warfarin and metronidazole

Metronidazole inhibits the hepatic cytochrome P450 enzyme CYP2C9, which is primarily responsible for the metabolism of the more potent S-enantiomer of warfarin. This inhibition reduces warfarin clearance and increases its plasma concentration, leading to an enhanced anticoagulant effect. Additionally, metronidazole may displace warfarin from plasma protein binding sites, further increasing the free fraction of warfarin.

Co-administration of warfarin and metronidazole can result in a significant increase in the International Normalised Ratio (INR) and a markedly increased risk of serious bleeding complications, including gastrointestinal and intracranial haemorrhage. The onset of this interaction is typically within 3 to 5 days of starting metronidazole, but may be delayed. Patients may present with signs of excessive anticoagulation, such as easy bruising, epistaxis, haematuria, or melaena.

Avoid concomitant use if possible. If co-administration is necessary, monitor the INR frequently (e.g., every 2 to 3 days) for the first week of metronidazole therapy and for several days after discontinuation, and adjust the warfarin dose accordingly to maintain the target INR. Consider using an alternative antibiotic with no known interaction (e.g., a penicillin or macrolide, depending on the infection). Educate the patient about signs of bleeding and the need for prompt medical review.

This interaction is well established and documented in multiple clinical reports and studies, as well as in the prescribing information for both drugs. It is included in major drug interaction databases and is a recognised cause of elevated INR and bleeding in patients on warfarin.