Risperidone

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 )] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions ( 5.8 )] Potential for cognitive and motor impairment [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.10 )] Dysphagia [see Warnings and Precautions ( 5.11 )] Priapism [see Warnings and Precautions ( 5.12 )] Disruption of body temperature regulation [see Warnings and Precautions ( 5.13 )] Patients with Phenylketonuria [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. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Solco Healthcare US, LLC at 1-866-257-2597 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 Risperidone 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 Drymouth 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 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 1–3 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. 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. 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 1–6 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 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 Risperidone + 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 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 0.5–2.5 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. 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

4 CONTRAINDICATIONS Risperidone is contraindicated in patients with a known hypersensitivity to Risperidone. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone. Known hypersensitivity to Risperidone ( 4 )

11 DESCRIPTION Risperidone is 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 Tablets, USP, are for oral administration and are available in 0.25 mg (dark yellow), 0.5 mg (brownish red), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (white) strengths. Risperidone tablets contain the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and tartaric acid. The 0.25 mg tablets also contain Opadry II yellow 85F12383, for purposes of coating, which contains the following: iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. The 0.5 mg tablets also contain Opadry II red 85F15362, for purposes of coating, which contains the following: iron oxide red, polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. The 1 mg and 4 mg tablets also contain Opadry II white 85F18422, for purposes of coating, which contains the following: polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. The 2 mg tablets also contain Opadry II red 85F15404, for purposes of coating, which contains the following: calcium carbonate, calcium sulfate, iron oxide red, polyethylene glycol 3350, polyvinyl alcohol, and talc. The 3 mg tablets also contain Opadry II yellow 03B12447, for purposes of coating, which contains the following: hypromellose 2910 6cP, iron oxide red, iron oxide yellow, polyethylene glycol 400, and titanium dioxide. Chemical Structure

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 Schiophrenia: 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) 2.1 Schizophrenia Adults Usual Initial Dose Risperidone 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. 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. 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 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 (10-15 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 )] .

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 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 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 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 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 )].

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).

9.1 Controlled Substance Risperidone is not a controlled substance.

9.3 Dependence Risperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Risperidone 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.

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.

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 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 Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference ) Risperidone Dose Recommendation Coadministered Drug Risperidone AUC Cmax 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 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. Clozapine Chronic administration of clozapine with Risperidone may decrease the clearance of risperidone.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of Risperidone, in schizophrenia, is unknown. However, it has been proposed that 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 [see Clinical Pharmacology (12.3) ] . Antagonism at receptors other than D 2 and 5HT 2 [see Clinical Pharmacology (12.1) ] may explain some of the other effects of Risperidone. 12.2 Pharmacodynamics Risperidone is a selective 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 acts as an antagonist at other receptors, but with lower potency. Risperidone has 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. 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, Risperidone 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 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. 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. 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 (n70) 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. 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 14C-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-Drug Interaction Studies [See Drug Interactions (7) ]. 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 unknown. However, it has been proposed that 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 [see Clinical Pharmacology (12.3) ] . Antagonism at receptors other than D 2 and 5HT 2 [see Clinical Pharmacology (12.1) ] may explain some of the other effects of Risperidone.

12.2 Pharmacodynamics Risperidone is a selective 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 acts as an antagonist at other receptors, but with lower potency. Risperidone has 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. 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, Risperidone 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 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. 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. 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 (n70) 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. 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 14C-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-Drug Interaction Studies [See Drug Interactions (7) ]. 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.

20230227

13

3 DOSAGE FORMS AND STRENGTHS Risperidone Tablets, USP are available in the following strengths and colors: 0.25 mg (dark yellow), 0.5 mg (brownish red), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (white). All are round shaped, biconvex film-coated and imprinted with “K” on one side and either “221”, “222”, “223”, “224”, “225”, or “226” on the other side according to their respective strengths. Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg ( 3 )

