Drug Interaction Report

GENERALLY AVOID: Coadministration with inducers of CYP450 2C8 and/or 3A4 may decrease 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. However, the interaction has not been evaluated in vivo.

MANAGEMENT: Concomitant use of enzalutamide with potent CYP450 2C8 and/or 3A4 inducers such as carbamazepine, lumacaftor, mitotane, phenobarbital, phenytoin, primidone (partially metabolized to phenobarbital), rifamycins, and St. John's wort should generally be avoided. Moderate inducers such as bosentan, efavirenz, etravirine, modafinil, nafcillin, and nevirapine should also be avoided if possible. The extent to which other, less potent CYP450 3A4 inducers may interact with enzalutamide is unknown. Caution is advised if they are used with enzalutamide.

ADJUST DOSING INTERVAL: Food may enhance the oral bioavailability of bexarotene. In one clinical study, bexarotene peak plasma concentration (Cmax) and systemic exposure (AUC) resulting from a 75 to 300 mg dose were 35% and 48% higher, respectively, when administered after a fat-containing meal relative to a glucose solution. In all clinical trials, patients were instructed to take bexarotene with or immediately following a meal.

Coadministration with inhibitors of CYP450 3A4 such as grapefruit juice may theoretically increase the plasma concentrations of bexarotene. In vitro studies suggest that bexarotene is metabolized by CYP450 3A4. However, concomitant administration with multiple doses of ketoconazole, a potent CYP450 3A4 inhibitor, did not alter bexarotene plasma concentrations, which would imply that bexarotene elimination is not substantially dependent on CYP450 3A4 metabolism in vivo.

MANAGEMENT: Because safety and efficacy data are based upon administration with food, bexarotene should be administered once daily with a meal. Patients may want to avoid consuming large amounts of grapefruit or grapefruit juice.