Intramuscular injectable formulation of atypical antipsychotic approved for the treatment of agitation associated with schizophrenia or bipolar disorder, manic or mixed
Aripiprazole injection for intramuscular use
BRISTOL-MYERS SQUIBB/OTSUKAintramuscular injectable formulation of atypical antipsychotic approved for the treatment of agitation associated with schizophrenia or bipolar disorder, manic or mixed
This agent's precise mechanism of action is unknown, but it has been proposed that the efficacy of aripiprazole is mediated through partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Aripiprazole oral solution, tablets, and orally disintegrating tablets were approved previously for the treatment of schizophrenia and acute manic and mixed episodes associated with bipolar disorder. This new formulation was approved on September 20, 2006, for the treatment of agitation associated with schizophrenia or bipolar disease, manic or mixed.
Efficacy. The efficacy of intramuscular (IM) aripiprazole for injection was evaluated in 3 short-term (24-hour), placebo-controlled trials in agitated inpatients diagnosed with schizophrenia or bipolar I disorder (manic or mixed episodes, with or without psychotic features). Each trial included a single active comparator treatment arm of either haloperidol injection (for schizophrenia) or lorazepam injection (for bipolar disorder). Eligible patients had to be judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatment with IM medication; patients also had to be exhibiting a level of agitation meeting a threshold total score of ≥15 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (poor impulse control, tension, hostility, uncooperativeness, and excitement), with ≥2 individual item scores ≥4 on a 7-point scoring scale (1, absent; 4, moderate; 7, extreme). Patients could receive ≤3 injections during the 24-hour treatment period, but the second injection could not be administered until after the initial 2-hour period when the primary efficacy outcome was measured. The primary efficacy measure was the change from baseline in the PANSS Excited Component score at 2 hours after injection. The Clinical Global Impression of Improvement scale was a key secondary measure. Across all studies, the mean baseline PANSS Excited Component score was 19 (range, 15–34; maximum possible score, 35). In the first trial, which included predominantly patients with schizophrenia (n=350), aripiprazole doses of 1, 5.25, 9.75, and 15 mg were evaluated; the 5.25-, 9.75-, and 15-mg doses were statistically superior to placebo for both end points. The second trial, also including predominantly patients with schizophrenia (n=445), evaluated a 9.75-mg dose of aripiprazole; this dose was statistically superior to placebo for both end points. The third study, which included patients with bipolar I disorder (n=291), evaluated 9.75- and 15-mg doses of aripiprazole; both doses were statistically superior to placebo on the PANSS Excited Component.
Dosing. The recommended dose of aripiprazole IM injection is 9.75 mg. A dose of 5.25 mg may be used if clinical factors warrant a lower dose. If a second dose is needed, cumulative doses ≤30 mg/d may be given. However, the efficacy of repeated aripiprazole injections and the safety of total daily doses >30 mg or injections administered more frequently than every 2 hours have not been systematically evaluated in controlled clinical trials. If ongoing aripiprazole therapy is clinically indicated, aripiprazole injection should be replaced with oral aripiprazole therapy as soon as possible.