Miconazole × Warfarin

Miconazole inhibits the liver enzymes CYP2C9 and CYP3A4 (miconazole labels), and these are the enzymes that break down warfarin. CYP2C9 breaks down the more potent S-enantiomer, and CYP1A2 and CYP3A4 the R-enantiomer (warfarin label, US Food and Drug Administration, FDA). According to the FDA warfarin label, inhibitors of these enzymes increase warfarin exposure and the international normalised ratio (INR). The Spanish warfarin label also lists miconazole among drugs that displace warfarin from plasma protein binding and potentiate its effect. The size of the effect depends on how much miconazole reaches the blood. A 60 mg dose of oral gel gives peak plasma levels of 31–49 ng/mL, and a 1200 mg vaginal ovule about 10–12 ng/mL. Less than 1% of a cream dose is absorbed (miconazole labels, Spanish Agency of Medicines and Medical Devices, AEMPS). The half-life of miconazole after oral gel is 20–25 hours (miconazole oral gel label, AEMPS).

The risk is bleeding: blood in the urine or stool, black tarry stools, heavy menstrual bleeding, petechiae, excessive bruising, prolonged bleeding from cuts, bleeding gums and nosebleeds (warfarin label, US Food and Drug Administration, FDA). Bleeding can also show as pain in the head, chest, abdomen or muscles, dizziness, shortness of breath, difficulty breathing or swallowing, unexplained swelling, weakness, low blood pressure or shock (warfarin label, Spanish Agency of Medicines and Medical Devices, AEMPS). Bleeding events, some fatal, have been reported with miconazole oral gel and warfarin (miconazole oral gel label, AEMPS). Bleeding and bruising have been reported after topical, vaginal and oral miconazole (miconazole buccal tablet label, FDA).

Warfarin is contraindicated with systemic miconazole and with miconazole oral gel (warfarin label, Spanish Agency of Medicines and Medical Devices, AEMPS). The miconazole oral gel label also contraindicates the gel with warfarin (AEMPS). Miconazole skin creams, spray and vaginal ovules are not contraindicated. Use them with warfarin cautiously, monitor the anticoagulant effect closely and titrate the warfarin dose (miconazole cream and vaginal ovule labels, AEMPS). Explain the signs of bleeding to the patient and advise them to stop miconazole at once and contact a doctor if these appear (same labels). Check the international normalised ratio (INR) more often when any antifungal is started or stopped (warfarin label, US Food and Drug Administration, FDA). The Spanish warfarin label requires strict coagulation monitoring whenever any drug is added or withdrawn (warfarin label, AEMPS). If miconazole oral gel and warfarin have been combined, monitor the prothrombin time or other suitable coagulation tests closely and adjust the warfarin dose (miconazole oral gel label, AEMPS). In warfarin overdose with an INR below 6 and no bleeding, stop warfarin temporarily and restart at a lower dose guided by the INR. With an INR above 6 and no severe bleeding, give 0.5 mg of vitamin K1 by continuous infusion over 20–30 minutes, or 1 mg if the INR reaches 10 (warfarin label, AEMPS). In severe bleeding, give 10–20 mg of vitamin K1 by slow infusion over 1 hour together with fresh frozen plasma, whole blood or a factor IX complex (warfarin label, AEMPS).