Is it safe to combine fluconazole and apixaban?

Fluconazole and Apixaban: Potential Drug Interaction

Combining fluconazole with apixaban is not recommended due to increased bleeding risk, particularly in patients taking apixaban. 1

Mechanism of Interaction

Apixaban is primarily metabolized by CYP3A4/5 and is also a substrate of P-glycoprotein (P-gp) 2. Fluconazole inhibits CYP enzymes, particularly:

• CYP2C9, CYP2C19, and CYP3A4 3
• This inhibition can lead to increased plasma concentrations of apixaban
• Higher apixaban levels significantly increase bleeding risk

Evidence of Interaction Risk

Recent evidence demonstrates a clear risk when combining these medications:

• A 2022 case-crossover study found that apixaban users had a significantly increased risk of bleeding when exposed to systemic fluconazole (OR 3.5; 95% CI, 1.4-10.6) 1
• No similar increased risk was found with rivaroxaban or dabigatran in the same study 1
• Analysis of the FDA Adverse Event Reporting System showed significant hemorrhagic signals with various azole antifungals and DOACs 4

Management Recommendations

For patients requiring both antifungal and anticoagulant therapy:

1. Preferred approach: Consider alternative anticoagulants

   • Switch to edoxaban if anticoagulation is necessary during fluconazole therapy 2
   • Edoxaban is minimally metabolized by CYP3A4, making drug interactions with this enzyme less relevant 2

2. If apixaban must be continued:

   • Reduce apixaban dose by 50% if on a regimen of 5-10 mg twice daily 2
   • Avoid concomitant use if already on the reduced dose of 2.5 mg twice daily 2
   • Monitor closely for signs of bleeding

3. Alternative antifungals:

   • Consider topical azoles when appropriate, as they showed no significant increase in bleeding risk with DOACs 1

Special Considerations

• Renal function: The interaction risk is heightened in patients with renal impairment due to decreased clearance of both medications 5
• Timing of administration: While separating administration times might help with some drug interactions, the long half-life of fluconazole (30+ hours) makes this strategy less effective 3
• Duration of therapy: Short courses of fluconazole may pose less risk than prolonged therapy, but caution is still warranted

Monitoring Recommendations

For patients who must receive both medications:

• Monitor for signs of bleeding more frequently
• Consider checking anti-Factor Xa levels if available
• Be vigilant for signs of bruising, epistaxis, gingival bleeding, or hematuria
• Educate patients about bleeding symptoms requiring immediate medical attention

The 2023 ACC/AHA/ACCP/HRS guideline for atrial fibrillation management emphasizes the importance of considering drug interactions when prescribing DOACs, with specific attention to combined P-glycoprotein and CYP3A4 inhibitors like azole antifungals 2.