Ketoconazole Antifungal

Ketoconazole is an imidazole antifungal. Oral use for fungal infection has been restricted or withdrawn in several regions because of hepatotoxicity, adrenal suppression and many dangerous interactions, and it is now reserved for endemic mycoses when safer azoles are unavailable. Topical ketoconazole remains widely used for skin infections.

Class. Imidazole antifungal.

Mechanism. Inhibits fungal CYP51, blocking ergosterol synthesis; also inhibits human steroid synthesis.

Pharmacokinetics. Oral absorption needs gastric acid and food; half life about 8 hours. Hepatic metabolism; poor cerebrospinal fluid penetration. Systemic absorption from topical use is minimal. Strong CYP3A4 inhibitor.

Systemic endemic mycoses (when itraconazole is unavailable). - Adults: 200 mg orally once daily with food, increased to 400 mg once daily if response is inadequate. - Duration: 6 months to 12 months for histoplasmosis and blastomycosis, individualised. - Maximum: 400 mg daily. Loading dose: none. - Children (over 2 years): 3.3 to 6.6 mg/kg once daily.

Topical. - Cream 2%: once or twice daily for 2 to 4 weeks (tinea and cutaneous candidiasis). - Shampoo 2%: seborrhoeic dermatitis, twice weekly for 2 to 4 weeks; pityriasis versicolor, once daily for 3 days.

Main alternative. Itraconazole for endemic mycoses; terbinafine or topical azoles for dermatophytosis.

Contraindications. Acute or chronic liver disease, hypersensitivity, and co-prescription of dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, ranolazine, simvastatin, lovastatin, triazolam, oral midazolam, ergot alkaloids and colchicine in kidney or liver impairment.

Serious adverse effects (boxed-warning-level). Severe hepatotoxicity (including fatal liver failure), QT prolongation and torsades de pointes, adrenal insufficiency, and suppression of testosterone with gynaecomastia and impotence.

Common adverse effects. Nausea, abdominal pain, rash, pruritus and raised liver enzymes. Topical: local irritation.

Interactions. Acid suppression reduces absorption; rifampicin and isoniazid lower levels. Raises levels of many CYP3A4 substrates, including ciclosporin, tacrolimus and warfarin.

Common prescribing errors. Using it for non-severe superficial infection, no baseline liver tests, giving it with acid suppression, and missing interactions.

Special groups. - Pregnancy: avoid systemic use; anti-androgen effects and animal teratogenicity. Topical use is acceptable. - Breastfeeding: avoid systemic use; topical acceptable. - Children: restricted to severe disease. - Older adults: usual dose with liver monitoring. - Kidney impairment: no adjustment. - Liver impairment: contraindicated.

Formulations. Tablets 200 mg; cream 2%; shampoo 2%.

Administration. Oral dose with a meal; an acidic drink helps when gastric acid is low.

Baseline. Liver tests, ECG, pregnancy test, drug review.

Monitoring. Liver tests weekly for the first month, then monthly; adrenal symptoms on prolonged use.

Stopping thresholds. Stop for ALT over three times the upper limit of normal, jaundice, symptomatic hepatitis, QTcF over 500 ms or adrenal insufficiency.

Referral and escalation. Specialist review for systemic mycoses requiring azole therapy.