Drug Interaction Report

MONITOR: Coadministration with mirabegron may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 2D6. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by mirabegron. In 12 healthy male volunteers, administration of a single 100 mg oral dose of metoprolol following pretreatment with immediate-release mirabegron 160 mg orally once daily for 5 days increased the metoprolol peak plasma concentration (Cmax) by 90% and systemic exposure (AUC) by 229% compared to administration of metoprolol alone. Likewise, in 28 healthy male and female volunteers, Cmax of desipramine increased by 79% and AUC increased by 241% when a single 50 mg oral dose of desipramine was administered after multiple-dose administration of extended-release mirabegron 100 mg once daily for 18 days.

MANAGEMENT: Caution is advised if mirabegron must be used concomitantly with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever mirabegron is added to or withdrawn from therapy.

GENERALLY AVOID: Concurrent use of ethanol and phenothiazines may result in additive CNS depression and psychomotor impairment. Also, ethanol may precipitate dystonic reactions in patients who are taking phenothiazines. The two drugs probably act on different sites in the brain, although the exact mechanism of the interaction is not known.

MANAGEMENT: Patients should be advised to avoid alcohol during phenothiazine therapy.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.

Food reduces the oral absorption and bioavailability of mirabegron. According to the product labeling, administration of a 50 mg tablet with a high-fat meal decreased mirabegron peak plasma concentration (Cmax) and systemic exposure (AUC) by 45% and 17%, respectively, whereas administration with a low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In phase 3 clinical studies demonstrating both safety and efficacy, mirabegron was administered without regards to food content and intake. Therefore, mirabegron can be taken with or without food at the recommended dosage.