What are common interactions with fluconazole (an antifungal medication)?

Fluconazole Common Drug Interactions

Critical CYP450 Enzyme Inhibition Profile

Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4, and a strong inhibitor of CYP2C19, creating significant interaction potential with drugs metabolized through these pathways. 1 The enzyme-inhibiting effect persists 4-5 days after discontinuation due to fluconazole's long half-life. 1

Major Drug Interactions by Category

Anticoagulants (Highest Clinical Priority)

• Warfarin interaction is one of the most clinically significant—fluconazole predictably increases INR and bleeding risk through CYP2C9 inhibition. 2, 1
• Even low-dose fluconazole (100 mg daily) progressively increases prothrombin times, with mean PT rising from 15.8 seconds at baseline to 21.9 seconds by day 8. 3
• Monitor INR closely when initiating or discontinuing fluconazole; warfarin dose reduction is typically necessary. 2, 1
• Post-marketing reports document bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena with concurrent use. 1

Immunosuppressants

• Cyclosporine levels increase significantly with fluconazole in renal transplant patients, requiring dose reduction of approximately 30-50%. 2, 1
• Tacrolimus concentrations can increase up to 5-fold when given orally (but not IV) due to CYP3A4 and P-glycoprotein inhibition in the intestines, risking nephrotoxicity. 1
• Reduce oral tacrolimus dose based on concentration monitoring when combining with fluconazole. 1
• Sirolimus plasma concentrations increase via CYP3A4 and P-glycoprotein inhibition, requiring dose adjustment. 1

Antiepileptics

• Phenytoin concentrations increase substantially with fluconazole, causing symptomatic toxicity even at fluconazole doses as low as 200 mg daily. 1, 4
• Carbamazepine levels increase by 30%, creating toxicity risk and necessitating dose adjustment based on concentration monitoring. 1

Cardiovascular Medications

• Calcium channel blockers (nifedipine, isradipine, amlodipine, verapamil, felodipine) have increased systemic exposure via CYP3A4 inhibition, requiring frequent monitoring for adverse effects. 1
• Amiodarone combined with fluconazole increases QT prolongation risk; use caution, particularly with high-dose fluconazole (800 mg). 1
• Statins (fluvastatin, lovastatin, rosuvastatin, simvastatin) interact with fluconazole, with simvastatin specifically carrying increased myopathy risk. 2

Hypoglycemic Agents

• Fluconazole reduces metabolism of tolbutamide, glyburide, and glipizide, precipitating clinically significant hypoglycemia; one fatality has been reported with glyburide. 1
• Monitor blood glucose carefully and reduce sulfonylurea doses as necessary when combining with fluconazole. 1

Benzodiazepines

• Midazolam concentrations and psychomotor effects increase substantially, particularly with oral fluconazole administration. 1
• Consider decreasing benzodiazepine dosage for short-acting agents metabolized by CYP3A4 when used with fluconazole. 1

NSAIDs

• Celecoxib exposure increases dramatically (Cmax by 68%, AUC by 134%) with fluconazole 200 mg daily; reduce celecoxib dose by half. 1
• Other NSAIDs (ibuprofen, naproxen, lornoxicam, meloxicam, diclofenac) require frequent monitoring for adverse events and toxicity. 1

Antimicrobials

• Rifampin enhances fluconazole metabolism, potentially requiring increased fluconazole dosing. 1
• Rifabutin levels increase up to 80% with fluconazole, with reports of uveitis; monitor patients carefully. 1

Cardiac QT Prolongation Risk

• Fluconazole causes QT prolongation via inhibition of Rectifier Potassium Channel current (IKr), with risk amplified by other QT-prolonging drugs. 1
• Erythromycin, pimozide, and quinidine are contraindicated with fluconazole due to torsades de pointes risk. 1
• Patients with hypokalemia, structural heart disease, or advanced cardiac failure are at highest risk for life-threatening ventricular arrhythmias. 1

Other Significant Interactions

• Corticosteroids (prednisone, methylprednisolone) have increased levels with fluconazole, potentially exacerbating immunosuppression. 2, 5
• Theophylline serum concentrations increase, requiring careful monitoring. 1
• Oral contraceptives: at 200 mg daily fluconazole, ethinyl estradiol AUC increases 40% and levonorgestrel 24%, though unlikely to affect contraceptive efficacy. 1
• Alfentanil clearance reduces with prolonged half-life, potentially requiring dosage adjustment. 1

Dose-Dependent Interaction Risk

Higher fluconazole doses (≥400 mg daily) carry greater interaction risk. 6 The interaction profile is clinically relevant even at lower doses (100-200 mg daily) for drugs with narrow therapeutic windows. 3, 4

Clinical Management Algorithm

1. Review complete medication list before initiating fluconazole, focusing on CYP2C9, CYP2C19, and CYP3A4 substrates with narrow therapeutic windows. 1
2. For warfarin users: obtain baseline INR, reduce warfarin dose preemptively, and monitor INR every 2-3 days initially. 2, 3
3. For immunosuppressants: reduce doses by 30-50% for cyclosporine, adjust tacrolimus/sirolimus based on levels. 2, 1
4. For phenytoin/carbamazepine: monitor drug levels closely even with fluconazole 200 mg daily. 1, 4
5. Avoid contraindicated combinations (erythromycin, pimozide, quinidine) entirely. 1
6. Remember interaction effects persist 4-5 days after fluconazole discontinuation—continue monitoring during this period. 1

Important Caveats

• Topical/vaginal miconazole can still cause systemic interactions with warfarin, while nystatin does not affect INR. 2
• Patients with renal dysfunction have decreased fluconazole clearance, potentially intensifying interactions. 1
• The interaction with dextromethorphan is theoretical via CYP3A4 inhibition; monitor for excessive CNS effects (drowsiness, confusion, dizziness) particularly in older adults. 6