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 to 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 to 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).
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 to 2.1 mg/day (equivalent to 0.05 to 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 to 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).
Risperidone tablets USP are available as:
0.25 mg dark yellow, film-coated, capsule-shaped, convex, debossed “5683” on one side and debossed “V” on the reverse side, supplied as follows:
Bottles of 60: NDC 0603-5683-20
Bottles of 500: NDC 0603-5683-28
0.5 mg reddish-brown, film-coated, capsule-shaped, convex, debossed “5684” on one side and debossed “V” on the reverse side, supplied as follows:
Bottles of 60: NDC 0603-5684-20
Bottles of 500: NDC 0603-5684-28
Bottles of 1000: NDC 0603-5684-32
1 mg white, film-coated, capsule-shaped, convex, debossed “5685” on one side and debossed “V” on the reverse side, supplied as follows:
Bottles of 60: NDC 0603-5685-20
Bottles of 500: NDC 0603-5685-28
Bottles of 1000: NDC 0603-5685-32
2 mg pink, film-coated, capsule-shaped, convex, debossed “5686” on one side and debossed “V” on the reverse side, supplied as follows:
Bottles of 60: NDC 0603-5686-20
Bottles of 500: NDC 0603-5686-28
Bottles of 1000: NDC 0603-5686-32
3 mg yellow, film-coated, capsule-shaped, convex, debossed “5687” on one side and debossed “V” on the reverse side, supplied as follows:
Bottles of 60: NDC 0603-5689-20
Bottles of 500: NDC 0603-5689-28
4 mg green, film-coated, capsule-shaped, convex, debossed “5688” on one side and debossed “V” on the reverse side, supplied as follows:
Bottles of 60: NDC 0603-5688-20
Bottles of 500: NDC 0603-5688-28
Risperidone tablets USP should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Protect from light and moisture.
Keep out of reach of children.
Physicians are advised to discuss the following issues with patients for whom they prescribe risperidone and their caregivers:
Advise patients and caregivers about the risk of orthostatic hypotension, especially during the period of initial dose titration [see Warnings and Precautions (5.7)].
Inform patients and caregivers that risperidone has the potential to impair judgment, thinking, or motor skills. Advise caution about operating hazardous machinery, including automobiles, until patients are reasonably certain that risperidone therapy does not affect them adversely [see Warnings and Precautions (5.9)].
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)].
Inform patients and caregivers that risperidone and its active metabolite are present in human breast milk; there is a potential for serious adverse reactions from risperidone in nursing infants. Advise patients that the decision whether to discontinue nursing or to discontinue the risperidone should take into account the importance of the drug to the patient [see Use in Specific Populations (8.3)].
Advise patients and caregivers to inform their physicians if the patient is taking, or plans to take, any prescription or over-the-counter drugs, because there is a potential for interactions [see Drug Interactions (7)].
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