Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of sirolimus and tacrolimus, both of which are primarily metabolized by the isoenzyme.

MANAGEMENT: Given the risk of organ rejection associated with inadequate immunosuppressant drug levels, caution is advised during concomitant therapy with CYP450 3A4 inducers. Sirolimus and tacrolimus blood levels should be checked frequently and the dosage adjusted accordingly whenever a CYP450 3A4 inducer is added to or withdrawn from therapy.

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

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.