Risperidone (Page 15 of 16)

Pediatrics

The efficacy of Risperidone in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder. Patients were randomized into one of three treatment groups: Risperidone 0.5–2.5 mg/day (n = 50, mean modal dose = 1.9 mg), Risperidone 3–6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases, study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10. The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score.

Results of this study demonstrated efficacy of Risperidone in both dose groups compared with placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary parameter in the 3–6 mg/day dose group was comparable to the 0.5–2.5 mg/day dose group. Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.

14.3 Bipolar Mania-Adjunctive Therapy with Lithium or Valproate

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 1–6 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 1–6 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 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

Short-Term Efficacy

The efficacy of Risperidone in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16–104.3 kg).

Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression — Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.

The results of these trials are as follows:

  • In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or Risperidone 0.5–3.5 mg/day on a weight-adjusted basis. Risperidone, starting at 0.25 mg/day or 0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day), significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with placebo.
  • In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged 5 to 12 years, Risperidone 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo.

A third trial was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects (N=96) 5 to 17 years of age with autistic disorder (defined by DSM-IV criteria) and associated irritability and related behavioral symptoms. Approximately 77% of patients were younger than 12 years of age (mean age = 9), and 88% were male. Most patients (73%) weighed less than 45 kg (mean weight = 40 kg). Approximately 90% of patients were antipsychotic-naïve before entering the study.

There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing ≥ 45 kg. The low dose was 0.125 mg per day for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing ≥ 45 kg. The dose was administered once daily in the morning, or in the evening if sedation occurred.

The primary efficacy endpoint was the mean change in the Aberrant Behavior Checklist-Irritability subscale (ABC-I) score from baseline to the end of Week 6. The study demonstrated the efficacy of high-dose risperidone, as measured by the mean change in ABC-I score. It did not demonstrate efficacy for low-dose risperidone. The mean baseline ABC-I scores were 29 in the placebo group (n = 35), 27 in the risperidone low-dose group (n = 30), and 28 in the risperidone high-dose group (n = 31). The mean changes in ABC-I scores were -3.5, -7.4, and -12.4 in the placebo, low-dose, and high-dose group respectively. The results in the high-dose group were statistically significant (p< 0.001) but not in the low-dose group (p=0.164).

Long-Term Efficacy

Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with Risperidone for 4 or 6 months (depending on whether they received Risperidone or placebo in the double-blind study). During this open-label treatment period, patients were maintained on a mean modal dose of Risperidone of 1.8–2.1 mg/day (equivalent to 0.05-0.07 mg/kg/day).

Patients who maintained their positive response to Risperidone (response was defined as 25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much improved’) during the 4-6 month open-label treatment phase for about 140 days, on average, were randomized to receive Risperidone or placebo during an 8-week, double-blind withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients who completed the withdrawal study (n=32), undertaken by an independent Data Safety Monitoring Board, demonstrated a significantly lower relapse rate in the Risperidone group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention. Relapse was defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase).

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Risperidone Tablets

Risperidone Tablets, USP are imprinted with “HH” on one side and either “221”, “222”, “223”, “224”, “225”, or “226” on the other side according to their respective strengths.

0.25 mg dark yellow, round, biconvex film-coated tablets:
NDC 0615-8196-39 Blistercards of 30
NDC 0615-8196-05 Blistercards of 15
NDC 0615-8196-30 Unit-Dose Boxes of 30

0.5 mg brownish red, round, biconvex film-coated tablets:
NDC 0615-8197-39 Blistercards of 30
NDC 0615-8197-05 Blistercards of 15
NDC 0615-8197-30 Unit-Dose Boxes of 30

Both 0.25 mg and 0.5 mg Risperidone Tablets only have 18 month shelf life, which is shorter than other strength tablets.

1 mg white, round, biconvex film-coated tablets:
NDC 0615-8198-39 Blistercards of 30
NDC 0615-8198-05 Blistercards of 15

2 mg orange, round, biconvex film-coated tablets:
NDC 0615-8288-39 Blistercards of 30

3 mg yellow, round, biconvex film-coated tablets:
NDC 0615-8265-39 Blistercards of 30

4 mg white, round, biconvex film-coated tablets:

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