Ketoconazole (Adrenal Indication)

How it works

It inhibits several cytochrome P450 enzymes in the adrenal cortisol synthesis pathway, lowering circulating cortisol concentrations.

Prescribing in practice

• Hepatotoxicity, including rare fatal liver injury, is the dominant risk, so liver function must be checked at baseline and monitored regularly, and the drug stopped if significant derangement occurs.
• It is a potent CYP3A4 inhibitor and QT-prolonging agent, causing many serious interactions, and requires gastric acidity for absorption so concurrent acid-suppressing drugs reduce its effect.
• Titrate against cortisol levels to avoid inducing adrenal insufficiency, and counsel on the need for steroid cover during intercurrent illness.

Monitoring

Monitor liver function closely (baseline and during treatment), serum or urinary cortisol for efficacy and over-suppression, and the ECG/QT interval as indicated.

Counselling the patient

• Report immediately any nausea, vomiting, abdominal pain, dark urine, pale stools or yellowing of the skin or eyes.
• Avoid alcohol and tell any prescriber you are taking this, as it interacts with many medicines.
• Symptoms of low cortisol such as severe tiredness, dizziness or vomiting need urgent review.

Evidence & guidelines

Ketoconazole is licensed in Europe for Cushing's syndrome and is an established second-line medical therapy in endocrine guidance when surgery is not curative or feasible.