Risperdal

[Risperidone]

Special Populations

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. RISPERDAL ® doses should be reduced in patients with renal disease ( see PRECAUTIONS and DOSAGE AND ADMINISTRATION) .

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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 1 -acid glycoprotein. RISPERDAL ® doses should be reduced in patients with liver disease ( see PRECAUTIONS and DOSAGE AND ADMINISTRATION) .

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) .

Race and Gender Effects

No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not dentify mportant differences in the disposition of risperidone due to gender ( whether corrected for body weight or not) or race.

Clinical Trials

Schizophrenia 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:

( 1) In a 6-week, placebo-controlled trial ( n= 160) nvolving titration of RISPERDAL ® in doses up to 10 mg/ day ( BID 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.

( 2) In an 8-week, placebo-controlled trial ( n= 513) nvolving 4 fixed doses of RISPERDAL ® ( 2, 6, 10, and 16 mg/ day, on a BID 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.

( 3) In an 8-week, dose comparison trial ( n= 1356) nvolving 5 fixed doses of RISPERDAL ® ( 1, 4, 8, 12, and 16 mg/ day, on a BID 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.

( 4) In a 4-week, placebo-controlled dose comparison trial ( n= 246) nvolving 2 fixed doses of RISPERDAL ® ( 4 and 8 mg/ day on a QD 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 ® ( 2-8 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.

Bipolar Mania

Monotherapy
The efficacy of RISPERDAL ® in the treatment of acute manic or mixed episodes was established in 2 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 n these trials was the Young Mania Rating Scale ( Y-MRS) , 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 nterest, 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 Y-MRS total score. The results of the trials follow:

( 1) In one 3-week placebo-controlled trial ( n= 246) , limited to patients with manic episodes, which involved a dose range of RISPERDAL ® 1-6 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 Y-MRS total score.

( 2) In another 3-week placebo-controlled trial ( n= 286) , which nvolved a dose range of 1-6 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 Y-MRS total score.

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 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.

( 1) In this 3-week placebo-controlled combination trial, 148 in-or outpatients on lithium or valproate therapy with nadequately 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 1-6 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 Y-MRS total score.

( 2) 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. RISPERDAL ® , in a dose range of 1-6 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 4-12 mcg/ mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of Y-MRS 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.

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