Topical Miconazole Cream and Warfarin Interaction: A Case Report

Warfarin is noted for many drug and food interactions, particularly those involving Cytochrome P450 (CYP) metabolism. ¹ We present a case to document a probable interaction between warfarin and topical miconazole cream in an older adult male.

An 85-year-old male prescribed warfarin for a history of recurrent deep vein thromboses was managed by a team of clinical pharmacists via collaborative practice agreement in a family medicine clinic for 11 years. His international normalized ratio (INR) goal was 2.5 (2.0-3.0). His INR was monitored monthly, and his weekly warfarin dose of 25 mg was stable for the 3 months prior to initiation of topical miconazole. The patient also received home hospice services with qualifying diagnoses of senile degeneration of brain and muscle weakness. Additional comorbidities included type 2 diabetes, hypertension, coronary artery disease, and chronic kidney disease. Other chronic medications included hydroxyzine, insulin lispro, insulin glargine, lovastatin, topical Neosporin® (neomycin-bacitracin-polymyxin) ointment, lidocaine 4% cream, vitamin-D3, and amlodipine.

After developing a large rash and sore to his buttocks and hips of fungal origin, Baza® Antifungal Cream (miconazole nitrate 2%) was prescribed for once daily application per the hospice team without the family medicine provider’s awareness. After 2 weeks of once daily application, the frequency was increased to 3 times daily, occurring approximately 2 weeks prior to the next routinely scheduled INR. That routinely scheduled INR was 10.0. The patient’s wife denied any changes in appetite, vitamin K intake or other foods known to affect warfarin, alcohol intake, warfarin dose, or other medications. The patient was hospitalized, where his subsequent INR was 14.1. He displayed swelling and ecchymosis in his left hand from recent injury, but denied melena, epistaxis, and hematuria with a hemoglobin of 12.2 g/dL. He received 4 units of fresh frozen plasma and 5 mg intravenous vitamin K, correcting the INR to 1.2. Miconazole cream was discontinued. The patient’s warfarin dose was adjusted as shown in Table 1 and titrated to his previously stable dose within 1 month.

Table 1.

Interaction of Miconazole Cream and Warfarin.

Date	Weekly warfarin dose (mg)	INR	Comments
4/21/21	25 mg	2.2
5/10/21	25 mg	2.3
6/1/21	25 mg	2.4
6/30/21	25 mg	10.0	Patient initiated miconazole 2% cream once daily applications 4 weeks prior and used the once daily application for 2 weeks total then increased to thrice daily administration 2 weeks prior
7/1/21		14.1	INR obtained upon hospital admission; miconazole cream discontinued.
7/2/21		1.2	After 4 units of fresh frozen plasma and 5 mg intravenous vitamin K
7/6/21	7.5 mg since discharge	1.5
7/8/21	20 mg	1.7
7/13/21	20 mg	1.7
7/26/21	22.5 mg	1.9
8/3/21	22.5 mg	1.9
8/11/21	25 mg	1.8
8/18/21	25 mg	2.1
8/26/21	25 mg	2.6
9/2/21	25 mg	2.8
9/8/21	25 mg	2.5
9/21/21	25 mg	2.6

Abbreviations: INR, international normalized ratio; mg, milligram.

Miconazole is an imidazole antifungal agent and CYP2C9 inhibitor. Miconazole oral and vaginal formulations are known to increase warfarin response.^1-3 There is 1 documented case of topical miconazole cream interacting with warfarin in an 80-year-old male when applied to the groin resulting in an INR of 21.4. ⁴ Two reports of econazole topical cream, also applied to the groin area of a 51-year-old male and a 79-year-old male with previously stable INRs, resulted in INRs of greater than 9.0 and 12.0, respectively.^5,6 Of note, the recommended twice daily application of miconazole topical cream was exceeded in this case, possibly increasing the risk of this interaction. ⁷

A Drug Interaction Probability Scale (DIPS) was completed, with a score of 7 (Table 2). This represents a probable drug interaction between miconazole topical cream and warfarin. ⁸

Table 2.

Drug Interaction Probability Scale Assessment of Miconazole Cream and Warfarin. ⁸

DIPS question	Answer/score	Comments
1. Are there previous credible reports of this interaction in humans?	Yes/+1	One other published case report was identified. 4
2. Is the observed interaction consistent with the known interactive properties of precipitant drug? a	Yes/+1	Miconazole inhibits the action of CYP2C9. 2
3. Is the observed interaction consistent with the known interactive properties of the object drug? b	Yes/+1	Warfarin is metabolized primarily by CYP2C9. 1
4. Is the event consistent with the known or reasonable time course of the interaction (onset and/or offset)?	Yes/+1	Patient utilized miconazole cream about 4 weeks prior to supratherapeutic INR which was ample time for interaction to occur.
5. Did the interaction remit upon dechallenge of the precipitant drug with no change in the object drug?	Yes / +1	Patient’s dose was eventually stabilized on prior chronic dose of warfarin 25 mg weekly following discontinuation of miconazole cream.
6. Did the interaction reappear when the precipitant drug was readministered in the presence of continued use of object drug?	NA/0	No rechallenge was attempted.
7. Are there reasonable alternative causes for the event?	No/+1	Patient’s wife denied any other changes in diet, medications, or lifestyle.
8. Was the object drug detected in the blood or other fluids in concentrations consistent with proposed interaction?	NA/0	Direct warfarin levels were not monitored.
9. Was the drug interaction confirmed by any objective evidence consistent with the effects on the object drug (other than drug concentrations from question 8)?	Yes/+1	As measured by INR, the effects of warfarin were increased with coadministration of miconazole cream.
10. Was the interaction greater when the precipitant drug dose was increased or less when the precipitant drug was decreased?	NA/0	There was no measure of the change in the precipitant drug dose
Total	7	Probable Interaction

Abbreviations: DIPS, Drug Interaction Probability Scale; INR, international normalized ratio; NA, not applicable.

^aPrecipitant drug is the drug that caused change to object drug; in this case miconazole cream was the precipitant drug.

^bObject drug is the drug that is affected; in this case warfarin was the object drug.

It is our opinion that an interaction between topical miconazole cream and warfarin resulted in an extremely elevated INR. Prescribers and users of warfarin should be alert to the possibility of such an interaction for both oral and topical formulations.