Aripiprazole Depot: Recommendation for Market Authorization in Europe

On September 19th, 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a recommendation for market authorization of aripiprazole depot to the EU Commission. Therefore, approval is to be expected  later this year. The FDA approved the depot preparation of aripiprazole as Abilify Maintena® as early as on February 28th, 2013, in the U.S. it is already available. In Europe, it is not realistic to expect market entry before mid-2014.The depot antipsychotic medication is injected once a month. There are doses of 300 mg and 400 mg (as a dry powder which is prepared with sterile water prior to injection) available. The standard recommended dosage is 400 mg once a month, if necessary, the dose may be reduced to 300 mg/month. After the first injection, it is recommended to administer additional oral aripiprazole (10-20 mg daily) for 14 days, since the absorption of the substance from the depot is very slow. Maximum plasma concentrations are measured 5-7 days after injection. The terminal elimination half-life is 29.9 days after administration of the 300 mg dose and 46.5 days after administration of the 400 mg dose. A steady-state, therefore, is only achieved after the fourth injection.

As with the administration of oral aripiprazole, drug interactions have to be considered if other medications are co-administered. Since aripiprazole is metabolized by CYP2D6 and CYP3A4, the dose has to be reduced to 300 mg/month, if respective enzyme inhibitors are administered (CYP2D6: e.g. paroxetine, fluoxetine; CYP3A4: e.g. ketoconazole). The same is true for CYP2D6 poor metabolizers. When a poor metabolizer is treated with an enzyme inhibitor, the dose may have to be reduced to 200 mg/month. Monitoring of plasma concentrations may help in decision making. Combination with CYP3A4 inducers such as carbamazepine should be avoided as adequate plasma concentrations are usually not obtained with such combination.

The efficacy of aripiprazole depot was shown in a study over 52 weeks (Kane et al., J Clin Psychiatry 2012, 73: 617-624). 710 patients with schizophrenia, for whom chronic treatment was considered necessary, were initially stabilized on oral aripiprazole (10-30 mg/day) for a duration of 4-12 weeks. Patients who were stable for at least four weeks under this treatment (n = 576 ) were then included in a twelve-week, open depot treatment phase in which they received an injection of 400 mg of aripiprazole depot every four weeks. A dose reduction to 300 mg/4 weeks was possible. Patients who were still stable (n = 403) were then randomized in a 2:1 ratio to the depot preparation or placebo. The primary endpoint was the time to exacerbation of psychosis or impending relapse over an observation period of 52 weeks. The study was terminated prematurely because an interim analysis revealed the superiority of treatment with the depot preparation (p < 0.0001). The risk of relapse on placebo was approximately five times higher than with aripiprazole (95 % confidence interval: 3.15 to 8.02). In the final analysis, the rate of impending relapse in the aripiprazole group was significantly lower (10.0%, n = 27/269) than in the placebo group (39.6%, n = 53/134). The most common adverse events of active treatment were restlessness, insomnia, tremor, headache, and pain at the injection site.

The tolerability of aripiprazole depot should be ensured by prior oral administration of the compound. However, Potkin et al. (Curr Med Res Opin 2013, 29: 1241-1251) in a group of 60 patients with schizophrenia showed that it is also possible to administer aripiprazole depot to patients who were stabilized on other oral antipsychotics. Personally, I would still advise against this, because if a patient experiences the typical adverse effects of aripiprazole (especially restlessness and sleep disturbance), they are likely to sustain longer after the depot injection than after discontinuation of the oral medication.

Aripiprazole depot is co-marketed by the Japanese company Otsuka and the Danish company Lundbeck.

This post is also available in: German

Leave a Reply

Your email address will not be published. Required fields are marked *