Introduction
Fluconazole is a synthetic triazole antifungal agent that has become a cornerstone in the treatment and prevention of systemic fungal infections. First approved by the FDA in 1990, it remains one of the most widely prescribed antifungal medications worldwide due to its excellent bioavailability, favorable safety profile, and broad spectrum of activity against many pathogenic fungi.
Mechanism of Action
Fluconazole exerts its antifungal effect by selectively inhibiting the fungal cytochrome P450 enzyme 14α-demethylase. This inhibition prevents the conversion of lanosterol to ergosterol, an essential component of fungal cell membranes. The resulting accumulation of toxic methylated sterols and depletion of ergosterol disrupts membrane integrity and function, leading to inhibition of fungal cell growth and replication.
Indications
FDA-approved indications include:
- Treatment of oropharyngeal and esophageal candidiasis
- Vaginal candidiasis (single-dose and multi-day regimens)
- Systemic candidiasis including candidemia, disseminated candidiasis, and peritonitis
- Cryptococcal meningitis (treatment and maintenance therapy to prevent relapse)
- Prophylaxis against fungal infections in patients undergoing bone marrow transplantation
Off-label uses include:
- Prophylaxis in other immunocompromised patients
- Treatment of coccidioidomycosis
- Treatment of certain cases of blastomycosis and histoplasmosis
Dosage and Administration
Standard dosing:- Oropharyngeal candidiasis: 200 mg on day 1, then 100 mg daily
- Esophageal candidiasis: 200 mg on day 1, then 100-200 mg daily
- Vaginal candidiasis: 150 mg single dose
- Systemic candidiasis: 400 mg on day 1, then 200-400 mg daily
- Cryptococcal meningitis: 400 mg on day 1, then 200-400 mg daily
- Renal impairment: Dose adjustment required based on creatinine clearance
- Hepatic impairment: Use with caution; no specific dosage adjustment recommended
- Pediatrics: 6-12 mg/kg/day depending on indication
- Elderly: Consider renal function when dosing
Pharmacokinetics
Absorption: Excellent oral bioavailability (>90%) unaffected by food or gastric pH Distribution: Widely distributed throughout body tissues and fluids, including CSF (60-80% of serum concentrations) Protein binding: Low (11-12%) Metabolism: Minimally hepatic metabolism (approximately 11%) Elimination: Primarily renal excretion (80% as unchanged drug), elimination half-life approximately 30 hours Steady-state: Achieved within 5-10 days with once-daily dosingContraindications
- Hypersensitivity to fluconazole or other azole antifungal agents
- Coadministration with drugs that prolong QT interval and are metabolized by CYP3A4 (cisapride, erythromycin, pimozide, quinidine)
- Known QT prolongation
Warnings and Precautions
- Hepatotoxicity: Cases of serious hepatic reactions reported; monitor liver function
- QT prolongation: Dose-related QT prolongation observed; use with caution in patients with risk factors
- Dermatologic reactions: Serious dermatologic reactions including Stevens-Johnson syndrome reported
- Renal impairment: Requires dosage adjustment
- Pregnancy: Category D - should not be used in pregnancy except for serious fungal infections
- Drug-resistant fungi: Emerging resistance, particularly in Candida species
Drug Interactions
Significant interactions:- Warfarin: ↑ INR and bleeding risk (monitor INR closely)
- Sulfonylureas: ↑ Hypoglycemic effect
- Phenytoin: ↑ Phenytoin levels (monitor levels)
- Cyclosporine: ↑ Cyclosporine levels (monitor levels)
- Rifampin: ↓ Fluconazole levels (may need dose adjustment)
- Oral contraceptives: Potential decreased efficacy
- Statins: ↑ Risk of rhabdomyolysis
- Voriconazole: ↓ Voriconazole levels (contraindicated combination)
Adverse Effects
Common (≥1%):- Headache (13%)
- Nausea (7%)
- Abdominal pain (6%)
- Diarrhea (3%)
- Rash (2%)
- Elevated transaminases (1-3%)
- Hepatotoxicity (including fatal hepatic failure)
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
- Anaphylaxis
- QT prolongation and torsades de pointes
- Seizures
- Leukopenia, thrombocytopenia
Monitoring Parameters
- Baseline: Liver function tests, renal function, electrolyte panel
- During therapy: Periodic LFTs, renal function assessment
- For long-term therapy: Regular monitoring of liver enzymes
- With interacting drugs: Therapeutic drug monitoring as appropriate (INR for warfarin, glucose for sulfonylureas)
- Clinical response: Signs and symptoms of infection resolution
- Adverse effects: Skin reactions, gastrointestinal symptoms
Patient Education
- Complete the full course of therapy even if symptoms improve
- Take at the same time each day, with or without food
- Report any signs of allergic reaction (rash, itching, swelling)
- Monitor for yellowing of skin/eyes, dark urine, or unusual fatigue (signs of liver problems)
- Inform all healthcare providers about fluconazole use, especially before new prescriptions
- Use additional contraception if taking oral contraceptives
- Diabetics should monitor blood glucose closely as fluctuations may occur
- Avoid alcohol consumption during treatment
- Report any dizziness, palpitations, or irregular heartbeat
References
1. Pfizer Inc. (2021). Diflucan (fluconazole) prescribing information. 2. Pappas PG, et al. (2016). Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases, 62(4):e1-e50. 3. Perfect JR, et al. (2010). Practice guidelines for the management of cryptococcal disease. Clinical Infectious Diseases, 50(3):291-322. 4. Lexicomp Online. (2023). Fluconazole monograph. 5. Micromedex Solutions. (2023). Fluconazole drug information. 6. FDA Drug Safety Communication. (2011). Serious liver injury with fluconazole. 7. Clinical Pharmacology [database online]. (2023). Fluconazole monograph.
Note: This information is intended for educational purposes only and should not replace professional medical advice. Always consult with a healthcare provider for personalized medical guidance.