Risperidone

RECENT MAJOR CHANGES Warning and Precautions 1/2025

1 INDICATIONS AND USAGE Risperidone orally disintegrating tablets are 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 orally disintegrating tablets are 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 orally disintegrating tablets are 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 orally disintegrating tablets 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 orally disintegrating tablets are indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years) [see Clinical Studies (14.4) ] .

2 DOSAGE AND ADMINISTRATION Table 1. Recommended Daily Dosage by Indication Initial Dose Titration (Increments) Target Dose Effective Dose Range Schizophrenia: adults (2.1) 2 mg 1 to 2 mg 4 to 8 mg 4 to 16 mg Schizophrenia: adolescents (2.2) 0.5 mg 0.5 to 1 mg 3 mg 1 to 6 mg Bipolar mania: adults (2.2) 2 to 3 mg 1 mg 1 to 6 mg 1 to 6 mg Bipolar mania: in children and adolescents (2.2) 0.5 mg 0.5 to 1 mg 1 to 2.5 mg 1 to 6 mg Irritability in autistic disorder (2.3) 0.25 mg Can increase to 0.5 mg by Day 4: (body weight less than 20 kg) 0.5 mg Can increase to 1 mg by Day 4: (body weight greater than or equal to 20 kg) After Day 4, at intervals of > 2 weeks: 0.25 mg (body weight less than 20 kg) 0.5 mg (body weight greater than or equal to 20 kg) 0.5 mg: (body weight less than 20 kg) 1 mg: (body weight greater than or equal to 20 kg) 0.5 to 3 mg Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of one week or longer. Recommended daily dosage Initial Dose Target Dose Effective Dose Range Schizophrenia: adults (2.1) 2 mg 4 to 8 mg 4 to 16 mg Schizophrenia: adolescents (2.1) 0.5 mg 3 mg 1 to 6 mg Bipolar mania: Adults (2.2) 2 to 3 mg 1 to 6 mg 1 to 6 mg Bipolar mania: in children and adolescents (2.2) 0.5 mg 1 to 2.5 mg 1 to 6 mg Irritability associated with autistic disorder (2.3) 0.25 mg (Weight <20 kg) 0.5 mg (Weight ≥20 kg) 0.5 mg (<20 kg) 1 mg (≥20 kg) 0.5 to 3 mg Severe Renal or Hepatic Impairment in Adults: Use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of at least one week. ( 2.4 ) Risperidone Orally Disintegrating Tablets: Open the blister only when ready to administer, and immediately place tablet on the tongue. Can be swallowed with or without liquid. ( 2.7 ) 2.1 Schizophrenia Adults Usual Initial Dose Risperidone orally disintegrating tablets 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 orally disintegrating tablets, the effectiveness of risperidone orally disintegrating tablets 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 bey …

3 DOSAGE FORMS AND STRENGTHS Risperidone Orally Disintegrating Tablets, USP are available containing 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg or 4 mg of risperidone, USP. The 0.25 mg tablets are white, round, flat-faced, beveled edge tablet debossed with R25 on one side of the tablet and blank on the other side. The 0.5 mg tablets are white, round, flat-faced, beveled edge tablet debossed with RN on one side of the tablet and blank on the other side. The 1 mg tablets are white, round, flat-faced, beveled edge tablet debossed with RN1 on one side of the tablet and blank on the other side. The 2 mg tablets are peach, round, flat-faced, beveled edge tablet debossed with RN2 on one side of the tablet and blank on the other side. The 3 mg tablets are green, round, flat-faced, beveled edge tablet debossed with RN3 on one side of the tablet and blank on the other side. The 4 mg tablets are blue, round, flat-faced, beveled edge tablet debossed with RN4 on one side of the tablet and blank on the other side. Orally disintegrating tablets: 0.25mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg ( 3 )

