What is the information for Rexulti (brexpiprazole)?

Rexulti (Brexpiprazole) Drug Information

Classification and Mechanism of Action

Rexulti (brexpiprazole) is a third-generation atypical antipsychotic that functions as a serotonin-dopamine activity modulator, acting as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A and adrenergic alpha1B/alpha2C receptors. 1, 2, 3, 4

• Compared to aripiprazole, brexpiprazole demonstrates greater potency at 5-HT1A receptors and displays less intrinsic activity at D2 receptors 3
• This unique receptor profile distinguishes it from other antipsychotics in its class 4, 5

FDA-Approved Indications

Brexpiprazole received FDA approval in July 2015 for two primary indications: 2, 4

• Monotherapy for schizophrenia 2, 3, 4
• Adjunctive treatment to antidepressants for major depressive disorder (MDD) 2, 4, 5

Dosing and Administration

Schizophrenia Dosing

The recommended dose range for schizophrenia is 2-4 mg once daily, with a maximum dose of 4 mg/day. 2, 3

• Titration schedule: Start with 1 mg/day on Days 1-4, increase to 2 mg/day on Days 5-7, then increase to 4 mg/day on Day 8 based on clinical response 2, 3
• Steady-state concentrations are attained within 10-12 days of dosing 2
• Can be administered with or without food 2

Major Depressive Disorder Dosing

The recommended target dose for MDD is 2 mg once daily, with a maximum dose of 3 mg/day. 2, 6

• Titration follows a similar schedule to schizophrenia dosing 2

Special Population Adjustments

Dose reductions are required for specific populations and drug interactions: 2

• Moderate to severe hepatic impairment: Maximum 2 mg/day for MDD, 3 mg/day for schizophrenia 2
• Renal impairment (CrCl <60 mL/min): Maximum 2 mg/day for MDD, 3 mg/day for schizophrenia 2
• Strong CYP2D6 or CYP3A4 inhibitors: Administer half the recommended dosage 2
• Combined strong/moderate CYP2D6 and CYP3A4 inhibitors: Administer one-quarter of the recommended dosage 2
• CYP2D6 poor metabolizers with strong/moderate CYP3A4 inhibitors: Administer one-quarter of the recommended dosage 2
• Strong CYP3A4 inducers: Double the recommended dosage and adjust based on clinical response 2
• Elderly patients, hepatic impairment, or CYP2D6 poor metabolizers: Lower doses recommended 7, 8

Clinical Efficacy

Schizophrenia

Brexpiprazole demonstrated significant efficacy in acute schizophrenia with a number needed to treat (NNT) of 7 for response. 3, 6

• Pooled responder rates from Phase 3 trials: 46% for brexpiprazole 2-4 mg/day vs. 31% for placebo 3, 6
• In a 52-week relapse prevention study, significantly fewer patients relapsed with brexpiprazole (13.5% vs. 38.5% placebo), yielding an NNT of 4 3, 6
• Two positive 6-week Phase 3 randomized controlled trials demonstrated superiority over placebo 3, 5

Major Depressive Disorder

As adjunctive therapy for MDD, brexpiprazole showed modest efficacy with an NNT of 12. 6

• Pooled response rates: 23.2% for brexpiprazole vs. 14.5% for placebo 6
• Indicated for patients with inadequate response to 1-3 antidepressant trials 5, 6

Safety Profile and Adverse Effects

Common Adverse Effects

The most common adverse effects differ by indication: 2, 3, 6

• Schizophrenia: Weight gain (≥4% incidence, at least twice placebo rate) 2, 3
• MDD: Weight gain, somnolence, and akathisia (≥5% incidence, at least twice placebo rate) 2
• General side effects: Headache, agitation, anxiety, insomnia, dizziness, drowsiness 7, 8

Akathisia

Akathisia rates were relatively low but higher in MDD trials: 3, 6

• Schizophrenia: 5.5% vs. 4.6% placebo (NNH = 112, non-significant) 3, 6
• MDD: 8.6% with modest NNH of 15 6
• Less likely to cause extrapyramidal symptoms than first-generation antipsychotics, though risk increases at higher doses 7, 8

Metabolic Effects

Short-term metabolic effects appear modest but require monitoring: 2, 3, 6

• Approximately 10% of patients receiving 1-4 mg/day gained ≥7% body weight vs. 4% placebo (NNH = 17) 3, 6
• More outliers with ≥7% weight gain evident in 52-week open-label studies 3, 6
• Small effects on glucose and lipids observed 3, 6
• Minimal effects on prolactin 3, 6

Discontinuation Rates

Brexpiprazole demonstrated favorable tolerability: 6

• Schizophrenia: Discontinuation rates due to adverse events were lower than placebo 6
• MDD: 3% discontinued due to adverse events vs. 1% placebo (NNH = 53) 6

Warnings and Precautions

Critical safety warnings include: 2

• Cerebrovascular adverse reactions in elderly patients with dementia-related psychosis: Increased incidence of stroke and transient ischemic attack 2
• Neuroleptic malignant syndrome: Requires immediate discontinuation and close monitoring 2
• Tardive dyskinesia: Consider discontinuation if clinically appropriate 2
• Metabolic changes: Monitor for hyperglycemia/diabetes, dyslipidemia, and weight gain 2
• Pathological gambling and other compulsive behaviors: Consider dose reduction or discontinuation 2
• Leukopenia, neutropenia, agranulocytosis: Perform CBC in patients with pre-existing low WBC or history of leukopenia/neutropenia 2
• Orthostatic hypotension and syncope: Monitor heart rate and blood pressure, especially in patients with cardiovascular/cerebrovascular disease 2
• Seizures: Use cautiously in patients with seizure history or conditions lowering seizure threshold 2
• Cognitive and motor impairment: Use caution when operating machinery 2

Pregnancy and Special Populations

Pregnancy considerations: 2

• May cause extrapyramidal and/or withdrawal symptoms in neonates with third-trimester exposure 2
• Pediatric use information exists but is subject to marketing exclusivity restrictions 2

Pharmacokinetics

Key pharmacokinetic parameters: 2

• Bioavailability: 95% oral bioavailability 2
• Peak concentration: Achieved within 4 hours after administration 2
• Protein binding: >99% bound to serum albumin and α1-acid glycoprotein 2
• Metabolism: Primarily via CYP3A4 and CYP2D6 enzymes 2
• Half-life: Terminal elimination half-life of 91 hours for brexpiprazole and 86 hours for major metabolite DM-3411 2
• Excretion: <1% unchanged in urine, approximately 14% unchanged in feces 2

Clinical Context and Positioning

Brexpiprazole is classified as a third-generation antipsychotic alongside aripiprazole, cariprazine, and lumateperone. 1

• May be particularly useful when a less sedating antipsychotic is desired 7, 8
• In combination therapy scenarios, lower doses may maintain efficacy while reducing side effects 8
• Real-world evidence from Finnish cohorts suggests certain antipsychotic polypharmacy combinations (including those with brexpiprazole-related agents like aripiprazole) may reduce hospitalization risk 1