Aprotinin - referral

Current status

European Commission final decision

Overview

The European Medicines Agency (EMEA) has looked at the safety of medicines containing aprotinin. The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the benefits of 'systemic' formulations of these medicines no longer outweigh their risks, and has recommended that all marketing authorisations for these medicines should be suspended throughout Europe. 'Systemic' formulations are those that affect the whole body, such as infusions (drips).

What is aprotinin?

Aprotinin-containing medicines are used to prevent the loss of blood. Aprotinin is an antifibrinolytic. This means that it stops the body breaking down blood clots.

Medicines containing aprotinin can be used as an infusion during surgery to prevent the need for blood transfusion in patients undergoing a coronary artery bypass (when the arteries that supply blood to the heart are replaced by blood vessels taken from another part of the body).

Systemic medicines containing aprotinin have been available since 1974. They are authorised in Austria, Belgium, Bulgaria, the Czech Republic, Cyprus, Germany, Denmark, Greece, Estonia, Finland, France, Hungary, Lithuania, Luxembourg, Latvia, Malta, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Sweden and the United Kingdom, under the trade names Acset, Antagosan, Antilysin Spofa, Gordox, Pantinol, Traskolan, Trasylol and Trasynin.

Aprotinin can also be used locally during surgery, in sealants (glues), to help stop bleeding. These medicines are not affected by this recommendation.

Why was aprotinin reviewed?

On 5 November 2007, the German medicines regulatory authority suspended the marketing authorisations for the aprotinin-containing medicines Trasylol and Trasynin, used as an infusion during bypass surgery. This decision was triggered by the preliminary results of a study called the BART study, which was looking at the use of aprotinin in around 3,000 heart surgery patients to reduce post-operative bleeding.

This study was stopped early because it showed that, 30 days after surgery, there were more deaths in the group of patients receiving aprotinin than in the group receiving alternative antifibrinolytic treatments (aminocaproic acid or tranexamic acid). On the basis of this finding, the German authority concluded that the benefits of aprotinin in this indication no longer outweighed its risks, and that the marketing authorisations should be suspended. Bayer, the company that makes Trasylol and Trasynin, subsequently decided to remove these medicines from the market worldwide.

As required by Article 107 of Directive 2001/83/EC as amended, the German authority informed the CHMP of its action so that the Committee could consider whether the marketing authorisations for all systemic products containing aprotinin should be maintained, changed, suspended or withdrawn across the European Union (EU) and European Economic Area (EEA).

Which data has the CHMP reviewed?

The CHMP looked at the data that its Pharmacovigilance Working Party (PhVWP) had already been considering in the context of its monitoring of the safety of medicines. The PhVWP review has been looking at the information obtained from three 'observational' studies¹, which looked at the outcomes of patients undergoing heart surgery and treated with aprotinin.

In the current review, the CHMP has also taken the new information from the BART study into account. Since the BART study is the first 'randomised' study that compares the effects of aprotinin with other medicines in a head-to-head manner, its results are considered to be more reliable than those previously available. 'Randomised' means that patients were allocated to receive either aprotinin or another medicine in a random manner, to avoid bias in the results.

¹ Mangano D, Tudor J, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Eng J Med (2006), 354:353-65, Mangano D et al., Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA (2007), 297:471-479 and 'i3' safety study results, 2007

What are the conclusions of the CHMP?

The PhVWP review had already identified some concerns over the benefit-risk balance of systemic aprotinin-containing medicines, especially their possible effect on the kidneys and the heart. These concerns led to measures being put in place to minimise the risk associated with their use. All healthcare professionals were notified of these measures.

At its November 2007 meeting, the CHMP considered all the available evidence, including the negative findings of the BART study and their impact on the benefit- risk balance of systemic aprotinin. The CHMP concluded that the benefits of aprotinin used systemically no longer outweigh its risks. Therefore, the Committee recommended that the marketing authorisations of systemic medicines containing aprotinin be suspended in all European Union and European Economic Area markets.

A European Commission Decision on this opinion will be issued in due course. It should be noted that the use of systemic aprotinin in surgery will be suspended throughout the EU once the European Commission has made the CHMP recommendation legally binding.

What are the recommendations for patients and prescribers?

• Surgeons should re-assess the need for antifibrinolytics for the prevention of excessive blood loss during bypass surgery. Depending on the country, there may be other medicines that are authorised for use. These include medicines containing aminocaproic acid or tranexamic acid.
• Patients who have received medicines containing aprotinin during surgery and have any questions should speak to their surgeon or the doctor who is currently looking after them.

Questions and answers on the European Medicines Agency recommendation to suspend the marketing authorisations for aprotinin-containing medicines

Adopted Reference Number: EMEA/533599/2007 corr

Key facts

About this medicine

• Approved name:
  Aprotinin
• International non-proprietary name (INN) or common name:
  aprotinin
• Associated names:
  Trasylol

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/533599/07
• Type:
  Article 107 procedures (prior to July 2012)

  This type of procedure was triggered when a Member State varied, suspended or revoked the marketing authorisation for a medicine in its territory because of a safety issue. This procedure has been replaced by Article 107i.

Key dates and outcomes

• CHMP opinion date:
  15/11/2007
• EC decision date:
  15/02/2008

All documents

Questions and answers on the European Medicines Agency recommendation to suspend the marketing authorisations for aprotinin-containing medicines

Adopted Reference Number: EMEA/533599/2007 corr

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.