RISPERDAL- risperidone_tablet

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 2 [see Clinical Pharmacology (12. 3) 2 2 [see Clinical Pharmacology (12. 1) Risperidone is a monoaminergic antagonist with high affinity (Ki of 0. 3 nM) for the serotonin Type 2 (5HT 2 2 1 2 1 1C 1D 1A 1 -5 1 2 Absorption Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution. Pharmacokinetic studies showed that RISPERDAL M-TAB Orally Disintegrating Tablets and RISPERDAL Oral Solution are bioequivalent to RISPERDAL Tablets. Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0. 5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5en dash6 days (measured in extensive metabolizers). Food Effect Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL can be given with or without meals. Distribution Risperidone is rapidly distributed. The volume of distribution is 1en dash2 L/kg. In plasma, risperidone is bound to albumin and alpha 1 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 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%en dash8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14 The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours. Drug Interaction Studies Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7) [see Drug Interactions (7) [see Drug Interactions (7) In vitro In vitro Specific Populations Renal and Hepatic Impairment [See Use in Specific Populations (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.

RISPERDAL is an atypical antipsychotic indicated for: Treatment of schizophrenia ( 1. 1 As monotherapy or adjunctive therapy with lithium or valproate, for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder ( 1. 2 Treatment of irritability associated with autistic disorder ( 1. 3 RISPERDAL (risperidone) is indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults [see Clinical Studies (14. 1) Monotherapy RISPERDAL is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) [see Clinical Studies (14. 2) Adjunctive Therapy RISPERDAL adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults [see Clinical Studies (14. 3) RISPERDAL is indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years) [see Clinical Studies (14.

DOSAGE AND ADMINISTRATION
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. 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. 5 to 1 mg 1 to 2. 5 mg 1 to 6 mg Irritability in autistic disorder (2. 25 mg After Day 4, at intervals of > 2 weeks: 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. 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. 5 mg 1 to 2. 5 mg 1 to 6 mg Irritability associated with autistic disorder ( 2. 5 to 3 mg Severe Renal or Hepatic Impairment in Adults: Use a lower starting dose of 0. 5 mg twice daily at intervals of at least one week. 4 Oral Solution: Can be administered directly from calibrated oral dosing syringe or mixed with beverage (water, coffee, orange juice, or low-fat milk). 6 M-TAB Orally Disintegrating Tablets: Open the blister only when ready to administer, and immediately place tablet on the tongue. Can be swallowed with or without liquid. 7 Adults Usual Initial Dose RISPERDAL can be administered once or twice daily. Initial dosing is 2 mg per day. May increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day, as tolerated, to a recommended dose of 4 to 8 mg per day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 mg to 16 mg per day. However, doses above 6 mg per day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg per day has not been evaluated in clinical trials [see Clinical Studies (14. 1) Adolescents The initial dose is 0. 5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0. 5 mg or 1 mg per day, as tolerated, to a recommended dose of 3 mg per day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg to 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied. Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily. Maintenance Therapy While it is unknown how long a patient with schizophrenia should remain on RISPERDAL, the effectiveness of RISPERDAL 2 mg per day to 8 mg per day at delaying relapse was demonstrated in a controlled trial in adult patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [see Clinical Studies (14. 1) Reinitiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off RISPERDAL, the initial titration schedule should be followed. Switching From Other Antipsychotics There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to RISPERDAL, or treating patients with concomitant antipsychotics. 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. 3) Pediatrics The initial dose is 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. Maintenance Therapy There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with RISPERDAL. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of RISPERDAL in such longer-term treatment (i. , beyond 3 weeks). The physician who elects to use RISPERDAL for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. The dosage of RISPERDAL should be individualized according to the response and tolerability of the patient. The total daily dose of RISPERDAL can be administered once daily, or half the total daily dose can be administered twice daily. For patients with body weight less than 20 kg, initiate dosing at 0. 25 mg per day. For patients with body weight greater than or equal to 20 kg, initiate dosing at 0. 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. 