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Adrenal Steroidogenesis Inhibitor (Antifungal with Adrenal Suppressing Properties) Pregnancy: Contraindicated — teratogenic in animals; androgen suppression may cause feminisation of male fetus. Do not use in pregnancy.

Ketoconazole (Adrenal Indication)

Brand names: Nizoral (oral — specialist use), HRA Pharma (licensed for Cushing's in EU)

Adult dose

Dose: Cushing's syndrome: 200mg BD–TDS initially (400–600mg daily); titrate up to 1200mg daily in divided doses based on cortisol response. Usual maintenance 600–800mg daily in 2–3 divided doses.
Route: Oral (take with food — requires gastric acid for absorption)
Frequency: Two to three times daily
Max: 1200mg daily (divided doses)
Inhibits multiple CYP450 enzymes in adrenal steroidogenesis (17-alpha-hydroxylase, 11-beta-hydroxylase, side-chain cleavage enzyme). Significant hepatotoxicity risk — MHRA restriction: oral ketoconazole for systemic fungal infections withdrawn in UK (2013) due to liver toxicity; remains available under specialist endocrinology supervision for Cushing's syndrome only. Requires gastric acid for absorption — avoid PPIs or H2-blockers; give with a cola drink or acidic food if hypochlorhydric.

Paediatric dose

Route: Oral
Frequency: Two to three times daily
Max: Individualised
Used under specialist paediatric endocrinology supervision for Cushing's syndrome in children. Seek specialist opinion. No licensed paediatric dose — use extrapolated adult dosing with close monitoring.

Dose adjustments

Renal

No dose adjustment required — primarily hepatically metabolised and excreted in bile.

Hepatic

Contraindicated in hepatic impairment — risk of severe hepatotoxicity. Check LFTs before starting; do not use if baseline LFTs abnormal.

Clinical pearls

  • MHRA 2013: oral ketoconazole withdrawn from UK market for antifungal indications due to hepatotoxicity risk (benefit-risk unfavourable for fungal infections when alternatives exist). Endocrine use (Cushing's) continues under specialist supervision — benefit outweighs risk in severe hypercortisolaemia.
  • Hepatotoxicity monitoring: LFTs weekly for first month, then monthly — stop immediately if LFTs >3× ULN
  • Absorption tip: give with cola (acidic beverage) in patients on PPIs or with low gastric acid — improves absorption significantly
  • Drug interaction burden is enormous (major CYP3A4 inhibitor) — always conduct full medication review before prescribing; many common drugs are contraindicated

Contraindications

  • Hepatic impairment or elevated baseline LFTs
  • Concomitant drugs that are narrow-therapeutic-index CYP3A4 substrates (simvastatin, lovastatin, triazolam, midazolam, cisapride, pimozide — risk of serious toxicity)
  • QT prolongation or drugs that prolong QT (ketoconazole itself prolongs QT)
  • Hypersensitivity to ketoconazole

Side effects

  • Hepatotoxicity (serious — including acute liver failure and death; MHRA warning)
  • Nausea and vomiting
  • Adrenal insufficiency (cortisol over-suppression)
  • QT prolongation
  • Gynaecomastia (anti-androgenic effect)
  • Decreased libido / erectile dysfunction (androgen suppression)
  • Rash

Interactions

  • Simvastatin, atorvastatin (high dose) — risk of rhabdomyolysis (CYP3A4 inhibition); avoid combination or use pravastatin/rosuvastatin instead
  • Warfarin — markedly increased anticoagulant effect; monitor INR closely
  • Cyclosporin, tacrolimus — significantly increased immunosuppressant levels; dose reduction and monitoring required
  • Midazolam, triazolam — prolonged sedation (CYP3A4 inhibition) — contraindicated
  • PPIs, H2 blockers, antacids — reduce ketoconazole absorption (requires acid for dissolution)
  • Rifampicin — reduces ketoconazole levels significantly

Monitoring

  • LFTs (weekly × 4 weeks, then monthly)
  • Urinary free cortisol / serum cortisol (guide dose titration — target normal cortisol)
  • QTc interval (ECG at baseline and if symptoms)
  • Blood pressure and potassium
  • Symptoms of adrenal insufficiency

Reference: BNFc; BNF 90; MHRA Ketoconazole Safety Update 2013; Endocrine Society Cushing's Syndrome Guidelines 2015. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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