Introduction
Diflucan (fluconazole) is a synthetic triazole antifungal agent that has become a cornerstone in the treatment and prevention of systemic fungal infections. Since its FDA approval in 1990, it has been widely used due to its excellent bioavailability, favorable safety profile, and broad spectrum of activity against various Candida species and Cryptococcus neoformans.
Mechanism of Action
Fluconazole exerts its antifungal effect through inhibition of the cytochrome P450 enzyme 14α-demethylase. This enzyme is essential for the conversion of lanosterol to ergosterol, a critical component of fungal cell membranes. By depleting ergosterol levels and accumulating toxic methylated sterols, fluconazole causes increased membrane permeability and inhibition of fungal cell growth and replication.
Indications
FDA-approved indications include:
- Treatment of oropharyngeal and esophageal candidiasis
- Vaginal candidiasis (single-dose therapy)
- Cryptococcal meningitis (treatment and maintenance therapy)
- Prevention of candidiasis in patients undergoing bone marrow transplantation
- Systemic Candida infections (including urinary tract infections, peritonitis, and pneumonia)
- Off-label uses include prophylaxis in other immunocompromised patients and treatment of certain endemic mycoses
Dosage and Administration
Standard dosing:- Oropharyngeal candidiasis: 200 mg loading dose, then 100 mg daily
- Esophageal candidiasis: 200 mg loading dose, then 100-200 mg daily
- Vaginal candidiasis: 150 mg single dose
- Cryptococcal meningitis: 400 mg loading dose, then 200-400 mg daily
- Prevention in transplant patients: 400 mg daily
- Renal impairment: Adjust dose based on creatinine clearance
- Hepatic impairment: Use with caution; monitor closely
- Pediatrics: 3-12 mg/kg/day based on indication
- Elderly: Consider renal function adjustments
Available as oral tablets, suspension, and intravenous formulation with complete bioavailability between routes.
Pharmacokinetics
Absorption: Rapid and complete oral bioavailability (>90%) unaffected by food Distribution: Widely distributed to tissues and body fluids, including CSF (60-80% of serum levels) Metabolism: Minimally hepatic (approximately 11%) via CYP2C9 and CYP3A4 Elimination: Primarily renal excretion (80% unchanged drug); elimination half-life 30 hours Protein binding: Low (11-12%)Contraindications
- Hypersensitivity to fluconazole or other azole antifungals
- Concurrent administration with cisapride (due to QT prolongation risk)
- Concurrent administration with erythromycin in patients with potential for QT prolongation
- Known QT prolongation or use of other QT-prolonging medications
Warnings and Precautions
- Hepatotoxicity: Cases of serious hepatic reactions reported; monitor liver function
- QT prolongation: Dose-related QT interval prolongation observed
- Anaphylaxis: Rare cases reported
- Dermatologic reactions: Serious skin disorders including Stevens-Johnson syndrome reported
- Renal impairment: Requires dosage adjustment
- Pregnancy: Category D - use only if potential benefit justifies potential risk
- Drug-resistant fungi: Emergence of resistant Candida species possible
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
- Theophylline: ↑ Theophylline levels (monitor levels)
- Oral contraceptives: Potential decreased efficacy
- Statins: Increased risk of myopathy/rhabdomyolysis
- QT-prolonging drugs: Additive effect on QT interval
Adverse Effects
Common (≥1%):- Headache (13%)
- Nausea (7%)
- Abdominal pain (6%)
- Diarrhea (3%)
- Rash (2%)
- Taste perversion (2%)
- Hepatotoxicity (elevated transaminases, hepatitis)
- 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, serum creatinine
- For specific indications: Culture and sensitivity results, imaging studies
- With prolonged therapy: Complete blood count, adrenal function assessment
- With concomitant medications: INR (warfarin), drug levels (phenytoin, cyclosporine), glucose levels (sulfonylureas)
- ECG monitoring: In patients with risk factors for QT prolongation
Patient Education
- Take as directed, with or without food
- Complete full course of therapy even if symptoms improve
- Report any signs of allergic reaction (rash, itching, swelling)
- Monitor for signs of liver problems (yellowing skin/eyes, dark urine, abdominal pain)
- Inform all healthcare providers of fluconazole use
- Use effective contraception during treatment (if using hormonal methods)
- Report any unusual heart rhythms, dizziness, or fainting
- Diabetic patients should monitor blood glucose closely
- Do not share medication with others
- Store at room temperature away from moisture
References
1. FDA Prescribing Information: Diflucan (fluconazole) [2023] 2. Patterson TF, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the IDSA. Clin Infect Dis. 2016;63(4):e1-e60 3. Pappas PG, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-e50 4. Lexicomp Online, Fluconazole Drug Information [2023] 5. Micromedex Solutions, Fluconazole Drug Monograph [2023] 6. Perfect JR, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010;50(3):291-322 7. Albengres E, et al. Systemic antifungal agents. Drug interactions of clinical significance. Drug Saf. 1998;18(2):83-97