What are the potential medication interactions with a one-time dose of Diflucan (fluconazole) PO?

Medication Interactions with a One-Time Dose of Diflucan (Fluconazole) PO

Even a single dose of fluconazole can cause clinically significant drug interactions, particularly with medications metabolized by CYP2C9, CYP2C19, and CYP3A4, because fluconazole's enzyme-inhibiting effects persist for 4-5 days after discontinuation due to its long half-life. 1

Critical High-Risk Interactions

Anticoagulants (Warfarin)

• Fluconazole significantly increases warfarin levels and bleeding risk through CYP2C9 inhibition, even with single-dose therapy. 2, 1
• Prothrombin time/INR may increase substantially, with documented cases showing INR rising from 2.0-2.7 to 5.2 within four days of fluconazole initiation 3
• Post-marketing reports include bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena 1
• Monitor INR closely if warfarin cannot be avoided, even after a single fluconazole dose 2, 1

QT-Prolonging Medications

• Avoid combining fluconazole with amiodarone, erythromycin, or other QT-prolonging drugs due to additive risk of torsade de pointes 1
• The combination of fluconazole and erythromycin should be avoided entirely due to potential for sudden cardiac death 1
• Patients with hypokalemia, structural heart disease, or advanced cardiac failure are at highest risk 1
• Other concerning combinations include fluoroquinolones, macrolides, ondansetron, and certain chemotherapies (nilotinib, panobinostat) 2

Antiretroviral Agents

• Fluconazole increases nevirapine exposure by 75-100% at doses of 400 mg, with associated hepatotoxicity risk 2
• Efavirenz levels increase by 16% with fluconazole 200-400 mg; higher fluconazole doses may have greater impact 2
• If high-dose fluconazole is necessary, efavirenz is preferred over nevirapine 2
• Rifampin accelerates fluconazole clearance, potentially requiring dose increases 2

Moderate-Risk Interactions Requiring Monitoring

Immunosuppressants and Transplant Medications

• Fluconazole inhibits CYP3A4, potentially increasing cyclosporine, tacrolimus, and sirolimus levels 2, 1
• Monitor drug levels closely and anticipate need for dose adjustments even after single fluconazole exposure 2
• Both addition and withdrawal of azoles can cause significant fluctuations in immunosuppressant levels 2

Anticonvulsants

• Carbamazepine levels may increase by 30% through metabolic inhibition, risking toxicity 1
• Phenytoin metabolism is affected; monitor levels if concurrent use is necessary 1, 4, 5

Analgesics and Anti-inflammatory Drugs

• Celecoxib exposure increases dramatically (Cmax +68%, AUC +134%) with fluconazole 200 mg daily 1
• Consider reducing celecoxib dose by 50% if fluconazole is administered 1
• Alfentanil clearance is reduced with prolonged half-life; dosage adjustment may be necessary 1

Cardiovascular Medications

• Calcium channel blockers (nifedipine, isradipine, amlodipine, verapamil, felodipine) metabolized by CYP3A4 may have increased systemic exposure 1
• Monitor frequently for adverse effects including hypotension and edema 1

Psychiatric Medications

• Amitriptyline and nortriptyline effects are enhanced by fluconazole 1
• Consider measuring drug levels at initiation and after one week, adjusting doses as needed 1

Lower-Risk but Documented Interactions

Oral Hypoglycemics

• Fluconazole may increase levels of sulfonylureas and other oral hypoglycemic agents 4, 5
• Monitor blood glucose more frequently after fluconazole administration 4, 5

Rifabutin

• Concurrent use with fluconazole increases rifabutin levels and risk of uveitis, particularly at doses >300 mg daily 2
• This interaction is dose-dependent and clinically significant with chronic fluconazole use 2

Abrocitinib

• Avoid concomitant use due to significantly increased systemic exposure of abrocitinib and active metabolites 1

Pharmacokinetic Considerations for Single-Dose Therapy

Duration of Interaction Risk

• Fluconazole's enzyme-inhibiting effects persist 4-5 days after discontinuation due to elimination half-life of 31-37 hours 1, 6, 7
• Steady-state requires minimum 6 days, but inhibitory effects begin immediately 7
• Even single 150 mg doses achieve therapeutic concentrations (Cmax ~2-3 mg/L) that can affect drug metabolism 6, 7

Absorption and Distribution

• Bioavailability exceeds 90% for oral formulations 6, 7
• Low protein binding (11-12%) means high free drug concentration available for enzyme inhibition 6, 7
• Extensive tissue distribution allows drug accumulation 6

Common Pitfalls to Avoid

• Do not assume single-dose fluconazole is free from interaction risk—the long half-life and immediate enzyme inhibition create a 4-5 day window of concern 1
• Failing to monitor INR in warfarin patients is a critical error, as bleeding complications can occur rapidly 2, 1, 3
• Overlooking QT-prolonging drug combinations in patients with cardiac risk factors or electrolyte abnormalities 1
• Not adjusting doses of narrow therapeutic index drugs (anticonvulsants, immunosuppressants, anticoagulants) when fluconazole is added 2, 1
• Assuming topical or vaginal azoles are safer—even miconazole oral gel and vaginal cream have caused warfarin interactions and bleeding 2

Medications with Minimal Interaction Risk

• Azithromycin shows no significant pharmacokinetic interaction with fluconazole 1
• Nystatin oral solution does not affect warfarin INR, making it a safer alternative for oral candidiasis in anticoagulated patients 2
• Amphotericin B has no direct pharmacokinetic interaction, though combination effects on fungal infections vary 1