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WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL is not approved for the treatment of patients with dementia-related psychosis. [see Warnings and Precautions (5.1) ] WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL is not approved for use in patients with dementia-related psychosis. ( 5.1 )

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1 INDICATIONS AND USAGE RISPERDAL is an atypical antipsychotic indicated for: Treatment of schizophrenia ( 1.1 ) As monotherapy or adjunctive therapy with lithium or valproate, for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder ( 1.2 ) Treatment of irritability associated with autistic disorder ( 1.3 ) 1.1 Schizophrenia RISPERDAL (risperidone) is indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults [see Clinical Studies (14.1) ] . 1.2 Bipolar Mania Monotherapy RISPERDAL is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) [see Clinical Studies (14.2) ] . Adjunctive Therapy RISPERDAL adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults [see Clinical Studies (14.3) ] . 1.3 Irritability Associated with Autistic Disorder RISPERDAL is indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years) [see Clinical Studies (14.4) ] .

2 DOSAGE AND ADMINISTRATION Table 1. Recommended Daily Dosage by Indication Initial Dose Titration (Increments) Target Dose Effective Dose Range Schizophrenia: adults (2.1) 2 mg 1 to 2 mg 4 to 8 mg 4 to 16 mg Schizophrenia: adolescents (2.2) 0.5 mg 0.5 to 1 mg 3 mg 1 to 6 mg Bipolar mania: adults (2.2) 2 to 3 mg 1 mg 1 to 6 mg 1 to 6 mg Bipolar mania: children and adolescents (2.2) 0.5 mg 0.5 to 1 mg 1 to 2.5 mg 1 to 6 mg Irritability in autistic disorder (2.3) 0.25 mg Can increase to 0.5 mg by Day 4: (body weight less than 20 kg) 0.5 mg Can increase to 1 mg by Day 4: (body weight greater than or equal to 20 kg) After Day 4, at intervals of > 2 weeks: 0.25 mg (body weight less than 20 kg) 0.5 mg (body weight greater than or equal to 20 kg) 0.5 mg: (body weight less than 20 kg) 1 mg: (body weight greater than or equal to 20 kg) 0.5 to 3 mg Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of one week or longer. Recommended daily dosage: Initial Dose Target Dose Effective Dose Range Schizophrenia: adults ( 2.1 ) 2 mg 4 to 8 mg 4 to 16 mg Schizophrenia: adolescents ( 2.1 ) 0.5 mg 3 mg 1 to 6 mg Bipolar mania: adults ( 2.2 ) 2 to 3 mg 1 to 6 mg 1 to 6 mg Bipolar mania: in children and adolescents ( 2.2 ) 0.5 mg 1 to 2.5 mg 1 to 6 mg Irritability associated with autistic disorder ( 2.3 ) 0.25 mg (Weight < 20 kg) 0.5 mg (Weight ≥20 kg) 0.5 mg (<20 kg) 1 mg (≥20 kg) 0.5 to 3 mg Severe Renal or Hepatic Impairment in Adults: Use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of at least one week. ( 2.4 ) Oral Solution: Can be administered directly from calibrated oral dosing syringe or mixed with beverage (water, coffee, orange juice, or low-fat milk). ( 2.6 ) M-TAB Orally Disintegrating Tablets: Open the blister only when ready to administer, and immediately place tablet on the tongue. Can be swallowed with or without liquid. ( 2.7 ) 2.1 Schizophrenia Adults Usual Initial Dose RISPERDAL can be administered once or twice daily. Initial dosing is 2 mg per day. May increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day, as tolerated, to a recommended dose of 4 to 8 mg per day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 mg to 16 mg per day. However, doses above 6 mg per day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg per day has not been evaluated in clinical trials [see Clinical Studies (14.1) ] . Adolescents The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to a recommended dose of 3 mg per day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg to 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied.

ose of 3 mg per day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg to 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied. Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily. Maintenance Therapy While it is unknown how long a patient with schizophrenia should remain on RISPERDAL, the effectiveness of RISPERDAL 2 mg per day to 8 mg per day at delaying relapse was demonstrated in a controlled trial in adult patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [see Clinical Studies (14.1) ] . Both adult and adolescent patients who respond acutely should generally be maintained on their effective dose beyond the acute episode. Patients should be periodically reassessed to determine the need for maintenance treatment. Reinitiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off RISPERDAL, the initial titration schedule should be followed. Switching From Other Antipsychotics There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to RISPERDAL, or treating patients with concomitant antipsychotics. 2.2 Bipolar Mania Usual Dose Adults The initial dose range is 2 mg to 3 mg per day. The dose may be adjusted at intervals of 24 hours or greater, in increments of 1 mg per day. The effective dose range is 1 mg to 6 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1 mg to 6 mg per day [see Clinical Studies (14.2 , 14.3) ] . RISPERDAL doses higher than 6 mg per day were not studied. Pediatrics The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to the recommended target dose of 1 mg to 2.5 mg per day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 mg and 6 mg per day, no additional benefit was observed above 2.5 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied. Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily. Maintenance Therapy There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with RISPERDAL. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of RISPERDAL in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use RISPERDAL for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. 2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents) The dosage of RISPERDAL should be individualized according to the response and tolerability of the patient. The total daily dose of RISPERDAL can be administered once daily, or half the total daily dose can be administered twice daily.

ritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents) The dosage of RISPERDAL should be individualized according to the response and tolerability of the patient. The total daily dose of RISPERDAL can be administered once daily, or half the total daily dose can be administered twice daily. For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day. For patients with body weight greater than or equal to 20 kg, initiate dosing at 0.5 mg per day. After a minimum of four days, the dose may be increased to the recommended dose of 0.5 mg per day for patients less than 20 kg and 1.0 mg per day for patients greater than or equal to 20 kg. Maintain this dose for a minimum of 14 days. In patients not achieving sufficient clinical response, the dose may be increased at intervals of 2 weeks or greater, in increments of 0.25 mg per day for patients less than 20 kg, or increments of 0.5 mg per day for patients greater than or equal to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available for children who weigh less than 15 kg. Once sufficient clinical response has been achieved and maintained, consider gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use RISPERDAL for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose. 2.4 Dosing in Patients with Severe Renal or Hepatic Impairment For patients with severe renal impairment (Clcr< 30 mL/min) or hepatic impairment (10–15 points on Child Pugh System), the initial starting dose is 0.5 mg twice daily. The dose may be increased in increments of 0.5 mg or less, administered twice daily. For doses above 1.5 mg twice daily, increase in intervals of one week or greater [see Use in Specific Populations (8.6 and 8.7) ]. 2.5 Dose Adjustments for Specific Drug Interactions When RISPERDAL is co-administered with enzyme inducers (e.g., carbamazepine), the dose of RISPERDAL should be increased up to double the patient's usual dose. It may be necessary to decrease the RISPERDAL dose when enzyme inducers such as carbamazepine are discontinued [see Drug Interactions (7.1) ] . Similar effect may be expected with co-administration of RISPERDAL with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital). When fluoxetine or paroxetine is co-administered with RISPERDAL, the dose of RISPERDAL should be reduced. The RISPERDAL dose should not exceed 8 mg per day in adults when co-administered with these drugs. When initiating therapy, RISPERDAL should be titrated slowly. It may be necessary to increase the RISPERDAL dose when enzyme inhibitors such as fluoxetine or paroxetine are discontinued [see Drug Interactions (7.1) ] . 2.6 Administration of RISPERDAL Oral Solution RISPERDAL Oral Solution can be administered directly from the calibrated oral dosing syringe, or can be mixed with a beverage prior to administration. RISPERDAL Oral Solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea. 2.7 Directions for Use of RISPERDAL M-TAB Orally Disintegrating Tablets Tablet Accessing RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in blister packs of 4 tablets each. Do not open the blister until ready to administer. For single tablet removal, separate one of the four blister units by tearing apart at the perforations. Bend the corner where indicated.

1 mg, and 2 mg RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in blister packs of 4 tablets each. Do not open the blister until ready to administer. For single tablet removal, separate one of the four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the tablet. RISPERDAL M-TAB Orally Disintegrating Tablets 3 mg and 4 mg RISPERDAL M-TAB Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a child-resistant pouch containing a blister with 1 tablet each. The child-resistant pouch should be torn open at the notch to access the blister. Do not open the blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push the tablet through the foil, because this could damage the tablet. Tablet Administration Using dry hands, remove the tablet from the blister unit and immediately place the entire RISPERDAL M-TAB Orally Disintegrating Tablet on the tongue. The RISPERDAL M-TAB Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be stored once removed from the blister unit. RISPERDAL M-TAB Orally Disintegrating Tablets disintegrate in the mouth within seconds and can be swallowed subsequently with or without liquid. Patients should not attempt to split or to chew the tablet.

3 DOSAGE FORMS AND STRENGTHS RISPERDAL Tablets are available in the following strengths and colors: 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All are capsule shaped, and imprinted with "JANSSEN" on one side and either "Ris 0.5", "R1", "R2", "R3", or "R4" on the other side according to their respective strengths. RISPERDAL Oral Solution is available in a 1 mg/mL strength. RISPERDAL M-TAB Orally Disintegrating Tablets are available in the following strengths, colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square), 3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with "R0.5", "R1", "R2", "R3", or "R4" according to their respective strengths. Tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg ( 3 ) Oral solution: 1 mg per mL ( 3 ) Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg ( 3 )

4 CONTRAINDICATIONS RISPERDAL is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the RISPERDAL formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone. Known hypersensitivity to risperidone, paliperidone, or to any excipients in RISPERDAL. ( 4 )

5 WARNINGS AND PRECAUTIONS Cerebrovascular events, including stroke, in elderly patients with dementia-related psychosis: RISPERDAL is not approved for use in patients with dementia-related psychosis. ( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of RISPERDAL and close monitoring. ( 5.3 ) Tardive dyskinesia: Consider discontinuing RISPERDAL if clinically indicated. ( 5.4 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. ( 5.5 ) Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.5 ) Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. ( 5.5 ) Weight Gain: Significant weight gain has been reported. Monitor weight gain. ( 5.5 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. ( 5.6 ) Orthostatic hypotension: For patients at risk, consider a lower starting dose and slower titration. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of clinically significant low white blood cell count (WBC). Consider discontinuing RISPERDAL if a clinically significant decline in WBC occurs in the absence of other causative factors. ( 5.9 ) Potential for cognitive and motor impairment: Use caution when operating machinery. ( 5.10 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.11 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus RISPERDAL when compared to patients treated with RISPERDAL alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. RISPERDAL (risperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning ] .

pared to patients treated with RISPERDAL alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. RISPERDAL (risperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning ] . 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73–97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. RISPERDAL is not approved for the treatment of patients with dementia-related psychosis. [see Boxed Warning and Warnings and Precautions (5.1) ]. 5.3 Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue RISPERDAL and provide symptomatic treatment and monitoring. 5.4 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, RISPERDAL should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on RISPERDAL, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain.

ome patients may require treatment with RISPERDAL despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including RISPERDAL. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including RISPERDAL, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including RISPERDAL, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of RISPERDAL. Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2. Table 2. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania RISPERDAL Placebo 1–8 mg/day >8–16 mg/day Mean change from baseline (mg/dL) n=555 n=748 n=164 Serum Glucose -1.4 0.8 0.6 Proportion of patients with shifts Serum Glucose (<140 mg/dL to ≥200 mg/dL) 0.6% (3/525) 0.4% (3/702) 0% (0/158) In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50). Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3. Table 3.

change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50). Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3. Table 3. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13–17 years of age), Bipolar Mania (10–17 years of age), or Autistic Disorder (5 to 17 years of age) RISPERDAL Placebo 0.5–6 mg/day Mean change from baseline (mg/dL) n=76 n=135 Serum Glucose -1.3 2.6 Proportion of patients with shifts Serum Glucose (<100 mg/dL to ≥126 mg/dL) 0% (0/64) 0.8% (1/120) In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119). Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4. Table 4. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania RISPERDAL Placebo 1–8 mg/day >8–16 mg/day Mean change from baseline (mg/dL) Cholesterol n=559 n=742 n=156 Change from baseline 0.6 6.9 1.8 Triglycerides n=183 n=307 n=123 Change from baseline -17.4 -4.9 -8.3 Proportion of patients With Shifts Cholesterol (<200 mg/dL to ≥240 mg/dL) 2.7% 4.3% 6.3% (10/368) (22/516) (6/96) Triglycerides (<500 mg/dL to ≥500 mg/dL) 1.1% (2/180) 2.7% (8/301) 2.5% (3/121) In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52). Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5–17 years of age) are presented in Table 5. Table 5. Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), or Autistic Disorder (5 to 17 Years of Age) RISPERDAL Placebo 0.5–6 mg/day Mean change from baseline (mg/dL) Cholesterol n=74 n=133 Change from baseline 0.3 -0.3 LDL n=22 n=22 Change from baseline 3.7 0.5 HDL n=22 n=22 Change from baseline 1.6 -1.9 Triglycerides n=77 n=138 Change from baseline -9.0 -2.6 Proportion of patients with shifts Cholesterol (<170 mg/dL to ≥200 mg/dL) 2.4% (1/42) 3.8% (3/80) LDL (<110 mg/dL to ≥130 mg/dL) 0% (0/16) 0% (0/16) HDL (≥40 mg/dL to <40 mg/dL) 0% (0/19) 10% (2/20) Triglycerides (<150 mg/dL to ≥200 mg/dL) 1.5% (1/65) 7.1% (8/113) In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120). Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6. Table 6.

of weight is recommended. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6. Table 6. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania RISPERDAL Placebo (n=597) 1–8 mg/day (n=769) >8–16 mg/day (n=158) Weight (kg) Change from baseline -0.3 0.7 2.2 Weight Gain ≥7% increase from baseline 2.9% 8.7% 20.9% In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203). Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), autistic disorder (5–17 years of age), or other psychiatric disorders (5–17 years of age) are presented in Table 7. Table 7. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5–17 Years of Age) Placebo (n=375) RISPERDAL 0.5–6 mg/day (n=448) Weight (kg) Change from baseline 0.6 2.0 Weight Gain ≥7% increase from baseline 6.9% 32.6% In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL was associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48 (n=242). In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of RISPERDAL treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index. In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to RISPERDAL. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index. In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL 0.5–2.5 mg group, 1.44 kg in the RISPERDAL 3–6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index. When treating pediatric patients with RISPERDAL for any indication, weight gain should be assessed against that expected with normal growth.

ERDAL 0.5–2.5 mg group, 1.44 kg in the RISPERDAL 3–6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index. When treating pediatric patients with RISPERDAL for any indication, weight gain should be assessed against that expected with normal growth. 5.6 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, RISPERDAL elevates prolactin levels and the elevation persists during chronic administration. RISPERDAL is associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1) ] . Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer. 5.7 Orthostatic Hypotension RISPERDAL may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of RISPERDAL-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see Dosage and Administration (2.1 , 2.4) ] . Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. RISPERDAL should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of RISPERDAL and antihypertensive medication. 5.8 Falls Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including RISPERDAL, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

d to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.9 Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including RISPERDAL. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of RISPERDAL should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue RISPERDAL and have their WBC followed until recovery. 5.10 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction associated with RISPERDAL treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (RISPERDAL 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of RISPERDAL 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reaction. Since RISPERDAL has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that RISPERDAL therapy does not affect them adversely. 5.11 Seizures During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of RISPERDAL-treated patients, two in association with hyponatremia. RISPERDAL should be used cautiously in patients with a history of seizures. 5.12 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. RISPERDAL and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [see Boxed Warning and Warnings and Precautions (5.1) ] . 5.13 Priapism Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention. 5.14 Body Temperature Regulation Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral RISPERDAL use. Caution is advised when prescribing for patients who will be exposed to temperature extremes. 5.15 Patients with Phenylketonuria Inform patients that RISPERDAL M-TAB Orally Disintegrating Tablets contain phenylalanine. Phenylalanine is a component of aspartame.

have been reported in association with oral RISPERDAL use. Caution is advised when prescribing for patients who will be exposed to temperature extremes. 5.15 Patients with Phenylketonuria Inform patients that RISPERDAL M-TAB Orally Disintegrating Tablets contain phenylalanine. Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.14 mg phenylalanine.

<table width="100%"><caption>Table 2. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania</caption><col width="35%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="35%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><thead><tr><th/><th/><th align="center" colspan="2">RISPERDAL</th></tr><tr styleCode="Botrule"><th/><th>Placebo</th><th>1&#x2013;8 mg/day</th><th>&gt;8&#x2013;16 mg/day</th></tr></thead><tbody><tr><td/><td colspan="3"><content styleCode="bold">Mean change from baseline (mg/dL)</content></td></tr><tr><td/><td><content styleCode="bold">n=555</content></td><td><content styleCode="bold">n=748</content></td><td><content styleCode="bold">n=164</content></td></tr><tr><td>Serum Glucose</td><td>-1.4</td><td>0.8</td><td>0.6</td></tr><tr><td/><td colspan="3"><content styleCode="bold">Proportion of patients with shifts</content></td></tr><tr><td>Serum Glucose (&lt;140 mg/dL to &#x2265;200 mg/dL) </td><td> 0.6% (3/525) </td><td> 0.4% (3/702) </td><td> 0% (0/158) </td></tr></tbody></table> <table width="100%"><caption>Table 3. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13&#x2013;17 years of age), Bipolar Mania (10&#x2013;17 years of age), or Autistic Disorder (5 to 17 years of age)</caption><col width="33%" align="left" valign="top"/><col width="34%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th/><th/><th>RISPERDAL</th></tr><tr styleCode="Botrule"><th/><th>Placebo</th><th>0.5&#x2013;6 mg/day</th></tr></thead><tbody><tr><td/><td colspan="2"><content styleCode="bold">Mean change from baseline (mg/dL)</content></td></tr><tr><td/><td><content styleCode="bold">n=76</content></td><td><content styleCode="bold">n=135</content></td></tr><tr><td>Serum Glucose</td><td valign="bottom">-1.3</td><td valign="bottom">2.6</td></tr><tr><td/><td colspan="2"><content styleCode="bold">Proportion of patients with shifts</content></td></tr><tr><td>Serum Glucose (&lt;100 mg/dL to &#x2265;126 mg/dL) </td><td valign="bottom"> 0% (0/64) </td><td valign="bottom"> 0.8% (1/120) </td></tr></tbody></table>

ign="bottom">-1.3</td><td valign="bottom">2.6</td></tr><tr><td/><td colspan="2"><content styleCode="bold">Proportion of patients with shifts</content></td></tr><tr><td>Serum Glucose (&lt;100 mg/dL to &#x2265;126 mg/dL) </td><td valign="bottom"> 0% (0/64) </td><td valign="bottom"> 0.8% (1/120) </td></tr></tbody></table> <table width="100%"><caption>Table 4. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania</caption><col width="35%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="35%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><thead><tr><th/><th/><th colspan="2">RISPERDAL</th></tr><tr styleCode="Botrule"><th/><th>Placebo</th><th>1&#x2013;8 mg/day</th><th>&gt;8&#x2013;16 mg/day</th></tr></thead><tbody><tr><td/><td colspan="3"><content styleCode="bold">Mean change from baseline (mg/dL)</content></td></tr><tr><td><content styleCode="bold">Cholesterol</content></td><td><content styleCode="bold">n=559</content></td><td><content styleCode="bold">n=742</content></td><td><content styleCode="bold">n=156</content></td></tr><tr><td>Change from baseline</td><td>0.6</td><td>6.9</td><td>1.8</td></tr><tr><td/><td/><td/><td/></tr><tr><td><content styleCode="bold">Triglycerides</content></td><td><content styleCode="bold">n=183</content></td><td><content styleCode="bold">n=307</content></td><td><content styleCode="bold">n=123</content></td></tr><tr><td>Change from baseline</td><td>-17.4</td><td>-4.9</td><td>-8.3</td></tr><tr><td/><td/><td/><td/></tr><tr><td/><td colspan="3"><content styleCode="bold">Proportion of patients With Shifts</content></td></tr><tr><td><content styleCode="bold">Cholesterol</content> (&lt;200 mg/dL to &#x2265;240 mg/dL) </td><td valign="bottom">2.7%</td><td valign="bottom">4.3%</td><td valign="bottom">6.3%</td></tr><tr><td/><td>(10/368)</td><td>(22/516)</td><td>(6/96)</td></tr><tr><td><content styleCode="bold">Triglycerides</content> (&lt;500 mg/dL to &#x2265;500 mg/dL) </td><td>1.1% (2/180) </td><td>2.7% (8/301) </td><td>2.5% (3/121) </td></tr></tbody></table>

7%</td><td valign="bottom">4.3%</td><td valign="bottom">6.3%</td></tr><tr><td/><td>(10/368)</td><td>(22/516)</td><td>(6/96)</td></tr><tr><td><content styleCode="bold">Triglycerides</content> (&lt;500 mg/dL to &#x2265;500 mg/dL) </td><td>1.1% (2/180) </td><td>2.7% (8/301) </td><td>2.5% (3/121) </td></tr></tbody></table> <table width="100%"><caption>Table 5. Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13&#x2013;17 Years of Age), Bipolar Mania (10&#x2013;17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)</caption><col width="33%" align="left" valign="top"/><col width="34%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th/><th/><th>RISPERDAL</th></tr><tr styleCode="Botrule"><th/><th>Placebo</th><th>0.5&#x2013;6 mg/day</th></tr></thead><tbody><tr><td/><td colspan="2"><content styleCode="bold">Mean change from baseline (mg/dL)</content></td></tr><tr><td><content styleCode="bold">Cholesterol</content></td><td><content styleCode="bold">n=74</content></td><td><content styleCode="bold">n=133</content></td></tr><tr><td>Change from baseline</td><td>0.3</td><td>-0.3</td></tr><tr><td/><td/><td/></tr><tr><td><content styleCode="bold">LDL</content></td><td><content styleCode="bold">n=22</content></td><td><content styleCode="bold">n=22</content></td></tr><tr><td>Change from baseline</td><td>3.7</td><td>0.5</td></tr><tr><td/><td/><td/></tr><tr><td><content styleCode="bold">HDL</content></td><td><content styleCode="bold">n=22</content></td><td><content styleCode="bold">n=22</content></td></tr><tr><td>Change from baseline</td><td>1.6</td><td>-1.9</td></tr><tr><td/><td/><td/></tr><tr><td><content styleCode="bold">Triglycerides</content></td><td><content styleCode="bold">n=77</content></td><td><content styleCode="bold">n=138</content></td></tr><tr><td>Change from baseline</td><td>-9.0</td><td>-2.6</td></tr><tr><td/><td/><td/></tr><tr><td/><td colspan="2"><content styleCode="bold">Proportion of patients with shifts</content></td></tr><tr><td><content styleCode="bold">Cholesterol</content> (&lt;170 mg/dL to &#x2265;200 mg/dL) </td><td>2.4% (1/42) </td><td>3.8% (3/80) </td></tr><tr><td><content styleCode="bold">LDL</content> (&lt;110 mg/dL to &#x2265;130 mg/dL) </td><td>0% (0/16) </td><td>0% (0/16) </td></tr><tr><td><content styleCode="bold">HDL</content> (&#x2265;40 mg/dL to &lt;40 mg/dL) </td><td>0% (0/19) </td><td>10% (2/20) </td></tr><tr><td><content styleCode="bold">Triglycerides</content> (&lt;150 mg/dL to &#x2265;200 mg/dL) </td><td>1.5% (1/65) </td><td>7.1% (8/113) </td></tr></tbody></table>

<td>0% (0/16) </td></tr><tr><td><content styleCode="bold">HDL</content> (&#x2265;40 mg/dL to &lt;40 mg/dL) </td><td>0% (0/19) </td><td>10% (2/20) </td></tr><tr><td><content styleCode="bold">Triglycerides</content> (&lt;150 mg/dL to &#x2265;200 mg/dL) </td><td>1.5% (1/65) </td><td>7.1% (8/113) </td></tr></tbody></table> <table width="100%"><caption>Table 6. Mean Change in Body Weight (kg) and the Proportion of Subjects with &#x2265;7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania</caption><col width="25%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th/><th/><th colspan="2">RISPERDAL</th></tr><tr styleCode="Botrule"><th/><th>Placebo (n=597) </th><th>1&#x2013;8 mg/day (n=769) </th><th>&gt;8&#x2013;16 mg/day (n=158) </th></tr></thead><tbody><tr><td><content styleCode="bold">Weight (kg)</content></td><td/><td/><td/></tr><tr><td>Change from baseline</td><td>-0.3</td><td>0.7</td><td>2.2</td></tr><tr><td><content styleCode="bold">Weight Gain</content></td><td/><td/><td/></tr><tr><td>&#x2265;7% increase from baseline</td><td>2.9%</td><td>8.7%</td><td>20.9%</td></tr></tbody></table> <table width="100%"><caption>Table 7. Mean Change in Body Weight (kg) and the Proportion of Subjects With &#x2265;7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13&#x2013;17 Years of Age), Bipolar Mania (10&#x2013;17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5&#x2013;17 Years of Age)</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th/><th>Placebo (n=375) </th><th>RISPERDAL 0.5&#x2013;6 mg/day (n=448) </th></tr></thead><tbody><tr><td><content styleCode="bold">Weight (kg)</content></td><td/><td/></tr><tr><td>Change from baseline</td><td>0.6</td><td>2.0</td></tr><tr><td><content styleCode="bold">Weight Gain</content></td><td/><td/></tr><tr><td>&#x2265;7% increase from baseline</td><td>6.9%</td><td>32.6%</td></tr></tbody></table>

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2) ] Neuroleptic malignant syndrome [see Warnings and Precautions (5.3) ] Tardive dyskinesia [see Warnings and Precautions (5.4) ] Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.5) ] Hyperprolactinemia [see Warnings and Precautions (5.6) ] Orthostatic hypotension [see Warnings and Precautions (5.7) ] Falls [see Warnings and Precautions (5.8) ] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.10) ] Seizures [see Warnings and Precautions (5.11) ] Dysphagia [see Warnings and Precautions (5.12) ] Priapism [see Warnings and Precautions (5.13) ] Disruption of body temperature regulation [see Warnings and Precautions (5.14) ] Patients with Phenylketonuria [see Warnings and Precautions (5.15) ]. The most common adverse reactions in clinical trials (>5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions, Discontinuations Due to Adverse Reactions (6.1) ] . The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of RISPERDAL for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received RISPERDAL while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with RISPERDAL varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs. The most common adverse reactions in clinical trials (≥5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc.

ach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 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. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia Adult Patients with Schizophrenia Table 8 lists the adverse reactions reported in 2% or more of RISPERDAL-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials. Table 8. Adverse Reactions in ≥2% of RISPERDAL-Treated Adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Reaction RISPERDAL System/Organ Class Adverse Reaction 2–8 mg per day (N=366) >8–16 mg per day (N=198) Placebo (N=225) Cardiac Disorders Tachycardia 1 3 0 Eye Disorders Vision blurred 3 1 1 Gastrointestinal Disorders Nausea 9 4 4 Constipation 8 9 6 Dyspepsia 8 6 5 Dry mouth 4 0 1 Abdominal discomfort 3 1 1 Salivary hypersecretion 2 1 <1 Diarrhea 2 1 1 General Disorders Fatigue 3 1 0 Chest pain 2 2 1 Asthenia 2 1 <1 Infections and Infestations Nasopharyngitis 3 4 3 Upper respiratory tract infection 2 3 1 Sinusitis 1 2 1 Urinary tract infection 1 3 0 Investigations Blood creatine phosphokinase increased 1 2 <1 Heart rate increased <1 2 0 Musculoskeletal and Connective Tissue Disorders Back pain 4 1 1 Arthralgia 2 3 <1 Pain in extremity 2 1 1 Nervous System Disorders Parkinsonism Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson's disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor. 14 17 8 Akathisia 10 10 3 Sedation 10 5 2 Dizziness 7 4 2 Dystonia 3 4 2 Tremor 2 3 1 Dizziness postural 2 0 0 Psychiatric Disorders Insomnia 32 25 27 Anxiety 16 11 11 Respiratory, Thoracic and Mediastinal Disorders Nasal congestion 4 6 2 Dyspnea 1 2 0 Epistaxis <1 2 0 Skin and Subcutaneous Tissue Disorders Rash 1 4 1 Dry skin 1 3 0 Vascular Disorders Orthostatic hypotension 2 1 0 Pediatric Patients with Schizophrenia Table 9 lists the adverse reactions reported in 5% or more of RISPERDAL-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial. Table 9. Adverse Reactions in ≥5% of RISPERDAL-Treated Pediatric Patients (and greater than placebo) with Schizophrenia in a Double-Blind Trial Percentage of Patients Reporting Reaction RISPERDAL System/Organ Class Adverse Reaction 1–3 mg per day (N=55) 4–6 mg per day (N=51) Placebo (N=54) Gastrointestinal Disorders Salivary hypersecretion 0 10 2 Nervous System Disorders Sedation 24 12 4 Parkinsonism Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration.

(N=54) Gastrointestinal Disorders Salivary hypersecretion 0 10 2 Nervous System Disorders Sedation 24 12 4 Parkinsonism Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration. 16 28 11 Tremor 11 10 6 Akathisia 9 10 4 Dizziness 7 14 2 Dystonia 2 6 0 Psychiatric Disorders Anxiety 7 6 0 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania Adult Patients with Bipolar Mania Table 10 lists the adverse reactions reported in 2% or more of RISPERDAL-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials. Table 10. Adverse Reactions in ≥2% of RISPERDAL-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials Percentage of Patients Reporting Reaction System/Organ Class Adverse Reaction RISPERDAL 1–6 mg per day (N=448) Placebo (N=424) Eye Disorders Vision blurred 2 1 Gastrointestinal Disorders Nausea 5 2 Diarrhea 3 2 Salivary hypersecretion 3 1 Stomach discomfort 2 <1 General Disorders Fatigue 2 1 Nervous System Disorders Parkinsonism Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis. 25 9 Sedation 11 4 Akathisia 9 3 Tremor 6 3 Dizziness 6 5 Dystonia 5 1 Lethargy 2 1 Table 11 lists the adverse reactions reported in 2% or more of RISPERDAL-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials. Table 11. Adverse Reactions in ≥2% of RISPERDAL-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Adjunctive Therapy Trials Percentage of Patients Reporting Reaction System/Organ Class RISPERDAL + Mood Stabilizer Placebo + Mood Stabilizer Adverse Reaction (N=127) (N=126) Cardiac Disorders Palpitations 2 0 Gastrointestinal Disorders Dyspepsia 9 8 Nausea 6 4 Diarrhea 6 4 Salivary hypersecretion 2 0 General Disorders Chest pain 2 1 Infections and Infestations Urinary tract infection 2 1 Nervous System Disorders Parkinsonism Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia. 14 4 Sedation 9 4 Akathisia 8 0 Dizziness 7 2 Tremor 6 2 Lethargy 2 1 Psychiatric Disorders Anxiety 3 2 Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 5 2 Cough 2 0 Pediatric Patients with Bipolar Mania Table 12 lists the adverse reactions reported in 5% or more of RISPERDAL-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial. Table 12. Adverse Reactions in ≥5% of RISPERDAL-Treated Pediatric Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Reaction RISPERDAL System/Organ Class Adverse Reaction 0.5–2.5 mg per day (N=50) 3–6 mg per day (N=61) Placebo (N=58) Eye Disorders Vision blurred 4 7 0 Gastrointestinal Disorders Abdominal pain upper 16 13 5 Nausea 16 13 7 Vomiting 10 10 5 Diarrhea 8 7 2 Dyspepsia 10 3 2 Stomach discomfort 6 0 2 General Disorders Fatigue 18 30 3 Metabolism and Nutrition Disorders Increased appetite 4 7 2 Nervous System Disorders Sedation 42 56 19 Dizziness 16 13 5 Parkinsonism Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms.

Fatigue 18 30 3 Metabolism and Nutrition Disorders Increased appetite 4 7 2 Nervous System Disorders Sedation 42 56 19 Dizziness 16 13 5 Parkinsonism Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia. 6 12 3 Dystonia 6 5 0 Akathisia 0 8 2 Psychiatric Disorders Anxiety 0 8 3 Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 10 3 5 Skin and Subcutaneous Tissue Disorders Rash 0 7 2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder Table 13 lists the adverse reactions reported in 5% or more of RISPERDAL-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study. Table 13. Adverse Reactions in ≥5% of RISPERDAL-Treated Pediatric Patients (and greater than placebo) Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Reaction System/Organ Class RISPERDAL 0.5–4.0 mg/day Placebo Adverse Reaction (N=107) (N=115) Gastrointestinal Disorders Vomiting 20 17 Constipation 17 6 Dry mouth 10 4 Nausea 8 5 Salivary hypersecretion 7 1 General Disorders and Administration Site Conditions Fatigue 31 9 Pyrexia 16 13 Thirst 7 4 Infections and Infestations Nasopharyngitis 19 9 Rhinitis 9 7 Upper respiratory tract infection 8 3 Investigations Weight increased 8 2 Metabolism and Nutrition Disorders Increased appetite 44 15 Nervous System Disorders Sedation 63 15 Drooling 12 4 Headache 12 10 Tremor 8 1 Dizziness 8 2 Parkinsonism Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness. 8 1 Renal and Urinary Disorders Enuresis 16 10 Respiratory, Thoracic and Mediastinal Disorders Cough 17 12 Rhinorrhea 12 10 Nasal congestion 10 4 Skin and Subcutaneous Tissue Disorders Rash 8 5 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of RISPERDAL in adults and pediatric patients.

congestion 10 4 Skin and Subcutaneous Tissue Disorders Rash 8 5 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of RISPERDAL in adults and pediatric patients. Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block Ear and Labyrinth Disorders: ear pain, tinnitus Endocrine Disorders: hyperprolactinemia Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal Immune System Disorders: drug hypersensitivity Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: decreased appetite, polydipsia, anorexia Musculoskeletal and Connective Tissue Disorders: joint stiffness, joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular, acne, hyperkeratosis, seborrheic dermatitis Vascular Disorders: hypotension, flushing Additional Adverse Reactions Reported with RISPERDAL CONSTA The following is a list of additional adverse reactions that have been reported during the premarketing evaluation of

us, rash papular, rash generalized, rash maculopapular, acne, hyperkeratosis, seborrheic dermatitis Vascular Disorders: hypotension, flushing Additional Adverse Reactions Reported with RISPERDAL CONSTA The following is a list of additional adverse reactions that have been reported during the premarketing evaluation of RISPERDAL CONSTA, regardless of frequency of occurrence: Cardiac Disorders: bradycardia Ear and Labyrinth Disorders: vertigo Eye Disorders: blepharospasm Gastrointestinal Disorders: toothache, tongue spasm General Disorders and Administration Site Conditions: pain Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis, subcutaneous abscess Injury and Poisoning: fall Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme increased Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain Nervous System Disorders: convulsion, paresthesia Psychiatric Disorders: depression Skin and Subcutaneous Tissue Disorders: eczema Vascular Disorders: hypertension Discontinuations Due to Adverse Reactions Schizophrenia - Adults Approximately 7% (39/564) of RISPERDAL-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo.

