Ketoconazole-containing medicines

• Oral (by mouth) ketoconazole has been suspended following a review of data showing higher liver toxicity with this medicine compared with other antifungal medicines.
• If you are currently taking oral ketoconazole for fungal infections, you should speak to your doctor at a routine appointment to discuss suitable alternative treatments.
• If you are taking topical formulations of ketoconazole (such as creams, ointments and shampoos), you can continue your treatment, as the amount of ketoconazole absorbed throughout the body is very low with these formulations.
• If you have any questions, you should contact your doctor or pharmacist.

Healthcare professionals should follow these recommendations:

• As oral ketoconazole is no longer recommended, doctors should review patients being treated with this medicine for fungal infections, with a view of stopping treatment or choosing an appropriate alternative treatment.
• Topical ketoconazole formulations have very low systemic absorption and may continue to be used as currently approved.
• Pharmacists should refer patients with a prescription of oral ketoconazole for fungal infections to their treating doctor.

The Agency's recommendations are based on a review by the Committee for Medicinal Products for Human Use (CHMP), which looked at available data on the benefits of oral ketoconazole and the risk of hepatotoxicity from pre-clinical and clinical studies, post-marketing spontaneous case reports, epidemiological studies and the scientific literature. The Committee also considered the advice from a group of experts in the treatment of infections.

• Although the potential for hepatotoxicity is a class effect with azole antifungals, the data assessed show that the incidence and seriousness of hepatotoxicity is higher with ketoconazole than with other antifungal agents.1 Reported cases of hepatotoxicity included hepatitis, cirrhosis and liver failure with fatal outcomes or requiring liver transplantation.
• The onset of hepatotoxicity occurred generally between 1 and 6 months after starting treatment, but has also been reported earlier than 1 month after starting treatment, and at the recommended daily dose of 200 mg.
• The efficacy studies on oral ketoconazole are limited and have not been carried out in line with the most recently agreed guidelines2. There are also inadequate data to support the efficacy of ketoconazole when other treatments have failed or are not tolerated, or resistance has been detected.
• The risk minimisation measures proposed, such as limiting the treatment duration or restricting the use to patients refractory or intolerant to alternative treatments and to physicians experienced in treating rare fungal infections, were not considered sufficient to reduce the risk of hepatotoxicity to an acceptable level.

References:

1. Garcia Rodriguez et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol 1999; 48(6):847-852.
2. Guideline on the clinical evaluation of antifungal agents for the treatment and prophylaxis of invasive fungal disease CHMP/EWP/1343/01 Rev. 1, Apr 2010.

Ketoconazole is an antifungal medicine used to treat infections caused by dermatophytes and yeasts. Ketoconazole taken orally (by mouth) has been authorised in the EU since 1980, and later topical (on the skin) formulations, such as creams, ointments and shampoos, have become available.

Oral formulations of ketoconazole have been authorised in the EU via national procedures, and are currently available in several EU Member States under various trade names, including Nizoral and Fungoral.

The review of oral ketoconazole was initiated in July 2011 at the request of France, under Article 31 of Directive 2001/83/EC. In June 2011, the French medicines agency concluded that the benefit-risk balance of oral ketoconazole was negative and suspended the existing marketing authorisations in France. Consequently, the French agency asked the EMA to carry out a full assessment of the benefit-risk balance of oral ketoconazole-containing medicines and to issue an opinion on whether their marketing authorisations should be maintained, varied, suspended or withdrawn across the EU.

The review of oral ketoconazole was carried out by EMA's Committee for Medicinal Products for Human Use (CHMP), responsible for all questions concerning medicines for human use, which adopted the EMA's final opinion.
The CHMP opinion was forwarded to the European Commission, which issued a final legally binding decision valid throughout the EU.

To lift the suspension, the marketing authorisation holder for oral ketoconazole will have to provide convincing data that identify a group of patients in whom the benefits of the medicine outweigh their risks.