Agreal - referral

Current status

European Commission final decision

Overview

The European Medicines Agency (EMEA) has completed a review of the safety and effectiveness of veralipride. The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that veralipride's benefits do not outweigh its risks, and that all marketing authorisations for medicines containing veralipride should be withdrawn throughout Europe. The review was carried out under an 'Article 31' referral¹.

The final opinion was converted into a Decision by the European Commission on 1 October 2007.

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¹ Article 31 of Directive 2001/83/EC as amended, referral under Community interest.

What is veralipride?

Veralipride is a medicine used to treat hot flushes associated with the menopause in women. It was first made available in 1979 and is still authorised in Belgium, France, Italy, Luxembourg and Portugal under the trade names Agreal and Agradil. It is only available with a prescription.

Veralipride is a neuroleptic. It works by blocking the activity of a neurotransmitter called dopamine.Neurotransmitters are chemicals in the nervous system that allow nerve cells to communicate with each other. The reasons why women have hot flushes is unclear, but since dopamine seems to be involved, veralipride can reduce these symptoms.

Why was veralipride reviewed?

Until June 2005, veralipride was also marketed in Spain. Following reports of serious side effects affecting the nervous system, the Spanish medicines regulatory authority reviewed the safety and effectiveness of the medicine and concluded that its benefits did not outweigh its risks. The Spanish authority therefore withdrew veralipride's marketing authorisation on 27 June 2005, meaning that the medicine could no longer be sold on the Spanish market. This was followed by a number of regulatory actions in other countries where veralipride is authorised, including making changes to veralipride's product information (the instructions on how a medicine should be used). These changes aimed to reduce the risk of patients developing side effects.

Consequently, the European Commission asked the CHMP to carry out a full assessment of the benefit-risk balance of veralipride and to issue an opinion on whether the marketing authorisations for products containing veralipride should be maintained, varied, suspended or withdrawn across the European Union.

Which data has the CHMP reviewed?

In this review, the CHMP has assessed all of the available information on the safety and effectiveness of veralipride. This included 11 studies involving a total of around 600 women, in which veralipride was compared with placebo (a dummy treatment), and two studies in a total of around 100 women where it was compared with conjugated oestrogens (a type of hormone replacement therapy [HRT], the standard treatment for the symptoms of the menopause). The CHMP also looked at other small studies and reports of side effects from women taking veralipride.

What are the conclusions of the CHMP?

Based on the information available, the CHMP has concluded that:

• Veralipride shows limited effectiveness in reducing the frequency and intensity of hot flushes.
• The use of veralipride can be associated with side effects, including depression, anxiety, sleep disorders, tremor (shaking) and tardive dyskinesia (an involuntary movement disorder which may be long-lasting or irreversible). Some of these side effects can occur not only during treatment, but also after it is stopped. It is also impossible to predict which women may be at risk.

The CHMP considered restricting the use of veralipride to a maximum of three months. However, it concluded that the risk of side effects would not be reduced sufficiently by this measure. In addition, hot flushes usually persist for up to two years.

Therefore, the CHMP concluded that the benefits of veralipride do not outweigh its risks. It recommended that the marketing authorisation of veralipride be withdrawn and that all veralipride-containing medicines be recalled from the European Union markets. It also recommended that the companies that market these medicines inform all healthcare professionals about the withdrawal directly.

What are the recommendations for patients and prescribers?

Based on the information available, the CHMP has concluded that:

• Patients who are taking veralipride for the treatment of hot flushes should consult their doctors to discuss what other treatment they can use.
• Prescribers should not issue any new prescriptions for veralipride and should switch patients currently taking the medicine to an alternative treatment if necessary. Since abrupt discontinuation of veralipride may lead to symptoms such as anxiety, insomnia (difficulty sleeping) and depression, prescribers should consider gradually reducing the dose of veralipride over one to two weeks.
• Patients who have any questions should speak to their doctor or pharmacist.

Questions and answers on the recommendation to withdraw the marketing authorisation of Veralipride

Adopted Reference Number: EMEA/299468/2007

Key facts

About this medicine

• Approved name:
  Agreal
• International non-proprietary name (INN) or common name:
  veralipride

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  CHMP/432352/07
• 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:
  19/07/2007
• EC decision date:
  01/10/2007

All documents

Agreal - Article 31 referral - Annex I, II

Adopted

Opinion following an Article 31 referral for Agreal and associated names (see annex I) International Non-Proprietary Name (INN): Veralipride: Background information

Adopted Reference Number: EMEA/CHMP/432352/2007

Questions and answers on the recommendation to withdraw the marketing authorisation of Veralipride

Adopted Reference Number: EMEA/299468/2007

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.