26 July 2013
`EMA/458028/2013
`
`
`
`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. The
`CHMP 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, the CHMP 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.
`
`
`
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`© European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged.
`
`An agency of the European Union
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2042, Page 1
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`

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`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.
`
`Information to patients
`
`•
`
`•
`
`•
`
`The European Medicines Agency has recommended the suspension of oral (by mouth) ketoconazole
`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.
`
`Information to healthcare professionals
`
`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.
`
`•
`
`•
`
`•
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`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
`
`
`European Medicines Agency recommends suspension of marketing authorisations for
`oral ketoconazole
`EMA/458028/2013
`
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`Page 2/3
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2042, Page 2
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`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.
`
`
`
`More about the medicine
`
`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.
`
`More about the procedure
`
`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 has been 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 will be forwarded to the European Commission, which will issue a final legally
`binding decision in due course.
`
`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.
`
`Contact our press officer
`Monika Benstetter
`
`Tel. +44 (0)20 7418 8427
`
`E-mail: press@ema.europa.eu
`
`
`European Medicines Agency recommends suspension of marketing authorisations for
`oral ketoconazole
`EMA/458028/2013
`
`
`
`
`Page 3/3
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2042, Page 3
`
`