Brexpiprazole

Class

Third Generation Antipsychotic

Neuroscience-based Nomenclature (NbN)

Pharmacological Target

Dopamine, serotonin

Mode of Action

Receptor Partial Agonist and Antagonist

Brand Name

Rexulti

Monograph

Monograph Link

Adverse Effects

  Weight gain not uncommon
  Sedation unusual
  Sexual dysfunction unusual
  Akathisia

Serious/Life-Threatening Adverse Effects

  Increased stroke and mortality rates vs. placebo have been observed in elderly patients with dementia treated with atypical antipsychotics.

Other

  In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities, compared to placebo-treated subjects.
  Metabolic parameters should be regularly monitored in all patients
  As with antipsychotics, there is a risk for extrapyramidal side effects and tardive dyskinesia

Smoking

Bioavailability

Oral: 95%

Volume of distribution (Vd)

1.56 L/Kg

Protein Binding

Greater than 99% (primarily to serum albumin and alpha1-acid glycoprotein)

Elimination half-life (Oral)

Brexpiprazole: 91 hours
Major metabolite not considered to be active

Time to peak (Tmax)

Oral: 4 hours

Metabolism

Primarily hepatic (CYP2D6 & CYP3A4)

Excretion

Urine: 25% (<1% unchanged)
Feces: 46% (approx. 14% unchanged)

Special populations

  Moderate, Severe or End-Stage Renal Impairment (CrCl < 60 mL/min): Maximum recommended dosage is 2 mg once daily for patients with Major Depressive Disorder and 3 mg once daily for patients with schizophrenia.
  Moderate to Severe Hepatic Impairment (Child-Pugh score greater or equal to 7): Maximum recommended dosage is 2 mg once daily for patients with Major Depressive Disorder and 3 mg once daily for patients with schizophrenia.

Special Populations

  Renal impairment (<60 mL/min): maximum recommended dosage of 2 mg/day for patients with MDD, and 3 mg/day for patients with schizophrenia.
  Hepatic impairment (Child-Pugh score ≥7): maximum recommended dosage of 2 mg/day for patients with MDD, and 3 mg/day for patients with schizophrenia.
  Cardiac impairment: may be used in these patients
  Elderly: Increased stroke and mortality rates vs. placebo have been observed in elderly patients with dementia treated with atypical antipsychotics. Brexpiprazole should be used with caution in this population.
  Children and adolescents: safety and efficacy in children and adolescents with major depressive disorder has not been evaluated- use with caution in this population after careful evaluation of risks Vs benefits and close monitoring

Other Potential Benefits

  Antipsychotic
  Augmentation of antidepressant effect in major depressive disorder

Strong CYP3A4 Inhibitors

  Concomitant use of brexpiprazole with strong CYP3A4 inhibitors increases the exposure of brexpiprazole compared to the use of brexpiprazole alone.
  Intervention: Reduce the dosage of brexpiprazole.
  Examples: Itraconazole, clarithromycin, ketoconazole

Strong CYP2D6 Inhibitors

  Concomitant use of brexpiprazole with strong CYP2D6 inhibitors increases the exposure of brexpiprazole compared to the use of brexpiprazole alone.
  Intervention: Reduce the dosage of brexpiprazole.
  Examples: Paroxetine, fluoxetine, quinidine

Both CYP3A4 Inhibitors and CYP2D6 Inhibitors

  Concomitant use of brexpiprazole with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, increased the exposure of brexpiprazole compared to the use of brexpiprazole alone. * Intervention: Reduce the dosage of brexpiprazole.
  Examples: 1) Itraconazole + quinidine; 2) fluconazole + paroxetine; 3) itraconazole + duloxetine; 4) fluconazole + duloxetine

Strong CYP3A4 Inducers

  Concomitant use of brexpiprazole with strong CYP3A4 inducers decreases the exposure of brexpiprazole compared to the use of brexpiprazole alone. * Intervention: Increase the dosage of brexpiprazole. * Examples: Rifampin, St. John’s wort

Drugs Having no Clinically Important Interactions With Brexpiprazole

  Based on pharmacokinetic studies, no dosage adjustment of brexpiprazole is required when administered concomitantly with CYP2B6 inhibitors (e.g., ticlopidine) or gastric pH modifiers (e.g., omeprazole). Additionally, no dosage adjustment for substrates of CYP2D6 (e.g., dextromethorphan), CYP3A4 (e.g., lovastatin), CYP2B6 (e.g., bupropion), BCRP (e.g., rosuvastatin), or P-gp (e.g., fexofenadine) is required when administered concomitantly with brexpiprazole.

Dosage Adjustment Due to Drug Interactions

• CYP isozymes: Dosage adjustments are recommended patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table below). If the co-administered drug is discontinued, adjust the brexpiprazole dosage to its original level. If the co-administered CYP3A4 inducer is discontinued, reduce the brexpiprazole dosage to the original level over 1 to 2 weeks.