Disorders: eczema Vascular Disorders: hypertension Discontinuations Due to Adverse Reactions Schizophrenia - Adults Approximately 7% (39/564) of RISPERDAL-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more RISPERDAL-treated patients were: Table 14. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL-Treated Adult Patients in Schizophrenia Trials RISPERDAL Adverse Reaction 2–8 mg/day (N=366) >8–16 mg/day (N=198) Placebo (N=225) Dizziness 1.4% 1.0% 0% Nausea 1.4% 0% 0% Vomiting 0.8% 0% 0% Parkinsonism 0.8% 0% 0% Somnolence 0.8% 0% 0% Dystonia 0.5% 0% 0% Agitation 0.5% 0% 0% Abdominal pain 0.5% 0% 0% Orthostatic hypotension 0.3% 0.5% 0% Akathisia 0.3% 2.0% 0% Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial. Schizophrenia - Pediatrics Approximately 7% (7/106), of RISPERDAL-treated patients discontinued treatment due to an adverse reaction in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one RISPERDAL-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%). Bipolar Mania - Adults In double-blind, placebo-controlled trials with RISPERDAL as monotherapy, approximately 6% (25/448) of RISPERDAL-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in RISPERDAL-treated patients were: Table 15. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL-Treated Adult Patients in Bipolar Mania Clinical Trials Adverse Reaction RISPERDAL 1–6 mg/day (N=448) Placebo (N=424) Parkinsonism 0.4% 0% Lethargy 0.2% 0% Dizziness 0.2% 0% Alanine aminotransferase increased 0.2% 0.2% Aspartate aminotransferase increased 0.2% 0.2% Bipolar Mania - Pediatrics In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one RISPERDAL-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%). Autistic Disorder - Pediatrics In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n=156), one RISPERDAL-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event. Dose Dependency of Adverse Reactions in Clinical Trials Extrapyramidal Symptoms Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with RISPERDAL treatment. Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of RISPERDAL (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS: Table 16.

nt. Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of RISPERDAL (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS: Table 16. Dose Groups Placebo RISPERDAL 2 mg RISPERDAL 6 mg RISPERDAL 10 mg RISPERDAL 16 mg Parkinsonism 1.2 0.9 1.8 2.4 2.6 EPS Incidence 13% 17% 21% 21% 35% Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of RISPERDAL (1, 4, 8, 12, and 16 mg/day): Table 17. Dose Groups RISPERDAL 1 mg RISPERDAL 4 mg RISPERDAL 8 mg RISPERDAL 12 mg RISPERDAL 16 mg Parkinsonism 0.6 1.7 2.4 2.9 4.1 EPS Incidence 7% 12% 17% 18% 20% Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Other Adverse Reactions Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of RISPERDAL (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration. Changes in Body Weight Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [see Warnings and Precautions (5.5) , Adverse Reactions (6) , and Use in Specific Populations (8.4) ]. Changes in ECG Parameters Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all RISPERDAL doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8–16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4–6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups. In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 – 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the RISPERDAL groups and 6.5 beats per minute in the placebo group. There were no other notable ECG changes. In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there were no significant changes in ECG parameters, other than the effect of RISPERDAL to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.

han the effect of RISPERDAL to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

<table width="100%"><caption>Table 8. Adverse Reactions in &#x2265;2% of RISPERDAL-Treated Adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-Controlled Trials</caption><col width="40%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th/><th colspan="3">Percentage of Patients Reporting Reaction</th></tr><tr><th/><th colspan="2">RISPERDAL</th><th/></tr><tr styleCode="Botrule"><th>System/Organ Class Adverse Reaction </th><th>2&#x2013;8 mg per day (N=366) </th><th>&gt;8&#x2013;16 mg per day (N=198) </th><th>Placebo (N=225) </th></tr></thead><tbody><tr><td><content styleCode="bold">Cardiac Disorders</content></td><td/><td/><td/></tr><tr><td> Tachycardia</td><td>1</td><td>3</td><td>0</td></tr><tr><td><content styleCode="bold">Eye Disorders</content></td><td/><td/><td/></tr><tr><td> Vision blurred</td><td>3</td><td>1</td><td>1</td></tr><tr><td><content styleCode="bold">Gastrointestinal Disorders</content></td><td/><td/><td/></tr><tr><td> Nausea</td><td>9</td><td>4</td><td>4</td></tr><tr><td> Constipation</td><td>8</td><td>9</td><td>6</td></tr><tr><td> Dyspepsia</td><td>8</td><td>6</td><td>5</td></tr><tr><td> Dry mouth</td><td>4</td><td>0</td><td>1</td></tr><tr><td> Abdominal discomfort</td><td>3</td><td>1</td><td>1</td></tr><tr><td> Salivary hypersecretion</td><td>2</td><td>1</td><td>&lt;1</td></tr><tr><td> Diarrhea</td><td>2</td><td>1</td><td>1</td></tr><tr><td><content styleCode="bold">General Disorders</content></td><td/><td/><td/></tr><tr><td> Fatigue</td><td>3</td><td>1</td><td>0</td></tr><tr><td> Chest pain</td><td>2</td><td>2</td><td>1</td></tr><tr><td> Asthenia</td><td>2</td><td>1</td><td>&lt;1</td></tr><tr><td><content styleCode="bold">Infections and Infestations</content></td><td/><td/><td/></tr><tr><td> Nasopharyngitis</td><td>3</td><td>4</td><td>3</td></tr><tr><td> Upper respiratory tract infection</td><td>2</td><td>3</td><td>1</td></tr><tr><td> Sinusitis</td><td>1</td><td>2</td><td>1</td></tr><tr><td> Urinary tract infection</td><td>1</td><td>3</td><td>0</td></tr><tr><td><content styleCode="bold">Investigations</content></td><td/><td/><td/></tr><tr><td> Blood creatine phosphokinase increased</td><td>1</td><td>2</td><td>&lt;1</td></tr><tr><td> Heart rate increased</td><td>&lt;1</td><td>2</td><td>0</td></tr><tr><td><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td><td/><td/><td/></tr><tr><td> Back pain</td><td>4</td><td>1</td><td>1</td></tr><tr><td> Arthralgia</td><td>2</td><td>3</td><td>&lt;1</td></tr><tr><td> Pain in extremity</td><td>2</td><td>1</td><td>1</td></tr><tr><td><content styleCode="bold">Nervous System Disorders</content></td><td/><td/><td/></tr><tr><td>Parkinsonism <footnote ID="table8a">Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson&apos;s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis.

l stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson&apos;s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.</footnote></td><td>14</td><td>17</td><td>8</td></tr><tr><td> Akathisia <footnoteRef IDREF="table8a"/></td><td>10</td><td>10</td><td>3</td></tr><tr><td> Sedation</td><td>10</td><td>5</td><td>2</td></tr><tr><td> Dizziness</td><td>7</td><td>4</td><td>2</td></tr><tr><td> Dystonia <footnoteRef IDREF="table8a"/></td><td>3</td><td>4</td><td>2</td></tr><tr><td> Tremor <footnoteRef IDREF="table8a"/></td><td>2</td><td>3</td><td>1</td></tr><tr><td> Dizziness postural</td><td>2</td><td>0</td><td>0</td></tr><tr><td><content styleCode="bold">Psychiatric Disorders</content></td><td/><td/><td/></tr><tr><td> Insomnia</td><td>32</td><td>25</td><td>27</td></tr><tr><td> Anxiety</td><td>16</td><td>11</td><td>11</td></tr><tr><td><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td><td/><td/><td/></tr><tr><td> Nasal congestion</td><td>4</td><td>6</td><td>2</td></tr><tr><td> Dyspnea</td><td>1</td><td>2</td><td>0</td></tr><tr><td> Epistaxis</td><td>&lt;1</td><td>2</td><td>0</td></tr><tr><td><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td><td/><td/><td/></tr><tr><td> Rash</td><td>1</td><td>4</td><td>1</td></tr><tr><td> Dry skin</td><td>1</td><td>3</td><td>0</td></tr><tr><td><content styleCode="bold">Vascular Disorders</content></td><td/><td/><td/></tr><tr><td> Orthostatic hypotension</td><td>2</td><td>1</td><td>0</td></tr></tbody></table>

</content></td><td/><td/><td/></tr><tr><td> Rash</td><td>1</td><td>4</td><td>1</td></tr><tr><td> Dry skin</td><td>1</td><td>3</td><td>0</td></tr><tr><td><content styleCode="bold">Vascular Disorders</content></td><td/><td/><td/></tr><tr><td> Orthostatic hypotension</td><td>2</td><td>1</td><td>0</td></tr></tbody></table> <table width="100%"><caption>Table 9. Adverse Reactions in &#x2265;5% of RISPERDAL-Treated Pediatric Patients (and greater than placebo) with Schizophrenia in a Double-Blind Trial</caption><col width="40%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th/><th colspan="3">Percentage of Patients Reporting Reaction</th></tr><tr><th/><th colspan="2">RISPERDAL</th><th/></tr><tr styleCode="Botrule"><th>System/Organ Class Adverse Reaction </th><th>1&#x2013;3 mg per day (N=55) </th><th>4&#x2013;6 mg per day (N=51) </th><th>Placebo (N=54) </th></tr></thead><tbody><tr><td><content styleCode="bold">Gastrointestinal Disorders</content></td><td/><td/><td/></tr><tr><td> Salivary hypersecretion</td><td>0</td><td>10</td><td>2</td></tr><tr><td><content styleCode="bold">Nervous System Disorders</content></td><td/><td/><td/></tr><tr><td> Sedation</td><td>24</td><td>12</td><td>4</td></tr><tr><td>Parkinsonism <footnote ID="table9a">Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration.</footnote></td><td>16</td><td>28</td><td>11</td></tr><tr><td> Tremor</td><td>11</td><td>10</td><td>6</td></tr><tr><td> Akathisia <footnoteRef IDREF="table9a"/></td><td>9</td><td>10</td><td>4</td></tr><tr><td> Dizziness</td><td>7</td><td>14</td><td>2</td></tr><tr><td> Dystonia <footnoteRef IDREF="table9a"/></td><td>2</td><td>6</td><td>0</td></tr><tr><td><content styleCode="bold">Psychiatric Disorders</content></td><td/><td/><td/></tr><tr><td> Anxiety</td><td>7</td><td>6</td><td>0</td></tr></tbody></table>

4</td></tr><tr><td> Dizziness</td><td>7</td><td>14</td><td>2</td></tr><tr><td> Dystonia <footnoteRef IDREF="table9a"/></td><td>2</td><td>6</td><td>0</td></tr><tr><td><content styleCode="bold">Psychiatric Disorders</content></td><td/><td/><td/></tr><tr><td> Anxiety</td><td>7</td><td>6</td><td>0</td></tr></tbody></table> <table width="100%"><caption>Table 10. Adverse Reactions in &#x2265;2% of RISPERDAL-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th/><th colspan="2">Percentage of Patients Reporting Reaction</th></tr><tr styleCode="Botrule"><th>System/Organ Class Adverse Reaction </th><th>RISPERDAL 1&#x2013;6 mg per day (N=448) </th><th>Placebo (N=424) </th></tr></thead><tbody><tr><td><content styleCode="bold">Eye Disorders</content></td><td/><td/></tr><tr><td> Vision blurred</td><td>2</td><td>1</td></tr><tr><td><content styleCode="bold">Gastrointestinal Disorders</content></td><td/><td/></tr><tr><td> Nausea</td><td>5</td><td>2</td></tr><tr><td> Diarrhea</td><td>3</td><td>2</td></tr><tr><td> Salivary hypersecretion</td><td>3</td><td>1</td></tr><tr><td> Stomach discomfort</td><td>2</td><td>&lt;1</td></tr><tr><td><content styleCode="bold">General Disorders</content></td><td/><td/></tr><tr><td> Fatigue</td><td>2</td><td>1</td></tr><tr><td><content styleCode="bold">Nervous System Disorders</content></td><td/><td/></tr><tr><td> Parkinsonism <footnote ID="table10a">Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis.</footnote></td><td>25</td><td>9</td></tr><tr><td> Sedation</td><td>11</td><td>4</td></tr><tr><td> Akathisia <footnoteRef IDREF="table10a"/></td><td>9</td><td>3</td></tr><tr><td> Tremor <footnoteRef IDREF="table10a"/></td><td>6</td><td>3</td></tr><tr><td> Dizziness</td><td>6</td><td>5</td></tr><tr><td> Dystonia <footnoteRef IDREF="table10a"/></td><td>5</td><td>1</td></tr><tr><td> Lethargy</td><td>2</td><td>1</td></tr></tbody></table>

eRef IDREF="table10a"/></td><td>9</td><td>3</td></tr><tr><td> Tremor <footnoteRef IDREF="table10a"/></td><td>6</td><td>3</td></tr><tr><td> Dizziness</td><td>6</td><td>5</td></tr><tr><td> Dystonia <footnoteRef IDREF="table10a"/></td><td>5</td><td>1</td></tr><tr><td> Lethargy</td><td>2</td><td>1</td></tr></tbody></table> <table width="100%"><caption>Table 11. Adverse Reactions in &#x2265;2% of RISPERDAL-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Adjunctive Therapy Trials</caption><col width="40%" align="left" valign="top"/><col width="35%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th/><th colspan="2">Percentage of Patients Reporting Reaction</th></tr><tr><th valign="bottom">System/Organ Class</th><th>RISPERDAL + Mood Stabilizer</th><th>Placebo + Mood Stabilizer</th></tr><tr styleCode="Botrule"><th> Adverse Reaction</th><th>(N=127)</th><th>(N=126)</th></tr></thead><tbody><tr><td><content styleCode="bold">Cardiac Disorders</content></td><td/><td/></tr><tr><td> Palpitations</td><td>2</td><td>0</td></tr><tr><td><content styleCode="bold">Gastrointestinal Disorders</content></td><td/><td/></tr><tr><td> Dyspepsia</td><td>9</td><td>8</td></tr><tr><td> Nausea</td><td>6</td><td>4</td></tr><tr><td> Diarrhea</td><td>6</td><td>4</td></tr><tr><td> Salivary hypersecretion</td><td>2</td><td>0</td></tr><tr><td><content styleCode="bold">General Disorders</content></td><td/><td/></tr><tr><td> Chest pain</td><td>2</td><td>1</td></tr><tr><td><content styleCode="bold">Infections and Infestations</content></td><td/><td/></tr><tr><td> Urinary tract infection</td><td>2</td><td>1</td></tr><tr><td><content styleCode="bold">Nervous System Disorders</content></td><td/><td/></tr><tr><td> Parkinsonism <footnote ID="table11a">Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia.</footnote></td><td>14</td><td>4</td></tr><tr><td> Sedation</td><td>9</td><td>4</td></tr><tr><td> Akathisia <footnoteRef IDREF="table11a"/></td><td>8</td><td>0</td></tr><tr><td> Dizziness</td><td>7</td><td>2</td></tr><tr><td> Tremor</td><td>6</td><td>2</td></tr><tr><td> Lethargy</td><td>2</td><td>1</td></tr><tr><td><content styleCode="bold">Psychiatric Disorders</content></td><td/><td/></tr><tr><td> Anxiety</td><td>3</td><td>2</td></tr><tr><td><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td><td/><td/></tr><tr><td> Pharyngolaryngeal pain</td><td>5</td><td>2</td></tr><tr><td> Cough</td><td>2</td><td>0</td></tr></tbody></table>

ic Disorders</content></td><td/><td/></tr><tr><td> Anxiety</td><td>3</td><td>2</td></tr><tr><td><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td><td/><td/></tr><tr><td> Pharyngolaryngeal pain</td><td>5</td><td>2</td></tr><tr><td> Cough</td><td>2</td><td>0</td></tr></tbody></table> <table width="100%"><caption>Table 12. Adverse Reactions in &#x2265;5% of RISPERDAL-Treated Pediatric Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Trials</caption><col width="40%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th/><th colspan="3">Percentage of Patients Reporting Reaction</th></tr><tr><th/><th colspan="2">RISPERDAL</th><th/></tr><tr styleCode="Botrule"><th>System/Organ Class Adverse Reaction </th><th>0.5&#x2013;2.5 mg per day (N=50) </th><th>3&#x2013;6 mg per day (N=61) </th><th>Placebo (N=58) </th></tr></thead><tbody><tr><td><content styleCode="bold">Eye Disorders</content></td><td/><td/><td/></tr><tr><td> Vision blurred</td><td>4</td><td>7</td><td>0</td></tr><tr><td><content styleCode="bold">Gastrointestinal Disorders</content></td><td/><td/><td/></tr><tr><td> Abdominal pain upper</td><td>16</td><td>13</td><td>5</td></tr><tr><td> Nausea</td><td>16</td><td>13</td><td>7</td></tr><tr><td> Vomiting</td><td>10</td><td>10</td><td>5</td></tr><tr><td> Diarrhea</td><td>8</td><td>7</td><td>2</td></tr><tr><td> Dyspepsia</td><td>10</td><td>3</td><td>2</td></tr><tr><td> Stomach discomfort</td><td>6</td><td>0</td><td>2</td></tr><tr><td><content styleCode="bold">General Disorders</content></td><td/><td/><td/></tr><tr><td> Fatigue</td><td>18</td><td>30</td><td>3</td></tr><tr><td><content styleCode="bold">Metabolism and Nutrition Disorders</content></td><td/><td/><td/></tr><tr><td> Increased appetite</td><td>4</td><td>7</td><td>2</td></tr><tr><td><content styleCode="bold">Nervous System Disorders</content></td><td/><td/><td/></tr><tr><td> Sedation</td><td>42</td><td>56</td><td>19</td></tr><tr><td> Dizziness</td><td>16</td><td>13</td><td>5</td></tr><tr><td>Parkinsonism <footnote ID="table12a">Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.</footnote></td><td>6</td><td>12</td><td>3</td></tr><tr><td> Dystonia <footnoteRef IDREF="table12a"/></td><td>6</td><td>5</td><td>0</td></tr><tr><td> Akathisia <footnoteRef IDREF="table12a"/></td><td>0</td><td>8</td><td>2</td></tr><tr><td><content styleCode="bold">Psychiatric Disorders</content></td><td/><td/><td/></tr><tr><td> Anxiety</td><td>0</td><td>8</td><td>3</td></tr><tr><td><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td><td/><td/><td/></tr><tr><td> Pharyngolaryngeal pain</td><td>10</td><td>3</td><td>5</td></tr><tr><td><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td><td/><td/><td/></tr><tr><td> Rash</td><td>0</td><td>7</td><td>2</td></tr></tbody></table>

y, Thoracic and Mediastinal Disorders</content></td><td/><td/><td/></tr><tr><td> Pharyngolaryngeal pain</td><td>10</td><td>3</td><td>5</td></tr><tr><td><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td><td/><td/><td/></tr><tr><td> Rash</td><td>0</td><td>7</td><td>2</td></tr></tbody></table> <table width="100%"><caption>Table 13. Adverse Reactions in &#x2265;5% of RISPERDAL-Treated Pediatric Patients (and greater than placebo) Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials</caption><col width="55%" align="left" valign="top"/><col width="25%" align="left" valign="top"/><col width="20%" align="left" valign="top"/><thead><tr><th/><th colspan="2" align="center">Percentage of Patients Reporting Reaction</th></tr><tr><th> System/Organ Class </th><th>RISPERDAL 0.5&#x2013;4.0 mg/day </th><th valign="bottom">Placebo</th></tr><tr styleCode="Botrule"><th> Adverse Reaction</th><th>(N=107)</th><th>(N=115)</th></tr></thead><tbody><tr><td><content styleCode="bold">Gastrointestinal Disorders</content></td><td/><td/></tr><tr><td> Vomiting</td><td>20</td><td>17</td></tr><tr><td> Constipation</td><td>17</td><td>6</td></tr><tr><td> Dry mouth</td><td>10</td><td>4</td></tr><tr><td> Nausea</td><td>8</td><td>5</td></tr><tr><td> Salivary hypersecretion</td><td>7</td><td>1</td></tr><tr><td><content styleCode="bold">General Disorders and Administration Site Conditions</content></td><td/><td/></tr><tr><td> Fatigue</td><td>31</td><td>9</td></tr><tr><td> Pyrexia</td><td>16</td><td>13</td></tr><tr><td> Thirst</td><td>7</td><td>4</td></tr><tr><td><content styleCode="bold">Infections and Infestations</content></td><td/><td/></tr><tr><td> Nasopharyngitis</td><td>19</td><td>9</td></tr><tr><td> Rhinitis</td><td>9</td><td>7</td></tr><tr><td> Upper respiratory tract infection</td><td>8</td><td>3</td></tr><tr><td><content styleCode="bold">Investigations</content></td><td/><td/></tr><tr><td> Weight increased</td><td>8</td><td>2</td></tr><tr><td><content styleCode="bold">Metabolism and Nutrition Disorders</content></td><td/><td/></tr><tr><td> Increased appetite</td><td>44</td><td>15</td></tr><tr><td><content styleCode="bold">Nervous System Disorders</content></td><td/><td/></tr><tr><td> Sedation</td><td>63</td><td>15</td></tr><tr><td> Drooling</td><td>12</td><td>4</td></tr><tr><td> Headache</td><td>12</td><td>10</td></tr><tr><td> Tremor</td><td>8</td><td>1</td></tr><tr><td> Dizziness</td><td>8</td><td>2</td></tr><tr><td> Parkinsonism <footnote ID="table13a">Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness.</footnote></td><td>8</td><td>1</td></tr><tr><td><content styleCode="bold">Renal and Urinary Disorders</content></td><td/><td/></tr><tr><td> Enuresis</td><td>16</td><td>10</td></tr><tr><td><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td><td/><td/></tr><tr><td> Cough</td><td>17</td><td>12</td></tr><tr><td> Rhinorrhea</td><td>12</td><td>10</td></tr><tr><td> Nasal congestion</td><td>10</td><td>4</td></tr><tr><td><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td><td/><td/></tr><tr><td> Rash</td><td>8</td><td>5</td></tr></tbody></table>

></tr><tr><td> Cough</td><td>17</td><td>12</td></tr><tr><td> Rhinorrhea</td><td>12</td><td>10</td></tr><tr><td> Nasal congestion</td><td>10</td><td>4</td></tr><tr><td><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td><td/><td/></tr><tr><td> Rash</td><td>8</td><td>5</td></tr></tbody></table> <table width="100%"><caption>Table 14. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL-Treated Adult Patients in Schizophrenia Trials</caption><col width="25%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th/><th colspan="2">RISPERDAL</th><th/></tr><tr styleCode="Botrule"><th valign="bottom">Adverse Reaction</th><th>2&#x2013;8 mg/day (N=366) </th><th>&gt;8&#x2013;16 mg/day (N=198) </th><th>Placebo (N=225) </th></tr></thead><tbody><tr><td>Dizziness</td><td>1.4%</td><td>1.0%</td><td>0%</td></tr><tr><td>Nausea</td><td>1.4%</td><td>0%</td><td>0%</td></tr><tr><td>Vomiting</td><td>0.8%</td><td>0%</td><td>0%</td></tr><tr><td>Parkinsonism</td><td>0.8%</td><td>0%</td><td>0%</td></tr><tr><td>Somnolence</td><td>0.8%</td><td>0%</td><td>0%</td></tr><tr><td>Dystonia</td><td>0.5%</td><td>0%</td><td>0%</td></tr><tr><td>Agitation</td><td>0.5%</td><td>0%</td><td>0%</td></tr><tr><td>Abdominal pain</td><td>0.5%</td><td>0%</td><td>0%</td></tr><tr><td>Orthostatic hypotension</td><td>0.3%</td><td>0.5%</td><td>0%</td></tr><tr><td>Akathisia</td><td>0.3%</td><td>2.0%</td><td>0%</td></tr></tbody></table> <table width="75%"><caption>Table 15. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL-Treated Adult Patients in Bipolar Mania Clinical Trials</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th valign="bottom">Adverse Reaction</th><th>RISPERDAL 1&#x2013;6 mg/day (N=448) </th><th valign="bottom">Placebo (N=424) </th></tr></thead><tbody><tr><td>Parkinsonism</td><td>0.4%</td><td>0%</td></tr><tr><td>Lethargy</td><td>0.2%</td><td>0%</td></tr><tr><td>Dizziness</td><td>0.2%</td><td>0%</td></tr><tr><td>Alanine aminotransferase increased</td><td>0.2%</td><td>0.2%</td></tr><tr><td>Aspartate aminotransferase increased</td><td>0.2%</td><td>0.2%</td></tr></tbody></table>

arkinsonism</td><td>0.4%</td><td>0%</td></tr><tr><td>Lethargy</td><td>0.2%</td><td>0%</td></tr><tr><td>Dizziness</td><td>0.2%</td><td>0%</td></tr><tr><td>Alanine aminotransferase increased</td><td>0.2%</td><td>0.2%</td></tr><tr><td>Aspartate aminotransferase increased</td><td>0.2%</td><td>0.2%</td></tr></tbody></table> <table width="100%"><caption>Table 16.</caption><col width="17%" align="left" valign="top"/><col width="17%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><thead><tr><th>Dose Groups</th><th>Placebo</th><th>RISPERDAL 2 mg</th><th>RISPERDAL 6 mg</th><th>RISPERDAL 10 mg</th><th>RISPERDAL 16 mg</th></tr></thead><tbody><tr><td>Parkinsonism</td><td>1.2</td><td>0.9</td><td>1.8</td><td>2.4</td><td>2.6</td></tr><tr><td>EPS Incidence</td><td>13%</td><td>17%</td><td>21%</td><td>21%</td><td>35%</td></tr></tbody></table> <table width="100%"><caption>Table 17.</caption><col width="17%" align="left" valign="top"/><col width="17%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><thead><tr><th>Dose Groups</th><th>RISPERDAL 1 mg</th><th>RISPERDAL 4 mg</th><th>RISPERDAL 8 mg</th><th>RISPERDAL 12 mg</th><th>RISPERDAL 16 mg</th></tr></thead><tbody><tr><td>Parkinsonism</td><td>0.6</td><td>1.7</td><td>2.4</td><td>2.9</td><td>4.1</td></tr><tr><td>EPS Incidence</td><td>7%</td><td>12%</td><td>17%</td><td>18%</td><td>20%</td></tr></tbody></table>

7 DRUG INTERACTIONS Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone. Increase the RISPERDAL dose up to double the patient's usual dose. Titrate slowly. ( 7.1 ) Fluoxetine, paroxetine, and other CYP 2D6 enzyme inhibitors increase plasma concentrations of risperidone. Reduce the initial dose. Do not exceed a final dose of 8 mg per day of RISPERDAL. ( 7.1 ) 7.1 Pharmacokinetic-related Interactions The dose of RISPERDAL should be adjusted when used in combination with CYP2D6 enzyme inhibitors (e.g., fluoxetine, and paroxetine) and enzyme inducers (e.g., carbamazepine) [see Table 18 and Dosage and Administration (2.5) ] . Dose adjustment is not recommended for RISPERDAL when co-administered with ranitidine, cimetidine, amitriptyline, or erythromycin [see Table 18 ]. Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference ) Risperidone Dose Recommendation Coadministered Drug Risperidone AUC C max Enzyme (CYP2D6) Inhibitors Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day 20 mg/day 4 mg/day 1.6 - 40 mg/day 4 mg/day 1.8 - Enzyme (CYP3A/PgP inducers) Inducers Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient's usual dose Enzyme (CYP3A) Inhibitors Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed Other Drugs Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed Effect of Risperidone on Other Drugs Lithium Repeated oral doses of RISPERDAL (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (n=13). Dose adjustment for lithium is not recommended. Valproate Repeated oral doses of RISPERDAL (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of RISPERDAL. Dose adjustment for valproate is not recommended. Digoxin RISPERDAL (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended. 7.2 Pharmacodynamic-related Interactions Centrally Acting Drugs and Alcohol Given the primary CNS effects of risperidone, caution should be used when RISPERDAL is taken in combination with other centrally acting drugs and alcohol. Drugs with Hypotensive Effects Because of its potential for inducing hypotension, RISPERDAL may enhance the hypotensive effects of other therapeutic agents with this potential. Levodopa and Dopamine Agonists RISPERDAL may antagonize the effects of levodopa and dopamine agonists. Methylphenidate Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS).

fects of other therapeutic agents with this potential. Levodopa and Dopamine Agonists RISPERDAL may antagonize the effects of levodopa and dopamine agonists. Methylphenidate Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of RISPERDAL and methylphenidate [see Adverse Reactions (6.2) ] . Clozapine Chronic administration of clozapine with RISPERDAL may decrease the clearance of risperidone.

<table width="100%" ID="table18"><caption>Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia</caption><col width="19%" align="left" valign="top"/><col width="19%" align="left" valign="top"/><col width="19%" align="left" valign="top"/><col width="12%" align="left" valign="top"/><col width="12%" align="left" valign="top"/><col width="19%" align="left" valign="top"/><thead><tr><th rowspan="2" styleCode="Lrule Rrule Botrule">Coadministered Drug</th><th colspan="2" styleCode="Rrule Botrule">Dosing Schedule</th><th colspan="2" styleCode="Rrule Botrule">Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio <footnote ID="table18a">Change relative to reference</footnote>) </th><th rowspan="2" styleCode="Rrule">Risperidone Dose Recommendation</th></tr><tr><th styleCode="Rrule">Coadministered Drug</th><th styleCode="Rrule">Risperidone</th><th styleCode="Rrule">AUC</th><th styleCode="Rrule">C _max</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Enzyme (CYP2D6) Inhibitors</td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fluoxetine</td><td styleCode="Rrule">20 mg/day</td><td styleCode="Rrule">2 or 3 mg twice daily</td><td styleCode="Rrule">1.4</td><td styleCode="Rrule">1.5</td><td styleCode="Rrule">Re-evaluate dosing. Do not exceed 8 mg/day</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Paroxetine</td><td styleCode="Rrule">10 mg/day</td><td styleCode="Rrule">4 mg/day</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">-</td><td rowspan="3" styleCode="Rrule">Re-evaluate dosing. Do not exceed 8 mg/day</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"/><td styleCode="Rrule">20 mg/day</td><td styleCode="Rrule">4 mg/day</td><td styleCode="Rrule">1.6</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"/><td styleCode="Rrule">40 mg/day</td><td styleCode="Rrule">4 mg/day</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Enzyme (CYP3A/PgP inducers) Inducers</td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Carbamazepine</td><td styleCode="Rrule">573 &#xB1; 168 mg/day</td><td styleCode="Rrule">3 mg twice daily</td><td styleCode="Rrule">0.51</td><td styleCode="Rrule">0.55</td><td styleCode="Rrule">Titrate dose upwards.

"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Carbamazepine</td><td styleCode="Rrule">573 &#xB1; 168 mg/day</td><td styleCode="Rrule">3 mg twice daily</td><td styleCode="Rrule">0.51</td><td styleCode="Rrule">0.55</td><td styleCode="Rrule">Titrate dose upwards. Do not exceed twice the patient&apos;s usual dose</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Enzyme (CYP3A) Inhibitors</td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Ranitidine</td><td styleCode="Rrule">150 mg twice daily</td><td styleCode="Rrule">1 mg single dose</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">1.4</td><td styleCode="Rrule">Dose adjustment not needed</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cimetidine</td><td styleCode="Rrule">400 mg twice daily</td><td styleCode="Rrule">1 mg single dose</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">Dose adjustment not needed</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Erythromycin</td><td styleCode="Rrule">500 mg four times daily</td><td styleCode="Rrule">1 mg single dose</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">0.94</td><td styleCode="Rrule">Dose adjustment not needed</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Other Drugs</td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Amitriptyline</td><td styleCode="Rrule">50 mg twice daily</td><td styleCode="Rrule">3 mg twice daily</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">Dose adjustment not needed</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including RISPERDAL, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including RISPERDAL, during pregnancy (see Clinical Considerations ) . Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area. 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 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including RISPERDAL, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

ugs, including RISPERDAL, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area: maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m 2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m 2 and the only dose tested in the study. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations ). There is no information on the effects of risperidone on milk production.

of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations ). There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for RISPERDAL and any potential adverse effects on the breastfed child from RISPERDAL or from the mother's underlying condition. Clinical Considerations Infants exposed to RISPERDAL through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of risperidone (D 2 receptor antagonism), treatment with RISPERDAL may result in an increase in serum prolactin levels , which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.6) ]. 8.4 Pediatric Use Approved Pediatric Indications Schizophrenia The efficacy and safety of RISPERDAL in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 to 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [see Indications and Usage (1.1) , Adverse Reactions (6.1) , and Clinical Studies (14.1) ]. Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia. Safety and effectiveness of RISPERDAL in children less than 13 years of age with schizophrenia have not been established. Bipolar I Disorder The efficacy and safety of RISPERDAL in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 to 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications and Usage (1.2) , Adverse Reactions (6.1) , and Clinical Studies (14.2) ] . Safety and effectiveness of RISPERDAL in children less than 10 years of age with bipolar disorder have not been established. Autistic Disorder The efficacy and safety of RISPERDAL in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3) , Adverse Reactions (6.1) and Clinical Studies (14.4) ] . Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of RISPERDAL as patients treated for irritability associated with autistic disorder. A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms. There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg.

d doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone. Adverse Reactions in Pediatric Patients Tardive Dyskinesia In clinical trials in 1885 children and adolescents treated with RISPERDAL, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL treatment [see also Warnings and Precautions (5.4) ] . Weight Gain Weight gain has been observed in children and adolescents during treatment with RISPERDAL. Clinical monitoring of weight is recommended during treatment. Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for RISPERDAL-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. In these trials, approximately 33% of the RISPERDAL group had weight gain ≥7%, compared to 7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at Week 24 and 8 kg at Week 48 [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ]. Somnolence Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. Somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these adverse reactions were most often of early onset and transient in duration [see Adverse Reactions (6.1 and 6.2) ] . Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see Dosage and Administration (2.1 , 2.2 , and 2.3) ] . Hyperprolactinemia RISPERDAL has been shown to elevate prolactin levels in children and adolescents as well as in adults [see Warnings and Precautions (5.6) ] . In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received RISPERDAL had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82–87% of patients who received RISPERDAL had elevated levels of prolactin compared to 3–7% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications. In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of RISPERDAL-treated patients and gynecomastia was reported in 2.3% of RISPERDAL-treated patients. Growth and Sexual Maturation The long-term effects of RISPERDAL on growth and sexual maturation have not been fully evaluated in children and adolescents.

n 1885 children and adolescents, galactorrhea was reported in 0.8% of RISPERDAL-treated patients and gynecomastia was reported in 2.3% of RISPERDAL-treated patients. Growth and Sexual Maturation The long-term effects of RISPERDAL on growth and sexual maturation have not been fully evaluated in children and adolescents. Juvenile Animal Studies Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period. Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/day for children. 8.5 Geriatric Use Clinical studies of RISPERDAL in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4 , 2.5) ] . While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [see Warnings and Precautions (5.7) ] . Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4) ] . 8.6 Renal Impairment In patients with moderate to severe (Clcr 59 to 15 mL/min) renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60%, compared to young healthy subjects. RISPERDAL doses should be reduced in patients with renal disease [see Dosage and Administration (2.4) ] .

] . 8.6 Renal Impairment In patients with moderate to severe (Clcr 59 to 15 mL/min) renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60%, compared to young healthy subjects. RISPERDAL doses should be reduced in patients with renal disease [see Dosage and Administration (2.4) ] . 8.7 Hepatic Impairment While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α 1 -acid glycoprotein. RISPERDAL doses should be reduced in patients with liver disease [see Dosage and Administration (2.4) ] . 8.8 Patients with Parkinson's Disease or Lewy Body Dementia Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to RISPERDAL. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including RISPERDAL, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including RISPERDAL, during pregnancy (see Clinical Considerations ) . Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area. 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 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including RISPERDAL, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects.

within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area: maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m 2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m 2 and the only dose tested in the study.

8.4 Pediatric Use Approved Pediatric Indications Schizophrenia The efficacy and safety of RISPERDAL in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 to 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [see Indications and Usage (1.1) , Adverse Reactions (6.1) , and Clinical Studies (14.1) ]. Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia. Safety and effectiveness of RISPERDAL in children less than 13 years of age with schizophrenia have not been established. Bipolar I Disorder The efficacy and safety of RISPERDAL in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 to 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications and Usage (1.2) , Adverse Reactions (6.1) , and Clinical Studies (14.2) ] . Safety and effectiveness of RISPERDAL in children less than 10 years of age with bipolar disorder have not been established. Autistic Disorder The efficacy and safety of RISPERDAL in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3) , Adverse Reactions (6.1) and Clinical Studies (14.4) ] . Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of RISPERDAL as patients treated for irritability associated with autistic disorder. A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms. There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone. Adverse Reactions in Pediatric Patients Tardive Dyskinesia In clinical trials in 1885 children and adolescents treated with RISPERDAL, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL treatment [see also Warnings and Precautions (5.4) ] . Weight Gain Weight gain has been observed in children and adolescents during treatment with RISPERDAL. Clinical monitoring of weight is recommended during treatment. Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders.

s during treatment with RISPERDAL. Clinical monitoring of weight is recommended during treatment. Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for RISPERDAL-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. In these trials, approximately 33% of the RISPERDAL group had weight gain ≥7%, compared to 7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at Week 24 and 8 kg at Week 48 [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ]. Somnolence Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. Somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these adverse reactions were most often of early onset and transient in duration [see Adverse Reactions (6.1 and 6.2) ] . Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see Dosage and Administration (2.1 , 2.2 , and 2.3) ] . Hyperprolactinemia RISPERDAL has been shown to elevate prolactin levels in children and adolescents as well as in adults [see Warnings and Precautions (5.6) ] . In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received RISPERDAL had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82–87% of patients who received RISPERDAL had elevated levels of prolactin compared to 3–7% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications. In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of RISPERDAL-treated patients and gynecomastia was reported in 2.3% of RISPERDAL-treated patients. Growth and Sexual Maturation The long-term effects of RISPERDAL on growth and sexual maturation have not been fully evaluated in children and adolescents. Juvenile Animal Studies Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

abolite paliperidone (9-hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period. Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/day for children.

8.5 Geriatric Use Clinical studies of RISPERDAL in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4 , 2.5) ] . While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [see Warnings and Precautions (5.7) ] . Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4) ] .

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance RISPERDAL (risperidone) is not a controlled substance. 9.2 Abuse RISPERDAL has not been systematically studied in animals or humans for its potential for abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of RISPERDAL misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). 9.3 Dependence RISPERDAL has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

9.2 Abuse RISPERDAL has not been systematically studied in animals or humans for its potential for abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of RISPERDAL misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

10 OVERDOSAGE 10.1 Human Experience Premarketing experience included eight reports of acute RISPERDAL overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure. Postmarketing experience includes reports of acute RISPERDAL overdosage, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to RISPERDAL overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of RISPERDAL and paroxetine. 10.2 Management of Overdosage For the most up to date information on the management of RISPERDAL overdosage, contact a certified poison control center (1-800-222-1222 or www.poison.org). Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to RISPERDAL.