Risperidone Risperidone RISPERIDONE RISPERIDONE SILICON DIOXIDE STARCH, CORN LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE TARTARIC ACID FERRIC OXIDE YELLOW POLYETHYLENE GLYCOL 3350 POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE dark yellow HH;221 Risperidone Risperidone RISPERIDONE RISPERIDONE SILICON DIOXIDE STARCH, CORN LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE TARTARIC ACID FERRIC OXIDE RED POLYETHYLENE GLYCOL 3350 POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE brownish red HH;222 Risperidone Risperidone RISPERIDONE RISPERIDONE SILICON DIOXIDE STARCH, CORN LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE TARTARIC ACID POLYETHYLENE GLYCOL 3350 POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE HH;223 Risperidone Risperidone RISPERIDONE RISPERIDONE SILICON DIOXIDE STARCH, CORN LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE TARTARIC ACID HYPROMELLOSE 2910 (6 MPA.S) FERRIC OXIDE RED FERRIC OXIDE YELLOW POLYETHYLENE GLYCOL 400 TITANIUM DIOXIDE HH;225 Risperidone Risperidone RISPERIDONE RISPERIDONE SILICON DIOXIDE STARCH, CORN LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE TARTARIC ACID CALCIUM CARBONATE CALCIUM SULFATE FERRIC OXIDE RED POLYETHYLENE GLYCOL 3350 TALC POLYVINYL ALCOHOL, UNSPECIFIED HH;224

13.2 Animal Toxicology Juvenile dogs were treated for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were observed with a no-effect dose of 0.31 mg/kg/day. This dose produced plasma AUC levels of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in sexual maturation was seen 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. In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a reversible impairment of performance in a test of learning and memory was observed in females only with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma AUC levels of risperidone plus paliperidone about half those observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest testable dose of 1.25 mg/kg/day. This dose produced plasma AUC levels of risperidone plus paliperidone which were about two thirds of those observed in humans at the MRHD.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 2, 9, and 38 times the maximum recommended human dose (MRHD) for schizophrenia of 16 mg/day on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m 2 body surface basis. 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 unknown [see Warnings and Precautions (5.6) ] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the Ames gene mutation test, the mouse lymphoma assay, the in vitro rat hepatocyte DNA-repair assay, the in vivo micronucleus test in mice, the sex-linked recessive lethal test in Drosophila , or the chromosomal aberration test in human lymphocytes or Chinese hamster ovary cells. Impairment of Fertility Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times the maximum recommended human dose (MRHD) on a mg/m 2 body surface area basis. The effect appeared to be in females, since impaired mating behavior was not noted in the Segment I study in which males only were treated. 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 on a mg/m 2 body surface area basis. 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 2, 9, and 38 times the maximum recommended human dose (MRHD) for schizophrenia of 16 mg/day on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m 2 body surface basis. 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 unknown [see Warnings and Precautions (5.6) ] . Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the Ames gene mutation test, the mouse lymphoma assay, the in vitro rat hepatocyte DNA-repair assay, the in vivo micronucleus test in mice, the sex-linked recessive lethal test in Drosophila , or the chromosomal aberration test in human lymphocytes or Chinese hamster ovary cells. Impairment of Fertility Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times the maximum recommended human dose (MRHD) on a mg/m 2 body surface area basis. The effect appeared to be in females, since impaired mating behavior was not noted in the Segment I study in which males only were treated. 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 on a mg/m 2 body surface area basis. 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. 13.2 Animal Toxicology Juvenile dogs were treated for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were observed with a no-effect dose of 0.31 mg/kg/day. This dose produced plasma AUC levels of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in sexual maturation was seen 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. In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a reversible impairment of performance in a test of learning and memory was observed in females only with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma AUC levels of risperidone plus paliperidone about half those observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest testable dose of 1.25 mg/kg/day. This dose produced plasma AUC levels of risperidone plus paliperidone which were about two thirds of those observed in humans at the MRHD.

