Drug interactions between Coumadin and Diflucan

MONITOR CLOSELY: Coadministration with fluconazole may significantly increase the plasma concentrations and hypoprothrombinemic effect of warfarin. The mechanism is fluconazole inhibition of CYP450 2C9, the isoenzyme responsible for the metabolic clearance of the biologically more active S(-) enantiomer of warfarin. Additionally, fluconazole inhibits CYP450 2C19 and 3A4, which are responsible for the metabolism of R(+) warfarin. In six healthy, nonsmoking volunteers, coadministration of fluconazole (400 mg once daily for 14 days) and racemic warfarin (0.75 mg/kg single oral dose) resulted in an increase in the mean systemic exposure (AUC) of S(-) and R(+) warfarin by 184% and 108%, respectively, compared to administration of warfarin alone. Likewise, the mean plasma half-life of S(-) and R(+) warfarin increased by 175% and 111%, respectively, in the presence of fluconazole. All subjects also had markedly elevated prothrombin time (PT) during fluconazole coadministration compared to warfarin alone, including one whose PT increased to 34.2 seconds at 120 hours post-warfarin dose. In another study, 11 patients stabilized on warfarin all exhibited progressive PT increases following fluconazole 100 mg/day for 8 days. Mean PT increased from 15.8 seconds at baseline to 21.9 seconds on day 8, and fluconazole was stopped early in three patients due to high PTs. Clinically, the interaction has been associated with bleeding complications including intraocular and gastrointestinal hemorrhage and spinal epidural hematoma. No data are available for other oral anticoagulants, although at least one other coumarin derivative is known to be metabolized by CYP450 2C9. MANAGEMENT: Given the potential for interaction and the high degree of interpatient variability with respect to warfarin metabolism, patients should be closely monitored during concomitant therapy with fluconazole. The INR should be checked frequently and warfarin dosage adjusted accordingly, particularly following initiation or discontinuation of fluconazole in patients who are stabilized on their warfarin regimen. The same precaution may be applicable during therapy with other oral anticoagulants, although clinical data are lacking. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.