11 DESCRIPTION RISPERDAL ® contains risperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23 H 27 FN 4 O 2 and its molecular weight is 410.49. The structural formula is: Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl. RISPERDAL ® Tablets are for oral administration and available in 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn). The 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The 0.5 mg tablets contain red iron oxide; the 2 mg tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake. RISPERDAL is also available as a 1 mg/mL oral solution. RISPERDAL ® Oral Solution contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and purified water. RISPERDAL ® M-TAB ® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg (light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL M-TAB Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite ® resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric oxide, and peppermint oil. In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL M-TAB Orally Disintegrating Tablets contain xanthan gum. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2 ) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology (12.3) ] . Antagonism at receptors other than D 2 and 5HT 2 may explain some of the other effects of risperidone [see Clinical Pharmacology (12.1) ] . 12.2 Pharmacodynamics Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2 ), dopamine Type 2 (D 2 ), α 1 and α 2 adrenergic, and H 1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C , 5HT 1D , and 5HT 1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 -5 M) for cholinergic muscarinic or β 1 and β 2 adrenergic receptors. 12.3 Pharmacokinetics Absorption Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution. Pharmacokinetic studies showed that RISPERDAL M-TAB Orally Disintegrating Tablets and RISPERDAL Oral Solution are bioequivalent to RISPERDAL Tablets. Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5–6 days (measured in extensive metabolizers). Food Effect Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL can be given with or without meals. Distribution Risperidone is rapidly distributed. The volume of distribution is 1–2 L/kg. In plasma, risperidone is bound to albumin and α 1 -acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance. Elimination Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N -dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone.

sm Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N -dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%–8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours. Drug Interaction Studies Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7) ] . This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given RISPERDAL do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug Interactions (7) ] . It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions (7) ] . In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, RISPERDAL is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, RISPERDAL did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.

In drug interaction studies, RISPERDAL did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. Specific Populations Renal and Hepatic Impairment [See Use in Specific Populations (8.6 and 8.7) ]. Elderly In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients [see Use in Specific Populations (8.5) ] . Pediatric The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight. Race and Gender Effects No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

12.1 Mechanism of Action The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2 ) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology (12.3) ] . Antagonism at receptors other than D 2 and 5HT 2 may explain some of the other effects of risperidone [see Clinical Pharmacology (12.1) ] .

12.2 Pharmacodynamics Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2 ), dopamine Type 2 (D 2 ), α 1 and α 2 adrenergic, and H 1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C , 5HT 1D , and 5HT 1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 -5 M) for cholinergic muscarinic or β 1 and β 2 adrenergic receptors.

12.3 Pharmacokinetics Absorption Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution. Pharmacokinetic studies showed that RISPERDAL M-TAB Orally Disintegrating Tablets and RISPERDAL Oral Solution are bioequivalent to RISPERDAL Tablets. Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5–6 days (measured in extensive metabolizers). Food Effect Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL can be given with or without meals. Distribution Risperidone is rapidly distributed. The volume of distribution is 1–2 L/kg. In plasma, risperidone is bound to albumin and α 1 -acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance. Elimination Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N -dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%–8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces.

xyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours. Drug Interaction Studies Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7) ] . This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given RISPERDAL do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug Interactions (7) ] . It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions (7) ] . In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, RISPERDAL is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, RISPERDAL did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. Specific Populations Renal and Hepatic Impairment [See Use in Specific Populations (8.6 and 8.7) ]. Elderly In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients [see Use in Specific Populations (8.5) ] . Pediatric The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight. Race and Gender Effects No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Multiples of Maximum Human Dose in mg/m 2 (mg/kg) Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas mouse Female 0.2 (2.4) none rat Female 0.4 (2.4) none rat Male 6.0 (37.5) 1.5 (9.4) Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5–6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions (5.6) ] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila . Impairment of Fertility Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD based on mg/m 2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

<table width="100%"><col width="35%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th colspan="3"/><th colspan="2" styleCode="Botrule">Multiples of Maximum Human Dose in mg/m ²(mg/kg) </th></tr><tr styleCode="Botrule"><th>Tumor Type</th><th>Species</th><th>Sex</th><th>Lowest Effect Level</th><th>Highest No-Effect Level</th></tr></thead><tbody><tr><td>Pituitary adenomas</td><td>mouse</td><td>Female</td><td>0.75 (9.4)</td><td>0.2 (2.4)</td></tr><tr><td>Endocrine pancreas adenomas</td><td>rat</td><td>Male</td><td>1.5 (9.4)</td><td>0.4 (2.4)</td></tr><tr><td>Mammary gland adenocarcinomas</td><td>mouse</td><td>Female</td><td>0.2 (2.4)</td><td>none</td></tr><tr><td/><td>rat</td><td>Female</td><td>0.4 (2.4)</td><td>none</td></tr><tr><td/><td>rat</td><td>Male</td><td>6.0 (37.5)</td><td>1.5 (9.4)</td></tr><tr><td>Mammary gland neoplasm, Total</td><td>rat</td><td>Male</td><td>1.5 (9.4)</td><td>0.4 (2.4)</td></tr></tbody></table>

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Multiples of Maximum Human Dose in mg/m 2 (mg/kg) Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas mouse Female 0.2 (2.4) none rat Female 0.4 (2.4) none rat Male 6.0 (37.5) 1.5 (9.4) Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5–6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions (5.6) ] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila . Impairment of Fertility Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD based on mg/m 2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

0.6 to 10 times the MRHD based on mg/m 2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog. Carcinogenesis Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Multiples of Maximum Human Dose in mg/m 2 (mg/kg) Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas mouse Female 0.2 (2.4) none rat Female 0.4 (2.4) none rat Male 6.0 (37.5) 1.5 (9.4) Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5–6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions (5.6) ] .

y, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions (5.6) ] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila . Impairment of Fertility Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD based on mg/m 2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

<table width="100%"><col width="35%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th colspan="3"/><th colspan="2" styleCode="Botrule">Multiples of Maximum Human Dose in mg/m ²(mg/kg) </th></tr><tr styleCode="Botrule"><th>Tumor Type</th><th>Species</th><th>Sex</th><th>Lowest Effect Level</th><th>Highest No-Effect Level</th></tr></thead><tbody><tr><td>Pituitary adenomas</td><td>mouse</td><td>Female</td><td>0.75 (9.4)</td><td>0.2 (2.4)</td></tr><tr><td>Endocrine pancreas adenomas</td><td>rat</td><td>Male</td><td>1.5 (9.4)</td><td>0.4 (2.4)</td></tr><tr><td>Mammary gland adenocarcinomas</td><td>mouse</td><td>Female</td><td>0.2 (2.4)</td><td>none</td></tr><tr><td/><td>rat</td><td>Female</td><td>0.4 (2.4)</td><td>none</td></tr><tr><td/><td>rat</td><td>Male</td><td>6.0 (37.5)</td><td>1.5 (9.4)</td></tr><tr><td>Mammary gland neoplasm, Total</td><td>rat</td><td>Male</td><td>1.5 (9.4)</td><td>0.4 (2.4)</td></tr></tbody></table> <table width="100%"><col width="35%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th colspan="3"/><th colspan="2" styleCode="Botrule">Multiples of Maximum Human Dose in mg/m ²(mg/kg) </th></tr><tr styleCode="Botrule"><th>Tumor Type</th><th>Species</th><th>Sex</th><th>Lowest Effect Level</th><th>Highest No-Effect Level</th></tr></thead><tbody><tr><td>Pituitary adenomas</td><td>mouse</td><td>Female</td><td>0.75 (9.4)</td><td>0.2 (2.4)</td></tr><tr><td>Endocrine pancreas adenomas</td><td>rat</td><td>Male</td><td>1.5 (9.4)</td><td>0.4 (2.4)</td></tr><tr><td>Mammary gland adenocarcinomas</td><td>mouse</td><td>Female</td><td>0.2 (2.4)</td><td>none</td></tr><tr><td/><td>rat</td><td>Female</td><td>0.4 (2.4)</td><td>none</td></tr><tr><td/><td>rat</td><td>Male</td><td>6.0 (37.5)</td><td>1.5 (9.4)</td></tr><tr><td>Mammary gland neoplasm, Total</td><td>rat</td><td>Male</td><td>1.5 (9.4)</td><td>0.4 (2.4)</td></tr></tbody></table>

14 CLINICAL STUDIES 14.1 Schizophrenia Adults Short-Term Efficacy The efficacy of RISPERDAL in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) were employed. The results of the trials follow: In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL in doses up to 10 mg/day (twice-daily schedule), RISPERDAL was generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the SANS. In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL (2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all 4 RISPERDAL groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest RISPERDAL dose groups were generally superior to placebo on the PANSS negative subscale. The most consistently positive responses on all measures were seen for the 6 mg dose group, and there was no suggestion of increased benefit from larger doses. In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL (1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the four highest RISPERDAL dose groups were generally superior to the 1 mg RISPERDAL dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The most consistently positive responses were seen for the 4 mg dose group. In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of RISPERDAL (4 and 8 mg/day on a once-daily schedule), both RISPERDAL dose groups were generally superior to placebo on several PANSS measures, including a response measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg dose group. Long-Term Efficacy In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to RISPERDAL (2–8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving RISPERDAL experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator.

for at least 4 weeks on an antipsychotic medication were randomized to RISPERDAL (2–8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving RISPERDAL experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator. Pediatrics The efficacy of RISPERDAL in the treatment of schizophrenia in adolescents aged 13–17 years was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at time of enrollment. In the first trial (study #1), patients were randomized into one of three treatment groups: RISPERDAL 1–3 mg/day (n=55, mean modal dose = 2.6 mg), RISPERDAL 4–6 mg/day (n=51, mean modal dose = 5.3 mg), or placebo (n=54). In the second trial (study #2), patients were randomized to either RISPERDAL 0.15–0.6 mg/day (n=132, mean modal dose = 0.5 mg) or RISPERDAL 1.5–6 mg/day (n=125, mean modal dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of the 0.15–0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to the target dosage range by approximately Day 7. Subsequently, dosage was increased to the maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable in all studies was the mean change from baseline in total PANSS score. Results of the studies demonstrated efficacy of RISPERDAL in all dose groups from 1–6 mg/day compared to placebo, as measured by significant reduction of total PANSS score. The efficacy on the primary parameter in the 1–3 mg/day group was comparable to the 4–6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day group in study #2. In study #2, the efficacy in the 1.5–6 mg/day group was statistically significantly greater than that in the 0.15–0.6 mg/day group. Doses higher than 3 mg/day did not reveal any trend towards greater efficacy. 14.2 Bipolar Mania - Monotherapy Adults The efficacy of RISPERDAL in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features. The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the YMRS total score. The results of the trials follow: In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of RISPERDAL 1–6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), RISPERDAL was superior to placebo in the reduction of YMRS total score. In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1–6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), RISPERDAL was superior to placebo in the reduction of YMRS total score. Pediatrics The efficacy of RISPERDAL in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder.

he efficacy of RISPERDAL in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder. Patients were randomized into one of three treatment groups: RISPERDAL 0.5–2.5 mg/day (n=50, mean modal dose = 1.9 mg), RISPERDAL 3–6 mg/day (n=61, mean modal dose = 4.7 mg), or placebo (n=58). In all cases, study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10. The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score. Results of this study demonstrated efficacy of RISPERDAL in both dose groups compared with placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary parameter in the 3–6 mg/day dose group was comparable to the 0.5–2.5 mg/day dose group. Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy. 14.3 Bipolar Mania – Adjunctive Therapy with Lithium or Valproate The efficacy of RISPERDAL with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course. In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive RISPERDAL, placebo, or an active comparator, in combination with their original therapy. RISPERDAL, in a dose range of 1–6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score. In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive RISPERDAL or placebo, in combination with their original therapy. RISPERDAL, in a dose range of 1–6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4–12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone. 14.4 Irritability Associated with Autistic Disorder Short-Term Efficacy The efficacy of RISPERDAL in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16–104.3 kg). Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).

most weighed over 20 kg (16–104.3 kg). Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies. The results of these trials are as follows: In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL 0.5–3.5 mg/day on a weight-adjusted basis. RISPERDAL, starting at 0.25 mg/day or 0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day), significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with placebo. In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged 5 to 12 years, RISPERDAL 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo. A third trial was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects (N=96) 5 to 17 years of age with autistic disorder (defined by DSM-IV criteria) and associated irritability and related behavioral symptoms. Approximately 77% of patients were younger than 12 years of age (mean age = 9), and 88% were male. Most patients (73%) weighed less than 45 kg (mean weight = 40 kg). Approximately 90% of patients were antipsychotic-naïve before entering the study. There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The dose was administered once daily in the morning, or in the evening if sedation occurred. The primary efficacy endpoint was the mean change in the Aberrant Behavior Checklist – Irritability subscale (ABC-I) score from baseline to the end of Week 6. The study demonstrated the efficacy of high-dose risperidone, as measured by the mean change in ABC-I score. It did not demonstrate efficacy for low-dose risperidone. The mean baseline ABC-I scores were 29 in the placebo group (n=35), 27 in the risperidone low-dose group (n=30), and 28 in the risperidone high-dose group (n=31). The mean changes in ABC-I scores were -3.5, -7.4, and -12.4 in the placebo, low-dose, and high-dose group respectively. The results in the high-dose group were statistically significant (p< 0.001) but not in the low-dose group (p=0.164). Long-Term Efficacy Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with RISPERDAL for 4 or 6 months (depending on whether they received RISPERDAL or placebo in the double-blind study). During this open-label treatment period, patients were maintained on a mean modal dose of RISPERDAL of 1.8–2.1 mg/day (equivalent to 0.05 – 0.07 mg/kg/day).

label study extension where they were treated with RISPERDAL for 4 or 6 months (depending on whether they received RISPERDAL or placebo in the double-blind study). During this open-label treatment period, patients were maintained on a mean modal dose of RISPERDAL of 1.8–2.1 mg/day (equivalent to 0.05 – 0.07 mg/kg/day). Patients who maintained their positive response to RISPERDAL (response was defined as ≥ 25% improvement on the ABC-I subscale and a CGI-C rating of 'much improved' or 'very much improved') during the 4–6 month open-label treatment phase for about 140 days, on average, were randomized to receive RISPERDAL or placebo during an 8-week, double-blind withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients who completed the withdrawal study (n=32), undertaken by an independent Data Safety Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention. Relapse was defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase).

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied RISPERDAL ® (risperidone) Tablets RISPERDAL ® (risperidone) Tablets are imprinted " JANSSEN " on one side and either "Ris 0.5", "R1", "R2", "R3", or "R4" according to their respective strengths. 0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500 NDC 50458-302-50, and hospital unit dose blister packs of 100 NDC 50458-302-01. 1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, bottles of 500 NDC 50458-300-50, and hospital unit dose blister packs of 100 NDC 50458-300-01. 2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, bottles of 500 NDC 50458-320-50, and hospital unit dose blister packs of 100 NDC 50458-320-01. 3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, bottles of 500 NDC 50458-330-50, and hospital unit dose blister packs of 100 NDC 50458-330-01. 4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06 and hospital unit dose blister packs of 100 NDC 50458-350-01. RISPERDAL ® (risperidone) Oral Solution RISPERDAL ® (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL bottles with a calibrated (in milliliters) oral dosing syringe. The minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL. RISPERDAL ® M-TAB ® (risperidone) Orally Disintegrating Tablets RISPERDAL ® M-TAB ® (risperidone) Orally Disintegrating Tablets are etched on one side with "R0.5", "R1", "R2", "R3", or "R4" according to their respective strengths. RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of 4 (2 × 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant pouch containing a blister with 1 tablet. 0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC 50458-395-28, and long-term care blister packaging of 30 tablets NDC 50458-395-30. 1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC 50458-315-28, and long-term care blister packaging of 30 tablets NDC 50458-315-30. 2 mg coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC 50458-325-28. 3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28. 4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28. 16.2 Storage and Handling RISPERDAL Tablets should be stored at controlled room temperature 15 °C to 25 °C (59 °F to 77 °F). Protect from light and moisture. RISPERDAL 1 mg/mL Oral Solution should be stored at controlled room temperature 15 °C to 25 °C (59 °F to 77 °F). Protect from light and freezing. RISPERDAL M-TAB Orally Disintegrating Tablets should be stored at controlled room temperature 15 °C to 25 °C (59 °F to 77 °F). Keep out of reach of children.

16.2 Storage and Handling RISPERDAL Tablets should be stored at controlled room temperature 15 °C to 25 °C (59 °F to 77 °F). Protect from light and moisture. RISPERDAL 1 mg/mL Oral Solution should be stored at controlled room temperature 15 °C to 25 °C (59 °F to 77 °F). Protect from light and freezing. RISPERDAL M-TAB Orally Disintegrating Tablets should be stored at controlled room temperature 15 °C to 25 °C (59 °F to 77 °F). Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION Advise patients using RISPERDAL oral solution to read the FDA-approved patient labeling (Instructions for Use) for RISPERDAL oral solution. Physicians are advised to discuss the following issues with patients for whom they prescribe RISPERDAL. Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3) ] . Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.4) ] . Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5) ] . Orthostatic Hypotension Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.7) ] . Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking RISPERDAL [see Warnings and Precautions (5.9) ] . Hyperprolactinemia Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of RISPERDAL. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males. [see Warnings and Precautions (5.6) ] . Interference with Cognitive and Motor Performance Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle until they are reasonably certain that RISPERDAL therapy does not affect them adversely [see Warnings and Precautions (5.10) ] . 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 (5.13) ] . Heat Exposure and Dehydration Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.14) ] . Phenylketonurics Inform patients with Phenylketonuria and caregivers that RISPERDAL M-TAB Orally Disintegrating Tablets contain phenylalanine. Phenylalanine is a component of aspartame.

hydration Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.14) ] . Phenylketonurics Inform patients with Phenylketonuria and caregivers that RISPERDAL M-TAB Orally Disintegrating Tablets contain phenylalanine. Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.14 mg phenylalanine [see Warnings and Precautions (5.15) ] . Concomitant Medication Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter drugs, as there is a potential for interactions [see Drug Interactions (7) ] . Alcohol Advise patients to avoid alcohol while taking RISPERDAL [see Drug Interactions (7.2) ] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with RISPERDAL. Advise patients that RISPERDAL may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to RISPERDAL during pregnancy [see Use in Specific Populations (8.1) ] . Lactation Advise breastfeeding women using RISPERDAL to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2) ] . Infertility Advise females of reproductive potential that RISPERDAL may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3) ].

RISPERDAL Tablets, RISPERDAL M-TAB Orally Disintegrating Tablets, and RISPERDAL Oral Solution are manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © Johnson & Johnson and its affiliates 2007

INSTRUCTIONS FOR USE RISPERDAL ® (RISS-per-dal) (risperidone) Oral Solution Read these Instructions for Use before you start using RISPERDAL Oral Solution and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Important information you need to know before taking RISPERDAL Oral Solution: Take RISPERDAL Oral Solution exactly as your healthcare provider tells you to take it. Each 1 mL contains 1 mg of RISPERDAL Oral Solution. Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose using the oral dosing syringe. Always use the oral dosing syringe that comes with RISPERDAL Oral Solution. Contact your healthcare provider or pharmacist if you lose or damage the oral dosing syringe, or if your carton does not come with one. RISPERDAL Oral Solution can be taken directly from the oral dosing syringe or mixed with water, coffee, orange juice, or low-fat milk. Do not mix RISPERDAL Oral Solution with cola or tea. Each RISPERDAL Oral Solution carton contains: 1 bottle of RISPERDAL Oral Solution 1 oral dosing syringe Gather and check supplies: Gather the RISPERDAL Oral Solution bottle and oral dosing syringe. Check the expiration date on the bottle. Do not use the bottle of RISPERDAL Oral Solution if the expiration date has passed. Check your dose in mLs as prescribed by your healthcare provider. Find this mL marking on the plunger of the oral dosing syringe. If your dose is more than 3 mL, you will need to divide your dose. Follow the instructions given to you by your healthcare provider or pharmacist on how to divide your dose. Preparing a dose of RISPERDAL Oral Solution: Step 1. Place the RISPERDAL Oral Solution bottle on a flat surface. Push down on the cap while turning it to the left (counterclockwise) to open the bottle. Step 2. Push the plunger of the oral dosing syringe all the way down. Step 3. With the bottle in an upright position, fully insert the oral dosing syringe into the opening of the bottle. Step 4. Withdraw the prescribed dose of RISPERDAL Oral Solution from the bottle. Hold down the barrel of the oral dosing syringe with one hand. With your other hand, slowly pull the plunger up until you reach the mL markings on the plunger for the prescribed dose. Step 5 . Remove the oral dosing syringe from the bottle by holding the outer barrel and pulling straight up. Be careful not to push down on the plunger during this step. Check the oral dosing syringe for air bubbles. If you see air bubbles, slowly push the plunger all the way down to return the oral solution into the bottle. Then repeat Step 4 to withdraw the prescribed dose. Step 6. RISPERDAL Oral Solution can be mixed with a drink or taken directly from the oral dosing syringe. Mix the dose of RISPERDAL Oral Solution with water, coffee, orange juice, or low-fat milk. Stir well and drink all of the mixture right away to ensure the full dose is taken. See Figure 6a . Do not mix RISPERDAL Oral Solution with cola or tea. Or To take the RISPERDAL Oral Solution dose directly from the oral dosing syringe, place the tip of the oral dosing syringe into the mouth and toward the cheek. Slowly push the plunger all the way down to gently release all of the medicine in the oral dosing syringe. Do not squirt or forcefully push the medicine into the back of the throat. See Figure 6b . Step 7.

rectly from the oral dosing syringe, place the tip of the oral dosing syringe into the mouth and toward the cheek. Slowly push the plunger all the way down to gently release all of the medicine in the oral dosing syringe. Do not squirt or forcefully push the medicine into the back of the throat. See Figure 6b . Step 7. Place the cap back on the RISPERDAL Oral Solution bottle and turn the cap to the right (clockwise) to close the bottle. Step 8. Rinse the oral dosing syringe with water after each use. Remove the plunger from the oral dosing syringe barrel. Rinse the oral dosing syringe barrel and plunger with water and let them air dry. When the oral dosing syringe barrel and plunger are dry, put the plunger back into the oral dosing syringe barrel for the next use. Do not throw away the oral dosing syringe. Storing RISPERDAL Oral Solution: Store RISPERDAL Oral Solution at room temperature between 59 °F to 77 °F (15 °C to 25 °C). Do not freeze RISPERDAL Oral Solution. Protect from light. Keep RISPERDAL Oral Solution and all medicines out of the reach of children. Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ, 08560, USA For patent information: www.jansenpatents.com © Johnson & Johnson and its affiliates 2007 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 2/2025 Figure Step 1 Step 2 Step 3 Step 4 Step 5 Figure 6a Figure 6b Step 7 Step 8

ssen Pharmaceuticals, Inc. Titusville, NJ, 08560, USA For patent information: www.jansenpatents.com © Johnson & Johnson and its affiliates 2007 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 2/2025 Figure Step 1 Step 2 Step 3 Step 4 Step 5 Figure 6a Figure 6b Step 7 Step 8 INSTRUCCIONES DE USO RISPERDAL ® (RISS-per-dal) (risperidona) Solución oral Lea estas Instrucciones de uso antes de comenzar a usar RISPERDAL Solución oral y cada vez que renueve su receta. Es posible que este material contenga información nueva. Esta información no reemplaza la consulta con su proveedor de atención médica acerca de su enfermedad o tratamiento. Información importante que debe saber antes de tomar RISPERDAL Solución oral: Tome RISPERDAL Solución oral exactamente como se lo indica su proveedor de atención médica. Cada 1 ml contiene 1 mg de RISPERDAL Solución oral. Pídale a su proveedor de atención médica o farmacéutico que le muestre cómo medir la dosis recetada con la jeringa de dosificación oral. Utilice siempre la jeringa de dosificación oral que viene con RISPERDAL Solución oral. Comuníquese con su proveedor de atención médica o farmacéutico si pierde o daña la jeringa de dosificación oral, o si su caja no viene con una. RISPERDAL Solución oral se puede tomar directamente de la jeringa de dosificación oral o se puede mezclar con agua, café, jugo de naranja o leche con bajo contenido de grasa. No mezcle RISPERDAL Solución oral con refrescos de cola o té. Cada caja de RISPERDAL Solución oral contiene lo siguiente: 1 frasco de RISPERDAL Solución oral 1 jeringa de dosificación oral Reúna y verifique los suministros: Reúna el frasco de RISPERDAL Solución oral y la jeringa de dosificación oral. Consulte la fecha de caducidad en el frasco. No utilice el frasco de RISPERDAL Solución oral si ha pasado la fecha de caducidad. Verifique su dosis en ml según lo prescrito por su proveedor de atención médica. Busque esta marca de ml en el émbolo de la jeringa de dosificación oral. Si su dosis supera los 3 ml, deberá dividir la dosis. Siga las instrucciones que le dé su proveedor de atención médica o farmacéutico sobre cómo dividir su dosis. Preparación de una dosis de RISPERDAL Solución oral: Paso 1. Coloque el frasco de RISPERDAL Solución oral sobre una superficie plana. Empuje hacia abajo la tapa mientras la gira hacia la izquierda (en sentido antihorario) para abrir el frasco. Paso 2. Empuje el émbolo de la jeringa de dosificación oral hasta el fondo. Paso 3. Con el frasco en posición vertical, inserte completamente la jeringa de dosificación oral en la abertura del frasco. Paso 4. Extraiga la dosis prescrita de RISPERDAL Solución oral del frasco. Sostenga el cilindro de la jeringa de dosificación oral con una mano. Con la otra mano, tire lentamente del émbolo hacia arriba hasta que alcance las marcas de ml en el émbolo para la dosis prescrita. Paso 5. Retire la jeringa de dosificación oral del frasco sujetando el cilindro exterior y tirando hacia arriba. Tenga cuidado de no empujar hacia abajo el émbolo durante este paso. Compruebe que no haya burbujas de aire en la jeringa de dosificación oral. Si ve burbujas de aire, empuje lentamente el émbolo hasta el fondo para devolver la solución oral al frasco. Luego repita el Paso 4 para retirar la dosis prescrita. Paso 6. RISPERDAL Solución oral se puede mezclar con una bebida o se puede tomar directamente de la jeringa de dosificación oral. Mezcle la dosis de RISPERDAL Solución oral con agua, café, jugo de naranja o leche con bajo contenido de grasa. Revuelva bien y beba toda la mezcla de inmediato para asegurarse de tomar la dosis completa. Consulte la Figura 6a . No mezcle RISPERDAL Solución oral con refrescos de cola o té.

jeringa de dosificación oral. Mezcle la dosis de RISPERDAL Solución oral con agua, café, jugo de naranja o leche con bajo contenido de grasa. Revuelva bien y beba toda la mezcla de inmediato para asegurarse de tomar la dosis completa. Consulte la Figura 6a . No mezcle RISPERDAL Solución oral con refrescos de cola o té. O Para tomar la dosis de RISPERDAL Solución oral directamente de la jeringa de dosificación oral, coloque la punta de la jeringa de dosificación oral en la boca y hacia la mejilla. Empuje lentamente el émbolo hasta el fondo para liberar suavemente todo el medicamento en la jeringa de dosificación oral. No rocíe ni empuje con fuerza el medicamento en la parte posterior de la garganta. Consulte la Figura 6b . Paso 7. Vuelva a colocar la tapa en el frasco de RISPERDAL Solución oral y gírela hacia la derecha (en el sentido de las agujas del reloj) para cerrar el frasco. Paso 8. Enjuague la jeringa de dosificación oral con agua después de cada uso. Retire el émbolo del cilindro de la jeringa de dosificación oral. Enjuague el cilindro de la jeringa de dosificación oral con agua y déjela secar al aire. Cuando el cilindro de la jeringa de dosificación oral y el émbolo estén secos, vuelva a colocar el émbolo en el cilindro de la jeringa de dosificación oral para el próximo uso. No deseche la jeringa de dosificación oral. Almacenamiento de RISPERDAL Solución oral Almacene RISPERDAL Solución oral a temperatura ambiente entre 59 °F y 77 °F (de 15 °C a 25 °C). No congelar RISPERDAL Solución oral. Proteger de la luz. Mantenga RISPERDAL Solución oral y todos los medicamentos fuera del alcance de los niños. Fabricado para: Janssen Pharmaceuticals, Inc. Titusville, NJ, 08560, USA Estas Instrucciones de uso han sido aprobadas por la Administración de Alimentos y Medicamentos (FDA) de los EE. UU. Para información sobre patentes : www.janssenpatents.com © Johnson & Johnson y sus afiliados 2007 Revisado: 2/2025 Figura Paso 1 Paso 2 Paso 3 Paso 4 Paso 5 Figura 6a Figura 6b Paso 7 Paso 8

<table width="100%" styleCode="Noautorules"><colgroup><col align="left" valign="top" width="60%"/><col align="center" valign="top" width="40%"/></colgroup><tbody><tr><td><content styleCode="bold">Each RISPERDAL Oral Solution carton contains:</content><list listType="unordered" styleCode="Disc"><item>1 bottle of RISPERDAL Oral Solution</item><item>1 oral dosing syringe</item></list></td><td><renderMultiMedia referencedObject="MM2"/></td></tr></tbody></table>

"/></colgroup><tbody><tr><td><content styleCode="bold">Each RISPERDAL Oral Solution carton contains:</content><list listType="unordered" styleCode="Disc"><item>1 bottle of RISPERDAL Oral Solution</item><item>1 oral dosing syringe</item></list></td><td><renderMultiMedia referencedObject="MM2"/></td></tr></tbody></table> <table width="100%" styleCode="Noautorules"><colgroup><col align="left" valign="top" width="60%"/><col align="center" valign="top" width="40%"/></colgroup><tbody><tr><td><content styleCode="bold">Step 1. </content>Place the RISPERDAL Oral Solution bottle on a flat surface. Push down on the cap while turning it to the left (counterclockwise) to open the bottle. </td><td><renderMultiMedia referencedObject="MM3"/></td></tr><tr><td><content styleCode="bold">Step 2. </content>Push the plunger of the oral dosing syringe all the way down. </td><td><renderMultiMedia referencedObject="MM4"/></td></tr><tr><td><content styleCode="bold">Step 3. </content>With the bottle in an upright position, fully insert the oral dosing syringe into the opening of the bottle. </td><td><renderMultiMedia referencedObject="MM5"/></td></tr><tr><td><content styleCode="bold">Step 4. </content>Withdraw the prescribed dose of RISPERDAL Oral Solution from the bottle. Hold down the barrel of the oral dosing syringe with one hand. With your other hand, slowly pull the plunger up until you reach the mL markings on the plunger for the prescribed dose. </td><td><renderMultiMedia referencedObject="MM5a"/></td></tr><tr><td><content styleCode="bold">Step 5</content>. Remove the oral dosing syringe from the bottle by holding the outer barrel and pulling straight up. Be careful not to push down on the plunger during this step. Check the oral dosing syringe for air bubbles. If you see air bubbles, slowly push the plunger all the way down to return the oral solution into the bottle. Then repeat <content styleCode="bold">Step 4 </content>to withdraw the prescribed dose. </td><td><renderMultiMedia referencedObject="MM5b"/></td></tr><tr><td><content styleCode="bold">Step 6. </content>RISPERDAL Oral Solution can be mixed with a drink or taken directly from the oral dosing syringe. <list listType="unordered" styleCode="Disc"><item>Mix the dose of RISPERDAL Oral Solution with water, coffee, orange juice, or low-fat milk. Stir well and drink all of the mixture right away to ensure the full dose is taken. <content styleCode="bold">See <linkHtml href="#Fig6a">Figure 6a</linkHtml>. </content> <content styleCode="bold">Do not mix </content>RISPERDAL Oral Solution with cola or tea. </item></list></td><td><renderMultiMedia referencedObject="MM5c"/></td></tr><tr><td><content styleCode="bold">Or</content><list listType="unordered" styleCode="Disc"><item>To take the RISPERDAL Oral Solution dose directly from the oral dosing syringe, place the tip of the oral dosing syringe into the mouth and toward the cheek. Slowly push the plunger all the way down to gently release all of the medicine in the oral dosing syringe. Do not squirt or forcefully push the medicine into the back of the throat. <content styleCode="bold">See <linkHtml href="#Fig6b">Figure 6b</linkHtml></content>. </item></list></td><td><renderMultiMedia referencedObject="MM5d"/></td></tr><tr><td><content styleCode="bold">Step 7. </content>Place the cap back on the RISPERDAL Oral Solution bottle and turn the cap to the right (clockwise) to close the bottle. </td><td><renderMultiMedia referencedObject="MM5e"/></td></tr><tr><td><content styleCode="bold">Step 8. </content>Rinse the oral dosing syringe with water after each use.

Code="bold">Step 7. </content>Place the cap back on the RISPERDAL Oral Solution bottle and turn the cap to the right (clockwise) to close the bottle. </td><td><renderMultiMedia referencedObject="MM5e"/></td></tr><tr><td><content styleCode="bold">Step 8. </content>Rinse the oral dosing syringe with water after each use. <list listType="unordered" styleCode="Disc"><item>Remove the plunger from the oral dosing syringe barrel.</item><item>Rinse the oral dosing syringe barrel and plunger with water and let them air dry.</item><item>When the oral dosing syringe barrel and plunger are dry, put the plunger back into the oral dosing syringe barrel for the next use.</item></list><content styleCode="bold">Do not throw away the oral dosing syringe.</content></td><td><renderMultiMedia referencedObject="MM5f"/></td></tr></tbody></table> <table width="100%" styleCode="Noautorules"><colgroup><col align="left" valign="top" width="60%"/><col align="center" valign="top" width="40%"/></colgroup><tbody><tr><td><content styleCode="bold">Cada caja de RISPERDAL Soluci&#xF3;n oral contiene lo siguiente:</content><list listType="unordered" styleCode="Disc"><item>1 frasco de RISPERDAL Soluci&#xF3;n oral</item><item>1 jeringa de dosificaci&#xF3;n oral</item></list></td><td><renderMultiMedia referencedObject="MM5g"/></td></tr></tbody></table>

tyleCode="bold">Cada caja de RISPERDAL Soluci&#xF3;n oral contiene lo siguiente:</content><list listType="unordered" styleCode="Disc"><item>1 frasco de RISPERDAL Soluci&#xF3;n oral</item><item>1 jeringa de dosificaci&#xF3;n oral</item></list></td><td><renderMultiMedia referencedObject="MM5g"/></td></tr></tbody></table> <table width="100%" styleCode="Noautorules"><colgroup><col align="left" valign="top" width="60%"/><col align="center" valign="top" width="40%"/></colgroup><tbody><tr><td><content styleCode="bold">Paso 1.</content>Coloque el frasco de RISPERDAL Soluci&#xF3;n oral sobre una superficie plana. Empuje hacia abajo la tapa mientras la gira hacia la izquierda (en sentido antihorario) para abrir el frasco. </td><td><renderMultiMedia referencedObject="MM5h"/></td></tr><tr><td><content styleCode="bold">Paso 2.</content>Empuje el &#xE9;mbolo de la jeringa de dosificaci&#xF3;n oral hasta el fondo. </td><td><renderMultiMedia referencedObject="MM5i"/></td></tr><tr><td><content styleCode="bold">Paso 3.</content>Con el frasco en posici&#xF3;n vertical, inserte completamente la jeringa de dosificaci&#xF3;n oral en la abertura del frasco. </td><td><renderMultiMedia referencedObject="MM5j"/></td></tr><tr><td><content styleCode="bold">Paso 4.</content>Extraiga la dosis prescrita de RISPERDAL Soluci&#xF3;n oral del frasco. Sostenga el cilindro de la jeringa de dosificaci&#xF3;n oral con una mano. Con la otra mano, tire lentamente del &#xE9;mbolo hacia arriba hasta que alcance las marcas de ml en el &#xE9;mbolo para la dosis prescrita. </td><td><renderMultiMedia referencedObject="MM5k"/></td></tr><tr><td><content styleCode="bold">Paso 5.</content>Retire la jeringa de dosificaci&#xF3;n oral del frasco sujetando el cilindro exterior y tirando hacia arriba. Tenga cuidado de no empujar hacia abajo el &#xE9;mbolo durante este paso. Compruebe que no haya burbujas de aire en la jeringa de dosificaci&#xF3;n oral. Si ve burbujas de aire, empuje lentamente el &#xE9;mbolo hasta el fondo para devolver la soluci&#xF3;n oral al frasco. Luego repita el <content styleCode="bold">Paso 4</content>para retirar la dosis prescrita. </td><td><renderMultiMedia referencedObject="MM5l"/></td></tr><tr><td><content styleCode="bold">Paso 6.</content>RISPERDAL Soluci&#xF3;n oral se puede mezclar con una bebida o se puede tomar directamente de la jeringa de dosificaci&#xF3;n oral. <list listType="unordered" styleCode="Disc"><item>Mezcle la dosis de RISPERDAL Soluci&#xF3;n oral con agua, caf&#xE9;, jugo de naranja o leche con bajo contenido de grasa. Revuelva bien y beba toda la mezcla de inmediato para asegurarse de tomar la dosis completa. <content styleCode="bold">Consulte la <linkHtml href="#Figura6a">Figura 6a</linkHtml>. </content> <content styleCode="bold">No mezcle</content>RISPERDAL Soluci&#xF3;n oral con refrescos de cola o t&#xE9;. </item></list></td><td><renderMultiMedia referencedObject="MM5m"/></td></tr><tr><td><content styleCode="bold">O</content><list listType="unordered" styleCode="Disc"><item>Para tomar la dosis de RISPERDAL Soluci&#xF3;n oral directamente de la jeringa de dosificaci&#xF3;n oral, coloque la punta de la jeringa de dosificaci&#xF3;n oral en la boca y hacia la mejilla. Empuje lentamente el &#xE9;mbolo hasta el fondo para liberar suavemente todo el medicamento en la jeringa de dosificaci&#xF3;n oral. No roc&#xED;e ni empuje con fuerza el medicamento en la parte posterior de la garganta. <content styleCode="bold">Consulte la <linkHtml href="#Figura6b">Figura 6b</linkHtml></content>.

a. Empuje lentamente el &#xE9;mbolo hasta el fondo para liberar suavemente todo el medicamento en la jeringa de dosificaci&#xF3;n oral. No roc&#xED;e ni empuje con fuerza el medicamento en la parte posterior de la garganta. <content styleCode="bold">Consulte la <linkHtml href="#Figura6b">Figura 6b</linkHtml></content>. </item></list></td><td><renderMultiMedia referencedObject="MM5n"/></td></tr><tr><td><content styleCode="bold">Paso 7.</content>Vuelva a colocar la tapa en el frasco de RISPERDAL Soluci&#xF3;n oral y g&#xED;rela hacia la derecha (en el sentido de las agujas del reloj) para cerrar el frasco. </td><td><renderMultiMedia referencedObject="MM5o"/></td></tr><tr><td><content styleCode="bold">Paso 8.</content>Enjuague la jeringa de dosificaci&#xF3;n oral con agua despu&#xE9;s de cada uso. <list listType="unordered" styleCode="Disc"><item>Retire el &#xE9;mbolo del cilindro de la jeringa de dosificaci&#xF3;n oral.</item><item>Enjuague el cilindro de la jeringa de dosificaci&#xF3;n oral con agua y d&#xE9;jela secar al aire.</item><item>Cuando el cilindro de la jeringa de dosificaci&#xF3;n oral y el &#xE9;mbolo est&#xE9;n secos, vuelva a colocar el &#xE9;mbolo en el cilindro de la jeringa de dosificaci&#xF3;n oral para el pr&#xF3;ximo uso.</item></list><content styleCode="bold">No deseche la jeringa de dosificaci&#xF3;n oral.</content></td><td><renderMultiMedia referencedObject="MM5p"/></td></tr></tbody></table>

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperidone is not approved for the treatment of patients with dementia-related psychosis [ see Warnings and Precautions (5.1 ) ]. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperidone is not approved for use in patients with dementia-related psychosis. ( 5.1 )

1 INDICATIONS AND USAGE Risperidone is an atypical antipsychotic indicated for: Treatment of schizophrenia ( 1.1 ) As monotherapy or adjunctive therapy with lithium or valproate, for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder ( 1.2 ) Treatment of irritability associated with autistic disorder ( 1.3 ) 1.1 Schizophrenia Risperidone oral solution is indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults [ see Clinical Studies (14.1) ]. 1.2 Bipolar Mania Monotherapy Risperidone oral solution is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) [ see Clinical Studies (14.2) ]. Adjunctive Therapy Risperidone oral solution adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults [ see Clinical Studies (14.3 ) ]. 1.3 Irritability Associated with Autistic Disorder Risperidone oral solution is indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years) [ see Clinical Studies (14.4) ].

