Medications That Interfere with Rexulti (Brexpiprazole)
Direct Answer
Rexulti requires dose reduction when combined with strong CYP3A4 inhibitors (like ketoconazole, itraconazole, clarithromycin) or strong CYP2D6 inhibitors (like paroxetine, fluoxetine, quinidine), and requires dose increase when combined with strong CYP3A4 inducers (like rifampin, carbamazepine, phenytoin). 1
Critical Drug Interactions Requiring Dose Adjustment
Strong CYP3A4 Inhibitors
- Reduce brexpiprazole dosage by 50% when combined with strong CYP3A4 inhibitors including ketoconazole, itraconazole, clarithromycin, ritonavir, or nefazodone 1
- These medications increase brexpiprazole exposure significantly by blocking its primary metabolic pathway 1, 2
Strong CYP2D6 Inhibitors
- Reduce brexpiprazole dosage by 50% when combined with strong CYP2D6 inhibitors such as paroxetine, fluoxetine, or quinidine 1
- Exception: In major depressive disorder trials, doses were not adjusted for CYP2D6 inhibitors, so standard MDD dosing already accounts for this interaction 1
Combined Moderate and Strong Inhibitors
- Reduce brexpiprazole dosage by 75% (to one-quarter of usual dose) when combining:
- Strong CYP3A4 inhibitor + strong CYP2D6 inhibitor, OR
- Moderate CYP3A4 inhibitor + strong CYP2D6 inhibitor, OR
- Strong CYP3A4 inhibitor + moderate CYP2D6 inhibitor, OR
- Moderate CYP3A4 inhibitor + moderate CYP2D6 inhibitor 1
- This combination dramatically increases brexpiprazole exposure and requires the most aggressive dose reduction 1
Strong CYP3A4 Inducers
- Increase brexpiprazole dosage when combined with strong CYP3A4 inducers including rifampin, carbamazepine, phenytoin, phenobarbital, or St. John's wort 1, 3
- These medications decrease brexpiprazole exposure by accelerating its metabolism 1
- St. John's wort should be avoided entirely as it decreases drug levels unpredictably 3
Medications With No Clinically Significant Interactions
- No dose adjustment needed for CYP2B6 inhibitors (ticlopidine), gastric pH modifiers (omeprazole, antacids), or when brexpiprazole is combined with substrates of CYP2D6, CYP3A4, CYP2B6, BCRP, or P-gp 1
- Brexpiprazole does not significantly alter the pharmacokinetics of dextromethorphan, lovastatin, bupropion, rosuvastatin, or fexofenadine 1, 4
Special Considerations for Serotonergic Medications
- Monitor for serotonin syndrome when combining brexpiprazole with other serotonergic agents, particularly during the first 24-48 hours after dosage changes 5
- Watch for mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity as warning signs 5
Clinical Pitfalls to Avoid
- Do not overlook renal or hepatic impairment: Dose adjustments may be required beyond drug interactions alone 2
- Avoid assuming all antidepressants require adjustment: Only strong CYP2D6 inhibitors (paroxetine, fluoxetine) require dose reduction; other antidepressants typically do not 1
- Remember the schizophrenia vs. MDD distinction: CYP2D6 inhibitor adjustments are already factored into MDD dosing recommendations but not schizophrenia dosing 1
- Account for multiple interacting medications: When patients take more than one inhibitor, use the combined inhibitor dosing guidance rather than adjusting for each separately 1
Mechanistic Understanding
- Brexpiprazole is metabolized primarily by CYP3A4 and CYP2D6 enzymes 1, 2, 4
- It exhibits weak inhibitory effects on most CYP enzymes (IC50 >13 μmol/L for CYP2C9, CYP2C19, CYP2D6, CYP3A4) and moderate inhibition of CYP2B6, but the systemic concentrations are too low to cause clinically relevant interactions 4
- Brexpiprazole does not induce CYP1A2, CYP2B6, or CYP3A4 expression 4
- Effects on P-gp and BCRP transporters are not clinically significant despite in vitro activity 4