Drug interactions between Arava and Miradon

anisindione ↔ leflunomide

Applies to:Miradon (anisindione) and Arava (leflunomide)

MONITOR: Available data suggest that leflunomide may potentiate the anticoagulant effect of warfarin. The proposed mechanism is leflunomide inhibition of CYP450 2C9, the isoenzyme responsible for the metabolic clearance of the more active S(-) enantiomer of warfarin. The interaction was suspected in a published report of a patient who developed increased INR shortly after switching from methotrexate to leflunomide for her rheumatoid arthritis. The patient's INR normalized after withholding of three warfarin doses and continual decrease of her warfarin dosage from 36 to 28 mg/week over the next three months while she continued taking leflunomide. In another report, a patient with stable INR developed gross hematuria requiring hospitalization after taking the second loading dose of leflunomide. The patient's INR declined following discontinuation of warfarin, administration of vitamin K 1 mg on the third day, and a decrease of the leflunomide dosage to 20 mg/day for maintenance. Warfarin was subsequently resumed at a lower dosage with no further incident. According to the author, the Committee on the Safety of Medicines in the U.K. had also received over 300 reports of elevated INR in patients treated with warfarin and leflunomide. 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 leflunomide. The INR should be checked frequently and warfarin dosage adjusted accordingly, particularly following initiation or discontinuation of leflunomide therapy 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.