Risperidone (Page 14 of 16)

Mutagenesis

No evidence of mutagenic or clastogenic potential for risperidone was found in the Ames gene mutation test, the mouse lymphoma assay, the in vitro rat hepatocyte DNA-repair assay, the in vivo micronucleus test in mice, the sex-linked recessive lethal test in Drosophila , or the chromosomal aberration test in human lymphocytes or Chinese hamster ovary cells.

Impairment of Fertility

Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times the maximum recommended human dose (MRHD) on a mg/m2 body surface area basis. The effect appeared to be in females, since impaired mating behavior was not noted in the Segment I study in which males only were treated. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD on a mg/m2 body surface area basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

13.2 Animal Toxicology

Juvenile dogs were treated for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were observed with a no-effect dose of 0.31 mg/kg/day. This dose produced plasma AUC levels of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a reversible impairment of performance in a test of learning and memory was observed in females only with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma AUC levels of risperidone plus paliperidone about half those observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest testable dose of 1.25 mg/kg/day. This dose produced plasma AUC levels of risperidone plus paliperidone which were about two thirds of those observed in humans at the MRHD.

14 CLINICAL STUDIES

14.1 Schizophrenia

Adults

Short-Term Efficacy

The efficacy of Risperidone 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 Risperidone in doses up to 10 mg/day (twice-daily schedule), Risperidone 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 Risperidone (2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all 4 Risperidone groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest Risperidone 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 (1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the four highest Risperidone dose groups were generally superior to the 1 mg Risperidone 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 Risperidone (4 and 8 mg/day on a once-daily schedule), both Risperidone 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 Risperidone (2–8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving Risperidone experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator.

Pediatrics

The efficacy of Risperidone in the treatment of schizophrenia in adolescents aged 13–17 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: Risperidone 1–3 mg/day (n = 55, mean modal dose = 2.6 mg), Risperidone 4–6 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 Risperidone 0.15–0.6 mg/day (n = 132, mean modal dose = 0.5 mg) or Risperidone 1.5–6 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 0.15–0.6 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 Risperidone in all dose groups from 1–6 mg/day compared to placebo, as measured by significant reduction of total PANSS score. The efficacy on the primary parameter in the 1–3 mg/day group was comparable to the 4–6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day group in study #2. In study #2, the efficacy in the 1.5–6 mg/day group was statistically significantly greater than that in the 0.15–0.6 mg/day group. Doses higher than 3 mg/day did not reveal any trend towards greater efficacy.

14.2 Bipolar Mania — Monotherapy

Adults

The 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:

  • In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of Risperidone 1–6 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 1–6 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.

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