Which antifungal can be given with warfarin (Coumadin)?

Antifungal Selection for Warfarin Users

Nystatin oral solution is the safest antifungal for warfarin users, as it does not affect INR or increase bleeding risk, unlike azole antifungals which significantly potentiate warfarin's anticoagulant effect. 1, 2

Preferred Agent: Nystatin

For oral candidiasis in warfarin users, nystatin oral solution (100,000 U/mL) 4-6 mL four times daily for 7-14 days is the recommended first-line therapy. 1, 2

• Nystatin oral solution does not appreciably affect INR (mean change 0.08; 95% CI -0.10 to 0.25) 1, 2
• Large national prescription database studies confirm nystatin's safety profile in warfarin users 1, 2
• Alternative formulation: nystatin pastilles (200,000 U each) 4 times daily for 7-14 days 1

Agents to Avoid or Use with Extreme Caution

Systemic Fluconazole

• Increases mean INR by 0.83 (95% CI 0.61-1.04) 2
• Proportion of patients with INR >5 increases from 4.3% to 15.3% after initiation 2
• Inhibits CYP2C9 (moderate) and CYP2C19 (strong), directly affecting warfarin metabolism 1, 3
• If absolutely necessary, requires preemptive warfarin dose reduction and INR monitoring every 2-3 days initially 4, 5

Miconazole Oral Gel

• Most dangerous interaction: increases mean INR by 1.27 (95% CI 0.94-1.59) 2
• Proportion of patients with INR >5 increases from 5.5% to 30.1% 2
• Even topical/vaginal miconazole formulations have been associated with supratherapeutic INR and bleeding events 1
• Should be avoided entirely in warfarin users 1, 2

Voriconazole

• Moderate CYP2C19 inhibitor and weak CYP2C9 inhibitor 1
• Requires careful initiation with increased INR monitoring 1
• Interaction peaks on day 7 after combination initiation 6

Other Azoles

• Ketoconazole: strong CYP3A4 inhibitor, moderate CYP2C19 inhibitor 1
• Itraconazole: strong CYP3A4 inhibitor 1, 7
• All triazole antifungals should be initiated carefully with increased INR monitoring 1

Clinical Management Algorithm

When treating fungal infections in warfarin users:

1. For oral candidiasis (mild disease): Use nystatin oral solution or pastilles 1, 2

2. For moderate-to-severe oral candidiasis requiring systemic therapy:

   • Consider switching from warfarin to alternative anticoagulation temporarily if clinically feasible
   • If fluconazole must be used: reduce warfarin dose preemptively, monitor INR every 2-3 days for first week, then weekly 4, 5

3. For esophageal candidiasis: Fluconazole 200-400 mg daily for 14-21 days is standard therapy 1, but requires intensive INR monitoring in warfarin users 1, 3

4. For systemic/invasive candidiasis: Consider echinocandins (caspofungin, micafungin, anidulafungin) or amphotericin B formulations, which do not interact with warfarin through CYP450 pathways 1

Critical Monitoring Considerations

• CYP450 enzyme inhibition by fluconazole persists 4-5 days after discontinuation due to long half-life 3
• Post-marketing surveillance reports bleeding events (bruising, epistaxis, GI bleeding, hematuria, melena) with fluconazole-warfarin combination 3
• The interaction between warfarin and azoles peaks on day 7 after combination initiation 6
• Careful monitoring of prothrombin time is mandatory when any azole is used with warfarin 3

Common Pitfalls to Avoid

• Do not assume topical azoles are safe: Even vaginal miconazole cream has been reported to potentiate bleeding in warfarin users 1
• Do not forget to adjust warfarin after azole discontinuation: The enzyme inhibition effect persists for days after stopping the antifungal 3
• Do not use miconazole oral gel in warfarin users: This combination has the highest risk of supratherapeutic INR 2