These highlights do not include all the information needed to use risperidone oral solution safely and effectively. See full prescribing information for risperidone oral solution. Risperidone Oral Solution for Oral use. Initial U.S. approval:1993

BOXED WARNING

RECENT MAJOR CHANGES

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1INDICATIONS AND USAGE

1.1Schizophrenia

AdultsRisperidone oral solution is indicated for the acute and maintenance treatment of schizophrenia [see Clinical Studies (14.1)].AdolescentsDue to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with schizophrenia. Pediatric use information for the treatment of pediatric patients with schizophrenia, 13 to 17 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.

1.2Bipolar Mania

1.3Irritability Associated with Autistic Disorder

2DOSAGE AND ADMINISTRATION

2.1Schizophrenia

2.2Bipolar Mania

2.3Irritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents)

2.4Dosage in Special Populations

2.5Co-Administration of Risperidone Oral Solution with Certain Other Medications

2.6Administration of Risperidone Oral Solution

3DOSAGE FORMS AND STRENGTHS

4CONTRAINDICATIONS

Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone. Therefore, risperidone is contraindicated in patients with a known hypersensitivity to the product.

5WARNINGS AND PRECAUTIONS

5.1Increased Mortality in Elderly Patients with Dementia-Related Psychosis

5.2Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

5.3Neuroleptic Malignant Syndrome (NMS)

5.4Tardive Dyskinesia

5.5Hyperglycemia and Diabetes Mellitus

5.6Hyperprolactinemia

5.7Orthostatic Hypotension

5.8Leukopenia, Neutropenia, and Agranulocytosis

5.9Potential for Cognitive and Motor Impairment

5.10Seizures

5.11Dysphagia

5.12Priapism

5.13Body Temperature Regulation

5.14Antiemetic Effect

5.15Suicide

5.16Use in Patients with Concomitant Illness

5.17Monitoring: Laboratory Tests

6ADVERSE REACTIONS

• 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)]
• Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension [see Warnings and Precautions (5.7)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Dysphagia [see Warnings and Precautions (5.11)]
• Priapism [see Warnings and Precautions (5.12)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.13)]
• Antiemetic effect [see Warnings and Precautions (5.14)]
• Suicide [see Warnings and Precautions (5.15)]
• Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.16)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions (5.16)]

