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U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves REXULTI (Brexpiprazole)

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FDA Approves REXULTI® (Brexpiprazole) for the Treatment of Schizophrenia and Adjunctive Treatment of Major Depressive Disorder  

On July 10, 2015, the FDA approved REXULTI (brexpiprazole) immediate-release tablets for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder (MDD).

Dosage and Administration

  • Treatment of Schizophrenia: The recommended starting dose for REXULTI in the treatment of patients with schizophrenia is 1 mg once daily (QD). The dose should be increased to 2 mg after Day 4 and may subsequently be increased to 4 mg after Day 7 based on the patient’s clinical response and tolerability. The maximum recommended dose is 4 mg QD.
  • Adjunctive Treatment of MDD: The recommended starting dose for REXULTI as adjunctive treatment for MDD is 0.5 mg/day or 1 mg QD. Dose titration to 1 mg/day and up to the target dose of 2 mg/day should occur at intervals of up to 1 week based on the patient’s clinical response and tolerability. The maximum recommended dose is 3 mg QD.
  • REXULTI can be administered with or without food.

General Pharmacokinetics and Pharmacodynamics of Brexpiprazole

The mechanism of action of brexpiprazole is unknown.  However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.  

  • Dose Proportionality: Brexpiprazole Cmax and AUC are approximately dose proportional after oral administration in the therapeutic dosage range.
  • Accumulation: About 4-fold at steady state (time to steady state 10 to 12 days)
  • Absolute bioavailability (tablets): 95% (Tmax within 4 hours).
  • Plasma protein binding: Greater than 99%.
  • Terminal half-life (mean): 91 hours at steady state.
  • Metabolism: Extensive. Predominately by CYP3A and CYP2D6.
  • Excretion: About 14% and less than 1% of the dose is excreted as unchanged parent drug in the feces and urine, respectively.
  • Exposure-safety: At a dose 3 times the maximum recommended dose, REXULTI does not prolong the QT interval to any clinically relevant extent.

Drug Interaction Potential

  • An approximately 2-fold increase in brexpiprazole exposure (AUC) was observed following coadministration of a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole) with REXULTI. Decrease the REXULTI dosage by half if coadministration is required.  
  • An approximately 2-fold increase in brexpiprazole exposure was observed following coadministration of a strong CYP2D6 inhibitor (e.g., quinidine, fluoxetine, paroxetine) with REXULTI. Decrease the REXULTI dosage by half if coadministration is required for the treatment of schizophrenia. A REXULTI dosage reduction is not required with coadministration in patients with MDD because this effect was factored into the general dosing recommendations (i.e., coadministration was permitted without dosage adjustment in the clinical trials supporting this indication).
  • An approximately 5.1-fold increase in steady-state brexpiprazole exposure is expected when extensive CYP2D6 metabolizers are coadministered REXULTI with both strong CYP2D6 and CYP3A4 inhibitors. Similarly, an approximately 4.8-fold increase in steady-state brexpiprazole exposure is expected when poor CYP2D6 metabolizers are coadministered REXULTI with strong CYP3A4 inhibitors. Decrease the REXULTI dosage by 75% if coadministration is required in patients with these polymorphisms.
  • An approximately 73% decrease in brexpiprazole exposure was observed following coadministration with a strong CYP3A4 inducer (e.g., rifampin, carbamazepine, phenytoin) with REXULTI. Double the REXULTI dosage one to two weeks following strong CYP3A4 inducer coadministration.

Use in Specific Populations

  • A 26%, 73%, and 4% increase in brexpiprazole exposure was observed in subjects with mild, moderate, and severe hepatic impairment compared to subjects with normal hepatic function, respectively. The maximum recommended REXULTI dosage for patients with moderate to severe hepatic impairment (Child-Pugh score ≥ 7) is 2 mg QD for patients with MDD and 3 mg QD for patients with schizophrenia.
  • A 7%, 71%, and 72% increase in brexpiprazole exposure was observed or predicted in subjects or patients with mild, moderate, and severe renal impairment compared to subjects with normal renal function. The maximum recommended REXULTI dosage for patients with moderate or severe renal impairment (i.e., creatinine clearance less than 60 mL /minute) is 2 mg QD for patients with MDD and 3 mg QD for patients with schizophrenia.
  • Half of the usual dosage is recommended for patients with known CYP2D6 poor metabolizer status.

Safety and Efficacy

The efficacy and safety of REXULTI in schizophrenia was demonstrated in two 6-week controlled studies in adult patients at doses of 2 to 4 mg administered orally once daily. The primary efficacy endpoint in schizophrenia trials is change in PANSS Total Score from baseline to week 6. The efficacy and safety of REXULTI as an adjunctive therapy for MDD was evaluated in two 6-week controlled studies in adult patients at doses of 1 to 3 mg administered once daily, with one trial showing statistical superiority of REXULTI over placebo. The primary efficacy endpoint in MDD trials is the mean change in MADRS Total Score from baseline to week 6. Safety profiles were similar in MDD and schizophrenia patients. The most common treatment emergent adverse events were increased weight, headache, akathisia, somnolence, fatigue, anxiety, and increased appetite.


Full prescribing information is available at http://go.usa.gov/3fHVN.

The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (http://go.usa.gov/3fHpq).

We always welcome your thoughts regarding the format, content, and utility of information you receive via this Burst email initiative. Comments may be sent via email to ocp@fda.hhs.gov.

This burst was prepared by the Clinical Pharmacology Review Team including Huixia Zhang, PhD, Reviewer, and Hao Zhu, PhD, Team Leader, Division of Clinical Pharmacology I, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.


FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov


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