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

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2) ] Neuroleptic malignant syndrome [see Warnings and Precautions (5.3) ] Tardive dyskinesia [see Warnings and Precautions (5.4) ] Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.5) ] Hyperprolactinemia [see Warnings and Precautions (5.6) ] Orthostatic hypotension [see Warnings and Precautions (5.7) ] Falls [see Warnings and Precautions (5.8) ] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.10) ] Seizures [see Warnings and Precautions (5.11) ] Dysphagia [see Warnings and Precautions (5.12) ] Priapism [see Warnings and Precautions (5.13) ] Disruption of body temperature regulation [see Warnings and Precautions (5.14) ] Patients with Phenylketonuria [see Warnings and Precautions (5.15) ] The most common adverse reactions in clinical trials (>5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions, Discontinuations Due to Adverse Reactions (6.1) ]. The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of 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 Jubilant Cadista Pharmaceuticals Inc. at 1-800-313-4623 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 …

7 DRUG INTERACTIONS Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone. Increase the risperidone orally disintegrating tablet 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 orally disintegrating tablets. ( 7.1 ) 7.1 Pharmacokinetic-related Interactions The dose of risperidone orally disintegrating tablets should be adjusted when used in combination with CYP 2D6 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 orally disintegrating tablets when co-administered with ranitidine, cimetidine, amitriptyline, or erythromycin [see Table 18]. Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*) Risperidone Dose Recommendation Coadministered Drug Risperidone AUC C max Enzyme (CYP 2D6) Inhibitors Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4 1.5 Re-evaluate dosing. Do not exceed 8 mg/day Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. Do not exceed 8 mg/day 20 mg/day 4 mg/day 1.6 - 40 mg/day 4 mg/day 1.8 - Enzyme (CYP3A/PgP inducers) Inducers Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51 0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose Enzyme (CYP3A) Inhibitors Ranitidine 150 mg twice daily 1 mg single dose 1.2 1.4 Dose adjustment not needed Cimetidine 400 mg twice daily 1 mg single dose 1.1 1.3 Dose adjustment not needed Erythromycin 500 mg four times daily 1 mg single dose 1.1 0.94 Dose adjustment not needed Other Drugs Amitriptyline 50 mg twice daily 3 mg twice daily 1.2 1.1 Dose adjustment not needed * Change relative to reference Effect of Risperidone on Other Drugs Lithium Repeated oral doses of risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (n = 13). Dose adjustment for lithium is not recommended. Valproate Repeated oral doses of risperidone (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n = 21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of risperidone. Dose adjustment for valproate is not recommended. Digoxin Risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended. 7.2 Pharmacodynamic-related Interactions Centrally Acting Drugs and Alcohol Given the primary CNS effects of risperidone, caution should be used when Risperidone is taken in combination with other centrally acting drugs and alcohol. Drugs with Hypotensive Effects Because of its potential for inducing hypotension, risperidone may enhance the hypotensive effects of other therapeutic agents with this potential. Levodopa and Dopamine Agonists Risperidone may antagonize the effects of levodopa and dopamine agonists. Methylphenidate Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of risperidone and methylphenidate [see Adverse Reactions (6.2)]. Clozapine Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including risperidone, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-andresearch-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations) . Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including risperidone, during pregnancy (see Clinical Considerations) . Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a subgroup of 15 …

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

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

12.3 Pharmacokinetics Absorption Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution. Pharmacokinetic studies showed that Risperidone Orally Disintegrating Tablets and Risperidone Oral Solution are bioequivalent to Risperidone Tablets. Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 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 α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance. Elimination Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-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 met …

11 DESCRIPTION Risperidone, USP 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, USP is a white to almost white powder. It is soluble in methylene chloride, sparingly soluble in alcohol and practically insoluble in water. Risperidone Orally Disintegrating Tablets, USP are available in 0.5 mg (yellow), 1 mg (white), 2 mg (blue), 3 mg (orange), and 4 mg (pink) strengths. Risperidone Orally Disintegrating Tablets, USP contain the following inactive ingredients: acesulfame potassium, amino methacrylate copolymer, aspartame, colloidal silicon dioxide, low substituted hydroxypropyl cellulose, magnesium aluminometasilicate, mannitol, peppermint flavor, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate and talc. In addition, 0.5 mg strength contains ferric oxide yellow, 2 mg strength contains FD&C Blue #1 Aluminum lake, 3 mg strength contains FD&C Yellow #6 Aluminum lake, and 4 mg strength contains ferric oxide red. risperidone

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 orally disintegrating tablet 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 orally disintegrating tablets.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Risperidone oral disintegrating tablets 0.5 mg are available as pink colored, round, flat faced, beveled edged tablets, debossed with “ RE ” on one side and “ 8 ” on the other side. NDC 63304-949-30 Bottles of 30 NDC 63304-949-05 Bottles of 500 NDC 63304-949-17 Box of 10 Unit-Dose pouches Risperidone oral disintegrating tablets 1 mg are available as pink colored, round, flat faced, beveled edged tablets, debossed with “ RE ” on one side and “ 9 ” on the other side. NDC 63304-950-30 Bottles of 30 NDC 63304-950-05 Bottles of 500 NDC 63304-950-17 Box of 10 Unit-Dose pouches Risperidone oral disintegrating tablets 2 mg are available as pink colored, round, flat faced, beveled edged tablets, debossed with “ RE ” on one side and “ 10 ” on the other side. NDC 63304-951-30 Bottles of 30 NDC 63304-951-05 Bottles of 500 NDC 63304-951-17 Box of 10 Unit-Dose pouches Risperidone oral disintegrating tablets 3 mg are available as pink colored, round, flat faced, beveled edged tablets, debossed with “ RE ” and “ 43 ” on one side and plain on the other side. NDC 63304-643-30 Bottles of 30 NDC 63304-643-05 Bottles of 500 NDC 63304-643-69 Blister of 10 NDC 63304-643-17 Box of 10 Unit-Dose pouches Risperidone oral disintegrating tablets 4 mg are available as pink colored, round, flat faced, beveled edged tablets, debossed with “ RE ” and “ 44 ” on one side and plain on the other side. NDC 63304-644-30 Bottles of 30 NDC 63304-644-05 Bottles of 500 NDC 63304-644-69 Blister of 10 NDC 63304-644-17 Box of 10 Unit-Dose pouches 16.2 Storage and Handling Risperidone orally disintegrating tablets should be stored at 20° - 25° C (68° - 77° F) [See USP Controlled Room Temperature]. Protect from light and moisture. Keep out of reach of children.

16.1 How Supplied Risperidone oral disintegrating tablets 0.5 mg are available as pink colored, round, flat faced, beveled edged tablets, debossed with “ RE ” on one side and “ 8 ” on the other side. NDC 63304-949-30 Bottles of 30 NDC 63304-949-05 Bottles of 500 NDC 63304-949-17 Box of 10 Unit-Dose pouches Risperidone oral disintegrating tablets 1 mg are available as pink colored, round, flat faced, beveled edged tablets, debossed with “ RE ” on one side and “ 9 ” on the other side. NDC 63304-950-30 Bottles of 30 NDC 63304-950-05 Bottles of 500 NDC 63304-950-17 Box of 10 Unit-Dose pouches Risperidone oral disintegrating tablets 2 mg are available as pink colored, round, flat faced, beveled edged tablets, debossed with “ RE ” on one side and “ 10 ” on the other side. NDC 63304-951-30 Bottles of 30 NDC 63304-951-05 Bottles of 500 NDC 63304-951-17 Box of 10 Unit-Dose pouches Risperidone oral disintegrating tablets 3 mg are available as pink colored, round, flat faced, beveled edged tablets, debossed with “ RE ” and “ 43 ” on one side and plain on the other side. NDC 63304-643-30 Bottles of 30 NDC 63304-643-05 Bottles of 500 NDC 63304-643-69 Blister of 10 NDC 63304-643-17 Box of 10 Unit-Dose pouches Risperidone oral disintegrating tablets 4 mg are available as pink colored, round, flat faced, beveled edged tablets, debossed with “ RE ” and “ 44 ” on one side and plain on the other side. NDC 63304-644-30 Bottles of 30 NDC 63304-644-05 Bottles of 500 NDC 63304-644-69 Blister of 10 NDC 63304-644-17 Box of 10 Unit-Dose pouches