DI-041 Ketaconazole: medical treatment of cushing’s syndrome

Background In Cushing’s syndrome (CS), when surgery is unsuccessful or contraindicated, ketoconazole is the drug most frequently used to treat hypercortisolism. In July 2013, European Medicines Agency announced their negative risk-benefit assessment of oral ketoconazole as treatment of fungal infections, because it can cause liver damage and drug interactions due to cytochrome P450 inhibition. Ketoconazole was suspended as an antifungal in the European Union, but compassionate use is authorised for CS. Purpose To analyse the hormonal effects and tolerance of ketoconazole in CS over the last year. Material and methods Nine patients [32–83 years old] were treated in hospital. All patients were retrospectively studied with a follow-up of 26 months; their treatment had lasted from 12 days–25 years. One patient had ectopic ACTH production, two had pituitary adenoma, and six had adrenal neoplasia. Four patients had previously had surgery, but it was not effective in two cases. The dose of ketoconazole was between 200–1,200 mg/day. Liver tests checked: transaminases, total bilirubin and alkaline phosphatase. Hormonal control was observed with Nugent’s test and 24 h urinary free cortisol. The patient’s current treatment was noted to check for drug interactions. Results All patients were checked. No adrenal insufficiency was observed. Liver function tests were normal. Five patients stopped ketoconazole: two for surgery; two died of metastatic cancer; and one because of a potential drug interaction with calcium antagonism. 77.8% of the patients had some possible drug interactions, but only one stopped ketoconazole. Other interactions were with drugs metabolised by CYP450; or with proton pump inhibitors which reduce the pH-dependent absorption of ketoconazole. These problems were solved by changing the dose of the drugs concerned. Conclusion Ketoconazole seems to be a safe and efficacious treatment in CS. However, it is necessary to perform a bigger study to get significant conclusions. Reference Feelders RA, Hofland LJ, de Herder WW. Medical treatment of Cushing’s syndrome: adrenal-blocking drugs and ketoconazole. Neuroendocrinology 2010;92(Suppl 1):111–15 No conflict of interest.