Ketoconazole-containing medicines

  • Procedure started
  • Under evaluation
  • CHMP opinion
  • European Commission final decision
Current status
European Commission final decision

Overview

On 25 July 2013, the European Medicines Agency's Committee on Medicinal Products for Human Use (CHMP) 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 was sent to the European Commission, which endorsed it and adopted a final legally binding decision valid throughout the EU on 11 October 2013.

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.

Key facts

About this medicine
Approved name
Ketoconazole-containing medicines
International non-proprietary name (INN) or common name
ketoconazole
Associated names
  • Nizoral
  • Fungoral
Class
Antifungal
About this procedure
Current status
European Commission final decision
Reference number
EMEA/H/A-31/1314
Type
Article 31 referrals

This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Key dates and outcomes
CHMP opinion date
25/07/2013
EC decision date
11/10/2013

All documents

Opinion provided by Committee for Medicinal Products for Human Use

European Commission final decision

  • List item

    Ketoconazole Article-31 referral - Suspension of marketing authorisations for oral ketoconazole (PDF/80.31 KB)


    First published: 13/06/2014
    Last updated: 13/06/2014
    EMA/584237/2013

  • List item

    Ketoconazole Article-31 referral - Assessment report (PDF/218.63 KB)

    Adopted

    First published: 13/06/2014
    Last updated: 13/06/2014
    EMA/CHMP/580489/2013

  • List item

    Ketoconazole Article-31 referral - Annex I (PDF/164.17 KB)


    First published: 13/06/2014
    Last updated: 13/06/2014

  • List item

    Ketoconazole Article-31 referral - Annex II (PDF/99.35 KB)


    First published: 13/06/2014
    Last updated: 13/06/2014

  • List item

    Ketoconazole Article-31 referral - Annex III (PDF/38.55 KB)


    First published: 13/06/2014
    Last updated: 13/06/2014

  • Description of documents published

    Please note that some of the listed documents apply only to certain procedures.

    • Overview - lay-language summary of the stage of the procedure
    • Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
    • Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
    • List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
    • Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
    • List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
    • List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
    • Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
    • Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
    • Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
    • Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
    • Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
    • Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
    • Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
    • Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

    Note that older documents may have different titles.

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