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Other antipsychotics

Risperidone

Approved 16 Oct 2008OralTablet

The FDA lists this product in 60 strengths and forms.

Boxed warningThe FDA label of this medicine carries a boxed warning, the strongest warning the FDA gives. Read it under warnings and precautions.

Indications

1. INDICATIONS AND USAGE RISPERIDONE is an atypical antipsychotic indicated for:

Treatment of schizophrenia ( 1.1 )
As monotherapy or adjunctive therapy with lithium or valproate, for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder ( 1.2 )
Treatment of irritability associated with autistic disorder ( 1.3 )

1.1Schizophrenia

RISPERIDONE (risperidone) is indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults [see Clinical Studies ( 14.1 ) ].

1.2Bipolar Mania Monotherapy

RISPERIDONE is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) [see Clinical Studies ( 14.2 ) ]. Adjunctive Therapy RISPERIDONE adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder.

Efficacy was established in one short-term trial in adults [see Clinical Studies ( 14.3 ) ].

1.3Irritability Associated with Autistic Disorder Pediatrics

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

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Warnings and precautions

5. WARNINGS AND PRECAUTIONS

Cerebrovascular events, including stroke, in elderly patients with dementiarelated psychosis: RISPERIDONE is not approved for use in patients with dementia-related psychosis. ( 5.2 )
Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of RISPERIDONE and close monitoring. ( 5.3 )
Tardive dyskinesia: Consider discontinuing RISPERIDONE if clinically indicated. ( 5.4 )
Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. ( 5.5 )
Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.5 )
Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. ( 5.5 )
Weight Gain: Significant weight gain has been reported. Monitor weight gain. ( 5.5 )
Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. ( 5.6 )
Orthostatic hypotension: For patients at risk, consider a lower starting dose and slower titration. ( 5.7 )
Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of clinically significant low white blood cell count (WBC). Consider discontinuing RISPERIDONE if a clinically significant decline in WBC occurs in the absence of other causative factors. ( 5.8 )
Potential for cognitive and motor impairment: Use caution when operating machinery. ( 5.9 )
Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.10 )

5.1Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus RISPERIDONE when compared to patients treated with RISPERIDONE alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. RISPERIDONE (risperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning ].

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

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo.

RISPERIDONE is not approved for the treatment of patients with dementia-related psychosis [see also BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1) ].

5.3Neuroleptic Malignant Syndrome

Antipsychotic drugs including RISPERIDONE can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

The patient should be carefully monitored, since recurrences of NMS have been reported.

5.4Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, prescribe RISPERIDONE in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERIDONE, consider drug discontinuation. However, some patients may require treatment with RISPERIDONE despite the presence of the syndrome.

5.5Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own spe

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Interactions

7. DRUG INTERACTIONS

Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone. Increase the RISPERIDONE dose up to double the patient's usual dose. Titrate slowly. ( 7.1 )
Fluoxetine, paroxetine, and other CYP 2D6 enzyme inhibitors increase plasma concentrations of risperidone. Reduce the initial dose. Do not exceed a final dose of 8 mg per day of RISPERIDONE. ( 7.1 )

7.1Pharmacokinetic-related Interactions

The dose of RISPERIDONE should be adjusted when used in combination with CYP2D6 enzyme inhibitors (e.g., fluoxetine, and paroxetine) and enzyme inducers (e.g., carbamazepine) [see Table 18 and DOSAGE AND ADMINISTRATION ( 2.5 ) ]. Dose adjustment is not recommended for RISPERIDONE when coadministered with ranitidine, cimetidine, amitriptyline, or erythromycin [see Table 18 ]. Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia *Change relative to reference Coadministered Drug Dosing Schedule Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) Risperidone Dose Recommendation Coadministered Drug Risperidone AUC C max Enzyme (CYP2D6) Inhibitors Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.4

1.5 Re-evaluate dosing. Do not exceed 8 mg/day Paroxetine 10 mg/day 4 mg/day 1.3 - Re-evaluate dosing. 20 mg/day 4 mg/day 1.6 - Do not exceed 8 mg/day 40 mg/day 4 mg/day 1.8 - Enzyme (CYP3A/ PgP inducers) Carbamazepine 573 ± 168 mg/day 3 mg twice daily 0.51