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. For patients with severe renal impairment (Clcr< 30 mL/min) or hepatic impairment (10en dash15 points on Child Pugh System), the initial starting dose is 0. 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. 7) When RISPERDAL is co-administered with enzyme inducers (e. , carbamazepine), the dose of RISPERDAL should be increased up to double the patient''s usual dose. It may be necessary to decrease the RISPERDAL dose when enzyme inducers such as carbamazepine are discontinued [see Drug Interactions (7. 1) When fluoxetine or paroxetine is co-administered with RISPERDAL, the dose of RISPERDAL should be reduced. The RISPERDAL dose should not exceed 8 mg per day in adults when co-administered with these drugs. When initiating therapy, RISPERDAL should be titrated slowly. It may be necessary to increase the RISPERDAL dose when enzyme inhibitors such as fluoxetine or paroxetine are discontinued [see Drug Interactions (7. 1) RISPERDAL Oral Solution can be administered directly from the calibrated oral dosing syringe, or can be mixed with a beverage prior to administration. RISPERDAL Oral Solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea. Tablet Accessing RISPERDAL M-TAB Orally Disintegrating Tablets 0. 5 mg, 1 mg, and 2 mg RISPERDAL M-TAB Orally Disintegrating Tablets 0. 5 mg, 1 mg, and 2 mg are supplied in blister packs of 4 tablets each. Do not open the blister until ready to administer. For single tablet removal, separate one of the four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the tablet. RISPERDAL M-TAB Orally Disintegrating Tablets 3 mg and 4 mg RISPERDAL M-TAB Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a child-resistant pouch containing a blister with 1 tablet each. The child-resistant pouch should be torn open at the notch to access the blister. Peel back foil from the side to expose the tablet. DO NOT push the tablet through the foil, because this could damage the tablet. Tablet Administration Using dry hands, remove the tablet from the blister unit and immediately place the entire RISPERDAL M-TAB Orally Disintegrating Tablet on the tongue. The RISPERDAL M-TAB Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be stored once removed from the blister unit. RISPERDAL M-TAB Orally Disintegrating Tablets disintegrate in the mouth within seconds and can be swallowed subsequently with or without liquid. Patients should not attempt to split or to chew the tablet.
INSTRUCTIONS FOR USE
RISPERDAL registered Read these Instructions for Use before you start using RISPERDAL Oral Solution and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Important information you need to know before taking RISPERDAL Oral Solution: Take RISPERDAL Oral Solution exactly as your healthcare provider tells you to take it. Each 1 mL contains 1 mg of RISPERDAL Oral Solution. Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose using the oral dosing syringe. Always use the oral dosing syringe that comes with RISPERDAL Oral Solution. Contact your healthcare provider or pharmacist if you lose or damage the oral dosing syringe, or if your carton does not come with one. RISPERDAL Oral Solution can be taken directly from the oral dosing syringe or mixed with water, coffee, orange juice, or low-fat milk. Do not Each RISPERDAL Oral Solution carton contains: 1 bottle of RISPERDAL Oral Solution 1 oral dosing syringe Gather and check supplies: Gather the RISPERDAL Oral Solution bottle and oral dosing syringe. Check the expiration date on the bottle. Do not use the bottle of RISPERDAL Oral Solution if the expiration date has passed. Check your dose in mLs as prescribed by your healthcare provider. Find this mL marking on the plunger of the oral dosing syringe. If your dose is more than 3 mL, you will need to divide your dose. Follow the instructions given to you by your healthcare provider or pharmacist on how to divide your dose. Preparing a dose of RISPERDAL Oral Solution: Step 1. Step 5 Step 4 Step 6. Mix the dose of RISPERDAL Oral Solution with water, coffee, orange juice, or low-fat milk. Stir well and drink all of the mixture right away to ensure the full dose is taken. See Figure 6a Do not mix Or To take the RISPERDAL Oral Solution dose directly from the oral dosing syringe, place the tip of the oral dosing syringe into the mouth and toward the cheek. Slowly push the plunger all the way down to gently release all of the medicine in the oral dosing syringe. Do not squirt or forcefully push the medicine into the back of the throat. See Figure 6b Step 7. Remove the plunger from the oral dosing syringe barrel. Rinse the oral dosing syringe barrel and plunger with water and let them air dry. When the oral dosing syringe barrel and plunger are dry, put the plunger back into the oral dosing syringe barrel for the next use. Do not throw away the oral dosing syringe. Storing RISPERDAL Oral Solution: Store RISPERDAL Oral Solution at room temperature between 59 °F to 77 °F (15 °C to 25 °C). Do not freeze RISPERDAL Oral Solution. Protect from light. Keep RISPERDAL Oral Solution and all medicines out of the reach of children. Manufactured for: For patent information: www. jansenpatents. com copyright Johnson & Johnson and its affiliates 2007 This Instructions for Use has been approved by the U. Food and Drug Administration. Figure Step 1 Step 2 Step 3 Step 4 Step 5 Figure 6a Figure 6b Step 7 Step 8.
INSTRUCCIONES DE USO
RISPERDAL registered Lea estas Instrucciones de uso antes de comenzar a usar RISPERDAL Solución oral y cada vez que renueve su receta. Es posible que este material contenga información nueva. Esta información no reemplaza la consulta con su proveedor de atención médica acerca de su enfermedad o tratamiento. Información importante que debe saber antes de tomar RISPERDAL Solución oral: Tome RISPERDAL Solución oral exactamente como se lo indica su proveedor de atención médica. Cada 1 ml contiene 1 mg de RISPERDAL Solución oral. Pídale a su proveedor de atención médica o farmacéutico que le muestre cómo medir la dosis recetada con la jeringa de dosificación oral. Utilice siempre la jeringa de dosificación oral que viene con RISPERDAL Solución oral. Comuníquese con su proveedor de atención médica o farmacéutico si pierde o daña la jeringa de dosificación oral, o si su caja no viene con una. RISPERDAL Solución oral se puede tomar directamente de la jeringa de dosificación oral o se puede mezclar con agua, café, jugo de naranja o leche con bajo contenido de grasa. No Cada caja de RISPERDAL Solución oral contiene lo siguiente: 1 frasco de RISPERDAL Solución oral 1 jeringa de dosificación oral Reúna y verifique los suministros: Reúna el frasco de RISPERDAL Solución oral y la jeringa de dosificación oral. Consulte la fecha de caducidad en el frasco. No utilice el frasco de RISPERDAL Solución oral si ha pasado la fecha de caducidad. Verifique su dosis en ml según lo prescrito por su proveedor de atención médica. Busque esta marca de ml en el émbolo de la jeringa de dosificación oral. Si su dosis supera los 3 ml, deberá dividir la dosis. Siga las instrucciones que le dé su proveedor de atención médica o farmacéutico sobre cómo dividir su dosis. Preparación de una dosis de RISPERDAL Solución oral: Paso 1. Paso 4 Paso 6. Mezcle la dosis de RISPERDAL Solución oral con agua, café, jugo de naranja o leche con bajo contenido de grasa. Revuelva bien y beba toda la mezcla de inmediato para asegurarse de tomar la dosis completa. Consulte la Figura 6a No mezcle O Para tomar la dosis de RISPERDAL Solución oral directamente de la jeringa de dosificación oral, coloque la punta de la jeringa de dosificación oral en la boca y hacia la mejilla. Empuje lentamente el émbolo hasta el fondo para liberar suavemente todo el medicamento en la jeringa de dosificación oral. No rocíe ni empuje con fuerza el medicamento en la parte posterior de la garganta. Consulte la Figura 6b Paso 7. Retire el émbolo del cilindro de la jeringa de dosificación oral. Enjuague el cilindro de la jeringa de dosificación oral con agua y déjela secar al aire. Cuando el cilindro de la jeringa de dosificación oral y el émbolo estén secos, vuelva a colocar el émbolo en el cilindro de la jeringa de dosificación oral para el próximo uso. No deseche la jeringa de dosificación oral. Almacenamiento de RISPERDAL Solución oral Almacene RISPERDAL Solución oral a temperatura ambiente entre 59 °F y 77 °F (de 15 °C a 25 °C). No congelar RISPERDAL Solución oral. Proteger de la luz. Mantenga RISPERDAL Solución oral y todos los medicamentos fuera del alcance de los niños. Fabricado para: Janssen Pharmaceuticals, Inc. Titusville, NJ, 08560, USA Estas Instrucciones de uso han sido aprobadas por la Administración de Alimentos y Medicamentos (FDA) de los EE. Para información sobre patentes : www. janssenpatents. com copyright Johnson & Johnson y sus afiliados 2007 Revisado: 2/2025 Figura Paso 1 Paso 2 Paso 3 Paso 4 Paso 5 Figura 6a Figura 6b Paso 7 Paso 8.

