Ketoconazole

Generic Name

Ketoconazole

Chemical Class

Imidazole antifungal agent

Brand Names

Nizoral

Ketozole

Extina

Xolegel

Kuric

Ketoderm

Sebizole

Available in several dosage forms: tablets (systemic), cream, shampoo, foam, gel

Drug Class

Azole antifungal (imidazole subclass)

Systemic and topical antifungal agent

CYP450 enzyme inhibitor

Mechanism of Action

Ketoconazole inhibits the fungal cytochrome P450 enzyme 14-α-demethylase

This enzyme is essential for the conversion of lanosterol to ergosterol, a critical component of fungal cell membranes

Disruption of ergosterol synthesis impairs membrane fluidity and integrity, leading to increased membrane permeability, leakage of intracellular contents, and fungal cell death

At higher concentrations, ketoconazole also inhibits human steroid biosynthesis (e.g., cortisol, testosterone) by blocking adrenal and gonadal CYP450 enzymes

Fungal Spectrum

Active against a broad range of fungi

Dermatophytes: Trichophyton, Microsporum, Epidermophyton

Yeasts: Candida albicans, Candida tropicalis, Candida parapsilosis, Malassezia furfur

Dimorphic fungi: Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis

Limited activity against molds like Aspergillus spp

Indications

Systemic (oral use)

Only used when no alternative antifungal therapy is available due to its hepatotoxicity

Endemic fungal infections (e.g., histoplasmosis, coccidioidomycosis, blastomycosis)

Chronic mucocutaneous candidiasis

Candidiasis unresponsive to other antifungals

Cushing’s syndrome (off-label use for adrenal steroid inhibition)

Topical Use (cream, shampoo, gel)

Tinea corporis, cruris, pedis (ringworm, jock itch, athlete’s foot)

Tinea versicolor (caused by Malassezia)

Seborrheic dermatitis

Cutaneous candidiasis

Pityriasis versicolor

Scalp fungal infections

Seborrhea of the face, scalp, chest

Off-Label Uses

Prostate cancer (hormonal therapy)

Adrenocortical carcinoma (as adrenal steroidogenesis inhibitor)

Hormone-sensitive breast cancer

Hair loss: androgenetic alopecia and seborrheic dermatitis-associated hair loss (topical)

Dosage and Administration

Oral Ketoconazole (restricted use)

200 mg to 400 mg once daily orally

Take with food for optimal absorption (acidic environment improves bioavailability)

For fungal infections: duration varies from 2 weeks to several months depending on condition

In Cushing’s syndrome: starting dose 200–400 mg twice daily, adjusted based on cortisol levels

Topical Cream

Apply once or twice daily to affected area

Treatment duration:

– Tinea corporis/cruris: 2–4 weeks

– Tinea pedis: up to 6 weeks

– Cutaneous candidiasis: 2–3 weeks

– Seborrheic dermatitis: daily or alternate days as needed

Shampoo

Apply to wet scalp, leave for 3–5 minutes before rinsing

Used twice weekly for treatment, once weekly or every 2 weeks for prevention

Indicated for dandruff and seborrheic dermatitis

Gel/Foam

Applied daily or twice daily to affected area

Used for seborrheic dermatitis or tinea versicolor

Pediatric Use

Oral: generally avoided due to hepatotoxicity

Topical: may be used under medical guidance

Pharmacokinetics (Oral)

Bioavailability: ~75% with food

Peak levels: 1–2 hours post-dose

Highly protein-bound (~99%)

Metabolized extensively by liver via CYP3A4

Excreted in bile (main), urine (minor)

Half-life: ~8 hours

Contraindications

Known hypersensitivity to ketoconazole or azole antifungals

Acute or chronic liver disease

Coadministration with drugs metabolized by CYP3A4 that may lead to life-threatening QT prolongation (e.g., cisapride, dofetilide, pimozide, quinidine, erythromycin)

Pregnancy and lactation (oral use)

Warnings and Precautions

Hepatotoxicity (Black Box Warning)

Serious, sometimes fatal hepatotoxicity may occur

Monitor liver function tests (ALT, AST, bilirubin) before and during therapy

Use oral ketoconazole only when no alternative antifungal is available

Avoid alcohol and other hepatotoxic drugs

Adrenal Insufficiency

Inhibits adrenal steroidogenesis

Monitor adrenal function in long-term use or high doses

Risk increases in patients with adrenal insufficiency, sepsis, or stress

QT Prolongation and Arrhythmia Risk

Avoid concurrent use with other QT-prolonging agents

Risk of torsades de pointes with CYP3A4 substrates

Drug Interactions (Oral)

CYP3A4 Inhibition

Strong inhibitor

Increases plasma levels of many medications

Risk of serious or fatal arrhythmias with:

– Cisapride

– Pimozide

– Dofetilide

– Quinidine

– Methadone

– Ranolazine

– Certain statins (simvastatin, lovastatin)

– Eplerenone

– Triazolam, midazolam

Avoid coadministration with these agents

Drugs That Decrease Ketoconazole Levels

Antacids, H2 blockers, proton pump inhibitors

Separate dosing or avoid use

Rifampin, isoniazid, phenytoin, carbamazepine (enzyme inducers): reduce efficacy

Drugs Whose Levels Increase with Ketoconazole

Warfarin (↑ bleeding risk)

Cyclosporine, tacrolimus, sirolimus (↑ nephrotoxicity)

Benzodiazepines (↑ sedation)

Calcium channel blockers

Antineoplastics (e.g., vincristine, erlotinib)

Adverse Effects

Oral Ketoconazole

Gastrointestinal: nausea, vomiting, abdominal pain

Endocrine: gynecomastia, menstrual irregularities, adrenal insufficiency

Hepatic: elevated transaminases, hepatitis, hepatic failure

Skin: pruritus, rash, urticaria

CNS: headache, dizziness, photophobia

Rare: thrombocytopenia, anaphylaxis

Topical Ketoconazole

Generally well tolerated

Application site burning, irritation, dryness, erythema, pruritus

Allergic contact dermatitis (rare)

Hair texture changes with shampoo

Pregnancy and Lactation

Pregnancy Category

Oral: Category C (teratogenic in animals)

Avoid unless benefits outweigh risks

Topical: minimal systemic absorption; considered safe for short-term use

Lactation

Oral: avoid due to excretion in breast milk

Topical: use with caution; avoid application near breasts

Overdose Management

No specific antidote

Supportive care and monitoring

Activated charcoal may be used if ingestion is recent

Liver function tests and ECG monitoring recommended

Monitoring Parameters (Oral)

Baseline and periodic liver function tests (ALT, AST, bilirubin)

Monitor adrenal function (e.g., cortisol levels) in prolonged use

Serum testosterone if used for endocrine effects

ECG in patients at risk of QT prolongation

Comparative Pharmacology

Ketoconazole vs Fluconazole

Fluconazole has better CNS penetration and fewer drug interactions

Fluconazole preferred for candidiasis and cryptococcal infections

Ketoconazole mainly used topically now

Ketoconazole vs Itraconazole

Itraconazole is preferred systemically due to reduced hepatotoxicity

Ketoconazole has better skin penetration topically

Ketoconazole vs Terbinafine

Terbinafine is fungicidal and used for dermatophyte infections

Ketoconazole is fungistatic and used more for yeast and seborrhea

Legal and Regulatory Status

Oral use restricted or withdrawn in many countries due to liver toxicity

Still available in topical forms

Black Box Warning by FDA for oral formulations

Listed in WHO Essential Medicines (topical only)