Is there an interaction between warfarin (anticoagulant) and azithromycin (antibiotic)?

Warfarin-Azithromycin Interaction

Yes, azithromycin does interact with warfarin and increases bleeding risk, requiring close INR monitoring when these medications are co-administered. 1, 2, 3

Evidence for the Interaction

The FDA drug label for azithromycin explicitly states that "spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants" and mandates that "prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly." 2 This is particularly notable because the FDA specifically cited intravenous azithromycin as significantly increasing bleeding risk when co-administered with warfarin. 1

The American College of Cardiology guidelines identify azithromycin as a high-risk antibiotic that significantly increases bleeding risk when combined with warfarin. 1 This classification places azithromycin alongside other problematic antibiotics like sulfonamides, metronidazole, and fluoroquinolones. 1

Clinical Evidence of Risk

A large retrospective cohort study of 22,272 veterans demonstrated that azithromycin was associated with:

• 1.93-fold increased risk of bleeding as a primary diagnosis (HR 1.93; 95% CI, 1.13-3.30) 3
• 1.64-fold increased risk of serious bleeding as a primary or secondary diagnosis (HR 1.64; 95% CI, 1.16-2.33) 3

A geriatric study found statistically significant INR elevation after azithromycin exposure (p < 0.001), resulting in warfarin dose reductions from a mean weekly dose of 30 mg to 29.2 mg (p = 0.001). 4 While this study did not observe bleeding events, the INR changes were clinically meaningful enough to require dose adjustments. 4

Mechanism of Interaction

Unlike other macrolides (erythromycin and clarithromycin) that inhibit CYP3A4, azithromycin's mechanism of interaction with warfarin is not fully understood. 5 The American College of Cardiology notes that all antibiotics can potentially alter the gut microbiome, which is a source of vitamin K, thereby potentiating warfarin's anticoagulant effects. 1, 6

Contradictory Evidence (Lower Quality)

Two older, smaller studies from 1999-2000 showed conflicting results:

• A retrospective review of 52 patients found no significant interaction (p=0.18 for 30-day follow-up). 7
• A single case report from 1999 documented an INR of 15.16 six days after azithromycin initiation. 8

However, these older, smaller studies are superseded by the more recent, larger veteran cohort study and the explicit FDA warning. 2, 3

Management Recommendations

Monitor INR within 3-14 days of co-prescribing azithromycin with warfarin. 3 Early INR evaluation significantly reduces bleeding risk (HR 0.61; 95% CI, 0.42-0.88). 3

Specific monitoring steps:

• Check baseline INR before starting azithromycin 1
• Recheck INR 3-14 days after azithromycin initiation 3
• Be prepared to reduce warfarin dose by approximately 25-33% if INR becomes elevated 1, 6
• Continue monitoring for up to 4-8 days after azithromycin completion, as effects may be delayed 5

Clinical Pitfalls

• Do not assume azithromycin is safe simply because it lacks CYP450 inhibition like other macrolides—the interaction is real and clinically significant. 1, 2, 3
• Higher azithromycin doses increase interaction risk, with patients receiving higher maintenance doses developing more elevated INR values. 1
• The interaction can occur even with short courses (5 days) of azithromycin. 4, 8
• Patients may not experience bleeding despite INR elevation, but the risk is substantially increased. 4