Topical Miconazole and Increased Response to Warfarin: A Drug Interaction Easily Missed
Warfarin has been used as an oral anticoagulant for several decades, and its use continues to be widespread. Numerous factors affect the response to warfarin including age, diet, disease states, pharmacogenetics, and drug interactions.1
Among a long list of clinically relevant warfarin drug interactions, systemic azole antifungal agents are noteworthy.1-9 While many clinicians are familiar with the well documented and highly significant fluconazole warfarin interaction5-9, the effect of topical azoles on warfarin and other coumarin anticoagulants may be less familiar.10-20
Oral administration of miconazole has been shown to reduce the clearance of S-warfarin (the more active isomer of warfarin) by 5-fold and R-warfarin 2-fold.21
At first glance, practitioners may be tempted to think that topical agents would not be absorbed sufficiently to inhibit warfarin metabolism, resulting in an increased international normalized ratio (INR). However, several reports document that topical miconazole does enhance the response to warfarin as well as other coumarin anticoagulants.10-20
The purpose of this brief review is to focus on these interactions and to urge clinicians to be vigilant regarding patients who use topical miconazole with warfarin.
Miconazole Oral Gel
A possible warfarin-miconazole oral gel interaction was first reported in 1987.10 Since that initial case study of increased response to warfarin, several reports of this interaction (more than we will mention) have followed.15 Enhanced response to warfarin is usually seen after 1 to 2 weeks of concomitant treatment, but it can be seen as early as 2 days and has been reported as late as 1 month post-dosage. Specific details of selected case reports are shown in the Table.
Kovac et al15 conducted a retrospective study of 32 patients who used miconazole oral gel added to stable warfarin therapy. The mean weekly dose of warfarin was 15.7 mg with a corresponding mean INR 2.44 before miconazole therapy versus a weekly mean dose 10.8 mg and mean INR 8.8 after miconazole [p<0.0001]. Bleeding was observed in 15 of these 32 patients.
Intravaginal Miconazole
Potentiation of warfarin effect associated with the use of miconazole vaginal suppositories was reported in 2000.17 The patient experienced bleeding with a markedly elevated INR. The Table summarizes the key features of this case as well as a second report of increased response to warfarin apparently due to concurrent therapy with intravaginal miconazole cream.18 Fortunately, this patient did not hemorrhage, but did have elevated INR.
Dermatological Miconazole and Econazole
In 2002, Devaraj et al20 described an 80-year-old patient receiving warfarin therapy who experienced a very high INR after applying miconazole cream for a fungal infection over the groin area. A subsequent similar report in a 79-year-old patient described increased response to warfarin after adding econazole cream to the groin area for a fungal infection.22
Miconazole is also available as a powder and spray powder as well as other topical formulations. To our knowledge, there are no reports in the literature regarding these products and possible interaction with warfarin, but clinicians should be vigilant.
Topical miconazole (ie, oral gel, intravaginal, and skin cream) is documented to increase response to warfarin. In addition, 1 report suggests that dermatologic econazole enhances response to warfarin. Patients who use topical azoles should have close monitoring of the INR at baseline, during the course of the antifungal agent, and after it is stopped.
Physicians, pharmacists, dentists, and nurse practitioners need to be vigilant regarding this clinically relevant drug interaction. Since topical miconazole products are available without a prescription, it is especially important that patients taking warfarin receive education regarding use of miconazole with warfarin. Patients should be taught with frequent reminders to tell their healthcare professionals if they take any other prescription, nonprescription, or herbal medication while receiving warfarin therapy. ■
Timothy H. Self, PharmD, is a professor of clinical pharmacy at the University of Tennessee Health Science Center and director of the PGY2 internal medicine pharmacy residency at Methodist University Hospital in Memphis.
Amy M. Richardson, PharmD, is a PGY1 pharmacy resident at Providence St. Mary Medical Center in Walla Walla, Washington (2013-2014), and PGY2 internal medicine pharmacy resident at University of Tennessee Health Science Center and Methodist University Hospital (2014-15) in Memphis
Andrea S. Franks, PharmD, BCPS, is an associate professor of clinical pharmacy and family medicine at the University of Tennessee Health Science Center in Knoxville.
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