warfarin and trimethoprim

Trimethoprim inhibits CYP2C9, the enzyme that metabolises the more potent S-enantiomer of warfarin. This increases warfarin plasma concentrations, prolonging its anticoagulant effect. An additional pharmacodynamic contribution may occur through displacement of warfarin from protein binding sites, though this is less well defined.

Co-administration can cause a clinically significant rise in INR and an increased risk of bleeding, which may be severe or life threatening in susceptible patients, particularly in the first days to weeks of therapy.

Avoid co-prescription if an alternative antibiotic is suitable. If the combination is unavoidable, monitor INR more frequently (e.g., before starting, then 3–5 days later, and as needed), and consider a prophylactic warfarin dose reduction. Advise the patient to report signs of bleeding.

Well documented in clinical practice, with numerous case reports and pharmacokinetic studies confirming the CYP2C9 interaction. The magnitude of INR increase is variable, and guidelines generally advise caution.