Warfarin and Fluconazole: A Dangerous Pair

Warfarin is a racemic mixture, and the S-enantiomer is about three to five times more potent than the R-enantiomer. S-warfarin is metabolized mainly by CYP2C9, while R-warfarin is metabolized by CYP1A2 and CYP3A4. Fluconazole is a potent inhibitor of CYP2C9 and also inhibits CYP3A4. Starting fluconazole therefore reduces warfarin clearance, increasing plasma warfarin concentration and prolonging the prothrombin time. The effect begins within days and peaks over about a week, which fits her presentation on day 6. Her age, acute illness, and reduced oral intake may add to the risk. The INR of 9.8 with gum bleeding and bruising indicates over-anticoagulation with minor bleeding, not necessarily major hemorrhage. The normal platelets and creatinine make thrombocytopenia and renal failure unlikely contributors. The key point is that this is a predictable pharmacokinetic interaction, not an idiosyncratic reaction, and it could have been prevented by choosing a non-absorbed antifungal or by pre-emptively reducing the warfarin dose with close INR monitoring.

Stop warfarin. Because there is minor bleeding rather than major hemorrhage, give vitamin K 2.5-5 mg orally; if oral administration is unsafe or bleeding is more significant, give 1-2 mg vitamin K slowly intravenously. Do not routinely give fresh frozen plasma or prothrombin complex concentrate for an INR of 9.8 without major bleeding, because these products carry volume and thrombotic risks and are reserved for serious bleeding. Apply local measures for the gums and check a complete blood count. Recheck the INR in 24 hours, and more frequently if bleeding worsens. If she develops major bleeding, give four-factor prothrombin complex concentrate at about 25-50 units/kg plus intravenous vitamin K 10 mg. Avoid intramuscular injections. Do not give platelet transfusions because the platelet count is normal. Look for other bleeding sites, including neurological symptoms, and educate her about warning signs. The antifungal should be reviewed, because stopping fluconazole will allow warfarin metabolism to recover.

Restart warfarin when the INR is below about 3 and bleeding has stopped, but use a lower dose, such as 2.5-3 mg daily, because the interaction may still be resolving. Check the INR every 2-3 days initially and then weekly until stable. If fluconazole must continue, reduce the warfarin dose and monitor the INR twice weekly; the interaction persists for several days after the antifungal is stopped. A safer alternative for esophageal candidiasis may be a non-absorbed agent such as nystatin or, for severe disease, an echinocandin, depending on local availability and severity. If fluconazole is essential, document the interaction and give the patient written advice. Avoid other CYP2C9 inhibitors and high-dose paracetamol. Reassess the need for anticoagulation: she has atrial fibrillation and likely a CHA2DS2-VASc score that warrants it, so long-term anticoagulation should continue once the bleeding risk is controlled. Consider whether a direct oral anticoagulant would be preferable in the long term, but do not switch during acute over-anticoagulation. Arrange follow-up and reinforce adherence and INR monitoring.