The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5. 1) Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5. 2) Neuroleptic malignant syndrome [see Warnings and Precautions (5. 3) Tardive dyskinesia [see Warnings and Precautions (5. 4) Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5. 5) Hyperprolactinemia [see Warnings and Precautions (5. 6) Orthostatic hypotension [see Warnings and Precautions (5. 7) Falls [see Warnings and Precautions (5. 8) Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5. 9) Potential for cognitive and motor impairment [see Warnings and Precautions (5. 10) Seizures [see Warnings and Precautions (5. 11) Dysphagia [see Warnings and Precautions (5. 12) Priapism [see Warnings and Precautions (5. 13) Disruption of body temperature regulation [see Warnings and Precautions (5. 14) Patients with Phenylketonuria [see Warnings and Precautions (5. 15) The most common adverse reactions in clinical trials (>5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions, Discontinuations Due to Adverse Reactions (6. 1) The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of RISPERDAL for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received RISPERDAL while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with RISPERDAL varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs. The most common adverse reactions in clinical trials (>=5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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 en dash Schizophrenia Adult Patients with Schizophrenia Table 8 lists the adverse reactions reported in 2% or more of RISPERDAL-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials. Adverse Reactions in >=2% of RISPERDAL-Treated Adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Reaction RISPERDAL System/Organ Class 2en dash8 mg per day >8en dash16 mg per day Placebo Cardiac Disorders Tachycardia 1 3 0 Eye Disorders Vision blurred 3 1 1 Gastrointestinal Disorders Nausea 9 4 4 Constipation 8 9 6 Dyspepsia 8 6 5 Dry mouth 4 0 1 Abdominal discomfort 3 1 1 Salivary hypersecretion 2 1 <1 Diarrhea 2 1 1 General Disorders Fatigue 3 1 0 Chest pain 2 2 1 Asthenia 2 1 <1 Infections and Infestations Nasopharyngitis 3 4 3 Upper respiratory tract infection 2 3 1 Sinusitis 1 2 1 Urinary tract infection 1 3 0 Investigations Blood creatine phosphokinase increased 1 2 <1 Heart rate increased <1 2 0 Musculoskeletal and Connective Tissue Disorders Back pain 4 1 1 Arthralgia 2 3 <1 Pain in extremity 2 1 1 Nervous System Disorders Parkinsonism Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson's disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor. 14 17 8 Akathisia 10 10 3 Sedation 10 5 2 Dizziness 7 4 2 Dystonia 3 4 2 Tremor 2 3 1 Dizziness postural 2 0 0 Psychiatric Disorders Insomnia 32 25 27 Anxiety 16 11 11 Respiratory, Thoracic and Mediastinal Disorders Nasal congestion 4 6 2 Dyspnea 1 2 0 Epistaxis <1 2 0 Skin and Subcutaneous Tissue Disorders Rash 1 4 1 Dry skin 1 3 0 Vascular Disorders Orthostatic hypotension 2 1 0 Pediatric Patients with Schizophrenia Table 9 lists the adverse reactions reported in 5% or more of RISPERDAL-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial. Adverse Reactions in >=5% of RISPERDAL-Treated Pediatric Patients (and greater than placebo) with Schizophrenia in a Double-Blind Trial Percentage of Patients Reporting Reaction RISPERDAL System/Organ Class 1en dash3 mg per day 4en dash6 mg per day Placebo 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. 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 en dash Bipolar Mania Adult Patients with Bipolar Mania Table 10 lists the adverse reactions reported in 2% or more of RISPERDAL-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials. Adverse Reactions in >=2% of RISPERDAL-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials Percentage of Patients Reporting Reaction System/Organ Class RISPERDAL Placebo 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. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis. 25 9 Sedation 11 4 Akathisia 9 3 Tremor 6 3 Dizziness 6 5 Dystonia 5 1 Lethargy 2 1 Table 11 lists the adverse reactions reported in 2% or more of RISPERDAL-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials. Adverse Reactions in >=2% of RISPERDAL-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Adjunctive Therapy Trials Percentage of Patients Reporting Reaction System/Organ Class RISPERDAL + Mood Stabilizer Placebo + Mood Stabilizer Adverse Reaction (N=127) (N=126) Cardiac Disorders Palpitations 2 0 Gastrointestinal Disorders Dyspepsia 9 8 Nausea 6 4 Diarrhea 6 4 Salivary hypersecretion 2 0 General Disorders Chest pain 2 1 Infections and Infestations Urinary tract infection 2 1 Nervous System Disorders Parkinsonism Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia. 14 4 Sedation 9 4 Akathisia 8 0 Dizziness 7 2 Tremor 6 2 Lethargy 2 1 Psychiatric Disorders Anxiety 3 2 Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 5 2 Cough 2 0 Pediatric Patients with Bipolar Mania Table 12 lists the adverse reactions reported in 5% or more of RISPERDAL-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial. Adverse Reactions in >=5% of RISPERDAL-Treated Pediatric Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Reaction RISPERDAL System/Organ Class 0. 