What are the major drug interactions of fluconazole and how should they be monitored or managed?

Major Drug Interactions of Fluconazole

Fluconazole causes clinically significant drug interactions primarily through inhibition of CYP2C9, CYP2C19, and to a lesser extent CYP3A4, requiring careful monitoring of concomitant medications and dose adjustments to prevent serious adverse events including QT prolongation, bleeding, and toxicity from elevated drug levels. 1, 2

Mechanism of Drug Interactions

Fluconazole inhibits multiple cytochrome P450 enzymes with varying potency 1, 2:

• Strong inhibitor of CYP2C19 1, 2
• Moderate inhibitor of CYP2C9 1, 2
• Moderate inhibitor of CYP3A4 (less potent than ketoconazole or itraconazole) 1, 2, 3
• The enzyme inhibiting effect persists 4-5 days after discontinuation due to fluconazole's long half-life 2

Critical High-Risk Interactions

Anticoagulants (Warfarin)

• Fluconazole inhibits CYP2C9 and significantly increases INR, causing serious bleeding risk 1, 2
• Post-marketing reports document bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena 2
• Monitor INR closely at initiation, during therapy, and for 4-5 days after discontinuation 1, 2
• Warfarin dose reduction is typically necessary 1

QT-Prolonging Medications

• Fluconazole causes QT prolongation via inhibition of Rectifier Potassium Channel current (Ikr) 2
• Risk is amplified when combined with other QT-prolonging drugs including fluoroquinolones, macrolides, ondansetron, and certain chemotherapies (nilotinib, panobinostat) 1
• Concomitant use with amiodarone increases QT prolongation risk; use with caution, especially with high-dose fluconazole (800 mg) 2
• Avoid combination with erythromycin due to risk of torsade de pointes and sudden cardiac death 2
• Patients with hypokalemia, structural heart disease, or advanced cardiac failure are at highest risk 2

Immunosuppressants

• Cyclosporine and tacrolimus levels increase significantly through CYP3A4 inhibition 1, 2
• Both addition and withdrawal of fluconazole can result in either increased drug uptake or subtherapeutic exposure leading to transplant rejection or GVHD 1
• Monitor drug levels closely and adjust immunosuppressant doses accordingly 1

Antiepileptics

• Carbamazepine levels increase by 30% through metabolic inhibition 2
• Risk of carbamazepine toxicity requires dose adjustment based on concentration monitoring 2
• Phenytoin levels increase through CYP2C9 inhibition 2, 4
• Monitor phenytoin concentrations and adjust dose as needed 2

Benzodiazepines

• Midazolam, triazolam, and alprazolam levels increase through CYP3A4 inhibition 2, 3
• Enhanced sedation and respiratory depression may occur 2, 3
• Consider dose reduction or alternative anxiolytic 2

Calcium Channel Blockers

• Nifedipine, isradipine, amlodipine, verapamil, and felodipine levels increase through CYP3A4 inhibition 2
• Monitor frequently for hypotension, edema, and other adverse effects 2

Other Significant Interactions

• Celecoxib: Cmax and AUC increase by 68% and 134% respectively; consider halving celecoxib dose 2
• Alfentanil: Prolonged half-life and reduced clearance; dose adjustment may be necessary 2
• Amitriptyline/Nortriptyline: Enhanced effects requiring dose adjustment based on drug level monitoring 2
• Abrocitinib: Systemic exposure increases significantly; avoid concomitant use 2

Dose-Dependent Considerations

The magnitude of drug interactions with fluconazole is dose-dependent 1:

• Clinically significant interactions with CYP3A4 substrates generally occur only with fluconazole doses ≥200 mg/day 1
• Lower doses (50 mg) do not significantly alter antipyrine clearance 5
• CYP2C9 and CYP2C19 interactions can occur at lower doses 1

Monitoring Recommendations

Therapeutic Drug Monitoring

• Fluconazole does NOT require therapeutic drug monitoring due to linear pharmacokinetics 1
• Exception: Patients with renal failure require dose modification 1

Clinical Monitoring

• Obtain baseline hepatic enzymes before starting therapy 1
• Monitor at 2 weeks, 4 weeks, and every 3 months during therapy 1
• Monitor ECG in patients with risk factors for QT prolongation (hypokalemia, structural heart disease, concomitant QT-prolonging drugs) 2
• Check drug levels of concomitant narrow therapeutic index medications (warfarin INR, immunosuppressants, antiepileptics) 1, 2

Management Strategy

Before initiating fluconazole, review all concomitant medications for potential CYP2C9, CYP2C19, and CYP3A4 substrates 1, 2:

1. Identify all medications metabolized by these pathways 1, 2
2. Assess cardiac risk factors and baseline QTc interval 2
3. Consider alternative antifungal if multiple high-risk interactions exist 1
4. Consult infectious disease expert when incorporating azoles into treatment regimens with complex drug interactions 1
5. Plan for increased monitoring frequency during initiation and discontinuation 2
6. Anticipate need for dose adjustments of interacting medications 2

Common Pitfalls to Avoid

• Failing to account for the 4-5 day persistence of enzyme inhibition after fluconazole discontinuation 2
• Assuming all azoles have similar interaction profiles (fluconazole has less CYP3A4 inhibition than itraconazole/ketoconazole but more CYP2C9/2C19 inhibition) 1, 3, 4
• Overlooking dose-dependent nature of interactions (≥200 mg/day threshold for CYP3A4 effects) 1
• Not monitoring INR closely enough in warfarin patients 1, 2
• Combining multiple QT-prolonging agents without ECG monitoring 1, 2