6.1Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia

6.2Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania

6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder

6.4 Other Adverse Reactions Observed During the Premarketing Evaluation of Risperidone

6.5 Discontinuations Due to Adverse Reactions

6.6Dose Dependency of Adverse Reactions in Clinical Trials

6.7Changes in Body Weight

6.8Changes in ECG

6.9Postmarketing Experience

7DRUG INTERACTIONS

7.1Centrally-Acting Drugs and Alcohol

7.2Drugs with Hypotensive Effects

7.3Levodopa and Dopamine Agonists

7.4Amitriptyline

7.5Cimetidine and Ranitidine

7.6Clozapine

7.7Lithium

7.8Valproate

7.9Digoxin

7.10Drugs That Inhibit CYP 2D6 and Other CYP Isozymes

7.11Carbamazepine and Other Enzyme Inducers

7.12Drugs Metabolized by CYP 2D6

8USE IN SPECIFIC POPULATIONS

8.1Pregnancy

8.2Labor and Delivery

8.3Nursing Mothers

8.4Pediatric Use

8.5Geriatric Use

9DRUG ABUSE AND DEPENDENCE

9.1Controlled Substance

9.2Abuse

9.3Dependence

10OVERDOSAGE

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10.1 Human Experience

10.2 Management of Overdosage

11 DESCRIPTION

Risperidone is a psychotropic agent 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 C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Absorption Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution. Pharmacokinetic studies showed that risperidone orally disintegrating tablets and risperidone oral solution are bioequivalent to risperidone tablets. Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5 to 6 days (measured in extensive metabolizers). Food Effect Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can be given with or without meals.Distribution Risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine(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. Metabolism and Drug Interactions Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6% to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. 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 (7.12)]. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given risperidone do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with risperidone may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug Interactions (7.11)]. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions 7.12)]. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours. Renal Impairment In patients with moderate to severe renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60% compared to young healthy subjects. Risperidone doses should be reduced in patients with renal disease [see Dosage and Administration (2.4) and Warnings and Precautions (5.16)]. Hepatic Impairment While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein. Risperidone doses should be reduced in patients with liver disease [see Dosage and Administration (2.4) and Warnings and Precautions (5.16)]. 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 Dosage and Administration (2.4)]. Pediatric Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients withschizophrenia, bipolar mania or irritability associated with autistic disorder. Pharmacokinetic information for pediatric patients with schizophrenia, 13 to 17 years of age, bipolar mania, 10 to 17 years old, and irritability associated with autistic disorder, 5 to 16 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products. Race and Gender Effects No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The following table summarizes the multiples of the human dose on a mg/m2(mg/kg) basis at which these tumors occurred.

14 CLINICAL STUDIES

14.1 Schizophrenia

14.2 Bipolar Mania - Monotherapy

AdultsThe efficacy of risperidone in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features.The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the YMRS total score. The results of the trials follow:

PediatricsDue to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with bipolar mania. Clinical trial information for pediatric patients with bipolar mania, 10  to 17 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.

• In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of risperidone 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), risperidone was superior to placebo in the reduction of YMRS total score.
•  In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), risperidone was superior to placebo in the reduction of YMRS total score.

14.3 Bipolar Mania – Combination Therapy

The efficacy of risperidone with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course.

•  In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone, placebo, or an active comparator, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score.
•  In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone or placebo, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4  to 12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone.

14.4 Irritability Associated with Autistic Disorder

Due to Janssen Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with irritability associated with autistic disorder. Clinical trial information for pediatric patients with irritability associated with autistic disorder,5 to 16 years of age, is approved for Janssen Pharmaceuticals Corporation’s risperidone drug products.

16 HOW SUPPLIED/STORAGE AND HANDLING

Risperidone Oral SolutionRisperidone 1 mg/mL Oral Solution (NDC 64679-692-01) is supplied in 30 mL bottles with a calibrated (in milligrams and milliliters) syringe. The minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL.Storage and HandlingRisperidone 1 mg/mL Oral Solution should be stored at 200-250C (680-770F) [See USP Controlled Room Temperature]. Protect from light and freezing.Keep out of reach of children

17 PATIENT COUNSELING INFORMATION

17.1 Orthostatic Hypotension

17.2 Interference with Cognitive and Motor Performance

Since risperidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone therapy does not affect them adversely [see Warnings and Precautions (5.9)].

17.3 Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)].

17.4 Nursing

Patients should be advised not to breast-feed an infant if they are taking risperidone [see Use in Specific Populations (8.3)].

17.5 Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see Drug Interactions (7)].

17.6 Alcohol

SPL UNCLASSIFIED SECTION

• Push the plastic screw-cap on the bottle down while turning it counter clock-wise. Remove the unscrewed cap (see figure 1).
• Remove the adapter and dispensing syringe from the plastic pouch provided and fit the adapter properly into the neck of bottle. (see figure 2).
• Remove the tip cover of dispensing syringe and keep the tip cover in safe place, away from children.      
• Insert the tip of dispensing syringe in the adapter plug fitted on the bottle neck. (see figure 3)
• Holding the syringe properly, invert the bottle upside down.
• While holding the outer barrel of the syringe, pull the plunger up to the level (see marking on side) that equals the dosage prescribed by your physician. (see figure 4).
• Once the dose is removed, keep the bottle upright holding the outer barrel of the syringe, remove the entire syringe from the bottle, being careful not to depress the plunger prematurely (see figure 5).
• Empty the entire content of the syringe into 3 to 4 ounces (100 mL) of a beverage by pushing the plunger down inside the syringe barrel. Stir the mixture thoroughly before consuming. Risperidone oral solution is compatible with water, coffee, orange juice, or low-fat milk: IT IS NOT COMPATIBLE with cola or tea.
• Replace the plastic cap on the bottle by screwing it clock-wise; rinse the empty dispensing syringe thoroughly with water and put the tip cover on the tip of the dispensing syringe (see figure 6).
• Keep the bottle and syringe in safe place, away from children.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL