Fluconazole Side Effects
Fluconazole commonly causes gastrointestinal side effects, hepatotoxicity, skin reactions, and drug interactions, with serious adverse events occurring more frequently in immunocompromised patients. 1
Common Side Effects
Fluconazole is generally well tolerated, but several side effects can occur:
Gastrointestinal Effects
- Nausea (3.7% of patients)
- Vomiting (1.7%)
- Abdominal pain (1.7%)
- Diarrhea (1.5%)
- Dyspepsia (1%)
Neurological Effects
- Headache (1.9%, up to 13% in single-dose treatment for vaginal candidiasis)
- Dizziness (1%)
- Taste perversion (1%)
- Seizures (rare)
Dermatologic Effects
- Skin rash (1.8%)
- Xerosis (dry skin) (16.9% with long-term therapy)
- Alopecia (16.1% with long-term therapy) 2
Serious Side Effects
Hepatobiliary Effects
- Transient elevations in liver enzymes (common)
- Serious hepatic reactions (rare but potentially fatal)
- Clinical hepatitis
- Cholestasis
- Fulminant hepatic failure 1
Risk factors for hepatotoxicity include:
- Concomitant medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylureas
- Underlying conditions: AIDS, malignancies 1
Cardiovascular Effects
- QT prolongation
- Torsade de pointes 1
Immunologic Effects
- Anaphylaxis (rare)
- Angioedema
- Face edema
- Pruritus 1
Endocrine Effects
- Adrenal insufficiency (reversible) 1
Side Effects with Long-Term Use
Long-term fluconazole therapy (as used in cryptococcal meningitis or coccidioidomycosis) has additional considerations:
- 51.6% of patients on long-term therapy experience adverse effects
- 65.6% of those experiencing adverse effects require therapeutic intervention (dose reduction, discontinuation, or switch to another antifungal)
- Higher doses correlate with increased adverse effects (6.7 vs 5.7 mg/kg in those with and without adverse effects) 2
Drug Interactions
Fluconazole has significant drug interactions due to inhibition of cytochrome P-450 enzymes:
- Inhibits CYP3A4, CYP2C9, and CYP2C19 enzymes
- Can increase plasma concentrations of medications metabolized by these pathways
- May cause QT prolongation when combined with other QT-prolonging drugs (fluoroquinolones, macrolides, ondansetron) 3
Notable interactions include:
- Warfarin
- Phenytoin
- Cyclosporine
- Rifampin
- Oral hypoglycemic agents
- Certain HIV medications 1
Special Populations
HIV-Infected Patients
- Higher incidence of adverse events (21%) compared to non-HIV infected patients (13%) 1
- May require prolonged therapy for cryptococcal infections 3
Pregnant Women
- Teratogenic in high doses in animal studies
- Unusual cluster of craniofacial and skeletal defects reported after prolonged high-dose use in first trimester
- Single-dose treatment in first trimester has not shown increased anomalies 3
Monitoring Recommendations
For patients on fluconazole therapy, especially long-term:
- Monitor liver function tests
- Watch for signs of hepatotoxicity (dark urine, light-colored stools, jaundice)
- Be alert for skin reactions
- Consider dose reduction if adverse effects occur 1, 2
Pitfalls and Caveats
- Fluconazole resistance may develop with prolonged use, particularly in patients with low CD4+ counts (<100 cells/μL) 3
- Serious hepatic reactions may occur in patients with no identifiable risk factors 1
- Drug interactions are common and clinically significant; always review concomitant medications 3
- Higher doses and longer duration of therapy increase risk of adverse effects 2
When prescribing fluconazole, carefully weigh the benefits against potential risks, particularly for long-term therapy, and consider monitoring for adverse effects, especially hepatotoxicity.