Drug Interaction Report

MONITOR: Coadministration with bosentan may decrease the plasma concentrations and therapeutic effects of sirolimus and tacrolimus. The proposed mechanism is increased clearance due to bosentan-mediated induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of sirolimus and tacrolimus. In addition, concomitant use with sirolimus or tacrolimus may increase the plasma concentrations of bosentan. The mechanism for this interaction has not been delineated.

MANAGEMENT: Given the risk of therapeutic failure and organ rejection associated with inadequate immunosuppressant drug levels, caution is advised if bosentan is used concomitantly with sirolimus or tacrolimus. Sirolimus and tacrolimus blood levels should be checked frequently, and the dosage adjusted accordingly whenever bosentan is added to or withdrawn from therapy. In addition, patients should be monitored for adverse effects associated with bosentan, such as hepatotoxicity and decreases in hemoglobin and hematocrit.

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.