mg to 54 mg once daily 2.4 Recommended Methylphenidate Hydrochloride Extended-Release Tablets Dosage in Patients Switching from Another Methylphenidate Product See Table 2 for the recommended starting dosage of methylphenidate hydrochloride extended-release tablets in patients switching from an immediate-release methylphenidate product administered twice daily or three times daily (total daily dosage of 10 to 60 mg/day). Table 2: Recommended Starting Dosage in Patients Switching from Another Methylphenidate Product Previous Immediate-release Methylphenidate Daily Dosage Recommended Methylphenidate Hydrochloride Extended-Release Tablets Starting Dosage 5 mg Methylphenidate twice daily or three times daily 18 mg every morning 10 mg Methylphenidate twice daily or three times daily 36 mg every morning 15 mg Methylphenidate twice daily or three times daily 54 mg every morning 20 mg Methylphenidate twice daily or three times daily 72 mg every morning 1 1 Only for patients 12-65 years of age. In patients who have not achieved an optimal response at a lower dosage, increase the methylphenidate hydrochloride extended-release tablets dosage in 18 mg increments at weekly intervals. The maximum recommended dosage in pediatric patients 6 to 12 years of age is 54 mg/day, and the maximum recommended dosage in patients 12-65 years old is 72 mg/day. 2.5 Dosage Reduction and Discontinuation If paradoxical aggravation of ADHD symptoms or methylphenidate hydrochloride extended-release tablets -associated adverse reactions occur, reduce the methylphenidate hydrochloride extended-release tablets dosage or, if necessary, discontinue methylphenidate hydrochloride extended-release tablets. If ADHD improvement is not observed after appropriate dosage modification over a one-month period, discontinue methylphenidate hydrochloride extended-release tablets.
3 DOSAGE FORMS AND STRENGTHS Methylphenidate hydrochloride extended-release tablets, USP 72 mg are round, biconvex, light blue to blue colored, film-coated tablets, imprinted with “72”, with the presence of an orifice. Extended-release tablets: 72 mg (3)
4 CONTRAINDICATIONS Methylphenidate hydrochloride extended-release tablets are contraindicated in patients: Known to be hypersensitive to methylphenidate or other components of methylphenidate hydrochloride extended-release tablets. Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been reported in patients treated with methylphenidate hydrochloride extended-release tablets. [see Adverse Reactions (6)]. Receiving concomitant monoamine oxidase inhibitors (MAOIs), and within 14 days following discontinuation of treatment with a MAO inhibitor because of the risk of a hypertensive crisis [see Drug Interactions (7)]. Known hypersensitivity to methylphenidate or other components of the methylphenidate hydrochloride extended-release tablets (4) Receiving concomitant monoamine oxidase inhibitors and within 14 days following discontinuation of treatment with a MAO inhibitor (4)
5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease : Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. (5.2) Increased Blood Pressure and Heart Rate : Monitor blood pressure and pulse. (5.3) Psychiatric Adverse Reactions : Prior to initiating methylphenidate hydrochloride extended-release tablets, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release tablets. (5.4) Priapism : If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention (5.5) Peripheral Vasculopathy, including Raynaud’s Phenomenon : Carefully assess for digital changes during methylphenidate hydrochloride extended-release tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy (5.6) Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. (5.7) Risk of Gastrointestinal (GI) Obstruction in Patients with GI Narrowing : Only use in patients able to swallow the extended-release tablet whole, and should not ordinarily be used in patients with pre-existing severe GI narrowing. (5.8) Acute Angle Closure Glaucoma: Methylphenidate hydrochloride extended-release tablets-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. (5.9) Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe methylphenidate hydrochloride extended-release tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma. (5.10) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. (5.11) 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride extended-release tablets have a high potential for abuse and misuse. The use of methylphenidate hydrochloride extended-release tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction [see Drug Abuse and Dependence (9.1, 9.2)] . Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage (10)] , and this risk is increased with higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug.
with higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate hydrochloride extended-release tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride extended-release tablets to anyone else. Throughout methylphenidate hydrochloride extended-release tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate hydrochloride extended-release tablets use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute) [see Adverse Reactions (6)]. Some patients may have larger increases. Monitor all methylphenidate hydrochloride extended-release tablets-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Psychosis in Patients with a Psychotic Disorder CNS stimulants, including methylphenidate hydrochloride extended-release tablets, may exacerbate behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants, including methylphenidate hydrochloride extended-release tablets, may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating methylphenidate hydrochloride extended-release tablets treatment, screen patients for risk factors for developing a manic episode (e.g., history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms in Patients without a History of a Bipolar or Psychotic Disorder CNS stimulants (including methylphenidate hydrochloride extended-release tablets), at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release tablets. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in adult and pediatric male patients [see Adverse Reactions (6)]. Although priapism was not reported with methylphenidate initiation, priapism occurred in patients treated with methylphenidate after some time, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride extended-release tablets-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.
ten subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride extended-release tablets-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including methylphenidate hydrochloride extended-release tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon [see Adverse Reactions (6.2)]. Signs and symptoms of these cases of peripheral vasculopathy were usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms of peripheral vasculopathy generally improved after CNS stimulant dosage reduction or discontinuation. During methylphenidate hydrochloride extended-release tablets treatment, carefully assess for digital changes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride extended-release tablets-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients Methylphenidate hydrochloride extended-release tablets are not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)] . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Pediatric patients 7 to 13 years of age who received methylphenidate for 7 days per week for over 14 months to over 36 months had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in methylphenidate hydrochloride extended-release tablets -treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 Risk of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing Because methylphenidate hydrochloride extended-release tablets are nondeformable and do not appreciably change in shape in the gastrointestinal (GI) tract, methylphenidate hydrochloride extended-release tablets should not ordinarily be administered to patients with pre-existing severe pathologic or iatrogenic GI narrowing. There have been rare reports of obstructive GI symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable modified-release dosage forms. Methylphenidate hydrochloride extended-release tablets should be used only in patients who are able to swallow the extended-release tablets whole [see Dosage and Administration (2.2)]. 5.9 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate hydrochloride extended-release tablets treatment. Although the mechanism is not clear, methylphenidate hydrochloride extended-release tablets-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.10 Increased Intraocular Pressure and Glaucoma 5.11 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics [see Adverse Reactions (6)].
ant hyperopia) should be evaluated by an ophthalmologist. 5.10 Increased Intraocular Pressure and Glaucoma 5.11 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics [see Adverse Reactions (6)]. Worsening of Tourette’s syndrome has also been reported. Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history for tics or Tourette’ syndrome and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride extended-release tablets-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue methylphenidate hydrochloride extended-release tablets treatment if clinically appropriate. 5.12 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.5)]. Prescribe methylphenidate hydrochloride extended-release tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride extended-release tablets-treated patients with a history of abnormally increased IOP or open angle glaucoma 5.13 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics [see Adverse Reactions (6.2 , 6.5)]. Worsening of Tourette’s syndrome has also been reported. Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride extended-release tablets-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2)] Hypersensitivity Reactions [see Contraindications (4)] Monoamine Oxidase Inhibitors [see Contraindications (4), Drug Interactions (7)] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)] Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)] Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)] Priapism [see Warnings and Precautions (5.5)] Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions (5.6)] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7)] Risks of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing [see Warnings and Precautions (5.8)] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.9)] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.10)] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.11)] The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients 6 to 17 years: upper abdominal pain. (6.1) Adults up to 65 years of age: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 clinical trials of another drug and may not reflect the rates observed in clinical practice. The data below is based on a total of 3,906 patients in clinical studies who received methylphenidate hydrochloride extended-release tablets. Patients aged 6 up to 65 years old with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies [see Table 3]. Table 3: Methylphenidate Hydrochloride Extended-Release Tablets-treated Patients in Double-Blind and Open-Label Clinical Studies Patient Population N Dosage Range Pediatric patients 6 to 12 years of age 2,216 18 to 54 mg once daily Adolescents 502 18 to 72 mg once daily Adults up to 65 years of age 1,188 18 to 108 mg once daily The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients: upper abdominal pain [see Table 4]. Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis [see Table 5]. The most common adverse reactions associated with methylphenidate hydrochloride extended-release tablets discontinuation (≥1%) from the pediatric and adult clinical trials were anxiety, irritability, insomnia, and increased blood pressure. Most Common Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.