Ketoconazole: Clinical Uses and Current Role
Ketoconazole is an oral antifungal agent now restricted to treating systemic fungal infections (blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis) only when other effective antifungal therapy is not available or tolerated, due to significant hepatotoxicity and endocrine adverse effects. 1
FDA-Approved Systemic Indications
Oral ketoconazole tablets should be used only as a last-resort option for specific systemic fungal infections:
- Approved systemic infections: Blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis 1
- Explicitly NOT indicated for: Onychomycosis (nail infections), cutaneous dermatophyte infections, or Candida infections 1
- Contraindicated for: Fungal meningitis due to poor cerebrospinal fluid penetration 1
Historical Context and Restrictions
The use of oral ketoconazole has been dramatically curtailed due to safety concerns:
- Hepatotoxicity risk: Symptomatic drug-induced hepatitis occurs in approximately 1 in 12,000 patients, with asymptomatic transaminase elevations in 1-13% of patients 2, 3
- Regulatory actions: Withdrawn from European and Australian markets in 2013; strict relabeling and prescription restrictions imposed in the United States 4
- Guideline exclusions: Explicitly excluded from pediatric antifungal prophylaxis guidelines due to hepatotoxicity, adrenal suppression, and drug interactions 2
Limited Current Clinical Applications
Systemic Fungal Infections (Alternative Therapy Only)
For mild to moderate blastomycosis when itraconazole is not available:
- Dosing: 400-800 mg/day 2
- Cure rates: 70% at 400 mg/day, 85% at 800 mg/day 2
- Critical caveat: Itraconazole has replaced ketoconazole as the preferred treatment option due to better absorption, enhanced antimycotic activity, and superior tolerability 2
Recalcitrant Yeast Infections (Highly Restricted)
For severe, treatment-resistant cases only:
- May be used in some recalcitrant cases of yeast infection affecting the nails, but cannot be prescribed for dermatophyte onychomycosis due to hepatotoxicity problems 2
- For HIV-related oropharyngeal candidiasis: Less effective than fluconazole due to variable absorption; not reasonable to use if other options are available 2
Topical Formulations (Safe and Effective)
Topical ketoconazole remains widely used and safe:
- First-line treatment for tinea versicolor 4
- Effective for seborrheic dermatitis and superficial fungal infections 5
- Can be used safely for angular cheilitis (fungal component) with no significant systemic absorption when applied to intact skin 6
- Available as shampoo, cream, foam, and gel formulations 5
Critical Safety Considerations
Major Adverse Effects
- Hepatotoxicity: Transient liver enzyme elevations common; symptomatic hepatitis rare but serious 2, 3
- Endocrine effects: Adrenal insufficiency, gynecomastia, and interference with testosterone/cortisol synthesis 2, 3
- Gastrointestinal: Nausea and vomiting are most common side effects 7
Significant Drug Interactions
Ketoconazole has the strongest cytochrome P-450 inhibitory effect among azoles:
- Warfarin, cyclosporin, oral contraceptive pills 2
- Chlordiazepoxide, methylprednisolone 8
- Requires careful evaluation before initiation, particularly with antiretroviral drugs 2
Absorption and Administration Pitfalls
Ketoconazole absorption is highly pH-dependent:
- Requires gastric acidity for absorption - better absorbed from acidic aqueous solutions 7
- Antacids significantly reduce absorption 7, 8
- Should be taken with food to enhance absorption 7
- Variable absorption in renal failure and bone marrow transplantation 8
Clinical Bottom Line
In modern practice, oral ketoconazole has been relegated to a last-resort agent for endemic systemic mycoses when safer alternatives (itraconazole, fluconazole, amphotericin B) are not available or tolerated. 1, 4 Topical ketoconazole formulations remain safe, effective, and widely prescribed for superficial mycoses. 4, 5