5 mg per day 3en dash6 mg per day Placebo 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 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder Table 13 lists the adverse reactions reported in 5% or more of RISPERDAL-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study. Adverse Reactions in >=5% of RISPERDAL-Treated Pediatric Patients (and greater than placebo) Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Reaction RISPERDAL Placebo Adverse Reaction (N=107) (N=115) Gastrointestinal Disorders Vomiting 20 17 Constipation 17 6 Dry mouth 10 4 Nausea 8 5 Salivary hypersecretion 7 1 General Disorders and Administration Site Conditions Fatigue 31 9 Pyrexia 16 13 Thirst 7 4 Infections and Infestations Nasopharyngitis 19 9 Rhinitis 9 7 Upper respiratory tract infection 8 3 Investigations Weight increased 8 2 Metabolism and Nutrition Disorders Increased appetite 44 15 Nervous System Disorders Sedation 63 15 Drooling 12 4 Headache 12 10 Tremor 8 1 Dizziness 8 2 Parkinsonism Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness. 8 1 Renal and Urinary Disorders Enuresis 16 10 Respiratory, Thoracic and Mediastinal Disorders Cough 17 12 Rhinorrhea 12 10 Nasal congestion 10 4 Skin and Subcutaneous Tissue Disorders Rash 8 5 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of RISPERDAL in adults and pediatric patients. Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block Ear and Labyrinth Disorders: ear pain, tinnitus Endocrine Disorders: hyperprolactinemia Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal Immune System Disorders: drug hypersensitivity Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: decreased appetite, polydipsia, anorexia Musculoskeletal and Connective Tissue Disorders: joint stiffness, joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular, acne, hyperkeratosis, seborrheic dermatitis Vascular Disorders: hypotension, flushing Additional Adverse Reactions Reported with RISPERDAL CONSTA The following is a list of additional adverse reactions that have been reported during the premarketing evaluation of RISPERDAL CONSTA, regardless of frequency of occurrence: Cardiac Disorders: bradycardia Ear and Labyrinth Disorders: vertigo Eye Disorders: blepharospasm Gastrointestinal Disorders: toothache, tongue spasm General Disorders and Administration Site Conditions: pain Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis, subcutaneous abscess Injury and Poisoning: fall Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme increased Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain Nervous System Disorders: convulsion, paresthesia Psychiatric Disorders: depression Skin and Subcutaneous Tissue Disorders: eczema Vascular Disorders: hypertension Discontinuations Due to Adverse Reactions Schizophrenia - Adults Approximately 7% (39/564) of RISPERDAL-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more RISPERDAL-treated patients were: Table 14. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL-Treated Adult Patients in Schizophrenia Trials RISPERDAL Adverse Reaction 2en dash8 mg/day >8en dash16 mg/day Placebo Dizziness 1. 0% 0% Nausea 1. 4% 0% 0% Vomiting 0. 8% 0% 0% Parkinsonism 0. 8% 0% 0% Somnolence 0. 8% 0% 0% Dystonia 0. 5% 0% 0% Agitation 0. 5% 0% 0% Abdominal pain 0. 5% 0% 0% Orthostatic hypotension 0. 5% 0% Akathisia 0. 0% 0% Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3. 4% in active control-treated patients in a double-blind, placebo- and active-controlled trial. Schizophrenia - Pediatrics Approximately 7% (7/106), of RISPERDAL-treated patients discontinued treatment due to an adverse reaction in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one RISPERDAL-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%). Bipolar Mania - Adults In double-blind, placebo-controlled trials with RISPERDAL as monotherapy, approximately 6% (25/448) of RISPERDAL-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in RISPERDAL-treated patients were: Table 15. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL-Treated Adult Patients in Bipolar Mania Clinical Trials Adverse Reaction RISPERDAL Placebo Parkinsonism 0. 4% 0% Lethargy 0. 2% 0% Dizziness 0. 2% 0% Alanine aminotransferase increased 0. 2% Aspartate aminotransferase increased 0. 2% Bipolar Mania - Pediatrics In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one RISPERDAL-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%). Autistic Disorder - Pediatrics In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n=156), one RISPERDAL-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event. Dose Dependency of Adverse Reactions in Clinical Trials Extrapyramidal Symptoms Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with RISPERDAL treatment. Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of RISPERDAL (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS: Table 16. Dose Groups Placebo RISPERDAL 2 mg RISPERDAL 6 mg RISPERDAL 10 mg RISPERDAL 16 mg Parkinsonism 1. 6 EPS Incidence 13% 17% 21% 21% 35% Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of RISPERDAL (1, 4, 8, 12, and 16 mg/day): Table 17. Dose Groups RISPERDAL 1 mg RISPERDAL 4 mg RISPERDAL 8 mg RISPERDAL 12 mg RISPERDAL 16 mg Parkinsonism 0. 