Warfarin with Miconazole Interaction Details

Brand Names Associated with Warfarin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 07, 2023

Interaction Effect

Increased INR and increased risk of bleeding

Interaction Summary

Miconazole is a CYP2C9 and CYP3A4 inhibitor and concomitant use with warfarin (a CYP2C9 and CYP3A4 substrate)  may result in increased warfarin exposure and effect (ie, increased INR and risk of bleeding). Concomitant administration of oral, topical, and vaginal formulations of miconazole and coumarin anticoagulants has resulted in enhancement of the anticoagulant effect . If miconazole therapy is required in a patient taking warfarin, more frequent monitoring of INR, prothrombin time, and other appropriate anticoagulant tests, along with signs of bleeding is recommended , especially when miconazole is initiated and discontinued .

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concomitant use of miconazole and warfarin should be approached with caution as this may result in increased INR and thereby increase the risk for bleeding. When possible, substitute miconazole with an antifungal with a low-risk profile for bleeding. If concomitant use of miconazole and warfarin is required, more frequent monitoring of the patient's INR , prothrombin time, and other appropriate anticoagulation tests is recommended along with monitoring for evidence of bleeding , especially during initiation and discontinuation of miconazole .

Mechanism Of Interaction

Inhibition of CYP2C9- and CYP3A4-mediated warfarin metabolism

Literature Reports

A) A significant increase in mean INR of 1.27 (95% CI, 0.94 to 1.59) was observed in patients on warfarin who initiated treatment with oral miconazole gel for oral candidiasis (n=330). The proportion of patients with an INR greater than 5 following initiation of oral miconazole gel significantly increased from 5.5% to 30.1%. The maximum INR increase was seen 1.5 weeks after miconazole initiation and normalized after 5 weeks. Miconazole is a strong inhibitor of CYP2C9, which catalyzes the metabolism of warfarin and leads to higher INR values .

B) Initiation of antibiotics in patients on continuous warfarin therapy resulted in a significantly increased risk of serious bleeding requiring hospitalization according to a nested case-control study of United States Medicare part D beneficiaries aged 65 years and older (n=38,762). Patients on warfarin who received any antibiotic were twice as likely to be hospitalized for bleeding compared with matched controls on warfarin who were not exposed to antibiotics (adjusted odds ratio (aOR), 2.01; 95% CI, 1.62 to 2.5). Additionally, continuous-warfarin users were twice as likely to have a bleeding event that required hospitalization within 60 days of antibiotic exposure compared with non-exposure. Antibiotic exposure greater than 60 days from the index bleed was not significantly associated with increased risk of bleeding. Specific antibiotics with the highest bleeding risk were azole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), followed by cotrimoxazole (aOR, 2.7; 95% CI, 1.46 to 5.05), cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), penicillins (aOR, 1.92; 95% CI, 1.21 to 2.07), macrolides (aOR, 1.86; 95% CI, 1.08 to 3.21), and quinolones (aOR, 1.69; 95% CI, 1.09 to 2.62) .

C) Concomitant administration of oral warfarin 1 mg daily and miconazole oral gel 5 mL 4 times daily was reported to result in potentiation of the hypoprothrombinemic effects of warfarin. It was suspected that sufficient miconazole was absorbed from the oral mucosa to potentiate the effects of warfarin, presumably secondary to inhibition of hepatic metabolism .

D) A case report describes an interaction between warfarin and miconazole oral gel in a 73-year-old man. The patient had been taking warfarin 1 mg to 3 mg daily for several years in addition to metoprolol, diltiazem, aspirin, isosorbide, and omeprazole. After using oral miconazole gel 125 mg for oral candidiasis 4 times a day for 2 weeks, the patient's INR increased from 1.5 to over 10. After discontinuation of warfarin and miconazole, the patient's INR decreased to 3 over the next 2 weeks. Warfarin was then reinstated at 2 mg daily and the patient's INR remained well-controlled in the range of 2 to 3 .

E) A 53-year-old woman who underwent mitral valve replacement was stabilized on warfarin 45 mg weekly with a mean corresponding INR of 2.69 for 18 months. Because of a vaginal yeast infection, a 3-day course of miconazole 200 mg vaginal suppositories was prescribed. On the third day of miconazole treatment, she presented to the anticoagulation clinic with complaints of ecchymosis on her legs and arms. Her INR was measured to be 9.77. Warfarin was withheld for a day, and her INR dropped to 6.93 the next day. Because of the persistence of her vaginal infection, a 7-day course of miconazole 100 mg suppositories was prescribed later the same week. The warfarin dose was empirically decreased 32.5 mg weekly, and 6 days later her INR was 3.27. She resumed her regular warfarin dose after the second course of miconazole, and was stabilized on such until another yeast infection developed a year later. Her warfarin dose was empirically reduced by 19% in anticipation of an interaction with another 7-day course of miconazole 100 mg vaginal suppositories. Her INR five days later was 7.13. Although only 1.4% of a vaginally administered miconazole dose is systemically absorbed in healthy volunteers, other factors such as dietary changes were ruled out as the cause of her supratherapeutic INR values .

F) Three case reports of potentiation of warfarin anticoagulant activity with concomitant use of miconazole oral gel and warfarin. All 3 patients were compliant with their medication and attended the anticoagulation clinic regularly. Between 7 and 15 days after initiation of treatment with oral miconazole gel, the INR of each patient increased significantly. Warfarin and oral miconazole gel were subsequently discontinued and INR values reversed. Anticoagulation returned to desired values upon reinitiation of warfarin treatment .

G) The US Food and Drug Administration has issued a warning regarding the use of the warfarin and vaginal miconazole preparations after reports of abnormal clotting tests in woman taking both agents .

H) A case report describes an 80 year-old man who had been on chronic warfarin therapy for atrial fibrillation. He had been taking 6 mg daily over the last 12 months which had kept his INR between 2.2 and 3.1. At his routine appointment his INR was found to be 21.4 without evidence of bruising or bleeding. Other medications included atenolol, isosorbide mononitrate 20 mg, and diltiazem 400 mg. Over the previous 2 weeks he had been using topical miconazole for a fungal infection in his right groin area. After being admitted to the hospital his warfarin and miconazole were withdrawn and he was administered fresh frozen plasma. His INR returned to 3.2 and warfarin 6 mg/day was reinstated 5 days later. Since his discharge he has remained on warfarin 6 mg/day with a stable INR. The author concludes that topical absorption of miconazole had occurred which led to loss of anticoagulant control. If topical miconazole cannot be avoided during warfarin treatment, close monitoring of anticoagulant therapy is advised .

I) A 73-year-old woman who was previously well was found to have a retroperitoneal hematoma on CT scan after experiencing severe lower abdominal pain and profuse vomiting. She was on long-term warfarin therapy for previous pulmonary embolism, and had been prescribed oral miconazole by her dentist 2 days prior to hospital presentation. She also had a submucosal intramural hematoma as revealed by small bowel enema. She was hospitalized for 3 weeks .

Warfarin Overview

• Warfarin is used to prevent blood clots from forming or growing larger in your blood and blood vessels. It is prescribed for people with certain types of irregular heartbeat, people with prosthetic (replacement or mechanical) heart valves, and people who have suffered a heart attack. Warfarin is also used to treat or prevent venous thrombosis (swelling and blood clot in a vein) and pulmonary embolism (a blood clot in the lung). Warfarin is in a class of medications called anticoagulants ('blood thinners'). It works by decreasing the clotting ability of the blood.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.