Fibrinogen-containing solutions for sealant authorised for administration by spray application - referral

Current status

European Commission final decision

Overview

On 15 November 2012, the European Medicines Agency completed a review of the safety and effectiveness of the fibrin sealants Evicel and Quixil given by spray application, following cases of gas embolisms reported with these medicines. The Agency's Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of these medicines given by spray application continue to outweigh their risks, but that appropriate measures have to be put in place to minimise the risk of gas embolism.

What are fibrin sealants?

Fibrin sealants are medicines that are used as a sealant (glue) during surgery to help reduce local bleeding. They are composed of two solutions, one containing fibrinogen and the other containing thrombin, which are both proteins involved in the blood clotting process. When the two solutions are mixed together, thrombin breaks fibrinogen up into smaller units called fibrin. The fibrin then aggregates (sticks together) and forms a fibrin clot that helps the wound to heal, stopping the bleeding.

Fibrin sealants can be applied by dripping or spraying the solution onto bleeding tissue. The solution is currently sprayed using either pressurised air or carbon dioxide (CO₂).

Evicel is the only centrally authorised fibrin sealant. It was authorised in October 2008 and is available in 11 European Union (EU) Member States¹. Other fibrin sealants in the EU are authorised nationally and these include Quixil, Tisseel, Tissucol, Artiss and Beriplast P (and associated names).

---

¹Austria, Denmark, Estonia, France, Finland, Germany, Ireland, Netherlands, Spain, Sweden and the United Kingdom, as well as Norway.

Why were fibrin sealants reviewed?

In August 2010, measures were taken to minimise the risk of gas embolism (presence of a gas bubble in the blood that affects the blood flow) following five reported cases involving Evicel or Quixil applied by spray. These included changes to the product information to specify the maximum spray pressure to use during application and the recommended distance from the tissue surface. However, since then, three further cases of gas embolism have been reported with Evicel, which were due to insufficient distance between the applicator and tissue or too high spray pressure. This indicates that the risk-minimisation measures have not been sufficient.

Consequently, in May 2012, the European Commission asked the CHMP to issue an opinion on whether further measures are necessary to ensure the safe use of Evicel and on whether its marketing authorisation should be maintained, varied, suspended or withdrawn across the EU. At the same time, the United Kingdom's medicines regulatory agency requested the CHMP to carry out the same assessment for Quixil and the other fibrin sealants available in the EU.

Which data has the CHMP reviewed?

The CHMP reviewed available safety data on fibrin sealants from clinical studies, post-marketing use and the published literature, focusing on reported cases of confirmed or suspected gas embolism. The Committee also considered the spray devices used together with these medicines, and the benefit of giving fibrin sealants by spray application. A group of experts in blood products, haemostasis (the stopping of bleeding) and surgery was also consulted.

What are the conclusions of the CHMP?

The CHMP noted that fibrin sealants have the potential to be life-saving in certain circumstances, and that applying these medicines by spray is considered to be of benefit when there is a large surface area of bleeding during certain surgical procedures. The CHMP also noted that, although cases of gas embolism are rare, there is a need to take further measures to prevent this life-threatening risk.

Based on the evaluation of the currently available data and the scientific discussion within the Committee, the CHMP concluded that the benefits of Evicel and Quixil continue to outweigh their risks, but that further risk minimisation measures should be implemented when these medicines are given by spray application to ensure that they are used correctly. The Committee recommended that:

• Evicel and Quixil should be sprayed using CO₂ only, instead of pressurised air, because the greater solubility of CO₂ in blood reduces the risk of embolism;
• the wording for the product information should be strengthened and educational materials updated to provide clear and consistent information to surgeons on the recommended pressure and distance during spray application;
• these medicines should not be sprayed in endoscopic surgery (a type of less invasive surgical procedure). In addition, care should be taken during laparoscopy (another type of less invasive surgical procedure) to ensure that the minimum safe distance from the tissues is observed;
• the company for Evicel and Quixil should ensure that these products are used with pressure regulators that do not exceed the maximum pressure required to deliver the fibrin sealant, and that contain labels stating the recommended pressure and distance.

The full changes made to the product information for Evicel and Quixil are available under the 'All documents' tab.

The Committee also agreed that the company marketing these medicines should provide a letter to relevant healthcare professionals in the EU explaining these risk-minimisation measures.

The CHMP is still reviewing four other fibrin sealants: Tisseel, Tissucol, Artiss and Beriplast P (and associated names).

What are the recommendations for surgeons?

Surgeons should note the potential risk of gas embolism with improper spray application of Evicel and Quixil and take the necessary precautions detailed in the updated prescribing advice for these medicines.

• Evicel and Quixil should be sprayed using CO₂ only.
• Spraying Evicel or Quixil in endoscopic surgery is contraindicated.
• Evicel or Quixil application by spray should only be considered if it is possible to accurately judge the spraying distance.

The European Commission issued a decision for Evicel on 13 February 2013 and for Quixil on 20 February 2013.

Questions and answers on the review of the fibrin sealants Evicel and Quixil given by spray application

AdoptedReference Number: EMEA/H/A-31/1337

Key facts

About this medicine

• Approved name:
  Fibrinogen-containing solutions for sealant authorised for administration by spray application
• International non-proprietary name (INN) or common name:
  fibrin
• Associated names:
  • Evicel
  • Quixil
• Class:
  Fibrin sealants

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1337
• 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:
  15/11/2012
• EC decision date:
  13/02/2013

All documents

Opinion provided by Committee for Medicinal Products for human Use

Questions and answers on the review of the fibrin sealants Evicel and Quixil given by spray application

AdoptedReference Number: EMEA/H/A-31/1337

European Commission final decision

Fibrinogen Article-31 referral - Annex II

Fibrinogen Article-31 referral - Annex III

Assessment report for fibrinogen-containing solutions for sealant authorised for administration by spray application

AdoptedReference Number: EMA/66729/2013

Fibrinogen Article-31 referral - Annex I

Fibrinogen Article-31 referral - Annex IV

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.