Kezona

Systemic (Oral) Ketoconazole

Used only when no other antifungal therapy is available and benefits outweigh risks:

• Blastomycosis
• Histoplasmosis
• Coccidioidomycosis
• Paracoccidioidomycosis
• Chromomycosis
• Candidiasis (non-life-threatening systemic forms)

Clinically accepted off-label uses (oral):

• Cushing’s syndrome – to reduce cortisol levels by inhibiting adrenal steroidogenesis
• Advanced prostate cancer – anti-androgenic effect (less commonly used now)

Topical Ketoconazole (Preferred Use)

• Seborrheic dermatitis (scalp, face, chest)
• Tinea infections (tinea corporis, cruris, pedis, versicolor)
• Cutaneous candidiasis
• Dandruff (1% or 2% shampoo)

Oral Ketoconazole (200 mg tablet)

Adults:

• Fungal infections: 200 mg once daily; may increase to 400 mg daily if needed
• Cushing’s syndrome: 400–1200 mg/day in 2–3 divided doses (off-label; specialist use)

Pediatrics (≥2 years):

• 3.3–6.6 mg/kg once daily
• Not recommended for children <2 years

Elderly:

• Same as adult dose; monitor liver function

Renal impairment:

• No dosage adjustment needed

Hepatic impairment:

• Contraindicated due to hepatotoxic risk

Topical Ketoconazole

Cream 2%:

• Apply once or twice daily to affected areas
• Duration: 2–4 weeks (depending on condition)

Shampoo 1% or 2%:

• Dandruff or seborrheic dermatitis: Apply to scalp twice weekly for 2–4 weeks
• Maintenance therapy: Once weekly or once every two weeks

Foam/Gel:

• Apply to affected skin once daily

Ketoconazole is an imidazole antifungal that inhibits 14α-demethylase, a cytochrome P450-dependent enzyme necessary for converting lanosterol to ergosterol in fungal cell membranes. Ergosterol is essential for maintaining fungal cell membrane structure and function. Inhibition of ergosterol synthesis leads to increased membrane permeability, causing leakage of cellular contents and cell death. Systemically, ketoconazole also inhibits steroid hormone biosynthesis by blocking adrenal enzymes like CYP11A1 and CYP17, reducing cortisol and androgen production.

Oral:

• Absorption: Requires gastric acid; reduced by antacids and acid suppressants
• Bioavailability: ~75% with acidic stomach pH
• Peak plasma level: 1–2 hours post-dose
• Distribution: High in skin, hair, nails, liver, adrenal glands; low CSF penetration
• Protein binding: >99%
• Metabolism: Extensively metabolized in the liver via CYP3A4
• Half-life: ~6–10 hours
• Elimination: Primarily via feces (biliary); minor renal excretion

Topical:

• Absorption: Minimal systemic absorption
• Action: Local only; no systemic effect under normal use

Pregnancy:

• Oral: FDA Category C – Use only if no alternatives; teratogenicity reported in animals
• Topical: Considered safe due to negligible systemic absorption

Lactation:

• Oral: Avoid – excreted in breast milk, potential for infant toxicity
• Topical: Generally safe; avoid application on or near the nipple

• Primary Class: Antifungal agent
• Subclass: Imidazole antifungal
• Other Role (Oral): Adrenal steroidogenesis inhibitor (off-label endocrinologic use)

• Known hypersensitivity to ketoconazole or excipients
• Active liver disease (oral form)
• Co-administration with drugs metabolized by CYP3A4 that may prolong QT interval (e.g., cisapride, pimozide, quinidine)
• Pregnancy and breastfeeding (oral use only)
• History of hepatic toxicity with ketoconazole

• Hepatotoxicity (oral):
• Black Box Warning – can cause fatal liver injury
• Monitor liver function before and during therapy
• Discontinue if liver enzymes rise significantly
• Adrenal suppression:
• Monitor cortisol in long-term high-dose therapy
• QT prolongation:
• Avoid with QT-prolonging drugs and monitor ECG if risk factors present
• Drug absorption:
• Avoid antacids or acid-reducing agents within 2 hours of dosing
• Topical use precautions:
• Discontinue if local irritation or allergic reaction occurs
• Avoid contact with eyes and mucous membranes

Oral:

Common:

• Nausea, vomiting
• Abdominal discomfort
• Headache
• Menstrual irregularities
• Gynecomastia
• Pruritus

Serious:

• Hepatitis, liver failure
• Adrenal insufficiency
• QT prolongation, arrhythmia
• Anaphylaxis, angioedema
• Stevens-Johnson syndrome (rare)

Topical:

Common:

• Burning or stinging at application site
• Local irritation
• Dry or oily scalp (shampoo use)
• Pruritus

Rare:

• Allergic dermatitis
• Skin rash
• Hair thinning (scalp use)

Oral Ketoconazole:

• Major CYP3A4 interactions (inhibitor):
• Increases levels of drugs like warfarin, cyclosporine, statins, benzodiazepines
• May cause QT prolongation when combined with drugs like pimozide, quinidine
• Reduced absorption with:
• Antacids, PPIs, H2-blockers (e.g., omeprazole, ranitidine)

Topical Ketoconazole:

No clinically relevant systemic interactions

• FDA (Black Box Warning for oral):
• Oral ketoconazole should only be used when other effective antifungal therapies are not available or tolerated
• Emphasis on liver monitoring and cardiac risk
• WHO/EMA:
• Oral use restricted to severe systemic infections; discouraged for skin or nail infections
• Topical use remains widely accepted and first-line in dermatologic fungal conditions
• Endocrine Society Guidelines:
• Ketoconazole remains a second-line option for Cushing’s disease when surgery is not feasible or has failed

Oral Tablets:

• Store at 20°C–25°C (68°F–77°F)
• Protect from moisture and light
• Keep container tightly closed

Topical Cream, Gel, Foam:

• Store between 15°C–30°C (59°F–86°F)
• Avoid freezing
• Use within expiration date

Shampoo (1% or 2%):

• Store below 25°C
• Shake well before use
• Protect from light
• Do not freeze