Does clavulanic acid (Clavulanate) interact with warfarin?

Clavulanate and Warfarin Interaction

Clavulanate can interact with warfarin, particularly at high doses, potentially causing significant elevation of INR and increased bleeding risk. 1, 2, 3

Mechanism of Interaction

The interaction between clavulanate (often administered as amoxicillin/clavulanate) and warfarin occurs through several mechanisms:

• Disruption of intestinal flora that produce vitamin K 1, 4
• Potential interference with warfarin metabolism 1
• The risk appears to be dose-dependent, with higher doses of amoxicillin/clavulanate posing greater risk 3

Evidence of Interaction

• A 2016 study found that 87.5% of patients prescribed high-dose amoxicillin/clavulanate (10-12g daily) had INR values ≥4 during hospital stays, compared to only 28.9% of patients on normal doses (up to 3.6g daily) 3

• Case reports document significant warfarin toxicity with amoxicillin/clavulanate:

  • A 53-year-old male developed severe bleeding after tooth extraction with an INR of 20.4 while taking amoxicillin/clavulanate 500/125mg twice daily 2
  • A 58-year-old woman developed elevated INR and hematuria due to this interaction 4

• However, a small randomized controlled trial with 12 patients on stable warfarin therapy found no significant interaction with a 7-day amoxicillin/clavulanate regimen compared to placebo 5

Risk Factors and Monitoring

The risk of interaction increases with:

• Higher doses of amoxicillin/clavulanate 3
• Polypharmacy (especially with other drugs that affect INR or bleeding risk) 3
• Longer duration of antibiotic therapy 1

Management Recommendations

1. Consider alternative antibiotics when possible:

   • Cephalosporins (e.g., cefazolin, cefuroxime) are considered safer options for patients on warfarin 1

2. If amoxicillin/clavulanate must be used:

   • Check baseline INR before starting the antibiotic 1
   • Recheck INR within 3-5 days of starting the antibiotic 1
   • Continue monitoring throughout the antibiotic course 1
   • Consider dose reduction of warfarin (10-20%) based on baseline INR and clinical factors 1
   • Recheck INR 3-5 days after completing the antibiotic course 1

3. Be especially cautious with:

   • High-dose amoxicillin/clavulanate regimens 3
   • Elderly patients or those with renal/hepatic impairment 1
   • Patients taking multiple medications that may interact with warfarin 3

Common Pitfalls to Avoid

• Failing to monitor INR after starting amoxicillin/clavulanate 1
• Not readjusting warfarin dose after completing the antibiotic course 1
• Overlooking the dose-dependent nature of this interaction 3
• Assuming all penicillin-class antibiotics have similar interaction profiles 1

While evidence is mixed regarding the magnitude of this interaction at standard doses, the potential for serious bleeding complications warrants close monitoring of INR when amoxicillin/clavulanate is administered to patients on warfarin therapy, particularly at higher doses.