1 EPS Incidence 7% 12% 17% 18% 20% Dystonia Class Effect: Other Adverse Reactions Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of RISPERDAL (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0. 05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration. Changes in Body Weight Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [see Warnings and Precautions (5. 5) Adverse Reactions (6) Use in Specific Populations (8. 4) Changes in ECG Parameters Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all RISPERDAL doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8en dash16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4en dash6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups. In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 en dash 16 years) mean changes in heart rate were an increase of 8. 4 beats per minute in the RISPERDAL groups and 6. 5 beats per minute in the placebo group. There were no other notable ECG changes. In a placebo-controlled acute mania trial in children and adolescents (aged 10 en dash 17 years), there were no significant changes in ECG parameters, other than the effect of RISPERDAL to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 en dash 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time. The following adverse reactions have been identified during postapproval use of risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

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

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. 1 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including RISPERDAL, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth. org/clinical-and-research-programs/pregnancyregistry/ Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations (see Data (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 2 2 2 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. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2en dash4% and 15en dash20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including RISPERDAL, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. 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. 56) and of cardiac malformations (RR=1. 26, 95% CI 0. 81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2 2 2 Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0. 16 to 5 mg/kg/day which are 0. 1 to 3 times the MRHD of 16 mg/day based on mg/m 2 2 In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m 2 Risk Summary Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2. 7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations Clinical Considerations Infants exposed to RISPERDAL through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). Infertility Females Based on the pharmacologic action of risperidone (D 2 , [see Warnings and Precautions (5. 6) Approved Pediatric Indications Schizophrenia The efficacy and safety of RISPERDAL in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 to 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [see Indications and Usage (1. 1) Adverse Reactions (6. 1) and Clinical Studies (14. 1) Safety and effectiveness of RISPERDAL in children less than 13 years of age with schizophrenia have not been established. Bipolar I Disorder The efficacy and safety of RISPERDAL in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 to 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications and Usage (1. 2) Adverse Reactions (6. 2) Safety and effectiveness of RISPERDAL in children less than 10 years of age with bipolar disorder have not been established. Autistic Disorder The efficacy and safety of RISPERDAL in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see Indications and Usage (1. 3) Adverse Reactions (6. 4) ] A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms. There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1. 25 mg per day for patients weighing 20 to < 45 kg, and it was 1. 75 mg per day for patients weighing >= 45 kg. The low dose was 0. 125 mg per day for patients for patients weighing 20 to < 45 kg, and it was 0. 175 mg per day for patients weighing >= 45 kg. The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone. Adverse Reactions in Pediatric Patients Tardive Dyskinesia In clinical trials in 1885 children and adolescents treated with RISPERDAL, 2 (0. 1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL treatment [see also Warnings and Precautions (5. 4) Weight Gain Weight gain has been observed in children and adolescents during treatment with RISPERDAL. Clinical monitoring of weight is recommended during treatment. Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for RISPERDAL-treated patients was 2 kg, compared to 0. 6 kg for placebo-treated patients. In these trials, approximately 33% of the RISPERDAL group had weight gain >=7%, compared to 7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5. 5 kg at Week 24 and 8 kg at Week 48 [see Warnings and Precautions (5. 5) 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. 2) [see Dosage and Administration (2. 