Aripiprazole (oral)

Class

Third Generation Antipsychotic

Neuroscience-based Nomenclature (NbN)

Pharmacological Target

Dopamine, serotonin

Mode of Action

Receptor Partial Agonist and Antagonist

Brand Name

Abilify

Monograph

Monograph Link

Adverse Effects

  Weight gain not unusual
  Sedation unusual
  Sexual dysfunction unusual
  Akathisia
  Restlessness

Serious/Life-Threatening Adverse Effects

  Increased mortality rate vs. placebo when used in elderly patients with dementia
  Rare cases of venous thromboembolism, including fatal pulmonary embolism, have been reported
  Rare cases of neuroleptic malignant syndrome have been reported

Other

  Increased mortality rates vs. placebo have been observed in elderly patients with dementia. Aripiprazole should be used with caution in this population.
  Metabolic parameters should be regularly monitored in all patients
  As with antipsychotics, there is a risk for extrapyramidal side effects and tardive dyskinesia

Bioavailability

Oral: 87%

Volume of distribution (Vd)

4.9 L/Kg

Protein Binding

Greater than 99% (primarily to albumin)

Elimination half-life (Oral)

   Aripiprazole: 75 hours (146 hours for CYP2D6 poor metabolizers)

   Dehydro-aripiprazole (active metabolite): 94 hours

Time to peak (Tmax)

   Oral: 3-5 hours
  With high fat meal: Aripiprazole: delayed by 3 hours; dehydro-aripiprazole (active metabolite): Delayed by 12 hours

Metabolism

Primarily hepatic (CYP2D6 & CYP3A4)

Excretion

  Urine: 25% (<1% unchanged)

  Feces: 55% (approx. 18% unchanged)

Special populations

  Renal impairment: no dosage adjustment required
  Hepatic impairment: no dosage adjustment required

Special Populations

  Renal impairment: no dosage adjustment required
  Hepatic impairment: no dosage adjustment required
  Cardiac impairment: in clinical trials with aripiprazole involving patients with schizophrenia or bipolar mania, the incidence of QT prolongation was comparable to placebo. As with other antipsychotics, caution should be exercised when aripiprazole is prescribed in patients with a history of cardiac arrhythmias, in patients with congenital or family history of long QT syndrome, and in concomitant use with drugs known to prolong the QT interval.
  Elderly: no significant differences in exposure based on age, although aripiprazole should be used with caution in elderly patients with dementia
  Children and adolescents: Has an indication for psychotic disorders in children in Canada and US; as with other antidepressants and antidepressant augmentation strategies, careful evaluation of risks vs. benefits and close monitoring for changes in behaviour and/or suicidality are recommended

Other Potential Benefits

  Antipsychotic
  Augmentation of antidepressant effect in major depressive disorder

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