DRUG INFORMATION
Class
Third Generation Antipsychotic
Neuroscience-based Nomenclature (NbN)
Pharmacological Target
Dopamine, serotonin
Mode of Action
Receptor Partial Agonist and Antagonist
Brand Name
Abilify
Monograph
DOSING AND ADMINISTRATION
Available Doses
300mg
300mg vial
400mg
400mg vial
Therapeutic Dose Range
Schizophrenia and Bipolar Disorder: 400 IM (deltoid or gluteal) once monthly
ONE injection start: On the day of treatment initiation, administer one injection of 400 mg aripiprazole LAI and continue treatment with 10 mg to 20 mg oral aripiprazole for 14 consecutive days to maintain therapeutic antipsychotic concentrations during initiation of therapy. Administer the next monthly 400 mg single injection no sooner than 26 days after the previous injection.
TWO injection start: On the day of treatment initiation, administer two separate injections of 400 mg aripiprazole LAI at separate injection sites, along with one 20 mg dose of oral aripiprazole. Administer the next monthly 400 mg single injection no sooner than 26 days after the previous injection.
If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered.
Switching from oral antipsychotics other than aripiprazole
ONE injection start (based on clinical study data): On the day of treatment initiation, administer one injection of 400 mg aripiprazole LAI and continue treatment with current oral antipsychotic for 14 days.
TWO injection start (based on modelling and simulation study data): On the day of treatment initiation, administer two separate injections of 400 mg aripiprazole LAI at separate injection sites and a single 20 mg dose of oral aripiprazole. Patients must discontinue their current oral antipsychotic upon initiation of aripiprazole LAI.
Dosage Adjustment for Known CYP2D6 poor metabolizers
ONE injection start: The starting and maintenance dose should be 300 mg.
TWO injection start: The starting dose should be 2 separate injections of 300 mg and the maintenance dose should be 300 mg.
Dosage Adjustment for Patients Known to be CYP2D6 poor metabolizers and concomitantly use a strong CYP3A4 inhibitor
ONE injection start: The starting and maintenance dose should be reduced to 200 mg.
TWO injection start is not to be used in patients who are known to be CYP2D6 poor metabolisers and concomitantly use a strong CYP3A4 inhibitor.
Time of Day
Not applicable
Effect of food
Not applicable
Effect of smoking
Smoking has no effect on aripiprazole LAI metabolism
ADVERSE EFFECTS
Adverse Reactions
Agitation
Anxiety
Insomnia
Akathisia
Warnings
Class Warning: Increased Mortality in Elderly Patients with Dementia Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo-controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Class Warning: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Smoking
A population pharmacokinetic analysis indicated that smoking, which induces CYP1A2, had no effect on the clearance of asenapine in smokers. In a crossover study in which 24 healthy male subjects (who were smokers) were administered a single 5 mg sublingual dose, concomitant smoking had no effect on the pharmacokinetics of asenapine.
PHARMACOKINETICS
Volume of distribution (Vd)
4.9 L/Kg
Protein Binding
Greater than 99% (primarily to albumin)
Elimination half-life
After multiple dose administration of 300 mg or 400 mg, the main aripiprazole terminal elimination half-life is 29.9 – 46.5 days
Time to peak (Tmax)
5 – 7 days
Metabolism
Primarily hepatic (CYP2D6 & CYP3A4)
After multiple dose administration, dehydro-aripiprazole, the active metabolite, represents about 29% of aripirazole AUC in plasma
Special populations
Renal impairment: no dosage adjustment required
Hepatic impairment: In a single-dose trial (15 mg of oral aripiprazole) in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C), the AUC of aripiprazole, compared to healthy subjects, increased 31% in mild hepatic impairment, increased 8% in moderate hepatic impairment, and decreased 20% in severe hepatic impairment, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.
MORE INFORMATION
Renal mpairment
- No dosage adjustment of aripiprazole LAI is required for patients with renal impairment.
Hepatic impairment
- No dosage adjustment of aripiprazole LAI is required for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously; use of oral aripiprazole should be considered.
DRUG-DRUG INTERACTIONS
Potential for Other Drugs to Affect Aripiprazole
- Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely.
- Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism. Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole clearance and lower blood levels. Inhibitors of CYP3A4 (e.g. ketoconazole) or CYP2D6 (e.g. quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause increased blood levels.
- Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). CYP2D6 metabolizing capacity should be considered when aripiprazole is co-administered with drugs that inhibit CYP2D6.
Potential for Aripiprazole to Affect Other Drugs
- Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo studies, 10-mg/day to 30-mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates. Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2- mediated metabolism in vitro.
- Due to its alpha-1 adrenergic receptor antagonist activity, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Drugs Having no Clinically Important Interactions With Aripiprazole
- Famotidine, Valproate, Lithium, Lamotrigine, Venlafaxine, Escitalopram, Dextromethorphan, Warfarin, Omeprazole, Lorazepam, Fluoxetine, Paroxetine, Sertraline