What medications interact with fluconazole (an antifungal medication) in patients with complex medical histories or impaired renal function?

Fluconazole Drug Interactions

Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor and a strong CYP2C19 inhibitor, requiring careful monitoring when combined with drugs metabolized through these pathways, particularly those with narrow therapeutic windows. 1

Critical Drug Interactions Requiring Monitoring or Avoidance

Cardiovascular Medications

• Amiodarone: Concomitant use increases QT prolongation risk, particularly with high-dose fluconazole (800 mg). Use with extreme caution and ECG monitoring. 1

• Erythromycin: This combination should be avoided entirely due to increased risk of cardiotoxicity, QT prolongation, torsade de pointes, and sudden cardiac death. 1

• Calcium channel blockers (nifedipine, isradipine, amlodipine, verapamil, felodipine): Fluconazole increases systemic exposure through CYP3A4 inhibition. Frequent monitoring for hypotension and edema is required. 1

Anticoagulants

• Warfarin: Prothrombin time increases significantly with concurrent use. Post-marketing reports document bleeding events including bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena. 1 This interaction may be more pronounced in patients with renal impairment. 2 Careful PT/INR monitoring is mandatory with warfarin dose adjustment as needed. 1

Immunosuppressants

• Cyclosporine: Fluconazole significantly increases cyclosporine levels in transplant patients regardless of renal function. 1 The interaction appears dose-dependent, with fluconazole doses >200 mg/day requiring cyclosporine dose reduction and closer monitoring of drug levels and renal function. 3 At fluconazole 100 mg/day, the interaction is minimal. 3

• Cyclophosphamide: Combination therapy increases serum bilirubin and creatinine. Monitor liver and renal function closely when using this combination. 1

Neurologic Medications

• Anticonvulsants: Fluconazole inhibits carbamazepine metabolism, increasing serum levels by 30% with risk of toxicity. 1 This is particularly important in CNS aspergillosis where both voriconazole and anticonvulsants may be used. 4

• Phenytoin: As a CYP2C9 substrate, phenytoin levels increase with fluconazole. Monitor levels and adjust phenytoin dosing accordingly. 5

Analgesics and Sedatives

• Alfentanil: Fluconazole reduces clearance and prolongs half-life through CYP3A4 inhibition. Alfentanil dose adjustment may be necessary. 1

• Midazolam: Frequently co-administered in hospitalized patients (17.5% of fluconazole-treated admissions), requiring monitoring for excessive sedation. 6

Anti-inflammatory Agents

• Celecoxib: Fluconazole 200 mg daily increases celecoxib Cmax by 68% and AUC by 134%. Consider reducing celecoxib dose by 50% when combined with fluconazole. 1

• Corticosteroids (prednisone, methylprednisolone): The most frequent moderate-to-major interaction in hospitalized patients (25.3% for prednisone, 14.1% for methylprednisolone). 6 Monitor for increased corticosteroid effects. 1

Antidepressants

• Amitriptyline and nortriptyline: Fluconazole increases effects of both drugs. Measure 5-nortriptyline and/or S-amitriptyline levels at initiation and after 1 week, adjusting doses as needed. 1

Other Azoles

• Amphotericin B: Animal studies show variable interactions depending on infection type—additive effects in systemic candidiasis, no interaction in cryptococcal CNS infection, and antagonism in aspergillosis. Clinical significance remains uncertain. 1

Special Populations Requiring Enhanced Vigilance

Renal Impairment

• Fluconazole clearance decreases proportionally with declining creatinine clearance (>90% excreted unchanged in urine). 7

• Drug interactions may be more pronounced in renal dysfunction due to reduced fluconazole clearance and accumulation. 2

• For CrCl ≤50 mL/min, reduce maintenance dose by 50% after loading dose. 7, 8

• Hemodialysis removes approximately 38-50% of fluconazole; administer supplemental dose post-dialysis. 7, 8

Cardiac Risk Factors

• Patients with hypokalemia, structural heart disease, advanced cardiac failure, or electrolyte abnormalities are at increased risk for life-threatening ventricular arrhythmias and torsade de pointes. 1

• Fluconazole prolongs QT interval via inhibition of Rectifier Potassium Channel current (Ikr), amplified when combined with other QT-prolonging drugs metabolized by CYP3A4. 1

Transplant Recipients

• Solid organ and hematopoietic stem cell transplant recipients frequently require multiple interacting medications (cyclosporine, corticosteroids, anticonvulsants). 4

• Fluconazole clearance may be further reduced by concurrent calcineurin inhibitors affecting renal function. 7

Duration of Interaction Risk

The enzyme-inhibiting effect of fluconazole persists 4-5 days after discontinuation due to its long half-life (22-32 hours). 1, 9 Continue monitoring for drug interactions during this washout period.

Clinical Context

Despite high frequency of potential interactions (70.3% of hospitalized patients on azoles experience potential drug-drug interactions), actual adverse drug events from fluconazole interactions are uncommon in clinical practice. 6 However, this does not negate the need for vigilant monitoring, particularly with narrow therapeutic index drugs.

Monitoring Recommendations

• Baseline assessment: Document all concomitant medications, particularly those metabolized by CYP2C9, CYP2C19, and CYP3A4. 1

• Renal function: Monitor creatinine clearance regularly, as changes necessitate dose adjustments and affect interaction severity. 7

• Drug-specific monitoring: PT/INR for warfarin, cyclosporine levels for transplant patients, phenytoin levels for anticonvulsants, ECG for QT-prolonging combinations. 1

• Oral hypoglycemics: Monitor blood glucose closely as fluconazole may enhance hypoglycemic effects. 5

• Antiretroviral drugs: Evaluate carefully due to CYP3A4 and CYP2C9 inhibition. 7