Drug Interaction Report

ADDITIONAL CONTRACEPTION RECOMMENDED: There are no data concerning the potential effect of bexarotene on hormonal contraceptives. Presumably, coadministration with bexarotene may decrease the efficacy of contraceptives containing low-dose estrogens and progestins due to its induction of CYP450 3A4, the isoenzyme that is primarily responsible for the metabolic clearance of sex hormones.

MANAGEMENT: Women using low-dose hormonal contraceptives should be advised of the risk of breakthrough bleeding and unintended pregnancy during concomitant therapy with bexarotene. Because use of bexarotene is likely associated with major birth defects, it is particularly important that patients not become pregnant during treatment. Therefore, hormonal contraceptives should not be used as the sole method of birth control in women of childbearing potential treated with bexarotene. Product labeling recommends that two reliable forms of contraception, one non-hormonal, be used simultaneously during bexarotene therapy and for at least one month following discontinuation of therapy. Input from a gynecologist or similar expert on adequate contraception, including emergency contraception, should be sought as needed. Intrauterine systems are unlikely to be significantly affected because of their local action.

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.