Drug Interaction Report

ADJUST DOSE: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of exemestane, which is primarily metabolized by the isoenzyme. In 10 healthy postmenopausal volunteers, administration of exemestane (25 mg single dose) following pretreatment with the potent inducer rifampin (600 mg daily for 14 days) resulted in a 41% decrease in exemestane peak plasma concentration (Cmax) and a 54% decrease in exemestane systemic exposure (AUC).

MANAGEMENT: The manufacturer recommends increasing the dosage of exemestane to 50 mg once daily when used with potent CYP450 3A4 inducers such as carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, primidone (partially metabolized to phenobarbital), rifamycins, and St. John's wort. However, it has also been suggested that suppression of estrogen levels is not affected by the interaction, thus dosage adjustment of exemestane is not required. The extent to which other, less potent CYP450 3A4 inducers may interact with exemestane is unknown. Caution is advised if they are used with exemestane.

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.