zafirlukast and Anisindione Interactions

Interactions between zafirlukast and Anisindione (anisindione)

anisindione and zafirlukast (Moderate Drug-Drug)

MONITOR: Coadministration with zafirlukast may increase the plasma concentrations and hypoprothrombinemic effect of warfarin. The proposed mechanism is zafirlukast inhibition of CYP450 2C9, the isoenzyme responsible for the metabolic clearance of the more active S(-) enantiomer of warfarin. In a drug interaction study conducted in 16 healthy volunteers, coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin resulted in a 63% increase in the mean systemic exposure (AUC) and a 36% increase in the half-life of S(-) warfarin. These changes were accompanied by an approximately 35% increase in mean prothrombin time. In contrast, warfarin had no significant effect on the pharmacokinetics of zafirlukast. No data are available regarding coadministration of other oral anticoagulants with zafirlukast, 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 zafirlukast. The INR should be checked frequently and warfarin dosage adjusted accordingly, particularly following initiation or discontinuation of zafirlukast 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.