0.55 Titrate dose upwards. Do not exceed twice the patient’s usual dose Enzyme (CYP3A) Inhibitors Ranitidine 150 mg twice daily 1 mg single dose 1.2

1.4 Dose adjustment not needed Cimetidine 400 mg twice daily 1 mg single dose 1.1

1.3 Dose adjustment not needed Erythromycin 500 mg four times daily 1 mg single dose 1.1

0.94 Dose adjustment not needed Other Drugs Amitriptyline 50 mg twice daily 3 mg twice daily 1.2

1.1 Dose adjustment not needed Effect of Risperidone on other drugs Lithium Repeated oral doses of RISPERIDONE (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13). Dose adjustment for lithium is not recommended. Valproate Repeated oral doses of RISPERIDONE (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21).

However, there was a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of RISPERIDONE. Dose adjustment for valproate is not recommended. Digoxin RISPERIDONE (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended.

7.2Pharmacodynamic-related Interactions Centrally-Acting Drugs and Alcohol Given

the primary CNS effects of risperidone, caution should be used when RISPERIDONE is taken in combination with other centrally-acting drugs and alcohol. Drugs with Hypotensive Effects Because of its potential for inducing hypotension, RISPERIDONE may enhance the hypotensive effects of other therapeutic agents with this potential. Levodopa and Dopamine Agonists RISPERIDONE may antagonize the effects of levodopa and dopamine agonists.

Clozapine Chronic administration of clozapine with RISPERIDONE may decrease the clearance of risperidone.

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Category C. Risk Summary Adequate

and well controlled studies with RISPERIDONE have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs (including RISPERIDONE) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There was no increase in the incidence of malformations in embryo-fetal studies in rats and rabbits at 0.4 to 6 times MHRD. Increased pup mortality was noted at all doses in peripostnatal studies in rats.

RISPERIDONE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization. Data Human Data There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in neonates following in utero exposure to antipsychotics in the third trimester.

These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. There was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero . The causal relationship to RISPERIDONE therapy is unknown Animal Data The teratogenic potential of risperidone was studied in three Segment II studies in Sprague- Dawley and Wistar rats (0.63 to 10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m 2 body surface area basis) and in one Segment II study in New Zealand rabbits (0.31 to 5 mg/kg or 0.4 to 6 times the MRHD on a mg/m 2 body surface area basis).

There were no teratogenic effects in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m 2 body surface area basis. In three reproductive studies in rats (two Segment III and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16 to 5 mg/kg or 0.1 to 3 times the MRHD on a mg/m 2 body surface area basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.

There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m 2 body surface area basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups were observed, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams.

In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m 2 body surface area basis.Placental transfer of risperidone occurs in rat pups.

17.3Pregnancy

Advise patients and caregivers to notify their physician if the patient becomes pregnant or intends to become pregnant during therapy [see USE IN SPECIFIC POPULATIONS ( 8.1 ) ].

Adverse reactions

6. ADVERSE REACTIONS 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 Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 (5.1564) ]
Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS ( 5.2 ) ]
Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS ( 5.3 ) ]
Tardive dyskinesia [see WARNINGS AND PRECAUTIONS ( 5.4 ) ]
Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [see WARNINGS AND PRECAUTIONS ( 5.5 ) ]
Hyperprolactinemia [see WARNINGS AND PRECAUTIONS ( 5.6 ) ]
Orthostatic hypotension [see WARNINGS AND PRECAUTIONS ( 5.7 ) ]
Leukopenia, neutropenia, and agranulocytosis [see WARNINGS AND PRECAUTIONS ( 5.8 ) ]
Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS ( 5.9 ) ]
Seizures [see WARNINGS AND PRECAUTIONS ( 5.10 ) ]
Dysphagia [see WARNINGS AND PRECAUTIONS ( 5.11 ) ]
Priapism [see WARNINGS AND PRECAUTIONS ( 5.12 ) ]
Disruption of body temperature regulation [see WARNINGS AND PRECAUTIONS ( 5.13 ) ] The most common adverse reactions in clinical trials (> 5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in > 1% of adults and/or > 2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [see ADVERSE REACTIONS, DISCONTINUATIONS DUE TO ADVERSE REACTIONS ( 6.1 ) ]. The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of RISPERIDONE for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received RISPERIDONE while participating in doubleblind, placebo-controlled trials. The conditions and duration of treatment with RISPERIDONE varied greatly and included (in overlapping categories) doubleblind, 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.