3) Hyperprolactinemia RISPERDAL has been shown to elevate prolactin levels in children and adolescents as well as in adults [see Warnings and Precautions (5. 6) In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0. 8% of RISPERDAL-treated patients and gynecomastia was reported in 2. 3% of RISPERDAL-treated patients. Growth and Sexual Maturation The long-term effects of RISPERDAL on growth and sexual maturation have not been fully evaluated in children and adolescents. Juvenile Animal Studies Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0. 25, or 5 mg/kg/day, which are 1. 5 times the MRHD of 6 mg/day for children, based on mg/m 2 Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0. 63 mg/kg/day which is 0. 5 times the MRHD of 6 mg/day for children, based on mg/m 2 Clinical studies of RISPERDAL in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12. 3) and Dosage and Administration (2. 5) [see Warnings and Precautions (5. 7) 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) In patients with moderate to severe (Clcr 59 to 15 mL/min) renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60%, compared to young healthy subjects. RISPERDAL doses should be reduced in patients with renal disease [see Dosage and Administration (2. 4) 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 alpha 1 [see Dosage and Administration (2. 4) Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to RISPERDAL. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone. Increase the RISPERDAL dose up to double the patient's usual dose. Titrate slowly. 1 Fluoxetine, paroxetine, and other CYP 2D6 enzyme inhibitors increase plasma concentrations of risperidone. Reduce the initial dose. Do not exceed a final dose of 8 mg per day of RISPERDAL. 1 The dose of RISPERDAL should be adjusted when used in combination with CYP2D6 enzyme inhibitors (e. , fluoxetine, and paroxetine) and enzyme inducers (e. , carbamazepine) [see Table 18 Dosage and Administration (2. 5) [see Table 18 Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference Risperidone Dose Recommendation Coadministered Drug Risperidone AUC C max Enzyme (CYP2D6) Inhibitors Fluoxetine 20 mg/day 2 or 3 mg twice daily 1. 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. 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. 4 Dose adjustment not needed Cimetidine 400 mg twice daily 1 mg single dose 1. 3 Dose adjustment not needed Erythromycin 500 mg four times daily 1 mg single dose 1. 94 Dose adjustment not needed Other Drugs Amitriptyline 50 mg twice daily 3 mg twice daily 1. 1 Dose adjustment not needed Effect of Risperidone on Other Drugs Lithium Repeated oral doses of RISPERDAL (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max Valproate Repeated oral doses of RISPERDAL (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (C max Digoxin RISPERDAL (0. 25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended. Centrally Acting Drugs and Alcohol Given the primary CNS effects of risperidone, caution should be used when RISPERDAL is taken in combination with other centrally acting drugs and alcohol. Drugs with Hypotensive Effects Because of its potential for inducing hypotension, RISPERDAL may enhance the hypotensive effects of other therapeutic agents with this potential. Levodopa and Dopamine Agonists RISPERDAL may antagonize the effects of levodopa and dopamine agonists. Methylphenidate Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of RISPERDAL and methylphenidate [see Adverse Reactions (6. 2) Clozapine Chronic administration of clozapine with RISPERDAL may decrease the clearance of risperidone.

OVERDOSAGE
Premarketing experience included eight reports of acute RISPERDAL overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug''s known pharmacological effects, i. , drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure. Postmarketing experience includes reports of acute RISPERDAL overdosage, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug''s known pharmacological effects, i. , drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to RISPERDAL overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of RISPERDAL and paroxetine. For the most up to date information on the management of RISPERDAL overdosage, contact a certified poison control center (1-800-222-1222 or www. Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to RISPERDAL.
NONCLINICAL TOXICOLOGY
Carcinogenesis Risperidone was administered in the diet at doses of 0. 5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0. 75, and 3 times (mice) and 0. 5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2 2 Multiples of Maximum Human Dose in mg/m 2 Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0. 4) Endocrine pancreas adenomas rat Male 1. 4) Mammary gland adenocarcinomas mouse Female 0. 4) none rat Female 0. 4) none rat Male 6. 4) Mammary gland neoplasm, Total rat Male 1. 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 5en dash6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions (5. 6) Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro in vivo Drosophila Impairment of Fertility Oral risperidone (0. 16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0. 1 to 3 times the MRHD of 16 mg/day based on mg/m 2 2.