ANDA077493

Risperidone

Risperidone

0615-8288

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 0.25 mg PRINCIPAL DISPLAY PANEL

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 Risperidone 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

17 PATIENT COUNSELING INFORMATION Physicians are advised to discuss the following issues with patients for whom they prescribe Risperidone and their caregivers: 17.1 Orthostatic Hypotension Advise patients and caregivers about the risk of orthostatic hypotension, especially during the period of initial dose titration [see Warnings and Precautions ( 5.7 )] . 17.2 Interference with Cognitive and Motor Performance Inform patients and caregivers that Risperidone has the potential to impair judgment, thinking, or motor skills. Advise caution about operating hazardous machinery, including automobiles, until patients are reasonably certain that Risperidone therapy does not affect them adversely [see Warnings and Precautions ( 5.9 )] . 17.3 Pregnancy Advise patients and caregivers to notify their physician if the patient becomes pregnant or intends to become pregnant during therapy [see Use in Specific Populations ( 8.1 )] . 17.4 Nursing Inform patients and caregivers that risperidone and its active metabolite are present in human breast milk; there is a potential for serious adverse reactions from Risperidone in nursing infants. Advise patients that the decision whether to discontinue nursing or to discontinue the Risperidone should take into account the importance of the drug to the patient [see Use in Specific Populations ( 8.3 )] . 17.5 Concomitant Medication Advise patients and caregivers to inform their physicians if the patient is taking, or plans to take, any prescription or over-the-counter drugs, because there is a potential for interactions [see Drug Interactions ( 7 )] . 17.6 Alcohol Advise patients to avoid alcohol while taking Risperidone [see Drug Interactions ( 7.2 )] . 17.8 Metabolic Changes Inform patients and caregivers that treatment with Risperidone can be associated with hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain [see Warnings and Precautions ( 5.5 )] . 17.9 Tardive Dyskinesia Inform patients and caregivers about the risk of tardive dyskinesia [see Warnings and Precautions ( 5.4 )] . Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd. Linhai, Zhejiang, China 317024 Distributed by: Solco Healthcare US, LLC Cranbury, NJ 08512, USA Revision: 05/2015 17122-01

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: 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. 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. In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of (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. 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 (2–8 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 13–17 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 1–3 mg/day (n = 55, mean modal dose = 2.6 mg), Risperidone 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 Risperidone 0.15–0.6 mg/day (n = 132, mean modal dose = 0.5 mg) or Risperidone 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 Risperidone 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 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: In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of Risperidone 1–6 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. 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), 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 0.5–2.5 mg/day (n = 50, mean modal dose = 1.9 mg), Risperidone 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 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 3–6 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 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. 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 1–6 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 Risperidone or placebo, in combination with their original therapy. Risperidone, 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 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 (16–104.3 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 Risperidone 0.5–3.5 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. 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). 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 1.8–2.1 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 4-6 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).

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) ] .

8.2 Labor and Delivery The effect of Risperidone on labor and delivery in humans is unknown.

8.3 Nursing Mothers Risperidone and 9-hydroxyrisperidone are present in human breast milk. Because of the potential for serious adverse reactions in nursing infants from risperidone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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 13-17 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 10-17 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 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, 82–87% of patients who received Risperidone 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 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 for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen, with a no-effect dose of 0.31 mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in sexual maturation was seen 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. In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus paliperidone about half those observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest testable dose (1.25 mg/kg/day). This dose produced plasma levels (AUC) of risperidone plus paliperidone which were about two thirds of those observed in humans at the MRHD.

8.1 Pregnancy Pregnancy Category C Risk Summary Adequate and well controlled studies with Risperidone have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs (including Risperidone) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There was no increase in the incidence of malformations in embryo-fetal studies in rats and rabbits at 0.4–6 times MHRD. Increased pup mortality was noted at all doses in peri-postnatal studies in rats. Risperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization. Data Human Data There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in neonates following in utero exposure to antipsychotics in the third trimester. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. There was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero . The causal relationship to Risperidone therapy is unknown. Animal Data The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-Dawley and Wistar rats (0.63–10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m 2 body surface area basis) and in one Segment II study in New Zealand rabbits (0.31–5 mg/kg or 0.4 to 6 times the MRHD on a mg/m 2 body surface area basis). There were no teratogenic effects in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m 2 body surface area basis. In three reproductive studies in rats (two Segment III and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16–5 mg/kg or 0.1 to 3 times the MRHD on a mg/m 2 body surface area basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams. There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m 2 body surface area basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups were observed, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m 2 body surface area basis. Placental transfer of risperidone occurs in rat pups.

