Fibrates - referral

Current status

European Commission final decision

Overview

The European Medicines Agency has completed a review of the safety and effectiveness of fibrates. The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the benefits of fibrates continue to outweigh their risks but that they should not be used as 'first line' in the treatment of blood lipid (fat) disorders, such as high cholesterol, except in rare cases. This means that newly diagnosed patients with blood lipid disorders should not be treated using these medicines in the first instance, unless they have very high levels of triglycerides (a type of fat). However, fibrates can be used in patients who cannot take statins (another type of medicine used to lower blood lipid levels).

What are fibrates?

Fibrates are a class of medicines that can be used to lower the level of lipids, such as cholesterol and triglycerides, in the blood. Blood lipid disorders are a risk factor of heart disease (such as heart attack and stroke) and fibrates are used to improve lipid levels in patients in whom dietary restrictions and exercise have not been enough.

Fibrates are 'PPAR agonists'. This means that they activate a type of receptor called the 'peroxisome proliferator activated receptor'. This receptor can be found in many cells throughout the body, where it is involved in breaking down dietary fat, especially triglycerides and cholesterol. When the receptors are activated, the break down of fats is accelerated, and this helps clear the blood of cholesterol and triglycerides.

Fibrates have been in use since the 1960s. Currently, four fibrates are available in the European Union:

• bezafibrate. This medicine has been available since 1977. It is marketed mainly under the trade names Bezalip, Cedur, Eulitop and Befizal, as well as generic medicines. It is sold in Austria, Belgium, Cyprus, Finland, France, Germany, Greece, Hungary, Italy, Luxembourg, Malta, the Netherlands, Portugal, Romania, Spain, Sweden and the United Kingdom (UK);
• ciprofibrate. This medicine has been available since 1995. It is marketed mainly under the trade name Lipanor or Modalim, as well as generic medicines. It is sold in Belgium, Bulgaria, Cyprus, the Czech Republic, Estonia, France, Greece, Hungary, Latvia, Lithuania, Luxembourg, the Netherlands, Poland, Portugal, Romania, Slovakia and the UK;
• fenofibrate. This medicine has been available since 1975. It is marketed mainly under the trade name Lipanthyl, as well as generic medicines. It is sold in all European Union (EU) Member States except Denmark and the Netherlands, as well as in Iceland and Norway;
• gemfibrozil. This medicine has been available since 1981. It is marketed mainly under the trade name Lopid, as well as generic medicines. It is sold in Austria, Cyprus, Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, the Netherlands, Portugal, Slovenia, Slovakia, Spain, Sweden and the UK.

These medicines have all been authorised via national procedures.

Why were fibrates reviewed?

In 2005, the CHMP's Pharmacovigilance Working Party (PhVWP) noted that there was limited evidence of the long-term benefit of fibrates in reducing cardiovascular risk, compared with the stronger evidence for statins (another type of medicine used for lowering blood cholesterol). As a result, the Working Party undertook a review of the benefits and risks of all fibrate-containing medicines on behalf of the medicines regulatory authorities of the countries where the medicines were marketed. The aim of the review was to establish how fibrates should be used, taking into account their safety, their effectiveness in lowering lipid levels and the availability of other lipid-lowering medicines that were not around when fibrates were first used. Looking at the data, the PhVWP came to the conclusion that there were no new safety issues with fibrates and that fibrate-containing medicines still had a role to play in improving lipid levels, but that they should not be used as first-line treatment.

The conclusions of the PhVWP were transmitted to the companies that market fibrates, so that they could implement the changes recommended by the Working Party. However, a number of them questioned the restriction. Consequently, the UK medicines regulatory agency referred the matter to the CHMP on 20 October 2009, to carry out a full assessment of the benefit-risk balance of fibrates and to issue an opinion on whether the marketing authorisations for fibrate-containing medicines should be maintained or varied across the EU.

Which data has the CHMP reviewed?

The CHMP looked at the information gathered by the PhVWP during its review, as well as the responses provided by the companies to specific questions. The Committee also looked at the latest data from clinical studies including a trial looking at the effect of using fenofibrate as an 'add-on' to statins.

What are the conclusions of the CHMP?

The Committee endorsed the conclusions of the PhVWP that fibrates are still a safe option for lowering lipid levels, but that their use as first-line treatment is not justified. Fibrates should be used only when statins are contra-indicated or not tolerated. However, the Committee noted that fibrates are more effective than statins in lowering triglyceride levels and therefore their use as a first-line treatment in patients with severe hypertriglyceridaemia (very high blood levels of triglycerides) is still appropriate.

The Committee also noted that there were new data for fenofibrate that supported a change to the PhVWP recommendations, based on the results of the add-on study. As a result, the Committee also allowed the use of fenofibrate together with a statin in some circumstances for patients at risk when using a statin on its own was not enough to completely control blood lipid levels.

Based on the evaluation of the currently available data and the scientific discussion within the Committee, the CHMP concluded that the benefits of fibrates continue to outweigh their risks within these restrictions. The Committee recommended specific changes to the information to doctors and patients for all four fibrates.

What are the recommendations for patients?

• Patients who are currently taking fibrates to lower their blood lipid levels should continue to do so. There are no new safety concerns with the medicines.
• However, patients taking a fibrate-containing medicine should arrange to see their doctor to check that the medicine is the most appropriate option to lower their blood lipid levels.
• Patients who have any questions should speak to their doctor or pharmacist.

What are the recommendations for prescribers?

• Doctors are reminded that fibrates should not be used as first-line treatment in patients with high lipid levels, except in specific groups:
  • patients with severe hypertriglyceridaemia;
  • patients for whom statins are contra-indicated or who cannot tolerate them.
• They should review the treatment of patients who are receiving fibrates to help control their lipid levels to ensure that the patient is receiving the most appropriate treatment.

The European Commission issued a decision on 28 February 2011.

Questions and answers on the review of medicines containing fibrates

Adopted Reference Number: EMA/643808/2010 Rev. 1

Key facts

About this medicine

• Approved name:
  Fibrates
• International non-proprietary name (INN) or common name:
  • bezafibrate
  • ciprofibrate
  • fenofibrate
  • gemfibrozil
• Associated names:
  • Bezalip
  • Lipanor
  • Lipanthyl
  • Lopid
• Class:
  fibrates

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/001238
• 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:
  21/10/2010
• EC decision date:
  28/02/2011

All documents

European Commission final decision

Assessment report for fenofibrate-, bezafibrate-, ciprofibrate- and gemfibrozil-containing medicinal products

Adopted Reference Number: EMA/CHMP/580013/2012

Fibrates Article-31 referral - Annex I

Fibrates Article-31 referral - Annex II

Fibrates Article-31 referral - Annex III

Fibrates (bezafibrate, ciprofibrate, fenofibrate and gemfibrozil) - Article-31 referral - changes to product information

Adopted

Questions and answers on the review of medicines containing fibrates

Adopted Reference Number: EMA/643808/2010 Rev. 1

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.