Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2C8 and/or 3A4 may increase the plasma concentrations of enzalutamide, which is primarily metabolized by CYP450 2C8 to its pharmacologically active metabolite, N-desmethyl enzalutamide, and to a lesser extent by CYP450 3A4. In healthy volunteers, administration of a single 160 mg oral dose of enzalutamide following multiple oral doses of the potent CYP450 2C8 inhibitor gemfibrozil resulted in a 2.2-fold increase in the composite systemic exposure (AUC) of enzalutamide plus N-desmethyl enzalutamide, with minimal effect on the peak plasma concentration (Cmax). Administration following multiple oral doses of the potent CYP450 3A4 inhibitor itraconazole resulted in a 1.3-fold increase in the composite AUC of enzalutamide plus N-desmethyl enzalutamide, with no effect on the Cmax.

MANAGEMENT: Pharmacologic response to enzalutamide should be monitored more closely whenever a CYP450 2C8 and/or 3A4 inhibitor is added to or withdrawn from therapy, and the dosage adjusted as necessary. Patients should be advised to contact their physician if they experience increased side effects such as seizure, asthenia, fatigue, diarrhea, arthralgia, musculoskeletal pain, paresthesia, hot flushes, peripheral edema, headache, dizziness, insomnia, hematuria, anxiety, and hypertension.