Major
metronidazole × warfarin
Imidazole derivatives (antiprotozoal / antibacterial)×Vitamin K antagonist anticoagulants
Mechanism
Metronidazole stereospecifically inhibits CYP2C9, the enzyme that metabolizes S-warfarin (the more potent enantiomer). Warfarin concentration rises and INR climbs substantially (often by 2–4 units) as early as days 3–5 of the course. Cases of INR above 10 and major bleeding have been reported (Stockley's Drug Interactions; FDA Drug Interaction Database).
Management
Pre-emptively reduce warfarin dose by 25–35 % before starting metronidazole. Check INR on days 3 and 7 of the course and again 7–10 days after completion. For high bleeding risk (age ≥ 75, HAS-BLED ≥ 3, recent bleeding), choose an alternative antibiotic where possible or pre-transition to a DOAC.
Sources
- Pharmaceutical Press: Stockley's Drug Interactions, 12th edition (2024)— Preston CL (ed.). Stockley's Drug Interactions. 12th ed. London: Pharmaceutical Press; 2024
- FDA: FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers (2024)— FDA Center for Drug Evaluation and Research, last updated 2024
- Lexicomp: Lexicomp Drug Interactions (2024)— Wolters Kluwer Clinical Drug Information, Inc. Lexi-Interact Online, 2024