2 DOSAGE AND ADMINISTRATION Table 1. Recommended Daily Dosage by Indication Initial Dose Titration (Increments) Target Dose Effective Dose Range Schizophrenia: adults ( 2.1 ) 2 mg 1 to 2 mg 4 to 8 mg 4 to 16 mg Schizophrenia: adolescents ( 2.1 ) 0.5 mg 0.5 to 1 mg 3 mg 1 to 6 mg Bipolar mania: adults ( 2.2 ) 2 to 3 mg 1 mg 1 to 6 mg 1 to 6 mg Bipolar mania: children and adolescents ( 2.2 ) 0.5 mg 0.5 to 1 mg 1 to 2.5 mg 1 to 6 mg Irritability in autistic disorder ( 2.3 ) 0.25 mg Can increase to 0.5 mg by Day 4: (body weight less than 20 kg) 0.5 mg Can increase to 1 mg by Day 4: (body weight greater than or equal to 20 kg) After Day 4, at intervals of > 2 weeks: 0.25 mg (body weight less than 20 kg) 0.5 mg (body weight greater than or equal to 20 kg) 0.5 mg: (body weight less than 20 kg) 1 mg: (body weight greater than or equal to 20 kg) 0.5 to 3 mg Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of one week or longer. Recommended daily dosage: Initial Dose Target Dose Effective Dose Range Schizophrenia: adults ( 2.1 ) 2 mg 4 to 8 mg 4 to 16 mg Schizophrenia: adolescents ( 2.1 ) 0.5 mg 3 mg 1 to 6 mg Bipolar mania: adults ( 2.2 ) 2 to 3 mg 1 to 6 mg 1 to 6 mg Bipolar mania: in children and adolescents ( 2.2 ) 0.5 mg 1 to 2.5 mg 1 to 6 mg Irritability associated with autistic disorder ( 2.3 ) 0.25 mg (Weight < 20 kg) 0.5 mg (Weight ≥ 20 kg) 0.5 mg (< 20 kg) 1 mg (≥ 20 kg) 0.5 to 3 mg Severe Renal or Hepatic Impairment in Adults: Use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of at least one week. ( 2.4 ) Oral Solution: Can be administered directly from calibrated oral dosing syringe or mixed with beverage (water, coffee, orange juice, or low-fat milk). ( 2.6 ) 2.1 Schizophrenia Adults Usual Initial Dose Risperidone oral solution can be administered once or twice daily. Initial dosing is 2 mg per day. May increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day, as tolerated, to a recommended dose of 4 to 8 mg per day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 mg to 16 mg per day. However, doses above 6 mg per day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg per day has not been evaluated in clinical trials [ see Clinical Studies (14.1) ]. Adolescents The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to a recommended dose of 3 mg per day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg to 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied. Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

renia at doses between 1 mg to 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied. Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily. Maintenance Therapy While it is unknown how long a patient with schizophrenia should remain on risperidone, the effectiveness of risperidone 2 mg per day to 8 mg per day at delaying relapse was demonstrated in a controlled trial in adult patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [ see Clinical Studies (14.1) ]. Both adult and adolescent patients who respond acutely should generally be maintained on their effective dose beyond the acute episode. Patients should be periodically reassessed to determine the need for maintenance treatment. Reinitiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off risperidone, the initial titration schedule should be followed. Switching From Other Antipsychotics There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to risperidone, or treating patients with concomitant antipsychotics. 2.2 Bipolar Mania Usual Dose Adults The initial dose range is 2 mg to 3 mg per day. The dose may be adjusted at intervals of 24 hours or greater, in increments of 1 mg per day. The effective dose range is 1 mg to 6 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1 mg to 6 mg per day [ see Clinical Studies ( 14.2 , 14.3 ) ]. Risperidone doses higher than 6 mg per day were not studied. Pediatrics The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to the recommended target dose of 1 mg to 2.5 mg per day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 mg and 6 mg per day, no additional benefit was observed above 2.5 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied. Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily. Maintenance Therapy There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with risperidone. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of risperidone in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. 2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents) The dosage of risperidone should be individualized according to the response and tolerability of the patient. The total daily dose of risperidone can be administered once daily, or half the total daily dose can be administered twice daily. For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day.

e dosage of risperidone should be individualized according to the response and tolerability of the patient. The total daily dose of risperidone can be administered once daily, or half the total daily dose can be administered twice daily. For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day. For patients with body weight greater than or equal to 20 kg, initiate dosing at 0.5 mg per day. After a minimum of four days, the dose may be increased to the recommended dose of 0.5 mg per day for patients less than 20 kg and 1 mg per day for patients greater than or equal to 20 kg. Maintain this dose for a minimum of 14 days. In patients not achieving sufficient clinical response, the dose may be increased at intervals of 2 weeks or greater, in increments of 0.25 mg per day for patients less than 20 kg, or increments of 0.5 mg per day for patients greater than or equal to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available for children who weigh less than 15 kg. Once sufficient clinical response has been achieved and maintained, consider gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose. 2.4 Dosing in Patients with Severe Renal or Hepatic Impairment For patients with severe renal impairment (CLcr< 30 mL/min) or hepatic impairment (10 to 15 points on Child Pugh System), the initial starting dose is 0.5 mg twice daily. The dose may be increased in increments of 0.5 mg or less, administered twice daily. For doses above 1.5 mg twice daily, increase in intervals of one week or greater [ see Use in Specific Populations ( 8.6 and 8.7 ) ]. 2.5 Dose Adjustments for Specific Drug Interactions When risperidone is co-administered with enzyme inducers (e.g., carbamazepine), the dose of risperidone should be increased up to double the patient’s usual dose. It may be necessary to decrease the risperidone dose when enzyme inducers such as carbamazepine are discontinued [ see Drug Interactions (7.1) ]. Similar effect may be expected with co-administration of risperidone with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital). When fluoxetine or paroxetine is co-administered with risperidone, the dose of risperidone should be reduced. The risperidone dose should not exceed 8 mg per day in adults when co-administered with these drugs. When initiating therapy, risperidone should be titrated slowly. It may be necessary to increase the risperidone dose when enzyme inhibitors such as fluoxetine or paroxetine are discontinued [ see Drug Interactions (7.1) ]. 2.6 Administration of Risperidone Oral Solution Risperidone oral solution can be administered directly from the calibrated oral dosing syringe, or can be mixed with a beverage prior to administration. Risperidone oral solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea.

4 CONTRAINDICATIONS Risperidone oral solution is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the risperidone formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone. Known hypersensitivity to risperidone, paliperidone, or to any excipients in risperidone oral solution ( 4 )

5 WARNINGS AND PRECAUTIONS Cerebrovascular events, including stroke, in elderly patients with dementia-related psychosis: Risperidone is not approved for use in patients with dementia-related psychosis. ( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of risperidone and close monitoring. ( 5.3 ) Tardive dyskinesia: Consider discontinuing risperidone if clinically indicated. ( 5.4 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. ( 5.5 ) Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.5 ) Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. ( 5.5 ) Weight Gain: Significant weight gain has been reported. Monitor weight gain. ( 5.5 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. ( 5.6 ) Orthostatic hypotension: For patients at risk, consider a lower starting dose and slower titration. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of clinically significant low white blood cell count (WBC). Consider discontinuing risperidone if a clinically significant decline in WBC occurs in the absence of other causative factors. ( 5.9 ) Potential for cognitive and motor impairment: Use caution when operating machinery. ( 5.10 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.11 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone when compared to patients treated with risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. Risperidone is not approved for the treatment of dementia-related psychosis [ see Boxed Warning ].

e when compared to patients treated with risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. Risperidone is not approved for the treatment of dementia-related psychosis [ see Boxed Warning ]. 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. Risperidone is not approved for the treatment of patients with dementia-related psychosis [ see Boxed Warning and Warnings and Precautions (5.1) ]. 5.3 Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue Risperidone Oral Solution and provide symptomatic treatment and monitoring. 5.4 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, risperidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on risperidone, drug discontinuation should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk.

n a patient on risperidone, drug discontinuation should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including risperidone, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone. Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2. Table 2. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania Risperidone Placebo 1 to 8 mg/day >8 to 16 mg/day Mean change from baseline (mg/dL) n = 555 n = 748 n = 164 Serum Glucose -1.4 0.8 0.6 Proportion of patients with shifts Serum Glucose (<140 mg/dL to ≥ 200 mg/dL) 0.6% (3/525) 0.4% (3/702) 0% (0/158) In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n = 151) and +4.1 mg/dL at Week 48 (n = 50). Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3. Table 3.

glucose of +2.8 mg/dL at Week 24 (n = 151) and +4.1 mg/dL at Week 48 (n = 50). Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3. Table 3. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 years of age), Bipolar Mania (10 to 17 years of age), or Autistic Disorder (5 to 17 years of age) Risperidone Placebo 0.5 to 6 mg/day Mean change from baseline (mg/dL) n = 76 n = 135 Serum Glucose -1.3 2.6 Proportion of patients with shifts Serum Glucose (<100 mg/dL to ≥126 mg/dL) 0% (0/64) 0.8% (1/120) In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n = 119). Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4. Table 4. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania Risperidone Placebo 1 to 8 mg/day >8 to16 mg/day Mean change from baseline (mg/dL) Cholesterol Change from baseline n = 559 0.6 n = 742 6.9 n = 156 1.8 Triglycerides Change from baseline n = 183 -17.4 n = 307 -4.9 n = 123 -8.3 Proportion of patients with shifts Cholesterol (<200 mg/dL to ≥240 mg/dL) 2.7% (10/368) 4.3% (22/516) 6.3% (6/96) Triglycerides (<500 mg/dL to ≥500 mg/dL) 1.1% (2/180) 2.7% (8/301) 2.5% (3/121) In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n = 231) and +5.5 mg/dL at Week 48 (n = 86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n = 52). Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 5. Table 5. Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), or Autistic Disorder (5 to 17 Years of Age) Placebo Risperidone0.5 to 6 mg/day Mean change from baseline (mg/dL) Cholesterol Change from baseline n = 74 0.3 n = 133 -0.3 LDL Change from baseline n = 22 3.7 n = 22 0.5 HDL Change from baseline n = 22 1.6 n = 22 -1.9 Triglycerides Change from baseline n= 77 -9 n = 138 -2.6 Proportion of patients with shifts Cholesterol (<170 mg/dL to ≥200 mg/dL) 2.4% (1/42) 3.8% (3/80) LDL (<110 mg/dL to ≥130 mg/dL) 0% (0/16) 0% (0/16) HDL (≥40 mg/dL to <40 mg/dL) 0% (0/19) 10% (2/20) Triglycerides (<150 mg/dL to ≥200 mg/dL) 1.5% (1/65) 7.1% (8/113) In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n = 114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n = 103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n = 103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n = 120). Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

1 mg/dL at Week 24 (n = 114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n = 103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n = 103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n = 120). Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6. Table 6. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania Risperidone Placebo (n = 597) 1 to 8 mg/day (n = 769) >8 to16 mg/day (n = 158) Weight (kg) Change from baseline -0.3 0.7 2.2 Weight Gain ≥7% increase from baseline 2.9% 8.7% 20.9% In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in weight of +4.3 kg at Week 24 (n = 395) and +5.3 kg at Week 48 (n = 203). Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), autistic disorder (5 to 17 years of age), or other psychiatric disorders (5 to 17 years of age) are presented in Table 7. Table 7. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5 to 17 Years of Age) Placebo(n = 375) Risperidone 0.5 to 6 mg/day(n = 448) Weight (kg) Change from baseline 0.6% 2% Weight Gain ≥7% increase from baseline 6.9% 32.6% In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in weight of +5.5 kg at Week 24 (n = 748) and +8 kg at Week 48 (n=242). In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9 kg was observed after 8 months of risperidone treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index. In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of risperidone treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to risperidone. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index. In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone groups than the placebo group, but not dose related (1.90 kg in the risperidone 0.5 to 2.5 mg group, 1.44 kg in the risperidone 3 to 6 mg group, and 0.65 kg in the placebo group).

en and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone groups than the placebo group, but not dose related (1.90 kg in the risperidone 0.5 to 2.5 mg group, 1.44 kg in the risperidone 3 to 6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index. When treating pediatric patients with risperidone for any indication, weight gain should be assessed against that expected with normal growth. 5.6 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [ see Nonclinical Toxicology (13.1) ]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer. 5.7 Orthostatic Hypotension Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [ see Dosage and Administration ( 2.1 , 2.4 ) ]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medication. 5.8 Falls Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including risperidone, which may lead to falls and, consequently, fractures or other fall-related injuries.

has been observed with concomitant use of risperidone and antihypertensive medication. 5.8 Falls Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including risperidone, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.9 Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm 3 ) should discontinue risperidone and have their WBC followed until recovery. 5.10 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction associated with risperidone treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reaction. Since risperidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone therapy does not affect them adversely. 5.11 Seizures During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone-treated patients, two in association with hyponatremia. Risperidone should be used cautiously in patients with a history of seizures. 5.12 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Risperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [ see Boxed Warning and Warnings and Precautions (5.1) ]. 5.13 Priapism Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention. 5.14 Body Temperature Regulation Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.

<table cellpadding="0" border="1"><col/><col/><col/><col/><thead><tr><th colspan="4" styleCode=" Botrule Toprule Lrule Rrule">Table 2. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule"/><th colspan="3" styleCode=" Botrule Toprule Lrule Rrule">Risperidone</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule"/><th styleCode=" Botrule Toprule Lrule Rrule">Placebo</th><th styleCode=" Botrule Toprule Lrule Rrule">1 to 8 mg/day</th><th styleCode=" Botrule Toprule Lrule Rrule">&gt;8 to 16 mg/day</th></tr></thead><tbody><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Mean change from baseline (mg/dL)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 555</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 748</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 164</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Serum Glucose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>-1.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Proportion of patients with shifts</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Serum Glucose</paragraph><paragraph>(&lt;140 mg/dL to &#x2265; 200 mg/dL)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.6%</paragraph><paragraph>(3/525)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.4%</paragraph><paragraph>(3/702)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph><paragraph>(0/158)</paragraph></td></tr></tbody></table>

ule Toprule Lrule Rrule"><paragraph>0.6%</paragraph><paragraph>(3/525)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.4%</paragraph><paragraph>(3/702)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph><paragraph>(0/158)</paragraph></td></tr></tbody></table> <table cellpadding="0" border="1"><col/><col/><col/><col/><thead><tr><th colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><th colspan="2" styleCode=" Botrule Toprule Lrule Rrule">Risperidone</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule"/><th colspan="2" styleCode=" Botrule Toprule Lrule Rrule">Placebo</th><th styleCode=" Botrule Toprule Lrule Rrule">0.5 to 6 mg/day</th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Mean change from baseline (mg/dL)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 76</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 135</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Serum Glucose</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>-1.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Proportion of patients with shifts</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Serum Glucose</paragraph><paragraph>(&lt;100 mg/dL to &#x2265;126 mg/dL)</paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph><paragraph>(0/64)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.8%</paragraph><paragraph>(1/120)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr></tbody></table>

td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.8%</paragraph><paragraph>(1/120)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"/></tr></tbody></table> <table cellpadding="0" border="1"><col/><col/><col/><col/><thead><tr><th colspan="4" styleCode=" Botrule Toprule Lrule Rrule">Table 4. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule"/><th colspan="3" styleCode=" Botrule Toprule Lrule Rrule">Risperidone</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule"/><th styleCode=" Botrule Toprule Lrule Rrule">Placebo</th><th styleCode=" Botrule Toprule Lrule Rrule">1 to 8 mg/day</th><th styleCode=" Botrule Toprule Lrule Rrule">&gt;8 to16 mg/day</th></tr></thead><tbody><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Mean change from baseline (mg/dL)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Cholesterol</content></paragraph><paragraph>Change from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 559</content></paragraph><paragraph>0.6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 742</content></paragraph><paragraph>6.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 156</content></paragraph><paragraph>1.8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Triglycerides</content></paragraph><paragraph>Change from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 183</content></paragraph><paragraph>-17.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 307</content></paragraph><paragraph>-4.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 123</content></paragraph><paragraph>-8.3</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Proportion of patients with shifts</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Cholesterol</content></paragraph><paragraph>(&lt;200 mg/dL to &#x2265;240 mg/dL)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.7%</paragraph><paragraph>(10/368)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.3%</paragraph><paragraph>(22/516)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6.3%</paragraph><paragraph>(6/96)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Triglycerides</content></paragraph><paragraph>(&lt;500 mg/dL to &#x2265;500 mg/dL)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.1%</paragraph><paragraph>(2/180)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.7%</paragraph><paragraph>(8/301)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.5%</paragraph><paragraph>(3/121)</paragraph></td></tr></tbody></table>

e Toprule Lrule Rrule"><paragraph>1.1%</paragraph><paragraph>(2/180)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.7%</paragraph><paragraph>(8/301)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.5%</paragraph><paragraph>(3/121)</paragraph></td></tr></tbody></table> <table width="276.45pt" cellpadding="0" border="1"><col/><col/><col/><thead><tr><th colspan="3" styleCode=" Botrule Toprule Lrule Rrule">Table 5.

e Toprule Lrule Rrule"><paragraph>1.1%</paragraph><paragraph>(2/180)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.7%</paragraph><paragraph>(8/301)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.5%</paragraph><paragraph>(3/121)</paragraph></td></tr></tbody></table> <table width="276.45pt" cellpadding="0" border="1"><col/><col/><col/><thead><tr><th colspan="3" styleCode=" Botrule Toprule Lrule Rrule">Table 5. Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule"/><th styleCode=" Botrule Toprule Lrule Rrule">Placebo</th><th styleCode=" Botrule Toprule Lrule Rrule">Risperidone0.5 to 6 mg/day</th></tr></thead><tbody><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Mean change from baseline (mg/dL)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Cholesterol</content></paragraph><paragraph>Change from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 74</content></paragraph><paragraph>0.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 133</content></paragraph><paragraph>-0.3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">LDL</content></paragraph><paragraph>Change from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 22</content></paragraph><paragraph>3.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 22</content></paragraph><paragraph>0.5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">HDL</content></paragraph><paragraph>Change from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 22</content></paragraph><paragraph>1.6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 22</content></paragraph><paragraph>-1.9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Triglycerides</content></paragraph><paragraph>Change from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n= 77</content></paragraph><paragraph>-9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">n = 138</content></paragraph><paragraph>-2.6</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Proportion of patients with shifts</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Cholesterol</content></paragraph><paragraph>(&lt;170 mg/dL to &#x2265;200 mg/dL)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4%</paragraph><paragraph>(1/42)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3.8%</paragraph><paragraph>(3/80)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">LDL</content></paragraph><paragraph>(&lt;110 mg/dL to &#x2265;130 mg/dL)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph><paragraph>(0/16)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph><paragraph>(0/16)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">HDL</content></paragraph><paragraph>(&

otrule Toprule Lrule Rrule"><paragraph>0%</paragraph><paragraph>(0/16)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph><paragraph>(0/16)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">HDL</content></paragraph><paragraph>(& #x2265;40 mg/dL to &lt;40 mg/dL)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph><paragraph>(0/19)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10%</paragraph><paragraph>(2/20)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Triglycerides</content></paragraph><paragraph>(&lt;150 mg/dL to &#x2265;200 mg/dL)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.5%</paragraph><paragraph>(1/65)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7.1%</paragraph><paragraph>(8/113)</paragraph></td></tr></tbody></table>

</content></paragraph><paragraph>(&lt;150 mg/dL to &#x2265;200 mg/dL)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.5%</paragraph><paragraph>(1/65)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7.1%</paragraph><paragraph>(8/113)</paragraph></td></tr></tbody></table> <table cellpadding="0" border="1"><col/><col/><col/><col/><thead><tr><th colspan="4" styleCode=" Botrule Toprule Lrule Rrule">Table 6. Mean Change in Body Weight (kg) and the Proportion of Subjects with &#x2265; 7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule"/><th styleCode=" Botrule Toprule Lrule Rrule"/><th colspan="2" styleCode=" Botrule Toprule Lrule Rrule">Risperidone</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule"/><th styleCode=" Botrule Toprule Lrule Rrule">Placebo (n = 597)</th><th styleCode=" Botrule Toprule Lrule Rrule">1 to 8 mg/day (n = 769)</th><th styleCode=" Botrule Toprule Lrule Rrule">&gt;8 to16 mg/day (n = 158)</th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Weight (kg)</content></paragraph><paragraph>Change from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>-0.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Weight Gain</content></paragraph><paragraph>&#x2265;7% increase from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.9%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8.7%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20.9%</paragraph></td></tr></tbody></table>

graph><paragraph>&#x2265;7% increase from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.9%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8.7%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20.9%</paragraph></td></tr></tbody></table> <table cellpadding="0" border="1"><col/><col/><col/><thead><tr><th colspan="3" styleCode=" Botrule Toprule Lrule Rrule">Table 7. Mean Change in Body Weight (kg) and the Proportion of Subjects With &#x2265;7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5 to 17 Years of Age)</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule"/><th styleCode=" Botrule Toprule Lrule Rrule">Placebo(n = 375)</th><th styleCode=" Botrule Toprule Lrule Rrule">Risperidone 0.5 to 6 mg/day(n = 448)</th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Weight (kg)</content></paragraph><paragraph>Change from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.6%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Weight Gain</content></paragraph><paragraph>&#x2265;7% increase from baseline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6.9%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>32.6%</paragraph></td></tr></tbody></table>

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [ see Boxed Warning and Warnings and Precautions ( 5.1 ) ] Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [ see Warnings and Precautions ( 5.2 ) ] Neuroleptic malignant syndrome [ see Warnings and Precautions ( 5.3 ) ] Tardive dyskinesia [ see Warnings and Precautions ( 5.4 ) ] Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [ see Warnings and Precautions ( 5.5 ) ] Hyperprolactinemia [ see Warnings and Precautions ( 5.6 ) ] Orthostatic hypotension [ see Warnings and Precautions ( 5.7 ) ] Falls [ see Warnings and Precautions ( 5.8 ) ] Leukopenia, neutropenia, and agranulocytosis [ see Warnings and Precautions ( 5.9 ) ] Potential for cognitive and motor impairment [ see Warnings and Precautions ( 5.10 ) ] Seizures [ see Warnings and Precautions ( 5.11 ) ] Dysphagia [ see Warnings and Precautions ( 5.12 ) ] Priapism [ see Warnings and Precautions ( 5.13 ) ] Disruption of body temperature regulation [ see Warnings and Precautions ( 5.14 ) ] The most common adverse reactions in clinical trials (>5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [ see Adverse Reactions , Discontinuations Due to Adverse Reactions ( 6.1 ) ]. The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of risperidone for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs. The most common adverse reactions in clinical trials (≥ 5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.

n, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Cranbury Pharmaceuticals, LLC at (732) 940-0358 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. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia Adult Patients with Schizophrenia Table 8 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials. Table 8. Adverse Reactions in ≥ 2% of Risperidone-Treated Adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Reaction R isperidone System/Organ Class Adverse Reaction 2 to 8 mg per day (n = 366) > 8 to 16 mg per day (n = 198) Placebo (n = 225) Cardiac Disorders Tachycardia 1 3 0 Eye Disorders Vision blurred 3 1 1 Gastrointestinal Disorders Nausea 9 4 4 Constipation 8 9 6 Dyspepsia 8 6 5 Dry mouth 4 0 1 Abdominal discomfort 3 1 1 Salivary hypersecretion 2 1 <1 Diarrhea 2 1 1 General Disorders Fatigue 3 1 0 Chest pain 2 2 1 Asthenia 2 1 <1 Infections and Infestations Nasopharyngitis 3 4 3 Upper respiratory tract infection 2 3 1 Sinusitis 1 2 1 Urinary tract infection 1 3 0 Investigations Blood creatine phosphokinase increased 1 2 <1 Heart rate increased <1 2 0 Musculoskeletal and Connective Tissue Disorders Back pain 4 1 1 Arthralgia 2 3 <1 Pain in extremity 2 1 1 Nervous System Disorders Parkinsonism* 14 17 8 Akathisia* 10 10 3 Sedation 10 5 2 Dizziness 7 4 2 Dystonia* 3 4 2 Tremor* 2 3 1 Dizziness postural 2 0 0 Psychiatric Disorders Insomnia 32 25 27 Anxiety 16 11 11 Respiratory, Thoracic and Mediastinal Disorders Nasal congestion 4 6 2 Dyspnea 1 2 0 Epistaxis <1 2 0 Skin and Subcutaneous Tissue Disorders Rash 1 4 1 Dry skin 1 3 0 Vascular Disorders Orthostatic hypotension 2 1 0 *Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor. Pediatric Patients with Schizophrenia Table 9 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial. Table 9. Adverse Reactions in ≥ 5% of Risperidone-Treated Pediatric Patients (and greater than placebo) with Schizophrenia in a Double-Blind Trial Percentage of Patients Reporting Reaction Risperidone System/Organ Class Adverse Reaction 1 to 3 mg per day (n = 55) 4 to 6 mg per day (n = 51) Placebo (n = 54) Gastrointestinal Disorders Salivary hypersecretion 0 10 2 Nervous System Disorders Sedation 24 12 4 Parkinsonism* 16 28 11 Tremor 11 10 6 Akathisia* 9 10 4 Dizziness 7 14 2 Dystonia* 2 6 0 Psychiatric Disorders Anxiety 7 6 0 * Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness.

vous System Disorders Sedation 24 12 4 Parkinsonism* 16 28 11 Tremor 11 10 6 Akathisia* 9 10 4 Dizziness 7 14 2 Dystonia* 2 6 0 Psychiatric Disorders Anxiety 7 6 0 * Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania Adult Patients with Bipolar Mania Table 10 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials. Table 10. Adverse Reactions in ≥ 2% of Risperidone-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials Percentage of Patients Reporting Reaction System/Organ Class Adverse Reaction Risperidone 1 to 6 mg per day (n = 448) Placebo (n = 424) Eye Disorders Vision blurred 2 1 Gastrointestinal Disorders Nausea 5 2 Diarrhea 3 2 Salivary hypersecretion 3 1 Stomach discomfort 2 <1 General Disorders Fatigue 2 1 Nervous System Disorders Parkinsonism* 25 9 Sedation 11 4 Akathisia* 9 3 Tremor* 6 3 Dizziness 6 5 Dystonia* 5 1 Lethargy 2 1 * Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis. Table 11 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials. Table 11. Adverse Reactions in ≥ 2% of Risperidone-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Adjunctive Therapy Trials Percentage of Patients Reporting Reaction System/Organ Class Adverse Reaction Risperidone + Mood Stabilizer (n = 127) Placebo + Mood Stabilizer (n = 126) Cardiac Disorders Palpitations 2 0 Gastrointestinal Disorders Dyspepsia 9 8 Nausea 6 4 Diarrhea 6 4 Salivary hypersecretion 2 0 General Disorders Chest pain 2 1 Infections and Infestations Urinary tract infection 2 1 Nervous System Disorders Parkinsonism* 14 4 Sedation 9 4 Akathisia* 8 0 Dizziness 7 2 Tremor 6 2 Lethargy 2 1 Psychiatric Disorders Anxiety 3 2 Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 5 2 Cough 2 0 * Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia. Pediatric Patients with Bipolar Mania Table 12 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial. Table 12.

trapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia. Pediatric Patients with Bipolar Mania Table 12 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial. Table 12. Adverse Reactions in ≥ 5% of Risperidone-Treated Pediatric Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Reaction Risperidone System/Organ Class Adverse Reaction 0.5 to 2.5 mg per day (n = 50) 3 to 6 mg per day (n = 61) Placebo (n = 58) Eye Disorders Vision blurred 4 7 0 Gastrointestinal Disorders Abdominal pain upper 16 13 5 Nausea 16 13 7 Vomiting 10 10 5 Diarrhea 8 7 2 Dyspepsia 10 3 2 Stomach discomfort 6 0 2 General Disorders Fatigue 18 30 3 Metabolism and Nutrition Disorders Increased appetite 4 7 2 Nervous System Disorders Sedation 42 56 19 Dizziness 16 13 5 Parkinsonism* 6 12 3 Dystonia* 6 5 0 Akathisia* 0 8 2 Psychiatric Disorders Anxiety 0 8 3 Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 10 3 5 Skin and Subcutaneous Tissue Disorders Rash 0 7 2 * Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder Table 13 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study. Table 13. Adverse Reactions in ≥ 5% of Risperidone-Treated Pediatric Patients (and greater than placebo) Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Reaction System/Organ Class Adverse Reaction Risperidone 0.5 to 4 mg/day (n = 107) Placebo (n = 115) Gastrointestinal Disorders Vomiting 20 17 Constipation 17 6 Dry mouth 10 4 Nausea 8 5 Salivary hypersecretion 7 1 General Disorders and Administration Site Conditions Fatigue 31 9 Pyrexia 16 13 Thirst 7 4 Infections and Infestations Nasopharyngitis 19 9 Rhinitis 9 7 Upper respiratory tract infection 8 3 Investigations Weight increased 8 2 Metabolism and Nutrition Disorders Increased appetite 44 15 Nervous System Disorders Sedation 63 15 Drooling 12 4 Headache 12 10 Tremor 8 1 Dizziness 8 2 Parkinsonism* 8 1 Renal and Urinary Disorders Enuresis 16 10 Respiratory, Thoracic and Mediastinal Disorders Cough 17 12 Rhinorrhea 12 10 Nasal congestion 10 4 Skin and Subcutaneous Tissue Disorders Rash 8 5 *Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness. Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of risperidone in adults and pediatric patients.

er, muscle rigidity, cogwheel rigidity, and muscle tightness. Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of risperidone in adults and pediatric patients. Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block Ear and Labyrinth Disorders: ear pain, tinnitus Endocrine Disorders: hyperprolactinemia Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal Immune System Disorders: drug hypersensitivity Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: decreased appetite, polydipsia, anorexia Musculoskeletal and Connective Tissue Disorders: joint stiffness, joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular, acne, hyperkeratosis, seborrheic dermatitis Vascular Disorders: hypotension, flushing Discontinuations Due to Adverse Reactions Schizophrenia - Adults Approximately 7% (39/564) of risperidone-treated patients in double-blind, placebo-controlled trials discontinued

us, rash papular, rash generalized, rash maculopapular, acne, hyperkeratosis, seborrheic dermatitis Vascular Disorders: hypotension, flushing Discontinuations Due to Adverse Reactions Schizophrenia - Adults Approximately 7% (39/564) of risperidone-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo.

us, rash papular, rash generalized, rash maculopapular, acne, hyperkeratosis, seborrheic dermatitis Vascular Disorders: hypotension, flushing Discontinuations Due to Adverse Reactions Schizophrenia - Adults Approximately 7% (39/564) of risperidone-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone-treated patients were: Table 14. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone- Treated Adult Patients in Schizophrenia Trials Risperidone Adverse Reaction 2 to 8 mg/day (n = 366) > 8 to 16 mg/day (n = 198) Placebo (n = 225) Dizziness 1.4% 1% 0% Nausea 1.4% 0% 0% Vomiting 0.8% 0% 0% Parkinsonism 0.8% 0% 0% Somnolence 0.8% 0% 0% Dystonia 0.5% 0% 0% Agitation 0.5% 0% 0% Abdominal pain 0.5% 0% 0% Orthostatic hypotension 0.3% 0.5% 0% Akathisia 0.3% 2% 0% Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial. Schizophrenia - Pediatrics Approximately 7% (7/106), of risperidone-treated patients discontinued treatment due to an adverse reaction in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one risperidone-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%). Bipolar Mania – Adults In double-blind, placebo-controlled trials with risperidone as monotherapy, approximately 6% (25/448) of risperidone-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in risperidone-treated patients were: Table 15. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Bipolar Mania Clinical Trials Adverse Reaction Risperidone 1 to 6 mg/day (n = 448) Placebo (n = 424) Parkinsonism 0.4% 0% Lethargy 0.2% 0% Dizziness 0.2% 0% Alanine aminotransferase increased 0.2% 0.2% Aspartate aminotransferase increased 0.2% 0.2% Bipolar Mania - Pediatrics In a double-blind, placebo-controlled trial 12% (13/111) of risperidone-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%). Autistic Disorder - Pediatrics In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one risperidone-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event. Dose Dependency of Adverse Reactions in Clinical Trials Extrapyramidal Symptoms Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone treatment. Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS: Table 16.

. Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS: Table 16. Dose Groups Placebo Risperidone 2 mg Risperidone 6 mg Risperidone 10 mg Risperidone 16 mg Parkinsonism 1.2 0.9 1.8 2.4 2.6 EPS Incidence 13% 17% 21% 21% 35% Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day): Table 17. Dose Groups Risperidone 1 mg Risperidone 4 mg Risperidone 8 mg Risperidone 12 mg Risperidone 16 mg Parkinsonism 0.6 1.7 2.4 2.9 4.1 EPS Incidence 7% 12% 17% 18% 20% Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Other Adverse Reactions Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration. Changes in Body Weight Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [ see Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6 ), and Use in Specific Populations ( 8.4 ) ]. Changes in ECG Parameters Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all risperidone doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8 to 16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4 to 6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups. In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 to 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the risperidone groups and 6.5 beats per minute in the placebo group. There were no other notable ECG changes. In a placebo-controlled acute mania trial in children and adolescents (aged 10 to 17 years), there were no significant changes in ECG parameters, other than the effect of risperidone to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 to 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.

the effect of risperidone to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 to 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

<table width="444.55pt" cellspacing="0" cellpadding="0" border="1"><col width="444.55pt"/><col/><col/><col/><tbody><tr><td align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Percentage of Patients Reporting Reaction</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="3"><paragraph><content styleCode="bold"> R</content><content styleCode="bold">isperidone</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">System/Organ Class</content></paragraph><paragraph>Adverse Reaction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">2 to 8 mg per day</content></paragraph><paragraph><content styleCode="bold">(n = 366)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">&gt; 8 to 16 mg per day</content></paragraph><paragraph><content styleCode="bold">(n = 198)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 225)</content></paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Cardiac Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Tachycardia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Eye Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vision blurred</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Constipation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspepsia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dry mouth</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCo

styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dry mouth</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCo de=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal discomfort</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Salivary hypersecretion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diarrhea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">General Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Chest pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Asthenia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>&lt;1</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Infections and Infestations</content></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>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</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>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sinusitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Urinary tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td

ode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Urinary tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Investigations</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/><td/><td/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Blood creatine phosphokinase increased</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Heart rate increased</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>&lt;1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Back pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Arthralgia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pain in extremity</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Parkinsonism*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Akathisia*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sedation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</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>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=

leCode=" 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>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode= " Botrule Toprule Lrule Rrule"><paragraph>Dystonia*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Tremor*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness postural</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Insomnia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>32</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>25</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>27</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anxiety</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nasal congestion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspnea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Epistaxis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>&lt;1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rash</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dry skin</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule

Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dry skin</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Vascular Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Orthostatic hypotension</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr></tbody></table>

rule Toprule Lrule Rrule"><paragraph>Orthostatic hypotension</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr></tbody></table> <table width="444.55pt" cellspacing="0" cellpadding="0" border="1"><col width="444.55pt"/><col/><col/><col/><tbody><tr><td align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Percentage of Patients Reporting Reaction</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td colspan="3"><paragraph><content styleCode="bold"> Risperidone</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">System/Organ Class</content></paragraph><paragraph>Adverse Reaction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">1 to 3 mg per day</content></paragraph><paragraph><content styleCode="bold">(n = 55)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">4 to 6 mg per day</content></paragraph><paragraph><content styleCode="bold">(n = 51)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 54)</content></paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Salivary hypersecretion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sedation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>24</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Parkinsonism*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>28</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Tremor</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Akathisia*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</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>14</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dystonia*</paragraph></td><td style

styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dystonia*</paragraph></td><td style Code=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anxiety</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr></tbody></table>

styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anxiety</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr></tbody></table> <table width="444.55pt" cellspacing="0" cellpadding="0" border="1"><col width="444.55pt"/><col/><col/><tbody><tr><td align="center" colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Percentage of Patients Reporting Reaction</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">System/Organ Class</content></paragraph><paragraph>Adverse Reaction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">1 to 6 mg per day</content></paragraph><paragraph><content styleCode="bold">(n = 448)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 424)</content></paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Eye Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vision blurred</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><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diarrhea</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>Salivary hypersecretion</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>Stomach discomfort</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>&lt;1</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">General Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</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><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Parkinsonism*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>25</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sedation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lru

Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sedation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>11</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lru le Rrule"><paragraph>Akathisia*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Tremor*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dystonia*</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>Lethargy</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr></tbody></table>

=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Lethargy</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr></tbody></table> <table width="444.55pt" cellspacing="0" cellpadding="0" border="1"><col width="444.55pt"/><col/><col/><tbody><tr><td align="center" colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Percentage of Patients Reporting Reaction</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">System/Organ Class</content></paragraph><paragraph>Adverse Reaction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone +</content></paragraph><paragraph><content styleCode="bold">Mood Stabilizer</content></paragraph><paragraph><content styleCode="bold">(n = 127)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo +</content></paragraph><paragraph><content styleCode="bold">Mood Stabilizer</content></paragraph><paragraph><content styleCode="bold">(n = 126)</content></paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Cardiac Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Palpitations</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspepsia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</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>Diarrhea</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>Salivary hypersecretion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">General Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Chest pain</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><content styleCode="bold">Infections and Infestations</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Urinary tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rr

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><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rr ule"><paragraph>Parkinsonism*</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>Sedation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Akathisia*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</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>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Tremor</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Lethargy</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><content styleCode="bold">Psychiatric Disorders</content></paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anxiety</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pharyngolaryngeal pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cough</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr></tbody></table>

ode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cough</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr></tbody></table> <table width="444.55pt" cellspacing="0" cellpadding="0" border="1"><col width="444.55pt"/><col/><col/><col/><tbody><tr><td align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Percentage of Patients Reporting</content><content styleCode="bold">Reaction</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td><paragraph><content styleCode="bold">Risperidone</content></paragraph></td><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">System/Organ Class</content></paragraph><paragraph>Adverse Reaction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">0.5 to 2.5 mg per day</content></paragraph><paragraph><content styleCode="bold">(n = 50)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">3 to 6 mg per day</content></paragraph><paragraph><content styleCode="bold">(n = 61)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 58)</content></paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Eye Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vision blurred</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal pain upper</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vomiting</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diarrhea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dyspepsia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</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 T

rule Toprule Lrule Rrule"><paragraph>Dyspepsia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</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 T oprule Lrule Rrule"><paragraph>Stomach discomfort</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">General Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>30</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Increased appetite</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sedation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>42</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>56</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>19</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Parkinsonism*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dystonia*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</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>Akathisia*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</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 colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Anxiety</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragrap

nxiety</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragrap h><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pharyngolaryngeal pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rash</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr></tbody></table>

<td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rash</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2</paragraph></td></tr></tbody></table> <table width="444.55pt" cellspacing="0" cellpadding="0" border="1"><col width="444.55pt"/><col/><col/><tbody><tr><td align="center" colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Percentage of Patients Reporting Reaction</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">System/Organ Class</content></paragraph><paragraph>Adverse Reaction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">0.5 to 4 mg/day</content></paragraph><paragraph><content styleCode="bold">(n = 107)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 115)</content></paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vomiting</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Constipation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dry mouth</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</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>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Salivary hypersecretion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">General Disorders and Administration Site Conditions</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>31</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pyrexia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Thirst</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Infections and Infestations</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nasopharyngitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>19</paragraph></

tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Infections and Infestations</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nasopharyngitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>19</paragraph></ td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rhinitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Upper respiratory tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Investigations</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Weight increased</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 colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Increased appetite</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sedation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>63</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Drooling</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><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>10</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Tremor</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</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>Parkinsonism*</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Renal and Urinary Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Enuresis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory, Thoracic and M

le"><paragraph>Enuresis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Respiratory, Thoracic and M ediastinal Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cough</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rhinorrhea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nasal congestion</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rash</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr></tbody></table>

Skin and Subcutaneous Tissue Disorders</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rash</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="6.45in"/><col/><col/><col/><tbody><tr><td align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">2 to 8 mg/day</content></paragraph><paragraph><content styleCode="bold">(n = 366)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">&gt; 8 to 16 mg/day</content></paragraph><paragraph><content styleCode="bold">(n = 198)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 225)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.4%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.4%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vomiting</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.8%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Parkinsonism</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.8%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Somnolence</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.8%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dystonia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.5%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Agitation</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.5%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.5%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td><

><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.5%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td>< /tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Orthostatic hypotension</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.3%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.5%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Akathisia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.3%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr></tbody></table>

ode=" Botrule Toprule Lrule Rrule"><paragraph>Akathisia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.3%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="198.9pt"/><col width="135pt"/><col width="121.5pt"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">1 to 6 mg/day</content></paragraph><paragraph><content styleCode="bold">(n = 448)</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 424)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Parkinsonism</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.4%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Lethargy</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.2%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.2%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Alanine aminotransferase increased</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.2%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.2%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Aspartate aminotransferase increased</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.2%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.2%</paragraph></td></tr></tbody></table>

graph>0.2%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Aspartate aminotransferase increased</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.2%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.2%</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="1.2in"/><col width="66.15pt"/><col width="76.95pt"/><col width="76.5pt"/><col width="69.75pt"/><col width="69.7pt"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Dose Groups</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Placebo</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">2 mg</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">6 mg</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">10 mg</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">16 mg</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Parkinsonism</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.6</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>EPS Incidence</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>21%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>21%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>35%</paragraph></td></tr></tbody></table>

tyleCode=" Botrule Toprule Lrule Rrule"><paragraph>17%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>21%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>21%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>35%</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="1"><col width="85.5pt"/><col width="67.05pt"/><col width="77.85pt"/><col width="1.05in"/><col width="69.75pt"/><col width="0.95in"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Dose Groups</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">1 mg</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">4 mg</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">8 mg</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">12 mg</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph><paragraph><content styleCode="bold">16 mg</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Parkinsonism</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.9</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.1</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>EPS Incidence</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>12%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>17%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>18%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20%</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone. Increase the risperidone dose up to double the patient’s usual dose. Titrate slowly. ( 7.1 ) Fluoxetine, paroxetine, and other CYP 2D6 enzyme inhibitors increase plasma concentrations of risperidone. Reduce the initial dose. Do not exceed a final dose of 8 mg per day of risperidone. ( 7.1 ) 7.1 Pharmacokinetic-related Interactions The dose of risperidone should be adjusted when used in combination with CYP2D6 enzyme inhibitors (e.g., fluoxetine, and paroxetine) and enzyme inducers (e.g., carbamazepine) [ see Table 18 and Dosage and Administration (2.5) ]. Dose adjustment is not recommended for risperidone when co-administered with ranitidine, cimetidine, amitriptyline, or erythromycin [ see Table 18 ]. Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia Co-administered Drug Dosing Schedule Effect on Active Moiety(Risperidone + 9- Hydroxy-Risperidone (Ratio*) Risperidone Dose Recommendation Co-administered Drug Risperidone AUC C max Enzyme (CYP2D6) Inhibitors Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day 20 mg/day 4 mg/day 1.6 - 40 mg/day 4 mg/day 1.8 - Enzyme (CYP3A/ PgP inducers) Inducers Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose Enzyme (CYP3A) Inhibitors Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed Other Drugs Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed *Change relative to reference Effect of Risperidone on Other Drugs Lithium Repeated oral doses of risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (n = 13). Dose adjustment for lithium is not recommended. Valproate Repeated oral doses of risperidone (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n = 21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of risperidone. Dose adjustment for valproate is not recommended. Digoxin Risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended. 7.2 Pharmacodynamic-related Interactions Centrally Acting Drugs and Alcohol Given the primary CNS effects of risperidone, caution should be used when risperidone is taken in combination with other centrally acting drugs and alcohol. Drugs with Hypotensive Effects Because of its potential for inducing hypotension, risperidone may enhance the hypotensive effects of other therapeutic agents with this potential. Levodopa and Dopamine Agonists Risperidone may antagonize the effects of levodopa and dopamine agonists. Methylphenidate Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS).

cts of other therapeutic agents with this potential. Levodopa and Dopamine Agonists Risperidone may antagonize the effects of levodopa and dopamine agonists. Methylphenidate Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of risperidone and methylphenidate [ see Adverse Reactions (6.2) ]. Clozapine Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

<table cellpadding="0" border="1"><col/><col/><col/><col/><col/><col/><thead><tr><th colspan="6" styleCode=" Botrule Toprule Lrule Rrule">Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule">Co-administered Drug</th><th colspan="2" styleCode=" Botrule Toprule Lrule Rrule">Dosing Schedule</th><th colspan="2" styleCode=" Botrule Toprule Lrule Rrule">Effect on Active Moiety(Risperidone + 9- Hydroxy-Risperidone (Ratio*)</th><th styleCode=" Botrule Toprule Lrule Rrule">Risperidone Dose Recommendation</th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Co-administered Drug</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Risperidone</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">AUC</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">C _max</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"/></tr><tr><td colspan="6" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Enzyme (CYP2D6) Inhibitors</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fluoxetine</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20 mg/day</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2 or 3 mg twice daily</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Re-evaluate dosing. Do not exceed 8 mg/day</paragraph></td></tr><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Paroxetine</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10 mg/day</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 mg/day</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>-</paragraph></td><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Re-evaluate dosing.

d><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 mg/day</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>-</paragraph></td><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Re-evaluate dosing. Do not exceed 8 mg/day</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20 mg/day</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 mg/day</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>-</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>40 mg/day</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 mg/day</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>-</paragraph></td></tr><tr><td colspan="6" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Enzyme (CYP3A/ PgP inducers) Inducers</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Carbamazepine</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>573 &#xB1; 168 mg/day</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 mg twice daily</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.51</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.55</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Titrate dose upwards.

<td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 mg twice daily</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.51</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.55</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Titrate dose upwards. Do not exceed twice the patient&#x2019;s usual dose</paragraph></td></tr><tr><td colspan="6" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Enzyme (CYP3A) Inhibitors</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Ranitidine</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>150 mg twice daily</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 mg single dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dose adjustment not needed</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Cimetidine</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>400 mg twice daily</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 mg single dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dose adjustment not needed</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Erythromycin</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>500 mg four times daily</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 mg single dose</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.94</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dose adjustment not needed</paragraph></td></tr><tr><td colspan="6" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Other Drugs</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Amitriptyline</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>50 mg twice daily</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 mg twice daily</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.1</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dose adjustment not needed</paragraph></td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including risperidone, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including risperidone, during pregnancy ( see Clinical Considerations ). Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area. 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 Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

s, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88- 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area: maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m 2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m 2 and the only dose tested in the study. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of risperidone and its metabolite, 9- hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone ( see Clinical Considerations ). There is no information on the effects of risperidone on milk production.

f the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone ( see Clinical Considerations ). There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for risperidone and any potential adverse effects on the breastfed child from Risperidone or from the mother’s underlying condition. Clinical Considerations Infants exposed to risperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of risperidone (D 2 receptor antagonism), treatment with risperidone may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [ see Warnings and Precautions (5.6) ]. 8.4 Pediatric Use Approved Pediatric Indications Schizophrenia The efficacy and safety of risperidone in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 to 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [ see Indications and Usage ( 1.1 ), Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.1 ) ]. Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia. Safety and effectiveness of risperidone in children less than 13 years of age with schizophrenia have not been established. Bipolar I Disorder The efficacy and safety of risperidone in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 to 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [ see Indications and Usage (1.2) , Adverse Reactions (6.1) , and Clinical Studies (14.2) ]. Safety and effectiveness of risperidone in children less than 10 years of age with bipolar disorder have not been established. Autistic Disorder The efficacy and safety of risperidone in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [ see Indications and Usage (1.3) , Adverse Reactions (6.1) and Clinical Studies (14.4) ]. Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of risperidone as patients treated for irritability associated with autistic disorder. A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms. There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg.

t-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone. Adverse Reactions in Pediatric Patients Tardive Dyskinesia In clinical trials in 1885 children and adolescents treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone treatment [ see also Warnings and Precautions (5.4) ]. Weight Gain Weight gain has been observed in children and adolescents during treatment with risperidone. Clinical monitoring of weight is recommended during treatment. Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for risperidone-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. In these trials, approximately 33% of the risperidone group had weight gain ≥7%, compared to 7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at Week 24 and 8 kg at Week 48 [ see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ]. Somnolence Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. Somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these adverse reactions were most often of early onset and transient in duration [ see Adverse Reactions ( 6.1 and 6.2 ) ]. Patients experiencing persistent somnolence may benefit from a change in dosing regimen [ see Dosage and Administration ( 2.1 , 2.2 , and 2.3 ) ]. Hyperprolactinemia Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in adults [ see Warnings and Precautions (5.6) ]. In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received risperidone had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82 to 87% of patients who received risperidone had elevated levels of prolactin compared to 3 to 7% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications. In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of risperidone-treated patients and gynecomastia was reported in 2.3% of risperidone-treated patients. Growth and Sexual Maturation The long-term effects of risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.

children and adolescents, galactorrhea was reported in 0.8% of risperidone-treated patients and gynecomastia was reported in 2.3% of risperidone-treated patients. Growth and Sexual Maturation The long-term effects of risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents. Juvenile Animal Studies Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9- hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period. Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/ day for children. 8.5 Geriatric Use Clinical studies of risperidone in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [ see Clinical Pharmacology (12.3) and Dosage and Administration ( 2.4 , 2.5 ) ]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [ see Warnings and Precautions (5.7) ]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [ see Dosage and Administration (2.4) ]. 8.6 Renal Impairment In patients with moderate to severe (Clcr 59 to 15 mL/min) renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60%, compared to young healthy subjects. Risperidone doses should be reduced in patients with renal disease [ see Dosage and Administration (2.4) ].

. 8.6 Renal Impairment In patients with moderate to severe (Clcr 59 to 15 mL/min) renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60%, compared to young healthy subjects. Risperidone doses should be reduced in patients with renal disease [ see Dosage and Administration (2.4) ]. 8.7 Hepatic Impairment While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α 1 -acid glycoprotein. Risperidone doses should be reduced in patients with liver disease [ see Dosage and Administration (2.4) ]. 8.8 Patients with Parkinson's Disease or Lewy Body Dementia Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience increased sensitivity to risperidone. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including risperidone, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including risperidone, during pregnancy ( see Clinical Considerations ). Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area. 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 Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects.

within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88- 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area: maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m 2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m 2 and the only dose tested in the study.

8.4 Pediatric Use Approved Pediatric Indications Schizophrenia The efficacy and safety of risperidone in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 to 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [ see Indications and Usage ( 1.1 ), Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.1 ) ]. Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia. Safety and effectiveness of risperidone in children less than 13 years of age with schizophrenia have not been established. Bipolar I Disorder The efficacy and safety of risperidone in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 to 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [ see Indications and Usage (1.2) , Adverse Reactions (6.1) , and Clinical Studies (14.2) ]. Safety and effectiveness of risperidone in children less than 10 years of age with bipolar disorder have not been established. Autistic Disorder The efficacy and safety of risperidone in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [ see Indications and Usage (1.3) , Adverse Reactions (6.1) and Clinical Studies (14.4) ]. Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of risperidone as patients treated for irritability associated with autistic disorder. A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms. There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone. Adverse Reactions in Pediatric Patients Tardive Dyskinesia In clinical trials in 1885 children and adolescents treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone treatment [ see also Warnings and Precautions (5.4) ]. Weight Gain Weight gain has been observed in children and adolescents during treatment with risperidone. Clinical monitoring of weight is recommended during treatment. Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders.

during treatment with risperidone. Clinical monitoring of weight is recommended during treatment. Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for risperidone-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. In these trials, approximately 33% of the risperidone group had weight gain ≥7%, compared to 7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at Week 24 and 8 kg at Week 48 [ see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ]. Somnolence Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. Somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these adverse reactions were most often of early onset and transient in duration [ see Adverse Reactions ( 6.1 and 6.2 ) ]. Patients experiencing persistent somnolence may benefit from a change in dosing regimen [ see Dosage and Administration ( 2.1 , 2.2 , and 2.3 ) ]. Hyperprolactinemia Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in adults [ see Warnings and Precautions (5.6) ]. In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received risperidone had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82 to 87% of patients who received risperidone had elevated levels of prolactin compared to 3 to 7% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications. In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of risperidone-treated patients and gynecomastia was reported in 2.3% of risperidone-treated patients. Growth and Sexual Maturation The long-term effects of risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents. Juvenile Animal Studies Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9- hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

bolite paliperidone (9- hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period. Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m 2 body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/ day for children.

8.5 Geriatric Use Clinical studies of risperidone in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [ see Clinical Pharmacology (12.3) and Dosage and Administration ( 2.4 , 2.5 ) ]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [ see Warnings and Precautions (5.7) ]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [ see Dosage and Administration (2.4) ].

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Risperidone oral solution is not a controlled substance. 9.2 Abuse Risperidone has not been systematically studied in animals or humans for its potential for abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of risperidone misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). 9.3 Dependence Risperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

9.2 Abuse Risperidone has not been systematically studied in animals or humans for its potential for abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of risperidone misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

10 OVERDOSAGE 10.1 Human Experience Premarketing experience included eight reports of acute risperidone overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure. Postmarketing experience includes reports of acute risperidone overdosage, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to risperidone overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of risperidone and paroxetine. 10.2 Management of Overdosage For the most up to date information on the management of risperidone overdosage, contact a certified poison control center (1-800-222-1222 or www.poison.org). Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to risperidone.

11 DESCRIPTION Risperidone oral solution contains risperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23 H 27 FN 4 O 2 and its molecular weight is 410.49. The structural formula is: Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl. Risperidone is also available as a 1 mg/mL oral solution. Risperidone Oral Solution contains the following inactive ingredients: benzoic acid, sodium hydroxide, sorbitol solution, tartaric acid, and purified water. Figure 1

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2 ) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [ see Clinical Pharmacology (12.3) ]. Antagonism at receptors other than D 2 and 5HT 2 may explain some of the other effects of risperidone [ see Clinical Pharmacology (12.1) ]. 12.2 Pharmacodynamics Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2 ), dopamine Type 2 (D 2 ), α 1 and α 2 adrenergic, and H 1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C , 5HT 1D , and 5HT 1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 -5 M) for cholinergic muscarinic or β 1 and β 2 adrenergic receptors. 12.3 Pharmacokinetics Absorption Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV = 25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV = 10%) when compared to a solution. Pharmacokinetic studies showed that Risperidone Orally Disintegrating Tablets and Risperidone Oral Solution are bioequivalent to Risperidone Tablets. Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5 to 6 days (measured in extensive metabolizers). Food Effect Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone oral solution can be given with or without meals. Distribution Risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. In plasma, risperidone is bound to albumin and α 1 -acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance. Elimination Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N -dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone.

sm Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N -dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6% to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. The apparent half-life of risperidone was 3 hours (CV = 30%) in extensive metabolizers and 20 hours (CV = 40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV = 20%) in extensive metabolizers and 30 hours (CV = 25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours. Drug Interaction Studies Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [ see Drug Interactions (7) ]. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given risperidone do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with risperidone may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [ see Drug Interactions (7) ]. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [ see Drug Interactions (7) ]. In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, risperidone is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.

drug interaction studies, risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. Specific Populations Renal and Hepatic Impairment [ See Use in Specific Populations (8.6 and 8.7 ) ]. Elderly In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients [ see Use in Specific Populations (8.5) ]. Pediatric The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight. Race and Gender Effects No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

12.1 Mechanism of Action The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2 ) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [ see Clinical Pharmacology (12.3) ]. Antagonism at receptors other than D 2 and 5HT 2 may explain some of the other effects of risperidone [ see Clinical Pharmacology (12.1) ].

12.3 Pharmacokinetics Absorption Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV = 25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV = 10%) when compared to a solution. Pharmacokinetic studies showed that Risperidone Orally Disintegrating Tablets and Risperidone Oral Solution are bioequivalent to Risperidone Tablets. Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5 to 6 days (measured in extensive metabolizers). Food Effect Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone oral solution can be given with or without meals. Distribution Risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. In plasma, risperidone is bound to albumin and α 1 -acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance. Elimination Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N -dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6% to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces.

xyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. The apparent half-life of risperidone was 3 hours (CV = 30%) in extensive metabolizers and 20 hours (CV = 40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV = 20%) in extensive metabolizers and 30 hours (CV = 25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours. Drug Interaction Studies Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [ see Drug Interactions (7) ]. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given risperidone do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with risperidone may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [ see Drug Interactions (7) ]. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [ see Drug Interactions (7) ]. In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, risperidone is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. Specific Populations Renal and Hepatic Impairment [ See Use in Specific Populations (8.6 and 8.7 ) ]. Elderly In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients [ see Use in Specific Populations (8.5) ]. Pediatric The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight. Race and Gender Effects No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Multiples of Maximum Human Dose in mg/m 2 (mg/kg) Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas mouse Female 0.2 (2.4) none rat Female 0.4 (2.4) none rat Male 6 (37.5) 1.5 (9.4) Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5 to 6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [ see Warnings and Precautions (5.6) ]. Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila . Impairment of Fertility Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD based on mg/m 2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

<table><col/><col/><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule" valign="top"> </th><th align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule" valign="top"><content styleCode="bold"> Multiples of Maximum Human Dose in mg/m ² (mg/kg) </content></th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule" valign="top"><content styleCode="bold"> Tumor Type</content></th><th styleCode=" Botrule Toprule Lrule Rrule" valign="top"><content styleCode="bold"> Species</content></th><th styleCode=" Botrule Toprule Lrule Rrule" valign="top"><content styleCode="bold"> Sex</content></th><th styleCode=" Botrule Toprule Lrule Rrule" valign="top"><content styleCode="bold"> Lowest Effect Level</content></th><th styleCode=" Botrule Toprule Lrule Rrule" valign="top"><content styleCode="bold"> Highest No-Effect Level</content></th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"> Pituitary adenomas</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> mouse</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> Female</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> 0.75 (9.4)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> 0.2 (2.4)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"> Endocrine pancreas adenomas</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> rat</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> Male</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> 1.5 (9.4)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> 0.4 (2.4)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"> Mammary gland adenocarcinomas</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> mouse</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> Female</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> 0.2 (2.4)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> none</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"> </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> rat</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> Female</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> 0.4 (2.4)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> none</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"> </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> rat</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> Male</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> 6 (37.5)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> 1.5 (9.4)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"> Mammary gland neoplasm, Total</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> rat</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> Male</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> 1.5 (9.4)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> 0.4 (2.4)</td></tr></tbody></table>

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Multiples of Maximum Human Dose in mg/m 2 (mg/kg) Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas mouse Female 0.2 (2.4) none rat Female 0.4 (2.4) none rat Male 6 (37.5) 1.5 (9.4) Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5 to 6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [ see Warnings and Precautions (5.6) ]. Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila . Impairment of Fertility Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD based on mg/m 2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

14 CLINICAL STUDIES 14.1 Schizophrenia Adults Short-Term Efficacy The efficacy of risperidone in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) were employed. The results of the trials follow: (1) In a 6-week, placebo-controlled trial (n = 160) involving titration of risperidone in doses up to 10 mg/day (twice-daily schedule), risperidone was generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the SANS. (2) In an 8-week, placebo-controlled trial (n = 513) involving 4 fixed doses of risperidone (2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all 4 risperidone groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest risperidone dose groups were generally superior to placebo on the PANSS negative subscale. The most consistently positive responses on all measures were seen for the 6 mg dose group, and there was no suggestion of increased benefit from larger doses. (3) In an 8-week, dose comparison trial (n = 1356) involving 5 fixed doses of risperidone (1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the four highest risperidone dose groups were generally superior to the 1 mg risperidone dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The most consistently positive responses were seen for the 4 mg dose group. (4) In a 4-week, placebo-controlled dose comparison trial (n = 246) involving 2 fixed doses of risperidone (4 and 8 mg/day on a once-daily schedule), both risperidone dose groups were generally superior to placebo on several PANSS measures, including a response measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg dose group. Long-Term Efficacy In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to risperidone (2 to 8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving risperidone experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator.

least 4 weeks on an antipsychotic medication were randomized to risperidone (2 to 8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving risperidone experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator. Pediatrics The efficacy of risperidone in the treatment of schizophrenia in adolescents aged 13 to 17 years was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at time of enrollment. In the first trial (study #1), patients were randomized into one of three treatment groups: risperidone 1 to 3 mg/day (n = 55, mean modal dose = 2.6 mg), risperidone 4 to 6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the second trial (study #2), patients were randomized to either risperidone 0.15 to 0.6 mg/day (n = 132, mean modal dose = 0.5 mg) or risperidone 1.5 to 6 mg/day (n = 125, mean modal dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of the 0.15 to 0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to the target dosage range by approximately Day 7. Subsequently, dosage was increased to the maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable in all studies was the mean change from baseline in total PANSS score. Results of the studies demonstrated efficacy of risperidone in all dose groups from 1 to 6 mg/day compared to placebo, as measured by significant reduction of total PANSS score. The efficacy on the primary parameter in the 1 to 3 mg/day group was comparable to the 4 to 6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5 to 6 mg/day group in study #2. In study #2, the efficacy in the 1.5 to 6 mg/day group was statistically significantly greater than that in the 0.15 to 0.6 mg/day group. Doses higher than 3 mg/day did not reveal any trend towards greater efficacy. 14.2 Bipolar Mania - Monotherapy Adults The efficacy of risperidone in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features. The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the YMRS total score. The results of the trials follow: (1) In one 3-week placebo-controlled trial (n = 246), limited to patients with manic episodes, which involved a dose range of risperidone 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), risperidone was superior to placebo in the reduction of YMRS total score. (2) In another 3-week placebo-controlled trial (n = 286), which involved a dose range of 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), risperidone was superior to placebo in the reduction of YMRS total score.

, risperidone was superior to placebo in the reduction of YMRS total score. (2) In another 3-week placebo-controlled trial (n = 286), which involved a dose range of 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), risperidone was superior to placebo in the reduction of YMRS total score. Pediatrics The efficacy of risperidone in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder. Patients were randomized into one of three treatment groups: risperidone 0.5 to 2.5 mg/day (n = 50, mean modal dose = 1.9 mg), risperidone 3 to 6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases, study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10. The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score. Results of this study demonstrated efficacy of risperidone in both dose groups compared with placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary parameter in the 3 to 6 mg/day dose group was comparable to the 0.5 to 2.5 mg/day dose group. Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy. 14.3 Bipolar Mania – Adjunctive Therapy with Lithium or Valproate The efficacy of risperidone with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course. (1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone, placebo, or an active comparator, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score. (2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone or placebo, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4 to 12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone. 14.4 Irritability Associated with Autistic Disorder Short-Term Efficacy The efficacy of risperidone in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder.

4 Irritability Associated with Autistic Disorder Short-Term Efficacy The efficacy of risperidone in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16 to 104.3 kg). Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies. The results of these trials are as follows: (1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n = 101), aged 5 to 16 years, received twice daily doses of placebo or risperidone 0.5 to 3.5 mg/day on a weight-adjusted basis. Risperidone, starting at 0.25 mg/day or 0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day), significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with placebo. (2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n = 55), aged 5 to 12 years, risperidone 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo. A third trial was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects (N = 96) 5 to 17 years of age with autistic disorder (defined by DSM-IV criteria) and associated irritability and related behavioral symptoms. Approximately 77% of patients were younger than 12 years of age (mean age = 9), and 88% were male. Most patients (73%) weighed less than 45 kg (mean weight = 40 kg). Approximately 90% of patients were antipsychotic-naïve before entering the study. There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The dose was administered once daily in the morning, or in the evening if sedation occurred. The primary efficacy endpoint was the mean change in the Aberrant Behavior Checklist – Irritability subscale (ABC-I) score from baseline to the end of Week 6. The study demonstrated the efficacy of high-dose risperidone, as measured by the mean change in ABC-I score. It did not demonstrate efficacy for low-dose risperidone. The mean baseline ABC-I scores were 29 in the placebo group (n = 35), 27 in the risperidone low-dose group (n = 30), and 28 in the risperidone high-dose group (n = 31). The mean changes in ABC-I scores were -3.5, -7.4, and -12.4 in the placebo, low-dose, and high-dose group respectively. The results in the high-dose group were statistically significant (p< 0.001) but not in the low-dose group (p = 0.164).

one low-dose group (n = 30), and 28 in the risperidone high-dose group (n = 31). The mean changes in ABC-I scores were -3.5, -7.4, and -12.4 in the placebo, low-dose, and high-dose group respectively. The results in the high-dose group were statistically significant (p< 0.001) but not in the low-dose group (p = 0.164). Long-Term Efficacy Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with risperidone for 4 or 6 months (depending on whether they received risperidone or placebo in the double-blind study). During this open-label treatment period, patients were maintained on a mean modal dose of risperidone of 1.8 to 2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day). Patients who maintained their positive response to risperidone (response was defined as ≥ 25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much improved’) during the 4 to 6 month open-label treatment phase for about 140 days, on average, were randomized to receive risperidone or placebo during an 8-week, double-blind withdrawal study (n = 39 of the 63 patients). A pre-planned interim analysis of data from patients who completed the withdrawal study (n = 32), undertaken by an independent Data Safety Monitoring Board, demonstrated a significantly lower relapse rate in the risperidone group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention. Relapse was defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase).

Risperidone Oral Solution, USP 1 mg/mL (NDC 27808-002-01) is supplied in 30 mL bottles with a calibrated (in milliliters) oral dosing syringe. The minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL. NDC: 70518-3741-00 NDC: 70518-3741-01 PACKAGING: 10 in 1 BOX PACKAGING: 2 mL in 1 CUP, UNIT DOSE Risperidone Oral Solution, USP 1 mg/mL should be stored at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light and freezing. Light Sensitive: Store in carton, away from direct sunlight. Keep out of reach of children. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

17 PATIENT COUNSELING INFORMATION Advise patients using Risperidone oral solution to read the FDA-approved patient labeling ( Instructions for Use ) for Risperidone oral solution. Physicians are advised to discuss the following issues with patients for whom they prescribe risperidone. Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [ see Warnings and Precautions (5.3) ]. Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [ see Warnings and Precautions (5.4) ]. Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [ see W arnings and Precautions (5.5) ]. Orthostatic Hypotension Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [ see Warnings and Precautions (5.7) ]. Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking risperidone [ see Wa rnings and Precautions (5.9) ]. Hyperprolactinemia Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of risperidone. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males. [See Warnings and Precautions (5.6) ] . Interference with Cognitive and Motor Performance Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle until they are reasonably certain that risperidone therapy does not affect them adversely [ see Warnings and Precautions (5.10) ]. 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 [ Warnings and Precautions (5.13) ]. Heat Exposure and Dehydration Counsel patients regarding appropriate care in avoiding overheating and dehydration [ see Warnings and Precautions (5.14) ]. Concomitant Medication Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter drugs, as there is a potential for interactions [ see Drug Interactions (7) ]. Alcohol Advise patients to avoid alcohol while taking risperidone [ see Drug Interactions (7.2) ]. Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with risperidone. Advise patients that risperidone may cause extrapyramidal and/or withdrawal symptoms in a neonate.

avoid alcohol while taking risperidone [ see Drug Interactions (7.2) ]. Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with risperidone. Advise patients that risperidone may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to risperidone during pregnancy [ see Use in Specific Populations (8.1) ]. Lactation Advise breastfeeding women using risperidone to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [ see Use in Specific Populations (8.2) ]. Infertility Advise females of reproductive potential that risperidone may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [ see Use in Specific Populations (8.3) ]. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

INSTRUCTIONS FOR USE RISPERIDONE ORAL SOLUTION, USP Read these Instructions for Use before you start using Risperidone Oral Solution and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Important information you need to know before taking Risperidone Oral Solution: Take Risperidone Oral Solution exactly as your healthcare provider tells you to take it. Each 1 mL contains 1 mg of Risperidone Oral Solution. Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose using the oral dosing syringe. Always use the oral dosing syringe that comes with Risperidone Oral Solution. Contact your healthcare provider or pharmacist if you lose or damage the oral dosing syringe, or if your carton does not come with one. Risperidone Oral Solution can be taken directly from the oral dosing syringe or mixed with water, coffee, orange juice, or low-fat milk. Do not mix Risperidone Oral Solution with cola or tea. Each Risperidone Oral Solution carton contains: 1 bottle of Risperidone Oral Solution 1 oral dosing syringe Gather and check supplies: Gather the Risperidone Oral Solution bottle and oral dosing syringe. Check the expiration date on the bottle. Do not use the bottle of Risperidone Oral Solution if the expiration date has passed. Check your dose in mLs as prescribed by your healthcare provider. Find this mL marking on the plunger of the oral dosing syringe. If your dose is more than 3 mL, you will need to divide your dose. Follow the instructions given to you by your healthcare provider or pharmacist on how to divide your dose. Preparing a dose of Risperidone Oral Solution: Step 1. Place the Risperidone Oral Solution bottle on a flat surface. Push down on the cap while turning it to the left (counterclockwise) to open the bottle. Figure 1 Step 2. Push the plunger of the oral dosing syringe all the way down. Figure 2 Step 3. With the bottle in an upright position, fully insert the oral dosing syringe into the opening of the bottle. Figure 3 Step 4. Withdraw the prescribed dose of Risperidone Oral Solution from the bottle. Hold down the barrel of the oral dosing syringe with one hand. With your other hand, slowly pull the plunger up until you reach the mL markings on the barrel for the prescribed dose. Figure 4 Step 5. Remove the oral dosing syringe from the bottle by holding the outer barrel and pulling straight up. Be careful not to push down on the plunger during this step. Check the oral dosing syringe for air bubbles. If you see air bubbles, slowly push the plunger all the way down to return the oral solution into the bottle. Then repeat Step 4 to withdraw the prescribed dose. Figure 5 Step 6. Risperidone Oral Solution can be mixed with a drink or taken directly from the oral dosing syringe. Mix the dose of Risperidone Oral Solution with water, coffee, orange juice, or low-fat milk. Stir well and drink all of the mixture right away to ensure the full dose is taken. See Figure 6a . Do not mix Risperidone Oral Solution with cola or tea. Figure 6a Or To take the Risperidone Oral Solution dose directly from the oral dosing syringe, place the tip of the oral dosing syringe into the mouth and toward the cheek. Slowly push the plunger all the way down to gently release all of the medicine in the oral dosing syringe. Do not squirt or forcefully push the medicine into the back of the throat.

ne Oral Solution dose directly from the oral dosing syringe, place the tip of the oral dosing syringe into the mouth and toward the cheek. Slowly push the plunger all the way down to gently release all of the medicine in the oral dosing syringe. Do not squirt or forcefully push the medicine into the back of the throat. See Figure 6b . Figure 6b Step 7. Place the cap back on the Risperidone Oral Solution bottle and turn the cap to the right (clockwise) to close the bottle. Figure 7 Step 8. Rinse the oral dosing syringe with water after each use. Remove the plunger from the oral dosing syringe barrel. Rinse the oral dosing syringe barrel and plunger with water and let them air dry. When the oral dosing syringe barrel and plunger are dry, put the plunger back into the oral dosing syringe barrel for the next use. Do not throw away the oral dosing syringe. Figure 8 Storing Risperidone Oral Solution: Store Risperidone Oral Solution at controlled room temperature 20° to 25°C (68° to 77°F). Do not freeze Risperidone Oral Solution. Protect from light. Keep Risperidone Oral Solution and all medicines out of the reach of children. Rev. 12 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 05/2025 Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762 New Image Step1 New Image Step 3 Step 4 Step 5 Step 6a Step 6b Step 7 Step 8

<table><colgroup><col/><col/></colgroup><tbody><tr><td><list listType="unordered" styleCode="Disc"><item>1 bottle of Risperidone Oral Solution</item><item>1 oral dosing syringe</item></list></td><td align="center"><renderMultiMedia referencedObject="MM2"/></td></tr></tbody></table>

<table><colgroup><col/><col/></colgroup><tbody><tr><td><list listType="unordered" styleCode="Disc"><item>1 bottle of Risperidone Oral Solution</item><item>1 oral dosing syringe</item></list></td><td align="center"><renderMultiMedia referencedObject="MM2"/></td></tr></tbody></table> <table width="866px"><colgroup><col/><col/></colgroup><tbody><tr><td align="center"><content styleCode="bold">Step 1.</content>Place the Risperidone Oral Solution bottle on a flat surface. Push down on the cap while turning it to the left (counterclockwise) to open the bottle. </td><td align="center"><renderMultiMedia referencedObject="MM3"/><paragraph>Figure 1</paragraph></td></tr><tr><td align="center"><content styleCode="bold">Step 2.</content>Push the plunger of the oral dosing syringe all the way down. </td><td align="center"><paragraph><renderMultiMedia referencedObject="MM4"/></paragraph><paragraph>Figure 2</paragraph></td></tr><tr><td align="center"><content styleCode="bold">Step 3.</content>With the bottle in an upright position, fully insert the oral dosing syringe into the opening of the bottle. </td><td align="center"><paragraph><renderMultiMedia referencedObject="MM5"/></paragraph><paragraph>Figure 3</paragraph></td></tr><tr><td align="center"><content styleCode="bold">Step 4.</content>Withdraw the prescribed dose of Risperidone Oral Solution from the bottle. Hold down the barrel of the oral dosing syringe with one hand. With your other hand, slowly pull the plunger up until you reach the mL markings on the barrel for the prescribed dose. </td><td align="center"><renderMultiMedia referencedObject="MM6"/><paragraph>Figure 4</paragraph></td></tr><tr><td align="center"><paragraph><content styleCode="bold">Step 5.</content>Remove the oral dosing syringe from the bottle by holding the outer barrel and pulling straight up. Be careful not to push down on the plunger during this step. </paragraph> Check the oral dosing syringe for air bubbles. If you see air bubbles, slowly push the plunger all the way down to return the oral solution into the bottle. Then repeat <content styleCode="bold">Step 4 </content>to withdraw the prescribed dose. </td><td align="center"><paragraph><renderMultiMedia referencedObject="MM7"/></paragraph><paragraph>Figure 5</paragraph></td></tr><tr><td align="center"><content styleCode="bold">Step 6.</content>Risperidone Oral Solution can be mixed with a drink or taken directly from the oral dosing syringe. <list listType="unordered" styleCode="Disc"><item>Mix the dose of Risperidone Oral Solution with water, coffee, orange juice, or low-fat milk. Stir well and drink all of the mixture right away to ensure the full dose is taken. <content styleCode="bold">See Figure 6a</content>. </item></list><content styleCode="bold">Do not mix</content>Risperidone Oral Solution with cola or tea. </td><td align="center"><paragraph><renderMultiMedia referencedObject="MM8"/></paragraph><paragraph>Figure 6a</paragraph></td></tr><tr><td align="center"><content styleCode="bold">Or</content> To take the Risperidone Oral Solution dose directly from the oral dosing syringe, place the tip of the oral dosing syringe into the mouth and toward the cheek. Slowly push the plunger all the way down to gently release all of the medicine in the oral dosing syringe. Do not squirt or forcefully push the medicine into the back of the throat. <content styleCode="bold">See Figure 6b</content>. </td><td align="center"><paragraph><renderMultiMedia referencedObject="MM9"/></paragraph><paragraph>Figure 6b</paragraph></td></tr><tr><td align="center"><content styleCode="bold">Step 7.</content>Place the cap back on the Risperidone Oral Solution bottle and turn the cap to the right (clockwise) to close the bottle.

