Safety and tolerability of aripiprazole in the treatment of irritability associated with autistic disorder in pediatric subjects (6-17 years old):results from a pooled analysis of 2 studies

Abstract

Background: With increasing use of atypical antipsychotics among pediatric patients, detailed information about safety and tolerability is crucial.

Method: Data were pooled from two 8-week, randomized, double-blind, multicenter, parallel-group trials comparing aripiprazole versus placebo in subjects aged 6 to 17 years with irritability associated with DSM-IV-TR-diagnosed autistic disorder: one flexibly dosed (aripiprazole 2-15 mg/d; target of 5, 10, or 15 mg/d), the other fixed-dose (aripiprazole 5, 10, or 15 mg/d). The first was conducted from June 2006-April 2008, and the second, from June 2006-June 2008. Adverse events were characterized with respect to incidence, duration, severity, timing of peak incidence of onset, and dose-response relationship. Extrapyramidal symptoms, drooling, and metabolic parameters were evaluated.

Results: Three hundred thirteen subjects comprised the safety sample (aripiprazole 212, placebo 101). Discontinuations due to adverse events with aripiprazole versus placebo were, overall, 10.4% versus 6.9%; subjects 6-12 years: 10.8% versus 5.1%; and subjects 13-17 years: 8.9% versus 13.6%. Common adverse events with aripiprazole versus placebo included sedation (20.8% vs 4.0%), fatigue (16.5% vs 2.0%), vomiting (13.7% vs 6.9%), increased appetite (12.7% vs 6.9%), somnolence (10.4% vs 4.0%), and tremor (9.9% vs 0.0%). Most adverse events were mild or moderate and occurred early. Only fatigue showed a dose-response relationship (P < .05). Mean body weight change (last observation carried forward, 1.6 vs 0.4 kg) was higher with aripiprazole than placebo (P < .001). There were no between-treatment differences in metabolic changes. The extrapyramidal symptom-related adverse event incidence with aripiprazole versus placebo was, overall, 20.8% vs 9.9%; the incidence of akathisia-related events was 3.3% vs 8.9%.

Conclusions: Aripiprazole was generally safe and well tolerated in subjects (6-17 years) with irritability associated with autistic disorder in these 8-week studies; clinicians should be aware of this clinical profile and strategies to manage adverse events if they occur.

Trial registration: clinicaltrials.gov Identifiers NCT00332241 and NCT00337571.

Figure 1

Reasons for Discontinuation Across the 2 Studies ^aReason for “other” was a high potassium level.

Figure 2

Median Percentage Change From Baseline to Endpoint Fasting Metabolic and Glucose Laboratory Measurements (safety sample, OC data set)^a,b

Figure 3

Incidence of Fasting Metabolic and Glucose Laboratory Measurements of Potential Clinical Relevance^a (safety sample, OC data set^b) ^aMedian values at baseline were as follows. Total cholesterol: placebo, 172.5 mg/dL; aripiprazole, 152.5 mg/dL; HDL-C: placebo, 56.0 mg/dL; aripiprazole, 50.0 mg/dL (n = 77); LDL-C: placebo, 99.0 mg/dL; aripiprazole, 85.0 mg/dL (n = 77); triglycerides: placebo, 82.0 mg/dL (n = 31); aripiprazole, 66.0 mg/dL; glucose: placebo, 89.0 mg/dL; aripiprazole, 90.0 mg/dL (n = 79). ^bFormal statistical testing was not performed. Abbreviations: HDL-C = high-density lipoprotein cholesterol, LDL-C = low-density lipoprotein cholesterol, OC = observed cases. ^aCriteria for identifying abnormalities (fasting): glucose ≥ 115 mg/dL, LDL-C ≥ 130 mg/dL, triglycerides ≥ 200 mg/dL, HDL-C < 40 mg/dL, total cholesterol ≥ 200 mg/dL. ^bSubjects who had a baseline measurement within normal limits and at least 1 on-treatment measurement. Abbreviations: HDL-C = high-density lipoprotein cholesterol, LDL-C = low-density lipoprotein cholesterol, OC = observed cases.