Drug interactions between clarithromycin and Coumadin

MONITOR CLOSELY: Coadministration with clarithromycin or erythromycin may infrequently but substantially enhance the hypoprothrombinemic effect of warfarin and other coumarin anticoagulants. The exact mechanism of interaction is unknown. Data from clinical studies have not supported a significant, predictable pharmacodynamic or pharmacokinetic interaction in general. Although both macrolides are potent inhibitors of CYP450 3A4 and can inhibit metabolism of the R(+) enantiomer of warfarin, the overall effect on racemic warfarin pharmacokinetics appears to be minor. In 12 normal subjects, the clearance of warfarin (1 mg/kg single dose) decreased by an average of 14% following pretreatment with erythromycin 250 mg four times a day for 8 days. In a study of eight patients stabilized on warfarin, the addition of erythromycin led to only a small increase in the effect of warfarin. Nevertheless, a population-based cohort study focusing on antibiotic use in outpatients treated with phenprocoumon or acenocoumarol at a Netherlands anticoagulant clinic identified clarithromycin use as a risk factor for overanticoagulation (INR greater than or equal to 6), even after adjustment for potential confounding factors. There have also been case reports of increased prothrombin time or INR and/or serious bleeding complications in patients stabilized on coumarin therapy following the addition of erythromycin or clarithromycin. The UK Committee on Safety of Medicines reported on a woman taking warfarin who suffered a fatal cerebrovascular bleed 3 days after starting clarithromycin. However, other influences such as fever, infection, malnutrition, and other concomitant underlying conditions on clotting mechanisms and coumarin pharmacokinetics should also be considered.

MANAGEMENT: Given the potential for clinically significant interaction and even fatality in the occasional, susceptible patient, close monitoring is recommended if clarithromycin or erythromycin is prescribed during coumarin anticoagulant therapy. The INR should be checked frequently and coumarin dosage adjusted accordingly, particularly following initiation or discontinuation of macrolide therapy in patients who are stabilized on their anticoagulant regimen. 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. The same precaution may be applicable during therapy with other oral anticoagulants (e.g., indandiones) and other similar macrolides (e.g., troleandomycin), although clinical data are lacking.