warfarin and fluconazole

Fluconazole inhibits the hepatic cytochrome P450 enzyme CYP2C9, which is the principal enzyme responsible for the metabolism of the pharmacologically active S-enantiomer of warfarin. This inhibition results in decreased clearance of S-warfarin and increased plasma concentrations, leading to enhanced anticoagulant activity. Fluconazole also inhibits CYP3A4, but the effect on warfarin is primarily through CYP2C9.

The interaction produces a clinically significant increase in the anticoagulant effect of warfarin, typically seen as a rise in the international normalised ratio (INR). This can lead to serious and potentially fatal bleeding complications, including intracranial haemorrhage and gastrointestinal bleeding. The onset is usually within several days of starting fluconazole and can persist for several days after stopping it.

Prescribers should avoid co-prescribing fluconazole with warfarin when possible. If concurrent use is unavoidable, a reduction in the warfarin dose may be required, and the INR must be monitored closely, especially during the first week of combined therapy and after any change in fluconazole dose. Alternative antifungal agents that do not inhibit CYP2C9 should be considered.

The interaction is well established and documented in clinical studies and case reports. It is listed in standard drug interaction compendia and is known to be clinically important. The CYP2C9 inhibitory effect of fluconazole is dose dependent, with higher doses producing greater effects.