. </td><td align="center"><paragraph><renderMultiMedia referencedObject="MM9"/></paragraph><paragraph>Figure 6b</paragraph></td></tr><tr><td align="center"><content styleCode="bold">Step 7.</content>Place the cap back on the Risperidone Oral Solution bottle and turn the cap to the right (clockwise) to close the bottle. </td><td align="center"><paragraph><renderMultiMedia referencedObject="MM10"/></paragraph><paragraph>Figure 7</paragraph></td></tr><tr><td align="center"><content styleCode="bold">Step 8.</content>Rinse the oral dosing syringe with water after each use. <list listType="unordered" styleCode="Disc"><item>Remove the plunger from the oral dosing syringe barrel.</item><item>Rinse the oral dosing syringe barrel and plunger with water and let them air dry.</item><item>When the oral dosing syringe barrel and plunger are dry, put the plunger back into the oral dosing syringe barrel for the next use. </item></list><content styleCode="bold">Do not throw away the oral dosing syringe.</content></td><td align="center"><paragraph><renderMultiMedia referencedObject="MM11"/></paragraph><paragraph>Figure 8</paragraph></td></tr></tbody></table>

<table width="100%" styleCode="Noautorules"><col width="81.950%" align="left"/><col width="18.050%" align="left"/><tbody><tr><td align="left" valign="top">Warnings and Precautions (<linkHtml href="#s23">5.6</linkHtml>) </td><td align="right" valign="top">1/2025</td></tr></tbody></table>

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. PERSERIS ® is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )]. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. PERSERIS is not approved for use in patients with dementia-related psychosis. ( 5.1 )

1 INDICATIONS AND USAGE PERSERIS is indicated for the treatment of schizophrenia in adults [see Clinical Studies ( 14 )] . PERSERIS is an atypical antipsychotic indicated for the treatment of schizophrenia in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Establish tolerability with oral risperidone prior to initiating PERSERIS. ( 2.1 ) Administer monthly by subcutaneous injection in the abdomen or back of the upper arm by a healthcare provider. Do not administer by any other route. ( 2.1 ) PERSERIS may be initiated at a dose of 90 mg or 120 mg once monthly. Do not administer more than one dose per month. ( 2.1 ) Supplementation with oral risperidone is not recommended. ( 2.1 ) See Full Prescribing Information for important preparation and administration information. Failure to fully mix the medication could result in incorrect dosage. ( 2.4 ) 2.1 Recommended Dosage Administer PERSERIS by a healthcare provider as a subcutaneous injection in the abdomen or back of the upper arm. Do not administer PERSERIS by any other route. For detailed preparation and administration instructions, see Dosage and Administration ( 2.4 ) . For patients who have never taken risperidone, establish tolerability with oral risperidone prior to initiating PERSERIS. Initiate PERSERIS at a dose of 90 mg or 120 mg once monthly by subcutaneous injection. Do not administer more than one dose (90 mg or 120 mg total) per month. For patients switching from oral risperidone: 3 mg of oral risperidone per day, administer a 90 mg PERSERIS dose one day after the last oral risperidone dose. 4 mg of oral risperidone per day, administer a 120 mg PERSERIS dose one day after the last oral risperidone dose. Patients who are on stable oral risperidone doses lower than 3 mg per day or higher than 4 mg per day may not be candidates for PERSERIS [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )] . Neither a loading dose nor any supplemental oral risperidone is recommended. When a dose of PERSERIS is missed, administer the next PERSERIS injection as soon as possible. 2.2 Dosage Recommendations for Patients with Renal or Hepatic Impairment Prior to initiating treatment with PERSERIS in patients with renal or hepatic impairment, titrate with oral risperidone up to at least 3 mg daily. Following oral titration, and based on clinical response and tolerability, the recommended dosage of PERSERIS is 90 mg once monthly [see Use in Specific Populations ( 8.6 , 8.7 ) and Clinical Pharmacology ( 12.3 )]. 2.3 Dosage Recommendations for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inducers Co-administration with Strong CYP2D6 Inhibitors Between 2 to 4 weeks prior to initiating a strong CYP2D6 inhibitor (such as fluoxetine or paroxetine), switch patients (if applicable) to the lowest PERSERIS dosage (90 mg once monthly) to adjust for the expected increase in plasma concentrations of risperidone [see Drug Interactions ( 7.1 )] . Co-administration with Strong CYP3A4 Inducers With concomitant use of PERSERIS 90 mg and strong CYP3A4 inducers (such as carbamazepine), increase the PERSERIS dosage to 120 mg once monthly and consider starting additional oral risperidone therapy. In patients already receiving PERSERIS 120 mg once monthly, additional oral risperidone therapy may need to be considered. Upon discontinuation of a strong CYP3A4 inducer in a patients receiving PERSERIS 120 mg once monthly, re-evaluate the dosage of PERSERIS or any additional oral risperidone therapy and, if necessary, decrease to adjust for the expected increase in plasma concentration of risperidone.

e therapy may need to be considered. Upon discontinuation of a strong CYP3A4 inducer in a patients receiving PERSERIS 120 mg once monthly, re-evaluate the dosage of PERSERIS or any additional oral risperidone therapy and, if necessary, decrease to adjust for the expected increase in plasma concentration of risperidone. Upon discontinuation of a strong CYP3A4 inducer in a patient receiving PERSERIS 90 mg once monthly, continue treatment with the 90 mg dose unless clinical judgment necessitates interruption of PERSERIS treatment [see Drug Interactions ( 7.1 )] . 2.4 Preparation and Administration Instructions Read the instructions for preparation and administration below and consider referring to the separate Healthcare Provider “Instructions for Use” for additional preparation and administration considerations. For subcutaneous injection only. Do not inject by any other route. Allow package to come to room temperature for at least 15 minutes prior to preparation. Prepare medication when you are ready to administer the dose. 1 CHECK CONTENTS Each carton of PERSERIS contains ( Figure 1 ): One Liquid Syringe ( ) prefilled with the delivery system. Inspect liquid solution for foreign particles. This is the syringe you will use to inject the patient. One Powder Syringe ( ) prefilled with Risperidone powder. Inspect syringe for consistency of powder color and for foreign particles. One sterile 18-gauge, 5/8-inch safety needle. Figure 1 2 TAP POWDER SYRINGE Hold the Powder Syringe upright and tap the barrel of the syringe to dislodge the packed powder ( Figure 2 ). Note: Powder can become packed during shipping. Figure 2 3 UNCAP LIQUID AND POWDER SYRINGES Remove the cap from the Liquid Syringe , then remove the cap from the Powder Syringe ( Figure 3 ). Holding both syringes in your non-dominant hand can help with this step. Figure 3 4 CONNECT THE SYRINGES Place the Liquid Syringe on top of the Powder Syringe (to prevent powder spillage) and connect the syringes by twisting approximately ¾ turn ( Figure 4 ). Do not over tighten. Keep your fingers off the plungers during this step to avoid spillage of the medication. Figure 4 5 MIX THE PRODUCT Failure to fully mix the medication could result in incorrect dosage. Premixing Transfer the contents of the Liquid Syringe into the Powder Syringe . Gently push the Powder Syringe plunger until you feel resistance (to wet powder and avoid compacting). Repeat this gentle back-and-forth process for 5 cycles . Complete mixing Continue mixing the syringes for an additional 55 cycles . This mixing can be more vigorous than when premixing. See Figure 5 for an illustration of a correct full cycle. Figure 5 When fully mixed, the product should be a cloudy suspension that is uniform in color. It can vary from white to yellow-green in color. If you see any clear areas in the mixture, continue to mix until the distribution of the color is uniform. The product is designed to deliver risperidone 90 mg or 120 mg. 6 PREPARE INJECTION SYRINGE Failure to aspirate the liquid from the Powder Syringe may result in incorrect dosage. First, transfer all contents into the Liquid Syringe ( Figure 6 ). Next, perform the following actions SIMULTANEOUSLY : maintain slight pressure on the Powder Syringe plunger and pull back gently on the Liquid Syringe plunger while twisting the syringes apart. Finally, attach the safety needle by twisting until finger tight. Check that medication is uniform in color and free from foreign particles. Figure 6 7 PREPARE THE SUBCUTANEOUS INJECTION SITE(S) This medication is to be injected subcutaneously in the abdomen or back of the upper arm ( Figure 7 ). Choose an injection site with adequate subcutaneous tissue that is free of skin conditions (e.g., nodules, lesions, excessive pigment).

ree from foreign particles. Figure 6 7 PREPARE THE SUBCUTANEOUS INJECTION SITE(S) This medication is to be injected subcutaneously in the abdomen or back of the upper arm ( Figure 7 ). Choose an injection site with adequate subcutaneous tissue that is free of skin conditions (e.g., nodules, lesions, excessive pigment). Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way. Clean the injection site well with an alcohol pad. To help minimize irritation, rotate injection sites following a pattern similar to the illustration. If you want to use the same injection site, make sure it is not the same spot on the injection site you used the last time. Figure 7 8 REMOVE EXCESS AIR FROM SYRINGE Hold the syringe upright for several seconds to allow air bubbles to rise. Remove needle cover and slowly depress the plunger to push out the excess air from the syringe ( Figure 8 ). If medication is seen at the needle tip, pull back slightly on the plunger to prevent medication spillage. Due to the viscous nature of the medication, bubbles will not rise as quickly as those in an aqueous solution. Figure 8 9 PINCH INJECTION SITE Pinch the skin around the injection area. Be sure to pinch enough skin to accommodate the size of the needle ( Figure 9 ). Lift the adipose tissue from the underlying muscle to prevent accidental intramuscular injection. Figure 9 10 INJECT THE MEDICATION Insert needle fully into the subcutaneous tissue. Inject the medication slow and steady ( Figure 10 ). PERSERIS is for subcutaneous administration only. Do not inject by any other route. Actual angle of injection will depend on the amount of subcutaneous tissue. Figure 10 11 WITHDRAW NEEDLE Withdraw the needle at the same angle used for insertion and release pinched skin ( Figure 11 ). Do not rub the injection area after the injection. If there is bleeding, apply a gauze pad or bandage but use minimal pressure. Figure 11 12 LOCK THE NEEDLE GUARD AND DISPOSE OF SYRINGE Lock the needle guard into place by pushing it against a hard surface such as a table ( Figure 12 ). Figure 12 13 INSTRUCT THE PATIENT The patient may have a lump for several weeks that will decrease in size over time ( Figure 13 ). It is important that the patient not rub or massage the injection site and to be aware of the placement of any belts, waistbands, sleeves, cuffs or other parts of clothing. Figure 13 Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

3 DOSAGE FORMS AND STRENGTHS PERSERIS (risperidone) for extended-release injectable suspension for subcutaneous use is available in strengths of 90 mg and 120 mg. Each strength is provided as a kit which includes: one pre-filled syringe containing a white to yellow risperidone powder in a sealed pouch, one pre-filled syringe containing a colorless to yellow delivery system in a sealed pouch, and one 18-gauge, 5/8-inch needle. For extended-release injectable suspension: 90 mg and 120 mg risperidone. ( 3 )

4 CONTRAINDICATIONS PERSERIS is contraindicated in patients with a known hypersensitivity to risperidone, its metabolite, paliperidone, or to any of its components. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone or paliperidone. Known hypersensitivity to risperidone, paliperidone, or other components of PERSERIS. ( 4 )

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions, in Elderly Patients with Dementia-Related Psychosis: Increased risk of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack). ( 5.2 ) Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring. ( 5.3 ) Tardive Dyskinesia: Discontinue treatment if clinically appropriate. ( 5.4 ) Metabolic Changes: Monitor for hyperglycemia, dyslipidemia, and weight gain. ( 5.5 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. ( 5.6 ) Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular disease or cerebrovascular disease, and risk of dehydration or syncope. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with a history of a clinically significant low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing PERSERIS if a clinically significant decline in WBC occurs in absence of other causative factors. ( 5.9 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery. ( 5.10 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.11 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10-weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. PERSERIS is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.2 )] . 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85-years; range 73 to 97) in trials of oral risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with oral risperidone compared to patients treated with placebo. PERSERIS is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )] . 5.3 Neuroleptic Malignant Syndrome (NMS) NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs.

eridone compared to patients treated with placebo. PERSERIS is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )] . 5.3 Neuroleptic Malignant Syndrome (NMS) NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue PERSERIS and provide symptomatic treatment and monitoring. 5.4 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase with the duration of treatment and the total cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, PERSERIS should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient treated with PERSERIS, drug discontinuation should be considered. However, some patients may require treatment with PERSERIS despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

psychotics including risperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including PERSERIS, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including PERSERIS, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including PERSERIS, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including PERSERIS, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone. Data from an 8-week double-blind, placebo-controlled study with PERSERIS in adult patients with schizophrenia are presented in Table 1 . Table 1 Changes in Fasting Glucose from Baseline to End of Study (EOS) and Postbaseline Abnormal Values of Glucose > 126 mg/dL in an 8-Week Double-Blind, Placebo-Controlled Study in Adult Patients with Schizophrenia † The “n”s in the Serum Glucose mean row are the number of patients with data at baseline and EOS visits. ‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator. PERSERIS 90 mg PERSERIS 120 mg Placebo n = 98 n = 106 n = 96 Serum Glucose, mg/dL, mean † Mean Change from Baseline to EOS 5.7 6.3 -0.9 Glucose, > 126 mg/dL Proportion of Patients with Postbaseline Abnormal Values ‡ 12/104 (11.5%) 14/111 (12.6%) 8/109 (7.3%) Similar changes from baseline in serum glucose were observed in patients receiving PERSERIS during an open-label, 12-month long-term safety study. Additionally, the mean HbA 1c increased from 5.6 to 5.7% over the 12-months. Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment. Data from an 8-week double-blind, placebo-controlled study with PERSERIS in adult patients with schizophrenia are presented in Table 2 . Table 2 Changes in Cholesterol from Baseline to End of Study (EOS) and Postbaseline Abnormal Values of Cholesterol ≥ 300 mg/dL in an 8-Week Double-Blind, Placebo-Controlled Study in Adult Patients with Schizophrenia † The “n”s in the Cholesterol mean row are the number of patients with data at baseline and EOS visits. ‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator.

bo-Controlled Study in Adult Patients with Schizophrenia † The “n”s in the Cholesterol mean row are the number of patients with data at baseline and EOS visits. ‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator. PERSERIS 90 mg PERSERIS 120 mg Placebo Cholesterol, mg/dL, mean † n = 98 n = 106 n = 96 Mean Change from Baseline to EOS -0.5 -0.5 1.1 Cholesterol, ≥ 300 mg/dL Proportion of Patients with Postbaseline Abnormal Values ‡ 2/104 (1.9%) 2/111 (1.8%) 2/109 (1.8%) Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Data from an 8-week double-blind, placebo-controlled study with PERSERIS in adult patients with schizophrenia are presented in Table 3 . Table 3 Changes in Body Weight from Baseline to End of Study (EOS) and ≥ 7% Increase from Baseline in an 8-Week Double-Blind, Placebo-Controlled Study in Adult Patients with Schizophrenia † The “n”s in the Weight Change mean row are the number of patients with data at baseline and end of study visits. ‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator. PERSERIS 90 mg PERSERIS 120 mg Placebo Weight † n = 105 n = 112 n = 107 Mean Change from Baseline to EOS, kg 4.4 5.3 2.6 Weight Gain ≥ 7% Increase from Baseline ‡ 35/107 (32.7%) 48/114 (42.1%) 20/111 (18.0%) In an open-label, 12-month long-term safety study, for all patients receiving PERSERIS, mean weight increased approximately 2 kg from baseline to Day 85, then remained stable for the remainder of the study. 5.6 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients [see Use in Specific Populations ( 8.3 )] . Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology ( 13.1 )] . Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer. 5.7 Orthostatic Hypotension and Syncope Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose, probably reflecting its alpha-adrenergic antagonistic properties.

7 Orthostatic Hypotension and Syncope Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose, probably reflecting its alpha-adrenergic antagonistic properties. PERSERIS should be used with particular caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication. 5.8 Falls Somnolence, postural hypotension, motor instability, and sensory instability have been reported with the use of antipsychotics, including PERSERIS, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.9 Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported. Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and a history of drug-induced leukopenia or neutropenia. In patients with a pre-existing history of a clinically significant low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of PERSERIS at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue PERSERIS in patients with absolute neutrophil count <1000/mm 3 and follow their WBC until recovery. 5.10 Potential for Cognitive and Motor Impairment PERSERIS, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, and motor skills. In an 8-week, double-blind, placebo-controlled study, somnolence/sedation was reported by 7.0% and 7.7% of patients treated with PERSERIS 90 mg and 120 mg, respectively. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that treatment with PERSERIS does not affect them adversely. 5.11 Seizures Seizures were observed during premarketing studies of risperidone in adult patients with schizophrenia. PERSERIS should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. 5.12 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Antipsychotic drugs, including PERSERIS, should be used cautiously in patients at risk for aspiration [see Warnings and Precautions ( 5.1 )] .

nd aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Antipsychotic drugs, including PERSERIS, should be used cautiously in patients at risk for aspiration [see Warnings and Precautions ( 5.1 )] . 5.13 Priapism Priapism has been reported during postmarketing surveillance for other risperidone products. Severe priapism may require surgical intervention. 5.14 Body Temperature Regulation Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use PERSERIS with caution in patients who may experience these conditions.

<table ID="t1" width="100%"><caption>Table 1 Changes in Fasting Glucose from Baseline to End of Study (EOS) and Postbaseline Abnormal Values of Glucose &gt; 126 mg/dL in an 8-Week Double-Blind, Placebo-Controlled Study in Adult Patients with Schizophrenia</caption><col width="44.075%" align="left"/><col width="18.675%" align="left"/><col width="18.625%" align="left"/><col width="18.625%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^&#x2020;The &#x201C;n&#x201D;s in the Serum Glucose mean row are the number of patients with data at baseline and EOS visits. </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^&#x2021;Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator. </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Lrule" valign="top"/><td align="center" styleCode="Toprule" valign="top"><content styleCode="bold">PERSERIS 90 mg </content></td><td align="center" styleCode="Toprule" valign="top"><content styleCode="bold">PERSERIS 120 mg </content></td><td align="center" styleCode="Toprule Rrule" valign="top"><content styleCode="bold">Placebo</content></td></tr><tr><td align="left" styleCode="Botrule Lrule" valign="top"/><td align="center" styleCode="Botrule" valign="top"><content styleCode="bold">n = 98</content></td><td align="center" styleCode="Botrule" valign="top"><content styleCode="bold">n = 106</content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">n = 96</content></td></tr><tr><td align="left" styleCode="Lrule" valign="top"><content styleCode="bold">Serum Glucose, mg/dL, mean</content>^&#x2020;</td><td align="center" valign="top"/><td align="center" valign="top"/><td align="center" styleCode="Rrule" valign="top"/></tr><tr><td align="left" styleCode="Botrule Lrule" valign="top">Mean Change from Baseline to EOS</td><td align="center" styleCode="Botrule" valign="top">5.7</td><td align="center" styleCode="Botrule" valign="top">6.3</td><td align="center" styleCode="Botrule Rrule" valign="top">-0.9</td></tr><tr><td align="left" styleCode="Lrule" valign="top"><content styleCode="bold">Glucose, &gt; 126 mg/dL</content></td><td align="center" valign="top"/><td align="center" valign="top"/><td align="center" styleCode="Rrule" valign="top"/></tr><tr><td align="left" styleCode="Botrule Lrule" valign="top">Proportion of Patients with Postbaseline Abnormal Values ^&#x2021;</td><td align="center" styleCode="Botrule" valign="top">12/104 (11.5%)</td><td align="center" styleCode="Botrule" valign="top">14/111 (12.6%)</td><td align="center" styleCode="Botrule Rrule" valign="middle">8/109 (7.3%)</td></tr></tbody></table>

oportion of Patients with Postbaseline Abnormal Values ^&#x2021;</td><td align="center" styleCode="Botrule" valign="top">12/104 (11.5%)</td><td align="center" styleCode="Botrule" valign="top">14/111 (12.6%)</td><td align="center" styleCode="Botrule Rrule" valign="middle">8/109 (7.3%)</td></tr></tbody></table> <table ID="t2" width="100%"><caption>Table 2 Changes in Cholesterol from Baseline to End of Study (EOS) and Postbaseline Abnormal Values of Cholesterol &#x2265; 300 mg/dL in an 8-Week Double-Blind, Placebo-Controlled Study in Adult Patients with Schizophrenia</caption><col width="48.412%" align="left"/><col width="18.155%" align="left"/><col width="16.879%" align="left"/><col width="16.554%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^&#x2020;The &#x201C;n&#x201D;s in the Cholesterol mean row are the number of patients with data at baseline and EOS visits. </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^&#x2021;Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator. </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule" valign="top"/><td align="center" styleCode="Toprule Botrule" valign="top"><content styleCode="bold">PERSERIS 90 mg </content></td><td align="center" styleCode="Toprule Botrule" valign="top"><content styleCode="bold">PERSERIS 120 mg </content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Placebo</content></td></tr><tr><td align="left" styleCode="Lrule" valign="top"><content styleCode="bold">Cholesterol, mg/dL, mean</content>^&#x2020;</td><td align="center" valign="top">n = 98</td><td align="center" valign="top">n = 106</td><td align="center" styleCode="Rrule" valign="top">n = 96</td></tr><tr><td align="left" styleCode="Botrule Lrule" valign="top">Mean Change from Baseline to EOS</td><td align="center" styleCode="Botrule" valign="top">-0.5</td><td align="center" styleCode="Botrule" valign="top">-0.5</td><td align="center" styleCode="Botrule Rrule" valign="top">1.1</td></tr><tr><td align="left" styleCode="Lrule" valign="top"><content styleCode="bold">Cholesterol, &#x2265; 300 mg/dL</content></td><td align="center" valign="top"/><td align="center" valign="top"/><td align="center" styleCode="Rrule" valign="top"/></tr><tr><td align="left" styleCode="Botrule Lrule" valign="top">Proportion of Patients with Postbaseline Abnormal Values ^&#x2021;</td><td align="center" styleCode="Botrule" valign="top">2/104 (1.9%)</td><td align="center" styleCode="Botrule" valign="top">2/111 (1.8%)</td><td align="center" styleCode="Botrule Rrule" valign="top">2/109 (1.8%)</td></tr></tbody></table>

top">Proportion of Patients with Postbaseline Abnormal Values ^&#x2021;</td><td align="center" styleCode="Botrule" valign="top">2/104 (1.9%)</td><td align="center" styleCode="Botrule" valign="top">2/111 (1.8%)</td><td align="center" styleCode="Botrule Rrule" valign="top">2/109 (1.8%)</td></tr></tbody></table> <table ID="t3" width="100%"><caption>Table 3 Changes in Body Weight from Baseline to End of Study (EOS) and &#x2265; 7% Increase from Baseline in an 8-Week Double-Blind, Placebo-Controlled Study in Adult Patients with Schizophrenia</caption><col width="43.250%" align="left"/><col width="22.150%" align="left"/><col width="17.325%" align="left"/><col width="17.275%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">^&#x2020;The &#x201C;n&#x201D;s in the Weight Change mean row are the number of patients with data at baseline and end of study visits. </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">&#x2021; Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator.</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule" valign="top"/><td align="center" styleCode="Toprule Botrule" valign="top"><content styleCode="bold">PERSERIS 90 mg </content></td><td align="center" styleCode="Toprule Botrule" valign="top"><content styleCode="bold">PERSERIS 120 mg </content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Placebo</content></td></tr><tr><td align="left" styleCode="Lrule" valign="top"><content styleCode="bold">Weight</content>^&#x2020;</td><td align="center" valign="top">n = 105</td><td align="center" valign="top">n = 112</td><td align="center" styleCode="Rrule" valign="top">n = 107</td></tr><tr><td align="left" styleCode="Botrule Lrule" valign="top">Mean Change from Baseline to EOS, kg</td><td align="center" styleCode="Botrule" valign="top">4.4</td><td align="center" styleCode="Botrule" valign="top">5.3</td><td align="center" styleCode="Botrule Rrule" valign="top">2.6</td></tr><tr><td align="left" styleCode="Lrule" valign="top"><content styleCode="bold">Weight Gain</content></td><td align="center" valign="top"/><td align="center" valign="top"/><td align="center" styleCode="Rrule" valign="top"/></tr><tr><td align="left" styleCode="Botrule Lrule" valign="top">&#x2265; 7% Increase from Baseline ^&#x2021;</td><td align="center" styleCode="Botrule" valign="top">35/107 (32.7%)</td><td align="center" styleCode="Botrule" valign="top">48/114 (42.1%)</td><td align="center" styleCode="Botrule Rrule" valign="top">20/111 (18.0%)</td></tr></tbody></table>

6 ADVERSE REACTIONS The following are discussed in more detail in previous sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.2 )] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions ( 5.3 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.4 )] Metabolic Changes [see Warnings and Precautions ( 5.5 )] Hyperprolactinemia [see Warnings and Precautions ( 5.6 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.7 )] Falls [see Warnings and Precautions ( 5.8 )] Leukopenia, Neutropenia and Agranulocytosis [see Warnings and Precautions ( 5.9 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Dysphagia [see Warnings and Precautions ( 5.12 )] Priapism [see Warnings and Precautions ( 5.13 )] Body Temperature Regulation [see Warnings and Precautions ( 5.14 )] The most common adverse reactions in clinical trials (≥ 5% and greater than twice placebo) were increased weight, sedation/somnolence, and musculoskeletal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-782-6966 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 safety of PERSERIS was evaluated in a total of 837 adult patients with schizophrenia who received at least 1 dose of PERSERIS during the clinical development program. A total of 322 patients were exposed to PERSERIS for at least 6 months, of which 234 patients were exposed to PERSERIS for at least 12 months; 281 and 176 of these, respectively, received the 120 mg dose. Adverse drug reactions in adult patients with schizophrenia (≥ 5% in any PERSERIS-treated group and greater than placebo) during the 8-week double-blind, placebo-controlled study) were weight increased, constipation, sedation/somnolence, pain in extremity, back pain, akathisia, anxiety, and musculoskeletal pain. In addition, the frequency of reported injection site reactions was similar across treatment groups with both PERSERIS and placebo; the most common (≥ 5%) of which were injection site pain, and erythema. The systemic safety profile for PERSERIS was consistent with the known safety profile of oral risperidone. Commonly-Observed Adverse Drug Reactions in Double-Blind, Placebo-Controlled Clinical Studies – Schizophrenia Adverse Reactions with an incidence of 2% or more and greater than placebo are shown in Table 4 .

hema. The systemic safety profile for PERSERIS was consistent with the known safety profile of oral risperidone. Commonly-Observed Adverse Drug Reactions in Double-Blind, Placebo-Controlled Clinical Studies – Schizophrenia Adverse Reactions with an incidence of 2% or more and greater than placebo are shown in Table 4 . Table 4 Adverse Drug Reactions in 2% or More of PERSERIS-Treated Patients (and Greater than Placebo) in an 8-Week Double-Blind, Placebo-Controlled Study * Sedation includes sedation and somnolence System Organ Class Preferred Term PERSERIS 90 mg (n = 115) PERSERIS 120 mg (n = 117) Placebo (n = 118) Percentage of Patients Reporting ADR Gastrointestinal disorders Constipation 7.0 7.7 5.1 Abdominal discomfort 2.6 2.6 1.7 Dry mouth 1.7 2.6 1.7 Investigations Weight increased 13.0 12.8 3.4 Metabolism and nutrition disorders Increased appetite 1.7 3.4 1.7 Musculoskeletal and connective tissue disorders Back pain 3.5 6.8 4.2 Pain in extremity 0.9 7.7 5.1 Musculoskeletal pain 5.2 5.1 2.5 Musculoskeletal stiffness 2.6 0.9 1.7 Muscle spasms 0 2.6 0 Nervous system disorders Sedation* 7.0 7.7 0 Akathisia 2.6 6.8 4.2 Extrapyramidal disorder 4.3 1.7 0.8 Psychiatric disorders Anxiety 2.6 6.8 5.1 Other Adverse Drug Reactions Observed During the Clinical Trial Evaluation of PERSERIS The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) which are part of the disease state, 3) for which a drug cause was remote, 4) which were so general as to be uninformative, or 5) which were not considered to have significant clinical implications.

PERSERIS The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) which are part of the disease state, 3) for which a drug cause was remote, 4) which were so general as to be uninformative, or 5) which were not considered to have significant clinical implications. Blood and Lymphatic System Disorders: neutropenia Ear and Labyrinth Disorders: vertigo Endocrine Disorders: hyperprolactinemia Eye Disorders: blepharospasm Gastrointestinal Disorders: nausea, dyspepsia, vomiting, diarrhea, abdominal pain upper, salivary hypersecretion, hypoesthesia oral, tongue movement disturbance General Disorders and Administration Site Conditions: injection site reaction (including injection site pain, induration, pruritus, bruising, erythema, inflammation, swelling and irritation) fatigue, edema peripheral, asthenia, chest discomfort Investigations: blood prolactin increased, blood glucose increased, glycosylated hemoglobin increased, electrocardiogram abnormal, electrocardiogram QT prolonged, blood creatine phosphokinase increased Metabolism and Nutrition Disorders: diabetes mellitus, decreased appetite Musculoskeletal, Connective Tissue, and Bone Disorders: arthralgia, muscle twitching, joint stiffness, trismus Nervous System Disorders: headache, dizziness, tremor, drooling, dyskinesia, lethargy, dystonia, hypoesthesia, oromandibular dystonia, tardive dyskinesia, cogwheel rigidity, dysarthria, balance disorder, parkinsonian rest tremor, parkinsonism, slow speech Psychiatric Disorders: insomnia, libido decreased, bruxism, restlessness, anorgasmia, loss of libido Reproductive System and Breast Disorders: erectile dysfunction, galactorrhea, breast tenderness, breast pain, amenorrhea, breast engorgement, ejaculation delayed, ejaculation disorder, gynecomastia, hypomenorrhea, breast discharge, breast enlargement, ejaculation failure, menstruation delayed, menstruation irregular, polymenorrhea Skin and Subcutaneous Tissue Disorders: night sweats Vascular Disorders: hypertension, hypotension, orthostatic hypotension Other Adverse Reactions Observed During the Clinical Trial Evaluations of Oral Risperidone The following is a list of additional ADRs that have been reported during the clinical trial evaluation of oral risperidone, regardless of frequency of occurrence: Blood and Lymphatic System Disorders: anemia, granulocytopenia Cardiac Disorders: tachycardia, sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block Ear and Labyrinth Disorders: ear pain, tinnitus Eye Disorders: vision blurred, oculogyration, ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism General Disorders: thirst, gait disturbance, chest pain, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal Immune System Disorders: drug hypersensitivity Infections and Infestations: nasopharyngitis, upper respiratory tract infection, sinusitis, urinary tract infection, pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, alanine aminotransferase increased, heart rate increased, eosinophil count increased, white blood cell c

lized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, alanine aminotransferase increased, heart rate increased, eosinophil count increased, white blood cell c ount decreased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia, anorexia Musculoskeletal, Connective Tissue, and Bone Disorders: joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, muscle rigidity, muscle contracture, rhabdomyolysis Nervous System Disorders: dizziness postural, disturbance in attention, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, bradykinesia, transient ischemic attack, coordination abnormal, cerebrovascular accident, masked facies, speech disorder, syncope, loss of consciousness, muscle contractions involuntary, Parkinson's disease, tongue paralysis, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders: vaginal discharge, menstrual disorder, retrograde ejaculation, sexual dysfunction Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea, epistaxis, wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: rash, dry skin, erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, acne, hyperkeratosis, seborrheic dermatitis, rash generalized, rash maculopapular Vascular Disorders: flushing Discontinuations Due to Adverse Drug Reactions (ADRs) There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in PERSERIS-treated patients and greater than placebo.

lar, acne, hyperkeratosis, seborrheic dermatitis, rash generalized, rash maculopapular Vascular Disorders: flushing Discontinuations Due to Adverse Drug Reactions (ADRs) There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in PERSERIS-treated patients and greater than placebo. Dose Dependency of Adverse Drug Reactions in Clinical Trials Changes in Body Weight Data from the double-blind placebo-controlled study indicated there was a dose-dependent increase in mean changes in weight from baseline to postdose assessments in the PERSERIS 90 mg and 120 mg groups compared with the placebo group [see Warnings and Precautions ( 5.5 ), Adverse Reactions (6.1, Table 4 )] . Increased Prolactin In the 8-week double-blind, placebo-controlled study, there was a typical increase in mean prolactin levels in fasting blood samples from baseline to the EOS assessments in both the PERSERIS 90 mg and 120 mg groups, while mean prolactin for the placebo group remained stable during the study. Changes in mean prolactin were dose-dependent and more pronounced in female patients than male patients. Extrapyramidal Symptoms (EPS) Several methods were used to measure EPS, including: (1) the Barnes Akathisia Rating Scale (BARS) global clinical rating score which evaluates akathisia, (2) the Abnormal Involuntary Movement Scale (AIMS) scores which evaluates dyskinesia, (3) the Simpson-Angus Scale (SAS) global score which broadly evaluates parkinsonism, and (4) the incidence of spontaneous reports of EPS-related adverse reactions. In the 8-week double-blind, placebo-controlled study, the mean changes from baseline in BARS, AIMS, and SAS total scores were comparable between PERSERIS- and placebo-treated patients. At all postbaseline assessments, mean changes from baseline were between -0.1 and 0.2 (inclusive) for the BARS, between 0 and 0.2 (inclusive) for the AIMS and between -0.1 and 0.2 (inclusive) for the SAS. The rates of ADRs associated with EPS were similar across treatment groups, including placebo. There was a higher incidence of akathisia in the PERSERIS 120 mg (6.8%) group compared with the PERSERIS 90 mg (2.6%) and placebo group (4.2%); reports of extrapyramidal disorders were higher in the PERSERIS 90 mg group (4.3%) compared with the PERSERIS 120 mg (1.7%) and placebo group (0.8%). In contrast, there was a higher incidence of dystonia in the placebo group (2.5%) compared with the PERSERIS groups (0 and 0.9%, respectively). Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia has been observed in males and younger age groups. Changes in ECG In the 8-week double-blind, placebo-controlled study, there were no clinically relevant differences in mean changes from baseline to EOS in ECG parameters, including QT c F (Fridericia's corrected QT interval), QRS and PR intervals, and heart rate, in patients in either PERSERIS treatment group (90 mg and 120 mg) compared with placebo. Similarly, in the 12-month, long-term safety study, there were no clinically relevant changes in mean ECG interval values from baseline to postdose assessments. Pain Assessment and Local Injection Site Reactions Local injection site pain was assessed using patient-reported VAS scales (0 = no pain to 100 = unbearably painful).

