Patients randomized to continue depot aripiprazole took longer to relapse or worsening of symptoms compared with the placebo group. Of 403 patients, 10% taking an active drug and 39.6% taking placebo relapsed within 360 days of randomization. This difference was statistically significant (P 1
Tolerability
One possible problem with any long-acting medication is increased duration of adverse effects (AEs), if they develop. Therefore, assessment of safety and tolerability is more important in depot formulations than in oral drugs. During the clinical trial, depot aripiprazole was well tolerated.6
During clinical trials, the most common AEs—insomnia (>5%), anxiety, and tremors—were mild to moderate and occurred within the first 4 weeks. Discontinuation of the medication because of AEs was low, and pain at the injection site was minimal.6 There were 2 deaths during the trial, which were unrelated to depot aripiprazole.6
Aripiprazole’s activity on the D2 receptor can cause extrapyramidal AEs. In head-to-head trials, patients taking aripiprazole had fewer extrapyramidal AEs than those taking risperidone or ziprasidone, but more than patients receiving olanzapine.7 Its moderate antagonism on α-adrenergic and histamine 1 (H1) receptors translates to low orthostatic hypotension, H1-mediated weight gain, and sedation. In clinical trials, weight gain and metabolic changes were comparable with placebo. In head-to-head trials, aripiprazole caused less weight gain and a higher incidence of increased cholesterol than olanzapine and risperidone, and less increase in blood glucose than olanzapine, but more than risperidone.8 Muscarinic 1-mediated cognitive impairment, dry mouth, constipation, urinary retention, and increased intraocular pressure were low.8 See Table 3 for aripiprazole's receptor binding profile.
Table 3
Aripiprazole’s receptor binding profile
| Affinity | Ki (nM)a | Effects associated with activity on the receptor | |
|---|---|---|---|
| D2 | High | 0.34 | Partial agonist |
| D3 | High | 0.8 | Partial agonist |
| 5-HT1A | High | 1.7 | Partial agonist |
| 5-HT2A | High | 3.4 | Antagonist |
| 5-HT2C | Moderate | 15 | Partial agonist |
| 5-HT7 | Moderate | 39 | Antagonist |
| D4 | Moderate | 44 | Partial agonist |
| α1-adrenergic | Moderate | 57 | Antagonist |
| H1 | Moderate | 61 | Antagonist |
| M1 | No appreciable activity | >1,000 | No appreciable activity |
| aKi dissociation constant: lower numbers indicate higher affinity of the compound for the receptor H1: histamine 1; M1: muscarinic 1 Source: References 1,6 | |||
Unique clinical issues
Clinical features for depot aripiprazole can be partially deduced based on data on oral aripiprazole. Advantages over other depot SGAs might include aripiprazole’s more favorable weight and metabolic profile.
Contraindications
Depot aripiprazole is contraindicated in patients with known sensitivity to aripiprazole or other components of the formulation. Because of pharmacokinetic drug-drug interactions, using depot aripiprazole should be avoided in patients taking strong CYP3A4 inducers (eg, rifampin and carbamazepine). Dose adjustment is recommended in patients who are taking moderate CYP2D6 and 3A4 inhibitors, such as paroxetine, fluoxetine, ketoconazole, or erythromycin.1 A “black-box” warning of increased mortality in older patients with dementia-related psychosis applies for depot aripiprazole as well as for other atypical antipsychotics.1
Depot aripiprazole is pregnancy category C and should be used in pregnant or breastfeeding mothers only when benefits outweigh the risks. Use of depot aripiprazole in geriatric and pediatric populations has not been studied; however, patients age ≥65 who received oral aripiprazole, 15 mg/d, showed decreased clearance by 20%.1
Dosing
Depot aripiprazole is available as a lyophilized powder that needs to be reconstituted in sterile water. The drug can be stored at room temperature. The kit includes two 21-gauge needles, a 1.5-inch needle for non-obese patients and a 2-inch needle for obese patients. Depot aripiprazole should be given to patients who demonstrate tolerability to oral aripiprazole. The starting and maintenance dose of depot aripiprazole is 400 mg injected into the gluteal muscle, once a month. If a patient develops an AE, decrease the monthly dose to 300 mg. Rotate the injection site between gluteal muscles to reduce AEs from injection.
Because of the potential for significant pharmacokinetic drug-drug interactions, dose adjustment is recommended for patients who are CYP2D6 poor metabolizers and those taking certain other medications (Table 4).1 See Table 4 for the recommended dosage adjustment in the case of missed doses.
Table 4
Adjusting depot aripiprazole after missed doses
| Doses missed since last injection | ||||
|---|---|---|---|---|
| Second or third dose | Fourth or subsequent dose | |||
| >4 weeks and | >5 weeks | >4 weeks and | >6 weeks | |
| Oral aripiprazole | Administer for 14 days | Administer for 14 days | ||
| Depot aripiprazole | Administer as soon as possible | Administer next injection | Administer as soon as possible | Administer next injection |
| Source: Reference 1 | ||||
After depot aripiprazole is injected into the gluteal muscle, the patient receives 10 to 20 mg/d of oral aripiprazole for 14 consecutive days to avoid a drop in plasma concentrations into subtherapeutic levels.
Related Resource
- Abilify Maintena [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Company; 2013.
Drug Brand Names