Drug Interactions between Astagraf XL and rifabutin

MONITOR CLOSELY: Coadministration with potent inducers of CYP450 3A4 and/or P-glycoprotein may significantly decrease the plasma concentrations and pharmacologic effects of tacrolimus. The mechanism probably involves reduced absorption as well as accelerated clearance of tacrolimus due to induction of both intestinal P-glycoprotein drug efflux transporter and hepatic/intestinal CYP450 3A4 isoenzymes. In a study of six healthy volunteers, a potent inducer of CYP450 3A4 and P-gp, rifampin (600 mg daily for 18 days) increased the average clearance of tacrolimus (0.1 mg/kg orally and 0.025 mg/kg/4 hours intravenously) by 47% and decreased its oral bioavailability from 14% to 7%. There have been case reports of transplant patients whose tacrolimus blood levels dropped significantly or became subtherapeutic as early as two days following the initiation of rifampin, subsequently requiring discontinuation of rifampin or substantial increases (up to ten-fold over several months) in tacrolimus dosage.

MANAGEMENT: Given the risk of organ rejection associated with inadequate immunosuppressant levels, caution is advised if tacrolimus must be coadministered with potent inducers of CYP450 3A4 and/or P-gp. Tacrolimus blood levels should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of inducer therapy in patients who are stabilized on their anti-rejection regimen.