Drug Interactions between fluconazole and sirolimus

MONITOR CLOSELY: Coadministration with fluconazole may significantly increase the oral bioavailability of sirolimus. The proposed mechanism is fluconazole inhibition of sirolimus metabolism via intestinal CYP450 3A4. There have been case reports of markedly increased sirolimus blood concentrations following the addition of fluconazole. In one patient with diabetic nephropathy receiving sirolimus following a kidney transplant, trough sirolimus blood concentration increased from approximately 10 ng/mL to 22.8 ng/mL four days after starting fluconazole 200 mg/day for esophageal candidiasis. This increase occurred despite a dosage reduction of sirolimus from 4 mg/day to 3 mg/day at the time fluconazole was initiated in anticipation of the interaction. Sirolimus dosage was further reduced to 2 mg/day on the fifth day of fluconazole therapy, whereupon the trough concentration continued to rise and reached a peak of 35.5 ng/mL before falling to 26.8 ng/mL on day 8 of fluconazole therapy. However, the patient died shortly thereafter from multi-organ failure following development of cardiorespiratory arrest associated with hyperkalemia. In another renal transplant patient receiving sirolimus 2 mg/day, sirolimus predose blood levels increased from 10.26 ng/mL to 48.44 ng/mL after approximately 3 weeks of fluconazole therapy (100 mg/day IV for 10 days, followed by 200 mg/day orally). Fluconazole dosage was reduced to 100 mg/day and sirolimus dosage to 1.5 mg/day, which led to a predose sirolimus blood concentration of 21.26 ng/mL eight days later.

MANAGEMENT: Extreme caution is advised if sirolimus is prescribed with fluconazole. Sirolimus blood levels should be closely monitored and the dosage adjusted accordingly, particularly following initiation, discontinuation, or change of dosage of fluconazole in patients who are stabilized on their antirejection regimen. Patients should be monitored for the development of sirolimus toxicity such as fluid retention, hypertension, hyperlipidemia, renal impairment, proteinuria, interstitial lung disease, infections, and various types of malignancies including lymphoma and skin cancer.