Drug interactions between Diflucan and tacrolimus

MONITOR CLOSELY: Coadministration with azole antifungal agents may significantly increase the blood concentrations of sirolimus and tacrolimus. The proposed mechanism is azole inhibition of CYP450 3A4 metabolism and intestinal P-glycoprotein drug efflux, resulting in enhanced bioavailability and reduced clearance of the immunosuppressants. In one study, ketoconazole (200 mg orally at bedtime for 12 days) increased the oral bioavailability of tacrolimus from 14% to 30% in six healthy volunteers. In another study, median tacrolimus trough plasma concentration increased 3.1-fold and 1.4-fold in eight transplant patients treated with oral fluconazole 200 mg/day and twelve who were treated with 100 mg/day, respectively. These increases were seen on day 1 after fluconazole administration and were associated with acute renal dysfunction and mental status changes in several patients. A median reduction of 56% in the tacrolimus dosage was subsequently required. Similarly, 17 post-transplant patients treated with clotrimazole troches (10 mg three times a day) had significantly higher blood tacrolimus trough levels by the third day compared to 18 patients treated with nystatin (5 mL four times a day). Levels were still higher in the clotrimazole group by day 7, although mean tacrolimus doses were significantly lower than in the nystatin group. Various case reports have also implicated itraconazole in the interaction, usually resulting in a 2- to 3-fold increase in tacrolimus concentrations. A retrospective study of transplant patients from one hospital found that, in seven patients on tacrolimus with itraconazole (750 mg +/- 300 mg/day), the mean tacrolimus dosage was three times lower and the mean trough blood concentration to dose ratio six times higher compared to seven patients not on itraconazole. In general, the interaction appears to occur primarily in the gut. In one study, high-dose fluconazole (400 mg/day) increased the mean steady-state concentrations of intravenously administered tacrolimus in 21 allogeneic bone marrow transplant patients by just 16%. However, the potential for an interaction following parenteral administration of these drugs has not been ruled out.

MANAGEMENT: Caution is advised if sirolimus or tacrolimus is given with an azole antifungal agent. Immunosuppressant blood levels should be closely monitored and the dosage adjusted accordingly, particularly following initiation, discontinuation, or change of dosage of azole therapy in patients who are stabilized on their antirejection regimen.