Risperidone

RISPERIDONE- risperidone solution
Taro Pharmaceuticals U.S.A., Inc.

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. 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. Risperidone is not approved for the treatment of patients with dementia-related psychosis. [See Warnings and Precautions (5.1)]

1 INDICATIONS AND USAGE

1.1 Schizophrenia

Adults

Risperidone is indicated for the acute and maintenance treatment of schizophrenia [see Clinical Studies (14.1)].

Adolescents

Risperidone is indicated for the treatment of schizophrenia in adolescents aged 13 — 17 years [see Clinical Studies (14.1)].

1.2 Bipolar Mania

Monotherapy — Adults and Pediatrics

Risperidone is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults and in children and adolescents aged 10 — 17 years [see Clinical Studies (14.2)].

Combination Therapy – Adults

The combination of risperidone with lithium or valproate is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical Studies (14.3)].

1.3 Irritability Associated with Autistic Disorder

Pediatrics

Risperidone is indicated for the treatment of irritability associated with autistic disorder in children and adolescents aged 5–16 years, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies (14.4)].

2 DOSAGE AND ADMINISTRATION

2.1 Schizophrenia

Adults

Usual Initial Dose

Risperidone can be administered once or twice daily. Initial dosing is generally 2 mg/day. Dose increases should then occur at intervals not less than 24 hours, in increments of 1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see Clinical Studies (14.1)]. However, doses above 6 mg/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/day has not been evaluated in clinical trials.

Maintenance Therapy

While it is unknown how long a patient with schizophrenia should remain on risperidone, the effectiveness of risperidone 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled trial in 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)]. Patients should be periodically reassessed to determine the need for maintenance treatment with an appropriate dose.

Adolescents

The dosage of risperidone should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above 3 mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

There are no controlled data to support the longer term use of risperidone beyond 8 weeks in adolescents with schizophrenia. The physician who elects to use risperidone for extended periods in adolescents with schizophrenia should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Reinitiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off risperidone, the initial titration schedule should be followed.

Switching From Other Antipsychotics

There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to risperidone, or treating patients with concomitant antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some schizophrenic patients, more gradual discontinuation may be most appropriate for others. The period of overlapping antipsychotic administration should be minimized. When switching schizophrenic patients from depot antipsychotics, initiate risperidone therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.

2.2 Bipolar Mania

Usual Dose

Adults

Risperidone should be administered on a once-daily schedule, starting with 2 mg to 3 mg per day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments/decrements of 1 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 1-6 mg per day [see Clinical Studies (14.2 , 14.3)]. Risperidone doses higher than 6 mg per day were not studied.

Pediatrics

The dosage of risperidone should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above 2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.

Maintenance Therapy

There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with risperidone. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of risperidone in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

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

The safety and effectiveness of risperidone in pediatric patients with autistic disorder less than 5 years of age have not been established.

The dosage of risperidone should be individualized according to the response and tolerability of the patient. The total daily dose of risperidone can be administered once daily, or half the total daily dose can be administered twice daily.

Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for patients 20 kg. After a minimum of four days from treatment initiation, the dose may be increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for patients 20 kg. This dose should be maintained for a minimum of 14 days. In patients not achieving sufficient clinical response, dose increases may be considered at 2-week intervals in increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients 20 kg. Caution should be exercised with dosage for smaller children who weigh less than 15 kg.

In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on ABC-I, [see Clinical Studies (14.4)]) received doses of risperidone between 0.5 mg and 2.5 mg per day. The maximum daily dose of risperidone in one of the pivotal trials, when the therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients 20 kg, or 3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.

Once sufficient clinical response has been achieved and maintained, consideration should be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose.

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