CLINICAL STUDIES
Adults Short-Term Efficacy The efficacy of RISPERDAL in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) were employed. The results of the trials follow: In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL in doses up to 10 mg/day (twice-daily schedule), RISPERDAL was generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the SANS. In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL (2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all 4 RISPERDAL groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest RISPERDAL dose groups were generally superior to placebo on the PANSS negative subscale. The most consistently positive responses on all measures were seen for the 6 mg dose group, and there was no suggestion of increased benefit from larger doses. In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL (1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the four highest RISPERDAL dose groups were generally superior to the 1 mg RISPERDAL dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The most consistently positive responses were seen for the 4 mg dose group. In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of RISPERDAL (4 and 8 mg/day on a once-daily schedule), both RISPERDAL dose groups were generally superior to placebo on several PANSS measures, including a response measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg dose group. Long-Term Efficacy In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to RISPERDAL (2en dash8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving RISPERDAL experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator. Pediatrics The efficacy of RISPERDAL in the treatment of schizophrenia in adolescents aged 13en dash17 years was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at time of enrollment. In the first trial (study #1), patients were randomized into one of three treatment groups: RISPERDAL 1en dash3 mg/day (n=55, mean modal dose = 2. 6 mg), RISPERDAL 4en dash6 mg/day (n=51, mean modal dose = 5. 3 mg), or placebo (n=54). In the second trial (study #2), patients were randomized to either RISPERDAL 0. 6 mg/day (n=132, mean modal dose = 0. 5 mg) or RISPERDAL 1. 5en dash6 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. 6 mg/day group in study #2, where the initial dose was 0. 05 mg/day) and titrated to the target dosage range by approximately Day 7. Subsequently, dosage was increased to the maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable in all studies was the mean change from baseline in total PANSS score. Results of the studies demonstrated efficacy of RISPERDAL in all dose groups from 1en dash6 mg/day compared to placebo, as measured by significant reduction of total PANSS score. The efficacy on the primary parameter in the 1en dash3 mg/day group was comparable to the 4en dash6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1. 5en dash6 mg/day group in study #2. In study #2, the efficacy in the 1. 5en dash6 mg/day group was statistically significantly greater than that in the 0. 6 mg/day group. Doses higher than 3 mg/day did not reveal any trend towards greater efficacy. Adults The efficacy of RISPERDAL in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features. The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the YMRS total score. The results of the trials follow: In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of RISPERDAL 1en dash6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4. 1 mg/day), RISPERDAL was superior to placebo in the reduction of YMRS total score. In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1en dash6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5. 6 mg/day), RISPERDAL was superior to placebo in the reduction of YMRS total score. Pediatrics The efficacy of RISPERDAL in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder. Patients were randomized into one of three treatment groups: RISPERDAL 0. 5 mg/day (n=50, mean modal dose = 1. 9 mg), RISPERDAL 3en dash6 mg/day (n=61, mean modal dose = 4. 7 mg), or placebo (n=58). 5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10. The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score. Results of this study demonstrated efficacy of RISPERDAL in both dose groups compared with placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary parameter in the 3en dash6 mg/day dose group was comparable to the 0. 5 mg/day dose group. Doses higher than 2. 5 mg/day did not reveal any trend towards greater efficacy. The efficacy of RISPERDAL with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course. In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive RISPERDAL, placebo, or an active comparator, in combination with their original therapy. RISPERDAL, in a dose range of 1en dash6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3. 8 mg/day), combined with lithium or valproate (in a therapeutic range of 0. 6 mEq/L to 1. 4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score. In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive RISPERDAL or placebo, in combination with their original therapy. 7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0. 4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4en dash12 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. Short-Term Efficacy The efficacy of RISPERDAL in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16en dash104. Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies. The results of these trials are as follows: In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL 0. 5 mg/day on a weight-adjusted basis. RISPERDAL, starting at 0. 25 mg/day or 0. 5 mg/day depending on baseline weight (< 20 kg and >= 20 kg, respectively) and titrated to clinical response (mean modal dose of 1. 9 mg/day, equivalent to 0. 06 mg/kg/day), significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with placebo. In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged 5 to 12 years, RISPERDAL 0. 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 en dash 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. 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. Long-Term Efficacy Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with RISPERDAL for 4 or 6 months (depending on whether they received RISPERDAL or placebo in the double-blind study). During this open-label treatment period, patients were maintained on a mean modal dose of RISPERDAL of 1. 1 mg/day (equivalent to 0. 05 en dash 0. 07 mg/kg/day). Patients who maintained their positive response to RISPERDAL (response was defined as >= 25% improvement on the ABC-I subscale and a CGI-C rating of ''much improved'' or ''very much improved'') during the 4en dash6 month open-label treatment phase for about 140 days, on average, were randomized to receive RISPERDAL or placebo during an 8-week, double-blind withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients who completed the withdrawal study (n=32), undertaken by an independent Data Safety Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention. Relapse was defined as >= 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase).

RISPERDAL M-TAB- risperidone_tablet, orally disintegrating

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