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European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole

Benefit of oral ketoconazole does not outweigh risk of liver injury in fungal infections

The European Medicines Agency’s Committee on Medicinal Products for Human Use (CHMP) has recommended that the marketing authorisations of oral ketoconazole-containing medicines should be suspended throughout the European Union (EU). The CHMP concluded that the risk of liver injury is greater than the benefits in treating fungal infections.
Patients currently taking oral ketoconazole for fungal infections should make a non-urgent appointment with their doctor to discuss suitable alternative treatments. Doctors should no longer prescribe oral ketoconazole and should review patients’ treatment options.

The EU-wide review of oral ketoconazole was triggered by the suspension of the medicine in France. The French medicine agency, the National Agency for the Safety of Medicine and Health Products (ANSM), concluded that the benefit-risk balance of oral ketoconazole was negative because of a high level of liver injury associated with the medicine and in view of the currently available alternative treatments, which are deemed to be safer. European legislation requires that there is a coordinated European approach when a Member State takes regulatory action in relation to a medicine that is authorised in more than one country.

Having assessed the available data on the risks with oral ketoconazole, the CHMP concluded that, although liver injury such as hepatitis is a known side effect of antifungal medicines, the incidence and the seriousness of liver injury with oral ketoconazole were higher than with other antifungals. TheCHMP was concerned that reports of liver injury occurred early after starting treatment with recommended doses, and it was not possible to identify measures to adequately reduce this risk. The Committee also concluded that the clinical benefit of oral ketoconazole is uncertain as data on its effectiveness are limited and do not meet current standards, and alternative treatments are available.

Taking into account the increased rate of liver injury and the availability of alternative antifungal treatments, theCHMP concluded that the benefits did not outweigh the risks. Topical formulations of ketoconazole (such as creams, ointments and shampoos) can continue to be used as the amount of ketoconazole absorbed throughout the body is very low with these formulations.

The CHMP opinion will now be sent to the European Commission for a legally binding decision.
The European Medicines Agency is aware that ketoconazole is used off-label for treating patients with Cushing’s syndrome. In order to ensure that these patients will not be left without treatment, national competent authorities may make these medicines available under controlled conditions.