ly, in the 12-month, long-term safety study, there were no clinically relevant changes in mean ECG interval values from baseline to postdose assessments. Pain Assessment and Local Injection Site Reactions Local injection site pain was assessed using patient-reported VAS scales (0 = no pain to 100 = unbearably painful). In the 8-week, double-blind placebo-controlled study, the mean patient-reported injection site pain VAS scores were similar for all treatment groups following both injections. Pain scores decreased from a mean of 27 (VAS score) 1 minute after the first dose to a range of 3 to 7 (VAS score) 30 to 60 minutes postdose. In the 12-month, long-term safety study, the 1-minute postdose injection site pain VAS scores were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following last injection). The local injection site was assessed by appropriately trained personnel. Throughout the clinical development program, the maximum reported intensity at any time point for each injection site assessment (pain, tenderness, inflammation/swelling and erythema) was none or mild for most patients receiving PERSERIS. Most patients (≥ 79%) reported no tenderness and most who had tenderness reported mild severity. Less than 1% of patients had moderate tenderness at any time point and 1 patient at Injections 1, 2, and 5 had severe tenderness. At each time point, most patients (≥ 75%) reported no pain on injection. Of patients who did have pain on injection, almost all of these were mild at each time point; only 1 or 2 patients at Injections 1, 2, 7, and 12 had moderate pain on injection. At least 92% of patients reported no erythema on each injection. All reports of erythema were of mild severity except for 2 cases of moderate erythema on Injection 1. Inflammation/swelling had a similar profile, with at least 88% of patients reporting no inflammation/swelling and only mild symptoms except for 1 case of moderate severity on Injection 1. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oral risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

<table ID="t4" width="100%"><caption>Table 4 Adverse Drug Reactions in 2% or More of PERSERIS-Treated Patients (and Greater than Placebo) in an 8-Week Double-Blind, Placebo-Controlled Study</caption><col width="51.237%" align="left"/><col width="16.271%" align="left"/><col width="16.271%" align="left"/><col width="16.221%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">* Sedation includes sedation and somnolence</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="bottom"><content styleCode="bold">System Organ Class</content> Preferred Term </td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">PERSERIS</content> <content styleCode="bold">90 mg</content> <content styleCode="bold">(n = 115)</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">PERSERIS</content> <content styleCode="bold">120 mg</content> <content styleCode="bold">(n = 117)</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 118)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom"/><td colspan="3" align="center" styleCode="Botrule Rrule" valign="bottom"><content styleCode="bold">Percentage of Patients Reporting ADR</content></td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Constipation</td><td align="center" styleCode="Botrule Rrule" valign="top">7.0</td><td align="center" styleCode="Botrule Rrule" valign="top">7.7</td><td align="center" styleCode="Botrule Rrule" valign="top">5.1</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Abdominal discomfort</td><td align="center" styleCode="Botrule Rrule" valign="top">2.6</td><td align="center" styleCode="Botrule Rrule" valign="top">2.6</td><td align="center" styleCode="Botrule Rrule" valign="top">1.7</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Dry mouth</td><td align="center" styleCode="Botrule Rrule" valign="top">1.7</td><td align="center" styleCode="Botrule Rrule" valign="top">2.6</td><td align="center" styleCode="Botrule Rrule" valign="top">1.7</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Investigations</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Weight increased</td><td align="center" styleCode="Botrule Rrule" valign="top">13.0</td><td align="center" styleCode="Botrule Rrule" valign="top">12.8</td><td align="center" styleCode="Botrule Rrule" valign="top">3.4</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Metabolism and nutrition disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Increased appetite</td><td align="center" styleCode="Botrule Rrule" valign="top">1.7</td><td align="center" styleCode="Botrule Rrule" valign="top">3.4</td><td align="center" styleCode="Botrule Rrule" valign="top">1.7</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Musculoskeletal and connective tissu

eCode="Botrule Rrule" valign="top">1.7</td><td align="center" styleCode="Botrule Rrule" valign="top">3.4</td><td align="center" styleCode="Botrule Rrule" valign="top">1.7</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Musculoskeletal and connective tissu e disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Back pain</td><td align="center" styleCode="Botrule Rrule" valign="top">3.5</td><td align="center" styleCode="Botrule Rrule" valign="top">6.8</td><td align="center" styleCode="Botrule Rrule" valign="top">4.2</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Pain in extremity</td><td align="center" styleCode="Botrule Rrule" valign="top">0.9</td><td align="center" styleCode="Botrule Rrule" valign="top">7.7</td><td align="center" styleCode="Botrule Rrule" valign="top">5.1</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Musculoskeletal pain</td><td align="center" styleCode="Botrule Rrule" valign="top">5.2</td><td align="center" styleCode="Botrule Rrule" valign="top">5.1</td><td align="center" styleCode="Botrule Rrule" valign="top">2.5</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Musculoskeletal stiffness</td><td align="center" styleCode="Botrule Rrule" valign="top">2.6</td><td align="center" styleCode="Botrule Rrule" valign="top">0.9</td><td align="center" styleCode="Botrule Rrule" valign="top">1.7</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Muscle spasms</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">2.6</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Nervous system disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Sedation*</td><td align="center" styleCode="Botrule Rrule" valign="top">7.0</td><td align="center" styleCode="Botrule Rrule" valign="top">7.7</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Akathisia</td><td align="center" styleCode="Botrule Rrule" valign="top">2.6</td><td align="center" styleCode="Botrule Rrule" valign="top">6.8</td><td align="center" styleCode="Botrule Rrule" valign="top">4.2</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Extrapyramidal disorder</td><td align="center" styleCode="Botrule Rrule" valign="top">4.3</td><td align="center" styleCode="Botrule Rrule" valign="top">1.7</td><td align="center" styleCode="Botrule Rrule" valign="top">0.8</td></tr><tr><td colspan="4" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Psychiatric disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Anxiety</td><td align="center" styleCode="Botrule Rrule" valign="top">2.6</td><td align="center" styleCode="Botrule Rrule" valign="top">6.8</td><td align="center" styleCode="Botrule Rrule" valign="top">5.1</td></tr></tbody></table>

7 DRUG INTERACTIONS The interactions of PERSERIS with co-administration of other drugs have not been studied. The drug interaction data provided in this section is based on studies with oral risperidone. Carbamazepine and other strong CYP3A4 inducers decrease plasma concentrations of risperidone. ( 2.3 , 7.1 ) Fluoxetine, paroxetine, and other strong CYP2D6 inhibitors increase risperidone plasma concentration. ( 2.3 , 7.1 ) 7.1 Drugs Having Clinically Important Interactions with PERSERIS Table 5 includes clinically significant drug interactions with PERSERIS. Table 5 Clinically Important Drug Interactions with PERSERIS Strong CYP2D6 Inhibitors Clinical Impact: Concomitant use of PERSERIS with strong CYP2D6 inhibitors may increase the plasma exposure of risperidone and lower the plasma exposure of a major active metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology ( 12.3 )] . Intervention: When initiation of strong CYP2D6 inhibitors is considered, patients may be placed on the lowest dose (90 mg) of PERSERIS between 2 to 4 weeks before the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors is initiated in patients receiving PERSERIS 90 mg, it is recommended to continue treatment with 90 mg unless clinical judgment necessitates interruption of PERSERIS treatment. The effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied [see Clinical Pharmacology ( 12.3 )] . Strong CYP3A4 Inducers Clinical Impact: Concomitant use of PERSERIS and a strong CYP3A4 inducer may cause decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone which could lead to decreased efficacy of PERSERIS [see Clinical Pharmacology ( 12.3 )] . Intervention: Changes in efficacy and safety should be carefully monitored with any dose adjustment of PERSERIS. At the initiation of therapy with a strong CYP3A4 inducer, patients should be closely monitored during the first 4 to 8 weeks. In patients receiving PERSERIS 90 mg, consider increasing the dose to 120 mg. In patients receiving PERSERIS 120 mg, additional oral risperidone therapy may need to be considered. On discontinuation of a strong CYP3A4 inducer, the dosage of PERSERIS or any additional oral risperidone therapy should be re-evaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone and 9-hydroxyrisperidone. For patients treated with PERSERIS 90 mg and discontinuing from a strong CYP3A4 inducer, it is recommended to continue treatment with the 90 mg dose unless clinical judgment necessitates interruption of PERSERIS treatment [see Dosage and Administration ( 2.3 )] . Centrally-Acting Drugs and Alcohol Clinical Impact: Due to additive pharmacologic effects, the concomitant use of centrally-acting drugs, including alcohol, may increase nervous system disorders. Intervention: Caution should be used when PERSERIS is administered in combination with other centrally-acting drugs or alcohol. Hypotensive Agents Clinical Impact: Because of its potential for inducing hypotension, PERSERIS may enhance the hypotensive effects of other therapeutic agents with this potential. Intervention: Caution should be used when PERSERIS is administered in combination with other therapeutic agents with hypotensive effects.

. Hypotensive Agents Clinical Impact: Because of its potential for inducing hypotension, PERSERIS may enhance the hypotensive effects of other therapeutic agents with this potential. Intervention: Caution should be used when PERSERIS is administered in combination with other therapeutic agents with hypotensive effects. Dopamine Agonists Clinical Impact: Agents with central antidopaminergic activity such as PERSERIS may antagonize the pharmacologic effects of dopamine agonists. Intervention: Caution should be used when PERSERIS is administered in combination with levodopa and dopamine agonists. Methylphenidate Clinical Impact: Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) [see Adverse Reactions ( 6.2 )] . Intervention: Monitor for symptoms of EPS with concomitant use of PERSERIS and methylphenidate. 7.2 Drugs Having No Clinically Important Interactions with PERSERIS Based on pharmacokinetic studies with oral risperidone, no dosage adjustment of PERSERIS is required when administered concomitantly with amitriptyline, cimetidine, ranitidine, clozapine, topiramate and moderate CYP3A4 inhibitors (erythromycin). Additionally, no dosage adjustment is necessary for lithium, valproate, topiramate, digoxin and CYP2D6 substrates (donepezil and galantamine) when co-administered with PERSERIS [see Clinical Pharmacology ( 12.3 )] .

<table ID="t5" width="100%"><caption>Table 5 Clinically Important Drug Interactions with PERSERIS</caption><col width="22.700%" align="left"/><col width="77.300%" align="left"/><tbody><tr><td colspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Strong CYP2D6 Inhibitors</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Concomitant use of PERSERIS with strong CYP2D6 inhibitors may increase the plasma exposure of risperidone and lower the plasma exposure of a major active metabolite, 9-hydroxyrisperidone <content styleCode="italics">[see Clinical Pharmacology ( <linkHtml href="#s76">12.3</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">When initiation of strong CYP2D6 inhibitors is considered, patients may be placed on the lowest dose (90 mg) of PERSERIS between 2 to 4 weeks before the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors is initiated in patients receiving PERSERIS 90 mg, it is recommended to continue treatment with 90 mg unless clinical judgment necessitates interruption of PERSERIS treatment. The effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied <content styleCode="italics">[see Clinical Pharmacology ( <linkHtml href="#s76">12.3</linkHtml>)] </content>. </td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Strong CYP3A4 Inducers</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Concomitant use of PERSERIS and a strong CYP3A4 inducer may cause decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone which could lead to decreased efficacy of PERSERIS <content styleCode="italics">[see Clinical Pharmacology ( <linkHtml href="#s76">12.3</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Changes in efficacy and safety should be carefully monitored with any dose adjustment of PERSERIS. At the initiation of therapy with a strong CYP3A4 inducer, patients should be closely monitored during the first 4 to 8 weeks. In patients receiving PERSERIS 90 mg, consider increasing the dose to 120 mg. In patients receiving PERSERIS 120 mg, additional oral risperidone therapy may need to be considered. On discontinuation of a strong CYP3A4 inducer, the dosage of PERSERIS or any additional oral risperidone therapy should be re-evaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone and 9-hydroxyrisperidone.

al oral risperidone therapy may need to be considered. On discontinuation of a strong CYP3A4 inducer, the dosage of PERSERIS or any additional oral risperidone therapy should be re-evaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone and 9-hydroxyrisperidone. For patients treated with PERSERIS 90 mg and discontinuing from a strong CYP3A4 inducer, it is recommended to continue treatment with the 90 mg dose unless clinical judgment necessitates interruption of PERSERIS treatment <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s8">2.3</linkHtml>)] </content>. </td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Centrally-Acting Drugs and Alcohol</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Due to additive pharmacologic effects, the concomitant use of centrally-acting drugs, including alcohol, may increase nervous system disorders.</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Caution should be used when PERSERIS is administered in combination with other centrally-acting drugs or alcohol.</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Hypotensive Agents</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Because of its potential for inducing hypotension, PERSERIS may enhance the hypotensive effects of other therapeutic agents with this potential.</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Caution should be used when PERSERIS is administered in combination with other therapeutic agents with hypotensive effects.</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Dopamine Agonists</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Agents with central antidopaminergic activity such as PERSERIS may antagonize the pharmacologic effects of dopamine agonists.</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Caution should be used when PERSERIS is administered in combination with levodopa and dopamine agonists.</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Methylphenidate</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) <content styleCode="italics">[see Adverse Reactions ( <linkHtml href="#s44">6.2</linkHtml>)] </content>.

/content></td><td align="left" styleCode="Botrule Rrule" valign="top">Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) <content styleCode="italics">[see Adverse Reactions ( <linkHtml href="#s44">6.2</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Monitor for symptoms of EPS with concomitant use of PERSERIS and methylphenidate.</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) Renal or Hepatic Impairment: Carefully titrate on oral risperidone up to at least 3 mg before initiating treatment with PERSERIS at a dose of 90 mg. ( 8.6 , 8.7 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including PERSERIS, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including PERSERIS, during pregnancy (see Clinical Considerations ) . Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the oral maximum recommended human dose (MRHD) of 16 mg/day with maternal toxicity observed at 4 times the MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6 times the oral MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5 times the oral MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6 times the oral MRHD and offspring mortality increased at doses 0.1 to 3 times the oral MRHD based on mg/m 2 body surface area. Subcutaneous administration of the delivery system to pregnant rats and rabbits during the period of organogenesis caused developmental toxicity that included post-implantation loss, decreased number of live fetuses, decreased fetal weight and fetal malformations (external, skeletal, and visceral), at doses that are 52 (rat) and 43 (rabbit) times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. These effects could be attributed to N -methyl-2-pyrrolidone (NMP) an excipient in the delivery system based on information in the published literature (see Data ) . Subcutaneous administration of the delivery system to pregnant and lactating rats had no effect on embryofetal and postnatal development at doses up to 17 times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. The estimated background risks 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.

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 Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR = 1.26, 95% CI 1.02 to 1.56) and of cardiac malformations (RR = 1.26, 95% CI 0.88 to 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal data No developmental toxicity studies were conducted with subcutaneous risperidone suspension. Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the oral MRHD of 16 mg/day based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the oral MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the oral MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the oral MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the oral MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the oral MRHD of 16 mg/day based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the oral MRHD based on mg/m 2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats.

t be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the oral MRHD based on mg/m 2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the oral MRHD based on mg/m 2 and the only dose tested in the study. Subcutaneous administration of the delivery system to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity (decreased body weight, weight gain and food intake), post-implantation loss, decrease in number of live fetuses and decrease in fetal weight at doses that are 52 (rat), and 43 (rabbit) times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. Developmental toxicity in both rat and rabbit included skeletal and visceral malformations at doses 35 (rat), and 43 (rabbit) times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. The NOAEL dose for these effects in both species is 17 times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. These effects could be related to N -methyl-2-pyrrolidone (NMP), an excipient present in the delivery system. In published animal developmental toxicity studies, NMP administered orally daily to pregnant rats during organogenesis produced developmental toxicity below maternally toxic levels and resulted in dose-dependent decrease in fetal body weights, increased incidence of post-implantation loss, incomplete ossification and increased incidence of external, visceral and skeletal malformations. These toxicities occurred at doses that are ~3 to 12 times the NMP amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3 and 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations). There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PERSERIS and any potential adverse effects on the breastfed child from PERSERIS or from the mother's underlying condition. Clinical Considerations Infants exposed to PERSERIS through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of risperidone (D 2 receptor antagonism), treatment with PERSERIS may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.6 ) and Nonclinical Toxicology ( 13.1 )].

Based on the pharmacologic action of risperidone (D 2 receptor antagonism), treatment with PERSERIS may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.6 ) and Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use Safety and effectiveness of PERSERIS have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of PERSERIS in the treatment of schizophrenia did not include patients aged 65 and older to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting 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. Elderly patients with dementia-related psychosis treated with PERSERIS are at an increased risk of death compared to placebo. PERSERIS is not approved for the treatment of patients with dementia related psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 , 5.2 )] . 8.6 Renal Impairment In patients with renal impairment, carefully titrate with oral risperidone (up to at least 3 mg) before initiating treatment with PERSERIS [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . PERSERIS was not studied in patients with renal impairment, however, such effect has been investigated with oral risperidone. 8.7 Hepatic Impairment In patients with hepatic impairment, carefully titrate with oral risperidone (up to at least 3 mg) before initiating treatment with PERSERIS [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . PERSERIS was not studied in patients with hepatic impairment, however, such effect has been investigated with oral risperidone. 8.8 Patients with Parkinson's Disease or Dementia with Lewy Bodies Patients with Parkinson's disease or dementia with Lewy bodies can experience increased sensitivity to risperidone. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including PERSERIS, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including PERSERIS, during pregnancy (see Clinical Considerations ) . Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the oral maximum recommended human dose (MRHD) of 16 mg/day with maternal toxicity observed at 4 times the MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6 times the oral MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5 times the oral MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6 times the oral MRHD and offspring mortality increased at doses 0.1 to 3 times the oral MRHD based on mg/m 2 body surface area. Subcutaneous administration of the delivery system to pregnant rats and rabbits during the period of organogenesis caused developmental toxicity that included post-implantation loss, decreased number of live fetuses, decreased fetal weight and fetal malformations (external, skeletal, and visceral), at doses that are 52 (rat) and 43 (rabbit) times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. These effects could be attributed to N -methyl-2-pyrrolidone (NMP) an excipient in the delivery system based on information in the published literature (see Data ) . Subcutaneous administration of the delivery system to pregnant and lactating rats had no effect on embryofetal and postnatal development at doses up to 17 times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. The estimated background risks 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 Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

o/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR = 1.26, 95% CI 1.02 to 1.56) and of cardiac malformations (RR = 1.26, 95% CI 0.88 to 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal data No developmental toxicity studies were conducted with subcutaneous risperidone suspension. Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the oral MRHD of 16 mg/day based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the oral MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the oral MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the oral MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the oral MRHD based on mg/m 2 body surface area; postnatal development and growth of the offspring were also delayed. Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the oral MRHD of 16 mg/day based on mg/m 2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the oral MRHD based on mg/m 2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams.

1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the oral MRHD based on mg/m 2 and the only dose tested in the study. Subcutaneous administration of the delivery system to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity (decreased body weight, weight gain and food intake), post-implantation loss, decrease in number of live fetuses and decrease in fetal weight at doses that are 52 (rat), and 43 (rabbit) times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. Developmental toxicity in both rat and rabbit included skeletal and visceral malformations at doses 35 (rat), and 43 (rabbit) times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. The NOAEL dose for these effects in both species is 17 times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area. These effects could be related to N -methyl-2-pyrrolidone (NMP), an excipient present in the delivery system. In published animal developmental toxicity studies, NMP administered orally daily to pregnant rats during organogenesis produced developmental toxicity below maternally toxic levels and resulted in dose-dependent decrease in fetal body weights, increased incidence of post-implantation loss, incomplete ossification and increased incidence of external, visceral and skeletal malformations. These toxicities occurred at doses that are ~3 to 12 times the NMP amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area.

8.5 Geriatric Use Clinical studies of PERSERIS in the treatment of schizophrenia did not include patients aged 65 and older to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting 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. Elderly patients with dementia-related psychosis treated with PERSERIS are at an increased risk of death compared to placebo. PERSERIS is not approved for the treatment of patients with dementia related psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 , 5.2 )] .

10 OVERDOSAGE 10.1 Human Experience No cases of overdose were reported in premarketing studies with PERSERIS. Because PERSERIS is to be administered by healthcare providers, the potential for overdosage by patients is low. 10.2 Management of Overdosage In case of overdosage, consult a Poison Control Center at 1-800-222-1222. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension. There is no specific antidote to risperidone. Appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers. Consider the long-acting nature of PERSERIS when assessing treatment needs and recovery.

11 DESCRIPTION PERSERIS contains risperidone, an atypical antipsychotic. Risperidone belongs to the chemical class of benzisoxazole derivatives. The chemical designation 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a] pyrimidin-4-one. Its molecular formula is C 23 H 27 FN 4 O 2 and its molecular weight is 410.5 g/mol. The structural formula is: Risperidone is a white to off-white powder. It is practically insoluble in water and soluble in methanol and 0.1 N HCl. PERSERIS is available as a sterile two-syringe mixing system: a liquid syringe prefilled with the delivery system (colorless to yellow solution), and a powder syringe prefilled with risperidone (white to yellow). PERSERIS for extended release injectable suspension, for subcutaneous use, is available in 90 mg and 120 mg risperidone strengths. The quantitative composition is provided below ( Table 6 ). Table 6 PERSERIS Constituted Product Delivered Mass *PLGH poly D,L(lactide co-glycolide); 80:20 molar ratio of lactide to glycolide Component PERSERIS 90 mg PERSERIS 120 mg Risperidone 90 mg 120 mg PLGH* 228 mg 304 mg N -methyl-pyrrolidine 282 mg 376 mg Total mass 600 mg 800 mg Total volume 0.6 mL 0.8 mL Structural Formula

<table ID="t6" width="100%"><caption>Table 6 PERSERIS Constituted Product Delivered Mass</caption><col width="33.311%" align="left"/><col width="33.344%" align="left"/><col width="33.344%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">*PLGH poly D,L(lactide co-glycolide); 80:20 molar ratio of lactide to glycolide</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top">Component</td><td align="center" styleCode="Toprule Botrule Rrule" valign="top">PERSERIS 90 mg</td><td align="center" styleCode="Toprule Botrule Rrule" valign="top">PERSERIS 120 mg</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Risperidone</td><td align="center" styleCode="Botrule Rrule" valign="top">90 mg</td><td align="center" styleCode="Botrule Rrule" valign="top">120 mg</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">PLGH*</td><td align="center" styleCode="Botrule Rrule" valign="top">228 mg</td><td align="center" styleCode="Botrule Rrule" valign="top">304 mg</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">N</content>-methyl-pyrrolidine </td><td align="center" styleCode="Botrule Rrule" valign="top">282 mg</td><td align="center" styleCode="Botrule Rrule" valign="top">376 mg</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Total mass</td><td align="center" styleCode="Botrule Rrule" valign="top">600 mg</td><td align="center" styleCode="Botrule Rrule" valign="top">800 mg</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Total volume</td><td align="center" styleCode="Botrule Rrule" valign="top">0.6 mL</td><td align="center" styleCode="Botrule Rrule" valign="top">0.8 mL</td></tr></tbody></table>

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of risperidone, in schizophrenia, is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2 ) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology ( 12.3 )] . Antagonism at receptors other than D 2 and 5HT 2 may explain some of the other effects of risperidone. 12.2 Pharmacodynamics Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2 ), dopamine Type 2 (D 2 ), α 1 and α 2 adrenergic, and H 1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C , 5HT 1D , and 5HT 1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations > 10 -5 M) for cholinergic muscarinic or β 1 and β 2 adrenergic receptors. 12.3 Pharmacokinetics The pharmacokinetics of risperidone and total active moiety following subcutaneous injection of PERSERIS was evaluated in patients with clinically stable schizophrenia after single doses (60 mg, 90 mg, and 120 mg) (n = 101) and repeated doses [60 mg, 90 mg, 120 mg, 180 mg (1.5 times the maximum recommended dosage of PERSERIS)] (n = 68) separated by 28 days for up to 4 doses following oral risperidone. Plasma concentrations of risperidone, 9-hydroxyrisperidone and total active moiety approached steady-state levels after the first dose of PERSERIS. Mean accumulation ratios for risperidone ranged from 1.2 to 1.7 based on mean area under the curve (AUC), and from 0.9 to 1.3 based on overall mean peak plasma concentrations (overall C max ), indicating no to modest accumulation. For 9-hydroxyrisperidone, accumulation ratios ranged from 1.2 to 1.6 (AUC) and 0.99 to 1.3 (overall C max ). For total active moiety, accumulation ratios ranged from 1.2 to 1.6 (AUC tau ) and 0.97 to 1.3 (overall C max ). Following multiple doses of PERSERIS, plasma exposure (AUC tau and C max ) of risperidone, 9-hydroxyrisperidone, and total active moiety increased in an approximately dose proportional manner over the dose range of 60 to 120 mg. At steady-state, a 2-fold increase in dose resulted in a 1.7-fold increase in C max (6.33 to 10.9 ng/mL) and AUC tau (2262 to 3891 ng*hr/mL) for risperidone. For 9-hydroxyrisperidone, a 2-fold increase in dose resulted in a 2.1-fold increase in C max (13.7 to 28.9 ng/mL) and 2-fold increase in AUC tau (5706 to 11658 ng*hr/mL). For total active moiety, a 2-fold increase in dose resulted in a 2.0-fold increase in C max (19.6 to 38.5 ng/mL) and a 1.9-fold increase in AUC tau (8102 to 15370 ng*hr/mL). Plasma exposures at steady-state were compared between oral risperidone and PERSERIS. The average plasma concentrations (C avg ) of total active moiety were 18.3 ng/mL and 18.1 ng/mL for 3 mg oral risperidone and 90 mg PERSERIS, respectively. The C avg of total active moiety were 25.2 ng/mL and 22.9 ng/mL for 4 mg oral risperidone and 120 mg PERSERIS, respectively. Absorption PERSERIS contains risperidone in a liquid delivery system. Following subcutaneous injection, it forms a depot that provides sustained plasma levels of risperidone over the monthly dosing interval.

total active moiety were 25.2 ng/mL and 22.9 ng/mL for 4 mg oral risperidone and 120 mg PERSERIS, respectively. Absorption PERSERIS contains risperidone in a liquid delivery system. Following subcutaneous injection, it forms a depot that provides sustained plasma levels of risperidone over the monthly dosing interval. After single subcutaneous injection, PERSERIS shows two absorption peaks for risperidone in plasma. The first peak of risperidone occurs with a T max of 4 to 6 hours and is due to an initial release of the drug during the depot formation process. A second peak of risperidone is observed at 10 to 14 days post-dose and is associated with the slow release of risperidone from the subcutaneous depot. The first and second peaks of risperidone are of similar magnitude. For both 9-hydroxyrisperidone and total active moiety, the median T max of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Distribution Following a subcutaneous injection of PERSERIS, the apparent volume of distribution is large. The extensively large values are because PERSERIS is administered as a depot injection. Risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. Elimination Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme cytochrome CYP2D6 with minor contribution by CYP3A4. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone). CYP2D6, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6 to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly. Plasma exposure to total active moiety was similar in CYP2D6 extensive, intermediate and poor metabolizers following subcutaneous injection with PERSERIS, supporting no need for dose adjustment based on genotype of CYP2D6. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered as solution to 3 healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. Following a single subcutaneous injection of PERSERIS, the apparent terminal half-life of risperidone ranges between 9 and 11 days on average. This half-life is related to the slow release of risperidone from the subcutaneous depot and subsequent absorption of risperidone into the systemic circulation. The mean apparent terminal half-life ranges between 8 to 9 days for both 9-hydroxyrisperidone and total active moiety. Drug Interaction Studies No specific drug interaction studies have been performed with PERSERIS. The drug interaction data provided in this section is based on studies with oral risperidone.

rculation. The mean apparent terminal half-life ranges between 8 to 9 days for both 9-hydroxyrisperidone and total active moiety. Drug Interaction Studies No specific drug interaction studies have been performed with PERSERIS. The drug interaction data provided in this section is based on studies with oral risperidone. Effects of other drugs on the exposures of risperidone, 9-hydroxyrisperidone and total active moiety as well as the effects of risperidone on the exposures of other drugs is summarized below. Effects of Other Drugs on Risperidone, 9-hydroxyrisperidone and Total Active Moiety Pharmacokinetics Strong CYP2D6 Inhibitors (Fluoxetine and Paroxetine) Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), potent CYP2D6 inhibitors, have been shown to increase the plasma concentration of risperidone by 2.5 to 2.8 folds and 3 to 9 folds, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. Moderate CYP3A4 Inhibitor (Erythromycin) There were no significant interactions between oral risperidone and erythromycin, a moderate CYP3A4 inhibitor. Strong CYP3A4 Inducer (Carbamazepine) Carbamazepine co-administration with oral risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of PERSERIS. Amitriptyline, Cimetidine, Ranitidine, Clozapine, Topiramate Clinically meaningful pharmacokinetic interaction between PERSERIS and other drugs, such as amitriptyline, cimetidine, ranitidine and clozapine, is not expected. Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone combined following concomitant administration with oral risperidone. Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%. Chronic administration of clozapine with oral risperidone have shown to affect the clearance of risperidone, however, clinical relevance is unknown. There was no clinically relevant effect of oral risperidone (1 to 6 mg/day) on the pharmacokinetics of topiramate 400 mg/day. Effects of Oral Risperidone on Pharmacokinetics of Other Drugs Lithium Repeated doses of oral risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (n = 13). Valproate Repeated doses of oral risperidone (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n = 21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of oral risperidone. Topiramate Oral risperidone administered at doses from 1 to 6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone C max and a 33% decrease in risperidone AUC 0-12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed.

at doses from 1 to 6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone C max and a 33% decrease in risperidone AUC 0-12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral risperidone on the pharmacokinetics of topiramate. Digoxin Oral risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. CYP2D6 Substrates (Donepezil and Galantamine) In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP2D6. Therefore, PERSERIS is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP2D6. Specific Populations Based on population pharmacokinetic analyses, age, sex and race do not have a clinically meaningful effect on the pharmacokinetics of PERSERIS. Renal Impairment PERSERIS was not studied in patients with renal impairment, however, such effect has been investigated with oral risperidone. In patients with moderate to severe renal disease treated with oral risperidone, the apparent clearance (CL/F) of total active moiety was decreased by 60% in patients with moderate to severe renal disease compared with young healthy subjects [see Use in Specific Populations ( 8.6 )]. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of PERSERIS has not been studied. The effect of hepatic impairment on the pharmacokinetics of oral risperidone has been evaluated in a dedicated phase I study. While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein [see Use in Specific Populations ( 8.7 )] .

12.1 Mechanism of Action The mechanism of action of risperidone, in schizophrenia, is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2 ) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology ( 12.3 )] . Antagonism at receptors other than D 2 and 5HT 2 may explain some of the other effects of risperidone.

12.2 Pharmacodynamics Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2 ), dopamine Type 2 (D 2 ), α 1 and α 2 adrenergic, and H 1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C , 5HT 1D , and 5HT 1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations > 10 -5 M) for cholinergic muscarinic or β 1 and β 2 adrenergic receptors.

12.3 Pharmacokinetics The pharmacokinetics of risperidone and total active moiety following subcutaneous injection of PERSERIS was evaluated in patients with clinically stable schizophrenia after single doses (60 mg, 90 mg, and 120 mg) (n = 101) and repeated doses [60 mg, 90 mg, 120 mg, 180 mg (1.5 times the maximum recommended dosage of PERSERIS)] (n = 68) separated by 28 days for up to 4 doses following oral risperidone. Plasma concentrations of risperidone, 9-hydroxyrisperidone and total active moiety approached steady-state levels after the first dose of PERSERIS. Mean accumulation ratios for risperidone ranged from 1.2 to 1.7 based on mean area under the curve (AUC), and from 0.9 to 1.3 based on overall mean peak plasma concentrations (overall C max ), indicating no to modest accumulation. For 9-hydroxyrisperidone, accumulation ratios ranged from 1.2 to 1.6 (AUC) and 0.99 to 1.3 (overall C max ). For total active moiety, accumulation ratios ranged from 1.2 to 1.6 (AUC tau ) and 0.97 to 1.3 (overall C max ). Following multiple doses of PERSERIS, plasma exposure (AUC tau and C max ) of risperidone, 9-hydroxyrisperidone, and total active moiety increased in an approximately dose proportional manner over the dose range of 60 to 120 mg. At steady-state, a 2-fold increase in dose resulted in a 1.7-fold increase in C max (6.33 to 10.9 ng/mL) and AUC tau (2262 to 3891 ng*hr/mL) for risperidone. For 9-hydroxyrisperidone, a 2-fold increase in dose resulted in a 2.1-fold increase in C max (13.7 to 28.9 ng/mL) and 2-fold increase in AUC tau (5706 to 11658 ng*hr/mL). For total active moiety, a 2-fold increase in dose resulted in a 2.0-fold increase in C max (19.6 to 38.5 ng/mL) and a 1.9-fold increase in AUC tau (8102 to 15370 ng*hr/mL). Plasma exposures at steady-state were compared between oral risperidone and PERSERIS. The average plasma concentrations (C avg ) of total active moiety were 18.3 ng/mL and 18.1 ng/mL for 3 mg oral risperidone and 90 mg PERSERIS, respectively. The C avg of total active moiety were 25.2 ng/mL and 22.9 ng/mL for 4 mg oral risperidone and 120 mg PERSERIS, respectively. Absorption PERSERIS contains risperidone in a liquid delivery system. Following subcutaneous injection, it forms a depot that provides sustained plasma levels of risperidone over the monthly dosing interval. After single subcutaneous injection, PERSERIS shows two absorption peaks for risperidone in plasma. The first peak of risperidone occurs with a T max of 4 to 6 hours and is due to an initial release of the drug during the depot formation process. A second peak of risperidone is observed at 10 to 14 days post-dose and is associated with the slow release of risperidone from the subcutaneous depot. The first and second peaks of risperidone are of similar magnitude. For both 9-hydroxyrisperidone and total active moiety, the median T max of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Distribution Following a subcutaneous injection of PERSERIS, the apparent volume of distribution is large. The extensively large values are because PERSERIS is administered as a depot injection. Risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites.

RIS is administered as a depot injection. Risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. Elimination Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme cytochrome CYP2D6 with minor contribution by CYP3A4. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone). CYP2D6, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6 to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly. Plasma exposure to total active moiety was similar in CYP2D6 extensive, intermediate and poor metabolizers following subcutaneous injection with PERSERIS, supporting no need for dose adjustment based on genotype of CYP2D6. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14 C-risperidone administered as solution to 3 healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. Following a single subcutaneous injection of PERSERIS, the apparent terminal half-life of risperidone ranges between 9 and 11 days on average. This half-life is related to the slow release of risperidone from the subcutaneous depot and subsequent absorption of risperidone into the systemic circulation. The mean apparent terminal half-life ranges between 8 to 9 days for both 9-hydroxyrisperidone and total active moiety. Drug Interaction Studies No specific drug interaction studies have been performed with PERSERIS. The drug interaction data provided in this section is based on studies with oral risperidone. Effects of other drugs on the exposures of risperidone, 9-hydroxyrisperidone and total active moiety as well as the effects of risperidone on the exposures of other drugs is summarized below. Effects of Other Drugs on Risperidone, 9-hydroxyrisperidone and Total Active Moiety Pharmacokinetics Strong CYP2D6 Inhibitors (Fluoxetine and Paroxetine) Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), potent CYP2D6 inhibitors, have been shown to increase the plasma concentration of risperidone by 2.5 to 2.8 folds and 3 to 9 folds, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. Moderate CYP3A4 Inhibitor (Erythromycin) There were no significant interactions between oral risperidone and erythromycin, a moderate CYP3A4 inhibitor. Strong CYP3A4 Inducer (Carbamazepine) Carbamazepine co-administration with oral risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%.