Pregnancy Category C Risk Summary Adequate and well controlled studies with Risperidone have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs (including Risperidone) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There was no increase in the incidence of malformations in embryo-fetal studies in rats and rabbits at 0.4–6 times MHRD. Increased pup mortality was noted at all doses in peri-postnatal studies in rats. Risperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization. Data Human Data There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in neonates following in utero exposure to antipsychotics in the third trimester. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. There was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero . The causal relationship to Risperidone therapy is unknown. Animal Data The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-Dawley and Wistar rats (0.63–10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m 2 body surface area basis) and in one Segment II study in New Zealand rabbits (0.31–5 mg/kg or 0.4 to 6 times the MRHD on a mg/m 2 body surface area basis). There were no teratogenic effects in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m 2 body surface area basis. In three reproductive studies in rats (two Segment III and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16–5 mg/kg or 0.1 to 3 times the MRHD on a mg/m 2 body surface area basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams. There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m 2 body surface area basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups were observed, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m 2 body surface area basis. Placental transfer of risperidone occurs in rat pups.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of drug to the mother. ( 8.3 ) 8.1 Pregnancy Pregnancy Category C Risk Summary Adequate and well controlled studies with Risperidone have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs (including Risperidone) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There was no increase in the incidence of malformations in embryo-fetal studies in rats and rabbits at 0.4–6 times MHRD. Increased pup mortality was noted at all doses in peri-postnatal studies in rats. Risperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization. Data Human Data There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in neonates following in utero exposure to antipsychotics in the third trimester. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. There was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero . The causal relationship to Risperidone therapy is unknown. Animal Data The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-Dawley and Wistar rats (0.63–10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m 2 body surface area basis) and in one Segment II study in New Zealand rabbits (0.31–5 mg/kg or 0.4 to 6 times the MRHD on a mg/m 2 body surface area basis). There were no teratogenic effects in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m 2 body surface area basis. In three reproductive studies in rats (two Segment III and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16–5 mg/kg or 0.1 to 3 times the MRHD on a mg/m 2 body surface area basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams. There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m 2 body surface area basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups were observed, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m 2 body surface area basis. Placental transfer of risperidone occurs in rat pups. 8.2 Labor and Delivery The effect of Risperidone on labor and delivery in humans is unknown. 8.3 Nursing Mothers Risperidone and 9-hydroxyrisperidone are present in human breast milk. Because of the potential for serious adverse reactions in nursing infants from risperidone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 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 13-17 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 10-17 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 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, 82–87% of patients who received Risperidone 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 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 for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen, with a no-effect dose of 0.31 mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in sexual maturation was seen 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. In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus paliperidone about half those observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest testable dose (1.25 mg/kg/day). This dose produced plasma levels (AUC) of risperidone plus paliperidone which were about two thirds of those observed in humans at the MRHD. 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) ] . 8.7 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Risperidone Tablets Risperidone Tablets, USP are imprinted with "HH" on one side and either "221", "222", "223", "224", "225", or "226" on the other side according to their respective strengths. 0.25 mg dark yellow, round, biconvex film-coated tablets: NDC 0615-8196-39 Blistercards of 30 NDC 0615-8196-05 Blistercards of 15 NDC 0615-8196-30 Unit-Dose Boxes of 30 0.5 mg brownish red, round, biconvex film-coated tablets: NDC 0615-8197-39 Blistercards of 30 NDC 0615-8197-05 Blistercards of 15 NDC 0615-8197-30 Unit-Dose Boxes of 30 Both 0.25 mg and 0.5 mg Risperidone Tablets only have 18 month shelf life, which is shorter than other strength tablets. 1 mg white, round, biconvex film-coated tablets: NDC 0615-8198-39 Blistercards of 30 NDC 0615-8198-05 Blistercards of 15 2 mg orange, round, biconvex film-coated tablets: NDC 0615-8288-39 Blistercards of 30 3 mg yellow, round, biconvex film-coated tablets: NDC 0615-8265-39 Blistercards of 30 4 mg white, round, biconvex film-coated tablets: 16.2 Storage and Handling Risperidone Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture. Keep out of reach of children.

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 )