Ketoconazole Safe for Cushing’s Treatment, But Liver Monitoring Advised, Study Reports

José Lopes, PhD avatar

by José Lopes, PhD |

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Ketoconazole is a safe treatment for Cushing’s syndrome patients, but close monitoring of liver function markers should be done for up to six months, a French study shows.

The study, “Hepatic safety of ketoconazole in Cushing’s syndrome: results of a compassionate use program in France,” appeared in the European Journal of Endocrinology.

In Cushing’s syndrome patients, medical treatment is provided to prepare them for the surgical removal of the pituitary adenoma, which is the first line of treatment. Medication is also used in cases when surgery is not possible, when it fails, or when there is disease recurrence post-surgery.

One of the medications used is ketoconazole, which acts on the brain’s adrenal cortex and prevents steroid production. It has long been used in Cushing’s patients on an off-label basis. Although this treatment effectively reduces Cushing’s manifestations, it may cause severe liver toxicity in rare cases.

Most reports of severe liver toxicity with ketoconazole come from its use as an antifungal therapy in patients without appropriate monitoring of liver function. Because other alternatives are equally effective and have lower risks, marketing authorization for ketoconazole as an antifungal therapy was removed in Europe in 2013. But the treatment remained available for Cushing’s syndrome patients while stocks lasted.

The U.S. Food and Drug Administration also limited the use of ketoconazole by approving label changes that removed antifungal indications in 2013 because of the risks of serious liver damage, adrenal gland problems, and harmful interactions with other medicines. It issued another warning in 2016 when a safety review found that physicians were still prescribing the medication as an antifungal therapy. Ketoconazole is not FDA-approved for Cushing’s syndrome, but it is still prescribed off-label.

At the same time, HRA Pharma filed a new drug application in Europe for the specific use of ketoconazole in the treatment of Cushing’s syndrome in adults and adolescents older than 12. Marketing authorization was granted by the European Commission at the end of 2014.

In the meantime, the therapy was made available in France on a compassionate use program, intended to allow access to unauthorized medications when there are no satisfactory alternatives.

Compassionate use was established on the condition that the safety of ketoconazole in the treatment of Cushing’s would be monitored throughout the program, which allowed the assessment of ketoconazole’s tolerability in a real-world setting.

Researchers in France analyzed the liver safety of ketoconazole in a group of 108 Cushing’s syndrome patients. They also compared liver safety according to treatment duration. The median dose was 600 mg/day, ranging from 200 to 1,200 mg/day.

The study divided participants into those who had never received ketoconazole (ketoconazole-naïve), which included 47 patients, and those who had already been treated with a different formulation of ketoconazole (ketoconazole-switch), which included 61 patients. Scientists monitored liver function markers — alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyltransferase, and bilirubin — at regular intervals.

Results revealed that most changes consisted of asymptomatic, mild increases of liver enzymes. Four ketoconazole-naïve and two ketoconazole-switch patients developed liver injury, which was attributed to the medicine in three cases, all of whom had never received ketoconazole, within the first month of treatment.

Data also revealed that five patients had mild abnormalities in liver function at the study’s start, with two cases of liver metastases. Two patients recovered to normal levels of liver enzymes after stopping ketoconazole treatment. The remaining patient died of causes unrelated to the medication.

No unexpected liver safety issues were observed. Although the treatment had to be discontinued in 36.1% patients, the reason for this discontinuation was most often unrelated to the medicine, the investigators observed. Among the patients who had to stop taking ketoconazole, four cases were due to lack of effectiveness, three to liver injury, two to adrenal insufficiency, and two to other adverse reactions.

“These new data collected prospectively highlight the need for close monitoring of liver enzymes especially at the beginning of treatment and up to six months. If care is taken to monitor liver function effectively, [ketoconazole] can be used safely in patients with [Cushing’s syndrome],” the investigators concluded.