(Erythromycin) There were no significant interactions between oral risperidone and erythromycin, a moderate CYP3A4 inhibitor. Strong CYP3A4 Inducer (Carbamazepine) Carbamazepine co-administration with oral risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of PERSERIS. Amitriptyline, Cimetidine, Ranitidine, Clozapine, Topiramate Clinically meaningful pharmacokinetic interaction between PERSERIS and other drugs, such as amitriptyline, cimetidine, ranitidine and clozapine, is not expected. Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone combined following concomitant administration with oral risperidone. Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%. Chronic administration of clozapine with oral risperidone have shown to affect the clearance of risperidone, however, clinical relevance is unknown. There was no clinically relevant effect of oral risperidone (1 to 6 mg/day) on the pharmacokinetics of topiramate 400 mg/day. Effects of Oral Risperidone on Pharmacokinetics of Other Drugs Lithium Repeated doses of oral risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (n = 13). Valproate Repeated doses of oral risperidone (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n = 21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of oral risperidone. Topiramate Oral risperidone administered at doses from 1 to 6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone C max and a 33% decrease in risperidone AUC 0-12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral risperidone on the pharmacokinetics of topiramate. Digoxin Oral risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. CYP2D6 Substrates (Donepezil and Galantamine) In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP2D6. Therefore, PERSERIS is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP2D6. Specific Populations Based on population pharmacokinetic analyses, age, sex and race do not have a clinically meaningful effect on the pharmacokinetics of PERSERIS. Renal Impairment PERSERIS was not studied in patients with renal impairment, however, such effect has been investigated with oral risperidone.

d by CYP2D6. Specific Populations Based on population pharmacokinetic analyses, age, sex and race do not have a clinically meaningful effect on the pharmacokinetics of PERSERIS. Renal Impairment PERSERIS was not studied in patients with renal impairment, however, such effect has been investigated with oral risperidone. In patients with moderate to severe renal disease treated with oral risperidone, the apparent clearance (CL/F) of total active moiety was decreased by 60% in patients with moderate to severe renal disease compared with young healthy subjects [see Use in Specific Populations ( 8.6 )]. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of PERSERIS has not been studied. The effect of hepatic impairment on the pharmacokinetics of oral risperidone has been evaluated in a dedicated phase I study. While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein [see Use in Specific Populations ( 8.7 )] .

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted with subcutaneous risperidone suspension. Carcinogenicity studies were conducted with oral risperidone in mice and rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the oral MHRD of 16 mg/day, based on a mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human oral dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Table 7 Summary of Tumor Occurrence at the Multiples of the Human Dose on a mg/m 2 (mg/kg) Basis with Oral Risperidone Dosing Multiples of Maximum Human Oral Dose in mg/m 2 (mg/kg) Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas mouse Female 0.2 (2.4) None rat Female 0.4 (2.4) None rat Male 6 (37.5) 1.5 (9.4) Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions ( 5.6 )] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila. No evidence of mutagenic potential was observed with risperidone subcutaneous injectable suspension or its delivery system alone at doses of 150 mg/kg risperidone or 943 mg/kg delivery system in an in vivo micronucleus test in rats. The safety margins of risperidone were 12 to 19 times the maximum monthly plasma risperidone concentration observed for humans at the monthly MRHD of 120 mg risperidone based on plasma exposure, and 13 times the delivery system amount present in monthly 120 mg risperidone. Impairment of Fertility No mating and fertility studies were conducted with subcutaneous risperidone suspension. Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the oral maximum recommended human dose (MRHD), of 16 mg/day based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study.

ridone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the oral maximum recommended human dose (MRHD), of 16 mg/day based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the oral MRHD based on mg/m 2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog. Subcutaneous administration of the delivery system to rats had no effect on fertility parameters in either sex up to a dose that is 17 (delivery system), and 23 ( N -methyl-2-pyrrolidone) times the amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m 2 body surface area, respectively.

<table ID="t7" width="100%" styleCode="Noautorules"><caption>Table 7 Summary of Tumor Occurrence at the Multiples of the Human Dose on a mg/m ²(mg/kg) Basis with Oral Risperidone Dosing </caption><col width="37.900%" align="left"/><col width="14.080%" align="left"/><col width="14.440%" align="left"/><col width="15.160%" align="left"/><col width="18.420%" align="left"/><tbody><tr><td colspan="3" align="left" valign="top"/><td colspan="2" align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Multiples of Maximum Human Oral Dose in mg/m</content><content styleCode="bold">²</content><content styleCode="bold">(mg/kg)</content></td></tr><tr><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Tumor Type</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Species</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Sex</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Lowest Effect Level</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Highest No-Effect Level</content></td></tr><tr><td align="left" valign="top"><content styleCode="bold">Pituitary adenomas</content></td><td align="left" valign="top"><content styleCode="bold">mouse</content></td><td align="left" valign="top"><content styleCode="bold">Female</content></td><td align="left" valign="top"><content styleCode="bold">0.75 (9.4)</content></td><td align="left" valign="top"><content styleCode="bold">0.2 (2.4)</content></td></tr><tr><td align="left" valign="top"><content styleCode="bold">Endocrine pancreas adenomas</content></td><td align="left" valign="top"><content styleCode="bold">rat</content></td><td align="left" valign="top"><content styleCode="bold">Male</content></td><td align="left" valign="top"><content styleCode="bold">1.5 (9.4)</content></td><td align="left" valign="top"><content styleCode="bold">0.4 (2.4)</content></td></tr><tr><td align="left" valign="top"><content styleCode="bold">Mammary gland adenocarcinomas</content></td><td align="left" valign="top"><content styleCode="bold">mouse</content></td><td align="left" valign="top"><content styleCode="bold">Female</content></td><td align="left" valign="top"><content styleCode="bold">0.2 (2.4)</content></td><td align="left" valign="top"><content styleCode="bold">None</content></td></tr><tr><td align="left" valign="top"/><td align="left" valign="top"><content styleCode="bold">rat</content></td><td align="left" valign="top"><content styleCode="bold">Female</content></td><td align="left" valign="top"><content styleCode="bold">0.4 (2.4)</content></td><td align="left" valign="top"><content styleCode="bold">None</content></td></tr><tr><td align="left" valign="top"/><td align="left" valign="top"><content styleCode="bold">rat</content></td><td align="left" valign="top"><content styleCode="bold">Male</content></td><td align="left" valign="top"><content styleCode="bold">6 (37.5)</content></td><td align="left" valign="top"><content styleCode="bold">1.5 (9.4)</content></td></tr><tr><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Mammary gland neoplasm, Total</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">rat</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Male</content></td><td align="left" styleCode="Botrule" valign

ule" valign="top"><content styleCode="bold">Mammary gland neoplasm, Total</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">rat</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Male</content></td><td align="left" styleCode="Botrule" valign ="top"><content styleCode="bold">1.5 (9.4)</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">0.4 (2.4)</content></td></tr></tbody></table>

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted with subcutaneous risperidone suspension. Carcinogenicity studies were conducted with oral risperidone in mice and rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the oral MHRD of 16 mg/day, based on a mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human oral dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Table 7 Summary of Tumor Occurrence at the Multiples of the Human Dose on a mg/m 2 (mg/kg) Basis with Oral Risperidone Dosing Multiples of Maximum Human Oral Dose in mg/m 2 (mg/kg) Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas mouse Female 0.2 (2.4) None rat Female 0.4 (2.4) None rat Male 6 (37.5) 1.5 (9.4) Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions ( 5.6 )] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila. No evidence of mutagenic potential was observed with risperidone subcutaneous injectable suspension or its delivery system alone at doses of 150 mg/kg risperidone or 943 mg/kg delivery system in an in vivo micronucleus test in rats. The safety margins of risperidone were 12 to 19 times the maximum monthly plasma risperidone concentration observed for humans at the monthly MRHD of 120 mg risperidone based on plasma exposure, and 13 times the delivery system amount present in monthly 120 mg risperidone. Impairment of Fertility No mating and fertility studies were conducted with subcutaneous risperidone suspension. Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the oral maximum recommended human dose (MRHD), of 16 mg/day based on mg/m 2 body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study.

14 CLINICAL STUDIES Efficacy for PERSERIS was demonstrated in an 8-week, randomized, double-blind, placebo-controlled study (Study 1, NCT #02109562). The study evaluated the efficacy, safety and tolerability of PERSERIS (90 and 120 mg subcutaneous every 4-weeks) compared with placebo in adults (age 18- to 55-years, inclusive) experiencing acute exacerbations of schizophrenia. Patients were required to have a Positive and Negative Syndrome Scale (PANSS) total score of 80- to 120-inclusive (moderate to severely ill) at the screening visit, occurring 3- to 8-days before the start of double-blind treatment, without an improvement in the PANSS total score of ≥ 20% between screening and the first dosing day. At the screening visit, all patients received two doses of 0.25 mg oral risperidone 24-hours apart to establish tolerability. Patients were then placed in an inpatient setting, if not already hospitalized, and tapered off their current oral antipsychotic medication (if they were taking one) over a period of 3- to 8-days. Patients were randomized to receive 2 doses of subcutaneous PERSERIS (90 mg or 120 mg) or placebo 28-days apart (on Day 1 and Day 29). No supplemental oral risperidone was permitted during the study. The primary endpoint was the change in PANSS total score from baseline to end of study (Day 57). Both PERSERIS 90 and 120 mg doses demonstrated a statistically significant improvement compared with placebo based on the primary endpoint ( Table 8 ). The results at each scheduled visit are displayed in Figure 14 . Characteristics of the patient population were balanced across the treatment groups. The mean baseline PANSS total score ranged from 94 to 96 across the groups. Most patients were male (74 to 83% per group), and the mean ages were 40 to 43 in each group. Most patients in this study were black or African American (71 to 75% per group). Of the 354 patients randomized to treatment, 337 were included in the intent-to-treat (ITT) population, and 259 (73%) completed the study. Subgroup analyses by gender, age, and race did not suggest any clear evidence of differential responsiveness to PERSERIS. Table 8 Primary Efficacy Analysis Results for Study 1 ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval ªDifference (drug minus placebo) in least-squares mean change from baseline *Doses that are statistically significantly superior to placebo Primary Efficacy Measure: PANSS Treatment Group N (# ITT patients) Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) PERSERIS 90 mg* 111 95.5 (9.23) -19.86 (1.56) -6.50 (-10.87, -2.13)* PERSERIS 120 mg* 114 94.9 (8.09) -23.61 (1.58) -10.24 (-14.64, -5.85)* Placebo 112 94.1 (8.89) -13.37 (1.58) -- Figure 14. Least Square Mean Change from Baseline (+/- Standard Error) in PANSS Total Scores by Days The secondary efficacy endpoint was defined as the CGI-S score at Day 57. Both PERSERIS treatment groups demonstrated statistically significantly better CGI-S scores versus placebo. Figure

<table ID="t8" width="100%"><caption>Table 8 Primary Efficacy Analysis Results for Study 1</caption><col width="20.260%" align="left"/><col width="14.780%" align="left"/><col width="19.580%" align="left"/><col width="22.360%" align="left"/><col width="23.020%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval</paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">&#xAA;Difference (drug minus placebo) in least-squares mean change from baseline</paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">*Doses that are statistically significantly superior to placebo</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule" valign="top"/><td align="center" styleCode="Toprule" valign="top"/><td colspan="3" align="center" styleCode="Toprule Botrule" valign="top"><content styleCode="bold">Primary Efficacy Measure: PANSS</content></td></tr><tr><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Treatment Group</content> </td><td align="center" styleCode="Botrule" valign="top"><content styleCode="bold">N</content> <content styleCode="bold">(# ITT patients)</content></td><td align="center" styleCode="Botrule" valign="top"><content styleCode="bold">Mean Baseline Score (SD)</content></td><td align="center" styleCode="Botrule" valign="top"><content styleCode="bold">LS Mean Change from Baseline (SE)</content></td><td align="center" styleCode="Botrule" valign="top"><content styleCode="bold">Placebo-subtracted</content> <content styleCode="bold">Difference</content><content styleCode="bold">^a</content><content styleCode="bold">(95% CI)</content></td></tr><tr><td align="left" valign="top">PERSERIS 90 mg*</td><td align="center" valign="top">111</td><td align="center" valign="top">95.5 (9.23)</td><td align="center" valign="top">-19.86 (1.56)</td><td align="center" valign="middle">-6.50 (-10.87, -2.13)* </td></tr><tr><td align="left" valign="top">PERSERIS 120 mg*</td><td align="center" valign="top">114</td><td align="center" valign="top">94.9 (8.09)</td><td align="center" valign="top">-23.61 (1.58)</td><td align="center" valign="middle">-10.24 (-14.64, -5.85)* </td></tr><tr><td align="center" styleCode="Botrule" valign="middle">Placebo</td><td align="center" styleCode="Botrule" valign="middle">112</td><td align="center" styleCode="Botrule" valign="middle">94.1 (8.89)</td><td align="center" styleCode="Botrule" valign="middle">-13.37 (1.58)</td><td align="center" styleCode="Botrule" valign="middle">--</td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING PERSERIS (risperidone) for extended-release injectable suspension, for subcutaneous use is, when fully mixed a viscous suspension that, varies from white to yellow-green and is available in dosage strengths of 90 mg and 120 mg. PERSERIS 90 mg is supplied in a single-dose kit, packaged in a carton (NDC 12496-0090-1), containing the following: One pouch with a sterile syringe (labelled ‘P’) prefilled with risperidone powder One pouch with a sterile syringe (labelled ‘L’) prefilled with the delivery system, and desiccant. One 18-gauge, 5/8-inch sterile safety needle. PERSERIS 120 mg is supplied in a single-dose kit, packaged in a carton (NDC 12496-0120-1), containing the following: One pouch with a sterile syringe (labelled ‘P') prefilled with risperidone powder. One pouch with a sterile syringe (labelled ‘L') prefilled with the delivery system, and desiccant. One 18-gauge, 5/8-inch sterile safety needle. Storage and Handling Store in refrigerator at 2°C to 8°C (36°F to 46°F). Allow PERSERIS kit to come to room temperature, 20°C to 25°C (68°F to 77°F), for at least 15 minutes prior to mixing. PERSERIS may be stored in its unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 30 days prior to administration. After removal from the refrigerator, use PERSERIS within 30 days or discard.

Storage and Handling Store in refrigerator at 2°C to 8°C (36°F to 46°F). Allow PERSERIS kit to come to room temperature, 20°C to 25°C (68°F to 77°F), for at least 15 minutes prior to mixing. PERSERIS may be stored in its unopened original packaging at room temperature, 20°C to 25°C (68°F to 77°F), for up to 30 days prior to administration. After removal from the refrigerator, use PERSERIS within 30 days or discard.

17 PATIENT COUNSELING INFORMATION General Instructions Advise patients not to rub or massage the injection site and to be aware of the placement of any belts or clothing waistbands, sleeves, cuffs, or other parts of clothing [see Dosage and Administration ( 2.4 )] . Neuroleptic Malignant Syndrome Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions ( 5.3 )] . Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions ( 5.4 )] . Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions ( 5.5 )] . Hyperprolactinemia Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of PERSERIS. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see Warnings and Precautions ( 5.6 )] . Orthostatic Hypotension and Syncope Educate patients of the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions ( 5.7 )]. Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking PERSERIS [see Warnings and Precautions ( 5.9 )] . Potential for Cognitive and Motor Impairment Inform patients that PERSERIS has the potential to impair judgment, thinking, and motor skills. Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that PERSERIS does not affect them adversely [see Warnings and Precautions ( 5.10 )] . 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 [Warnings and Precautions ( 5.13 )] . Heat Exposure and Dehydration Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions ( 5.14 )]. Concomitant Medication Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interaction [see Drug Interactions ( 7 )] . Alcohol Advise patients to avoid alcohol during treatment with PERSERIS [see Drug Interactions ( 7.1 )] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with PERSERIS. Advise patients that PERSERIS may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate.

ents to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with PERSERIS. Advise patients that PERSERIS may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to PERSERIS during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Advise breastfeeding women using PERSERIS to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )] . Infertility Advise females of reproductive potential that PERSERIS may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations ( 8.3 )]. Manufactured for: Indivior Inc., North Chesterfield, VA 23235. © 2025, Indivior UK Limited. All Rights Reserved. PERSERIS is a registered trademark of Indivior UK Limited. Powder syringe manufactured by Patheon Manufacturing Services, Greenville, NC 27834. Liquid syringe manufactured by Curia, Burlington, MA 01803.

INSTRUCTIONS FOR USE PERSERIS ® (risperidone) for extended-release injectable suspension 90 mg or 120 mg, sterile, single dose For subcutaneous injection only. Do not administer by any other route. IMPORTANT INFORMATION: To be administered by a healthcare professional only. Please read the instructions carefully before handling this product. Allow package to come to room temperature for at least 15 minutes prior to preparation. Only prepare medication when you are ready to administer the dose. As a universal precaution, always wear gloves. 1 CHECK CONTENTS One Liquid Syringe ( ) pre-filled with the delivery system – Inspect liquid solution for foreign particles. This is the syringe you will use to inject the patient. One Powder Syringe ( ) prefilled with Risperidone powder – Inspect syringe for consistency of powder color and for foreign particles. One sterile 18-gauge, 5/8-inch safety needle Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2 TAP POWDER SYRINGE Hold the Powder Syringe upright and tap the barrel of the syringe to dislodge the packed powder. Powder can become packed during shipping. 3 UNCAP LIQUID AND POWDER SYRINGES Remove the cap from the Liquid Syringe , then remove the cap from the Powder Syringe . Holding both syringes in your non-dominant hand can help with this step. 4 CONNECT THE SYRINGES Place the Liquid Syringe on top of the Powder Syringe (to prevent powder spillage) and connect the syringes by twisting approximately ¾ turn. Do not over tighten. Keep your fingers off the plungers during this step to avoid spillage of the medication. 5 MIX THE PRODUCT Failure to fully mix the medication could result in incorrect dosage. Premixing: Transfer the contents of the Liquid Syringe into the Powder Syringe . Gently push the Powder Syringe plunger until you feel resistance (to wet powder and avoid compacting). Repeat this gentle back-and-forth process for 5 Cycles . Complete mixing: Continue mixing the syringes for an additional 55 Cycles . This mixing can be more vigorous than when premixing. When fully mixed, the product should be a cloudy suspension that is uniform in color. It can vary from white to yellow-green in color. If you see any clear areas in the mixture, continue to mix until the distribution of the color is uniform. The product is designed to deliver risperidone 90 mg or 120 mg. Graphic to the right illustrates a correct full cycle. 6 PREPARE INJECTION SYRINGE Failure to aspirate the liquid from the Powder Syringe may result in incorrect dosage. First, transfer all contents into the Liquid Syringe . Next, perform the following actions SIMULTANEOUSLY : maintain slight pressure on the Powder Syringe plunger and pull back gently on the Liquid Syringe plunger while twisting the syringes apart. Finally, attach the safety needle by twisting until finger tight. Check that medication is uniform in color and free from foreign particles. PERSERIS ® Instructions for Use 7 PREPARE THE SUBCUTANEOUS INJECTION SITE This medication is to be injected subcutaneously in the abdomen (see figure) or back of upper arm (see figure). Choose an injection site with adequate subcutaneous tissue that is free of skin conditions (e.g. nodules, lesions, excessive pigment). Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way.

subcutaneously in the abdomen (see figure) or back of upper arm (see figure). Choose an injection site with adequate subcutaneous tissue that is free of skin conditions (e.g. nodules, lesions, excessive pigment). Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way. Clean the injection site well with an alcohol pad. To help minimize irritation, rotate injection sites following a pattern similar to the illustration. If you want to use the same injection site, make sure it is not the same spot on the injection site you used the last time. 8 REMOVE EXCESS AIR FROM SYRINGE Hold the syringe upright for several seconds to allow air bubbles to rise. Remove needle cover and slowly depress the plunger to push out the excess air from the syringe. If medication is seen at the needle tip, pull back slightly on the plunger to prevent medication spillage. Due to the viscous nature of the medication, bubbles will not rise as quickly as those in an aqueous solution. 9 PINCH INJECTION SITE Pinch the skin around the injection area. Be sure to pinch enough skin to accommodate the size of the needle. Lift the adipose tissue from the underlying muscle to prevent accidental intramuscular injection. 10 INJECT THE MEDICATION Insert needle fully into the subcutaneous tissue. Inject the medication slow and steady. PERSERIS is for subcutaneous administration only. Do not inject by any other route. Actual angle of injection will depend on the amount of subcutaneous tissue. 11 WITHDRAW NEEDLE Withdraw the needle at the same angle used for insertion and release pinched skin. Do not rub the injection area after the injection. If there is bleeding, apply a gauze pad or bandage but use minimal pressure. 12 LOCK THE NEEDLE GUARD AND DISPOSE OF SYRINGE Lock the needle guard into place by pushing it against a hard surface such as a table. Dispose of all syringe components in a secure sharps disposal container. 13 INSTRUCT THE PATIENT Advise the patient that they may have a lump for several weeks that will decrease in size over time. It is important that the patient not rub or massage the injection site and to be aware of the placement of any belts, waistbands, sleeves, cuffs or other parts of clothing. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised 12/2022 FREQUENTLY ASKED QUESTIONS Q What is the mixture supposed to look like? A When fully mixed, the product should be a cloudy suspension that is uniform in color. It can vary from white to yellow-green in color. If you see any clear areas in the mixture, continue to mix until the distribution of the color is uniform. Q Why is it important to put the liquid syringe on top? A The liquid is viscous and will not fall out when placing on top. However, powder may be lost if the powder syringe is inverted, which could affect the ultimate dosage. Q What do I do if there is residual left in the powder syringe? A A small ring of residual powder may be observed in the end of the powder syringe barrel after mixing. This is normal. If you have followed the instructions carefully and the rest of the mixture is a cloudy suspension that is uniform in color, proceed with the injection. Q What do I do if a foreign particle is found in either of the syringes? A Do not use if you suspect foreign particles in either of the syringes. Q How soon must I inject after mixing PERSERIS ® ? A This product should be used immediately following preparation. Q Can I inject into the leg? A This injection is only approved for injection into the subcutaneous tissue of abdomen and back of the upper arm. Q How do I get rid of large air gaps? A Small bubbles, also known as champagne bubbles, are not a problem and common with this medication.

ed immediately following preparation. Q Can I inject into the leg? A This injection is only approved for injection into the subcutaneous tissue of abdomen and back of the upper arm. Q How do I get rid of large air gaps? A Small bubbles, also known as champagne bubbles, are not a problem and common with this medication. Large air gaps, however, can be minimized by pulling back on the plunger rod to pop air bubbles prior to expelling the air very slowly. Air should be expelled very carefully to avoid loss of medication. Q Should I massage or put my finger on the injection site following the injection? A It is not advisable to palpate or massage the area following the injection. Q Will the deposit be palpable? A Depending on the patient's subcutaneous tissue, the deposit may be more or less palpable. Patients should be advised that a bump may be palpable (decreasing in size) for several weeks. Manufactured for: Indivior Inc., North Chesterfield, VA 23235. © 2022, Indivior UK Limited. All Rights Reserved. PERSERIS is a registered trademark of Indivior UK Limited. Powder syringe manufactured by Patheon Manufacturing Services, Greenville, NC 27834. Liquid syringe manufactured by Curia, Burlington, MA 01803. Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

<table width="100%"><col width="58.933%" align="left"/><col width="1.467%" align="left"/><col width="39.600%" align="left"/><tbody><tr><td colspan="3" align="center" styleCode="Toprule" valign="top"><content styleCode="bold">INSTRUCTIONS FOR USE</content></td></tr><tr><td colspan="3" align="left" valign="top"><content styleCode="bold">PERSERIS</content><content styleCode="bold">^&#xAE;</content><content styleCode="bold">(risperidone) for extended-release injectable suspension</content></td></tr><tr><td align="left" valign="top"><content styleCode="bold">90 mg or 120 mg, sterile, single dose</content></td><td colspan="2" rowspan="2" align="center" styleCode="Botrule" valign="middle"/></tr><tr><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">For subcutaneous injection only.</content> <content styleCode="bold">Do not administer by any other route.</content></td></tr><tr><td colspan="3" align="left" valign="top"> <content styleCode="bold">IMPORTANT INFORMATION:</content></td></tr><tr><td colspan="3" align="left" styleCode="Botrule" valign="top"><list listType="unordered" styleCode="Disc"><item>To be administered by a healthcare professional only.</item><item>Please read the instructions carefully before handling this product.</item><item>Allow package to come to room temperature for at least 15 minutes prior to preparation.</item><item>Only prepare medication when you are ready to administer the dose.</item><item>As a universal precaution, always wear gloves. </item></list></td></tr><tr><td colspan="2" align="left" styleCode="Botrule Rrule" valign="middle"><content styleCode="bold">1</content><content styleCode="bold">CHECK CONTENTS</content> <list listType="unordered" styleCode="Disc"><item><paragraph>One <content styleCode="bold">Liquid Syringe (</content><renderMultiMedia ID="f19" referencedObject="mm19"/>) pre-filled with the delivery system &#x2013; Inspect liquid solution for foreign particles. This is the syringe you will use to inject the patient. </paragraph></item><item><paragraph>One <content styleCode="bold">Powder Syringe</content>( <renderMultiMedia ID="f20" referencedObject="mm20"/>) prefilled with Risperidone powder &#x2013; Inspect syringe for consistency of powder color and for foreign particles. </paragraph></item><item>One sterile 18-gauge, 5/8-inch safety needle</item><item>Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.</item></list></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f21" referencedObject="mm21"/></td></tr></tbody></table>

m>Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.</item></list></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f21" referencedObject="mm21"/></td></tr></tbody></table> <table width="100%"><col width="60.400%" align="left"/><col width="39.600%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">2 TAP POWDER SYRINGE</content> <list listType="unordered" styleCode="Disc"><item>Hold the <content styleCode="bold">Powder Syringe</content>upright and tap the barrel of the syringe to dislodge the packed powder. </item></list><paragraph><renderMultiMedia ID="f22" referencedObject="mm22"/> Powder can become packed during shipping. </paragraph></td><td align="center" styleCode="Toprule Botrule" valign="middle"> <renderMultiMedia ID="f23" referencedObject="mm23"/></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="middle"><content styleCode="bold">3 UNCAP LIQUID AND POWDER SYRINGES</content> <list listType="unordered" styleCode="Disc"><item>Remove the cap from the <content styleCode="bold">Liquid Syringe</content>, then remove the cap from the <content styleCode="bold">Powder Syringe</content>. </item></list><paragraph><renderMultiMedia ID="f24" referencedObject="mm24"/> Holding both syringes in your non-dominant hand can help with this step. </paragraph></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f25" referencedObject="mm25"/></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="middle"><content styleCode="bold">4 CONNECT THE SYRINGES</content> <list listType="unordered" styleCode="Disc"><item>Place the <content styleCode="bold">Liquid Syringe</content>on top of the <content styleCode="bold">Powder Syringe</content>(to prevent powder spillage) and connect the syringes by twisting approximately &#xBE; turn. Do not over tighten. </item></list><paragraph><renderMultiMedia ID="f26" referencedObject="mm26"/> Keep your fingers off the plungers during this step to avoid spillage of the medication. </paragraph></td><td align="center" styleCode="Botrule" valign="middle"> <renderMultiMedia ID="f27" referencedObject="mm27"/></td></tr></tbody></table>

. </item></list><paragraph><renderMultiMedia ID="f26" referencedObject="mm26"/> Keep your fingers off the plungers during this step to avoid spillage of the medication. </paragraph></td><td align="center" styleCode="Botrule" valign="middle"> <renderMultiMedia ID="f27" referencedObject="mm27"/></td></tr></tbody></table> <table width="100%"><col width="50.000%" align="left"/><col width="50.000%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><paragraph><content styleCode="bold">5 MIX THE PRODUCT</content> <renderMultiMedia ID="f28" referencedObject="mm28"/> Failure to fully mix the medication could result in incorrect dosage. <content styleCode="bold">Premixing:</content> </paragraph><list listType="unordered" styleCode="Disc"><item>Transfer the contents of the <content styleCode="bold">Liquid Syringe</content>into the <content styleCode="bold">Powder Syringe</content>. </item><item>Gently push the <content styleCode="bold">Powder Syringe</content>plunger until you feel resistance (to wet powder and avoid compacting). </item><item>Repeat this gentle back-and-forth process for <content styleCode="bold">5 Cycles</content>. <content styleCode="bold">Complete mixing:</content> </item><item>Continue mixing the syringes for an additional <content styleCode="bold">55 Cycles</content>. </item><item><paragraph>This mixing can be more vigorous than when premixing. When fully mixed, the product should be a cloudy suspension that is uniform in color. It can vary from white to yellow-green in color. If you see any clear areas in the mixture, continue to mix until the distribution of the color is uniform. The product is designed to deliver risperidone 90 mg or 120 mg. <renderMultiMedia ID="f29" referencedObject="mm29"/> Graphic to the right illustrates a correct full cycle. </paragraph></item></list></td><td align="center" styleCode="Toprule Botrule" valign="middle"> <renderMultiMedia ID="f30" referencedObject="mm30"/></td></tr><tr><td align="left" styleCode="Rrule" valign="top"><paragraph><content styleCode="bold">6 PREPARE INJECTION SYRINGE</content> <renderMultiMedia ID="f31" referencedObject="mm31"/>Failure to aspirate the liquid from the <content styleCode="bold">Powder Syringe</content>may result in incorrect dosage. </paragraph><list listType="unordered" styleCode="Disc"><item>First, transfer all contents into the <content styleCode="bold">Liquid Syringe</content>. </item><item>Next, perform the following actions <content styleCode="bold">SIMULTANEOUSLY</content>: <list listType="unordered" styleCode="Disc"><item>maintain slight pressure on the <content styleCode="bold">Powder Syringe</content>plunger and </item><item>pull back <content styleCode="bold">gently</content>on the <content styleCode="bold">Liquid Syringe</content>plunger while twisting the syringes apart. </item></list></item><item><paragraph>Finally, attach the safety needle by twisting until finger tight. <renderMultiMedia ID="f32" referencedObject="mm32"/> Check that medication is uniform in color and free from foreign particles.

tent styleCode="bold">Liquid Syringe</content>plunger while twisting the syringes apart. </item></list></item><item><paragraph>Finally, attach the safety needle by twisting until finger tight. <renderMultiMedia ID="f32" referencedObject="mm32"/> Check that medication is uniform in color and free from foreign particles. </paragraph></item></list></td><td align="center" valign="middle"><paragraph><renderMultiMedia ID="f34" referencedObject="mm34"/></paragraph></td></tr><tr><td align="right" styleCode="Botrule Rrule" valign="top"><paragraph><renderMultiMedia ID="f33" referencedObject="mm33"/></paragraph></td><td align="center" styleCode="Botrule" valign="middle"/></tr><tr><td colspan="2" align="center" styleCode="Botrule" valign="top"><content styleCode="bold">PERSERIS</content><content styleCode="bold">^&#xAE;</content><content styleCode="bold"> Instructions for Use </content></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">7 PREPARE THE SUBCUTANEOUS INJECTION SITE</content> <list listType="unordered" styleCode="Disc"><item>This medication is to be injected subcutaneously in the abdomen (see figure) or back of upper arm (see figure).</item><item>Choose an injection site with adequate subcutaneous tissue that is free of skin conditions (e.g. nodules, lesions, excessive pigment).</item><item><content styleCode="bold">Do not</content>inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way. </item><item>Clean the injection site well with an alcohol pad.</item></list><paragraph><renderMultiMedia ID="f35" referencedObject="mm35"/>To help minimize irritation, rotate injection sites following a pattern similar to the illustration. If you want to use the same injection site, make sure it is not the same spot on the injection site you used the last time. </paragraph></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f36" referencedObject="mm36"/><renderMultiMedia ID="f37" referencedObject="mm37"/></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">8 REMOVE EXCESS AIR FROM SYRINGE</content> <list listType="unordered" styleCode="Disc"><item>Hold the syringe upright for several seconds to allow air bubbles to rise.</item><item>Remove needle cover and slowly depress the plunger to push out the excess air from the syringe.</item><item>If medication is seen at the needle tip, pull back slightly on the plunger to prevent medication spillage.</item></list><paragraph><renderMultiMedia ID="f38" referencedObject="mm38"/>Due to the viscous nature of the medication, bubbles will not rise as quickly as those in an aqueous solution. </paragraph></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f39" referencedObject="mm39"/></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">9 PINCH INJECTION SITE</content> <list listType="unordered" styleCode="Disc"><item>Pinch the skin around the injection area. Be sure to pinch enough skin to accommodate the size of the needle. Lift the adipose tissue from the underlying muscle to prevent accidental intramuscular injection.</item></list></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f40" referencedObject="mm40"/></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">10 INJECT THE MEDICATION</content> <list listType="unordered" styleCode="Disc"><item>Insert needle fully into the subcutaneous tissue.</item><item><paragraph>Inject the medication slow and steady. <renderMultiMedia ID="f41" referencedObject="mm41"/> PERSERIS is for subcutaneous administration only. Do not inject by any other route.

MEDICATION</content> <list listType="unordered" styleCode="Disc"><item>Insert needle fully into the subcutaneous tissue.</item><item><paragraph>Inject the medication slow and steady. <renderMultiMedia ID="f41" referencedObject="mm41"/> PERSERIS is for subcutaneous administration only. Do not inject by any other route. <renderMultiMedia ID="f42" referencedObject="mm42"/> Actual angle of injection will depend on the amount of subcutaneous tissue. </paragraph></item></list></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f43" referencedObject="mm43"/></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">11 WITHDRAW NEEDLE</content> <list listType="unordered" styleCode="Disc"><item>Withdraw the needle at the same angle used for insertion and release pinched skin.</item></list><paragraph><renderMultiMedia ID="f44" referencedObject="mm44"/> Do not rub the injection area after the injection. If there is bleeding, apply a gauze pad or bandage but use minimal pressure. </paragraph></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f45" referencedObject="mm45"/></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">12 LOCK THE NEEDLE GUARD AND DISPOSE OF SYRINGE</content> <list listType="unordered" styleCode="Disc"><item>Lock the needle guard into place by pushing it against a hard surface such as a table.</item><item>Dispose of all syringe components in a secure sharps disposal container.</item></list></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f46" referencedObject="mm46"/></td></tr><tr><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">13 INSTRUCT THE PATIENT</content> <list listType="unordered" styleCode="Disc"><item>Advise the patient that they may have a lump for several weeks that will decrease in size over time. It is important that the patient not rub or massage the injection site and to be aware of the placement of any belts, waistbands, sleeves, cuffs or other parts of clothing.</item></list></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f47" referencedObject="mm47"/></td></tr></tbody></table>

s important that the patient not rub or massage the injection site and to be aware of the placement of any belts, waistbands, sleeves, cuffs or other parts of clothing.</item></list></td><td align="center" styleCode="Botrule" valign="middle"><renderMultiMedia ID="f47" referencedObject="mm47"/></td></tr></tbody></table> <table width="100%"><col width="82.300%" align="left"/><col width="17.700%" align="left"/><tfoot><tr><td align="left" valign="top"><paragraph styleCode="footnote"><content styleCode="bold">This Instructions for Use has been approved by the U.S. Food and Drug Administration.</content></paragraph></td><td align="right" valign="top"><paragraph styleCode="footnote">Revised 12/2022</paragraph></td></tr></tfoot><tbody><tr><td colspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">FREQUENTLY ASKED QUESTIONS</content> <content styleCode="bold">Q What is the mixture supposed to look like?</content> <content styleCode="bold">A</content>When fully mixed, the product should be a cloudy suspension that is uniform in color. It can vary from white to yellow-green in color. If you see any clear areas in the mixture, continue to mix until the distribution of the color is uniform. <content styleCode="bold">Q Why is it important to put the liquid syringe on top?</content> <content styleCode="bold">A</content>The liquid is viscous and will not fall out when placing on top. However, powder may be lost if the powder syringe is inverted, which could affect the ultimate dosage. <content styleCode="bold">Q What do I do if there is residual left in the powder syringe?</content> <content styleCode="bold">A</content>A small ring of residual powder may be observed in the end of the powder syringe barrel after mixing. This is normal. If you have followed the instructions carefully and the rest of the mixture is a cloudy suspension that is uniform in color, proceed with the injection. <content styleCode="bold">Q What do I do if a foreign particle is found in either of the syringes?</content> <content styleCode="bold">A</content>Do not use if you suspect foreign particles in either of the syringes. <content styleCode="bold">Q How soon must I inject after mixing PERSERIS</content><content styleCode="bold">^&#xAE;</content><content styleCode="bold">?</content> <content styleCode="bold">A</content>This product should be used immediately following preparation. <content styleCode="bold">Q Can I inject into the leg?</content> <content styleCode="bold">A</content>This injection is only approved for injection into the subcutaneous tissue of abdomen and back of the upper arm. <content styleCode="bold">Q How do I get rid of large air gaps?</content> <content styleCode="bold">A</content>Small bubbles, also known as champagne bubbles, are not a problem and common with this medication. Large air gaps, however, can be minimized by pulling back on the plunger rod to pop air bubbles prior to expelling the air very slowly. Air should be expelled very carefully to avoid loss of medication. <content styleCode="bold">Q Should I massage or put my finger on the injection site following the injection?</content> <content styleCode="bold">A</content>It is not advisable to palpate or massage the area following the injection. <content styleCode="bold">Q Will the deposit be palpable?</content> <content styleCode="bold">A</content>Depending on the patient&apos;s subcutaneous tissue, the deposit may be more or less palpable. Patients should be advised that a bump may be palpable (decreasing in size) for several weeks. </td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top">Manufactured for: Indivior Inc., North Chesterfield, VA 23235. &#xA9; 2022, Indivior UK Limited. All Rights Reserved.

e or less palpable. Patients should be advised that a bump may be palpable (decreasing in size) for several weeks. </td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top">Manufactured for: Indivior Inc., North Chesterfield, VA 23235. &#xA9; 2022, Indivior UK Limited. All Rights Reserved. PERSERIS is a registered trademark of Indivior UK Limited. Powder syringe manufactured by Patheon Manufacturing Services, Greenville, NC 27834. Liquid syringe manufactured by Curia, Burlington, MA 01803. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"/><td align="left" styleCode="Botrule Rrule" valign="top"/></tr></tbody></table>