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Commonly-Observed Adverse Reactions in Doubleblind, Placebo-Controlled Clinical Trials Schizophrenia Adult Patients with Schizophrenia Table 8 lists the adverse reactions reported in 2% or more of RISPERIDONE-treated adult patients with schizophrenia in three 4 to 8 week, doubleblind, placebo-controlled trials.

Table 8Adverse Reactions in ≥ 2% of RISPERIDONE-Treated Adult Patients (and greater than placebo) with Schizophrenia in Doubleblind, Placebo-Controlled Trials *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. Percentage of Patients Reporting Reaction RISPERIDONE System/Organ Class Adverse Reaction 2 to 8 mg per day (N=366) > 8 to 16 mg per day (N=198) Placebo (N=225) Cardiac Disorders Tachycardia 1 3 0 Eye Disorders Vision blurred 3 1 1 Gastrointestinal Disorders Nausea 9 4 4 Constipation 8 9 6 Dyspepsia 8 6 5 Dry mouth 4 0 1 Abdominal discomfort 3 1 1 Salivary hypersecretion 2 1 <1 Diarrhea 2 1 1 General Disorders Fatigue 3 1 0 Chest pain 2 2 1 Asthenia 2 1 <1 Infections and Infestations Nasopharyngitis 3 4 3 Upper respiratory tract infection 2 3 1 Sinusitis 1 2 1 Urinary tract infection 1 3 0 Investigations Blood creatine phosphokinase increased 1 2 <1 Heart rate increased <1 2 0 Musculoskeletal and Connective Tissue Disorders Back pain 4 1 1 Arthralgia 2 3 <1 Pain in extremity 2 1 1 Nervous System Disorders Parkinsonism* 14 17 8 Akathisia* 10 10 3 Sedation 10 5 2 Dizziness 7 4 2 Dystonia* 3 4 2 Tremor* 2 3 1 Dizziness postural 2 0 0 Psychiatric Disorders Insomnia 32 25 27 Anxiety 16 11 11 Respiratory, Thoracic and Mediastinal Disorders Nasal congestion 4 6 2 Dyspnea 1 2 0 Epistaxis < 1 2 0 Skin and Subcutaneous Tissue Disorders Rash 1 4 1 Dry skin 1 3 0 Vascular Disorders Orthostatic hypotension 2 1 0 Pediatric Patients with Schizophrenia Table 9 lists the adverse reactions reported in 5% or more of RISPERIDONE-treated pediatric patients with schizophrenia in a 6 week doubleblind, placebo-controlled trial.

Table 9Adverse Reactions in ≥ 5% of RISPERIDONE-Treated Pediatric Patients (and greater than placebo) with Schizophrenia in a Doubleblind Trial * Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration. Percentage of Patients Reporting Reaction RISPERIDONE System/Organ Class Adverse Reaction 1 to 3 mg per day (N=55) 4 to 6 mg per day (N=51) Placebo (N=54) Gastrointestinal Disorders Salivary hypersecretion 0 10 2 Nervous System Disorders Sedation 24 12 4 Parkinsonism* 16 28 11 Tremor 11 10 6 Akathisia* 9 10 4 Dizziness 7 14 2 Dystonia* 2 6 0 Psychiatric Disorders Anxiety 7 6 0 Commonly-Observed Adverse Reactions in Doubleblind, Placebo-Controlled ClinicalTrials Bipolar Mania Adult Patients with Bipolar Mania Table 10 lists the adverse reactions reported in 2% or more of RISPERIDONE-treated adult patients with bipolar mania in four 3 week, doubleblind, placebo-controlled monotherapy trials.