Orlistat - referral

Current status

European Commission final decision

Overview

The European Medicines Agency has completed a review of orlistat-containing medicines, following concerns about the possible risk of severe liver injury with these medicines. The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the benefits of orlistat continue to outweigh its risks, and recommended that the marketing authorisations be maintained with minor amendments to the product information to ensure the same information on very rare liver-related side effects is provided for all orlistat-containing medicines.

What is orlistat?

Orlistat is an anti-obesity medicine, which does not affect appetite. Orlistat blocks the action of gastrointestinal lipases (enzymes that digest fat). When these enzymes are blocked, they cannot digest some fats in the diet, and this allows about a quarter of the fat eaten in the meal to be passed out in the stools undigested. The body does not absorb this fat and this helps the patient reduce their weight.

Two orlistat-containing medicines hold a European Union (EU)-wide marketing authorisation. Xenical was authorised in 1998 and is available as capsules (120 mg) which can only be obtained with a prescription. Alli was authorised in 2007 and is available as capsules (60 mg) and chewable tablets (27 mg) which can be obtained without a prescription ('over-the-counter').

A number of generic orlistat-containing medicines have also been authorised via national procedures in Belgium, Bulgaria, Denmark, Estonia, Latvia, Lithuania, Norway, Portugal, Slovakia, the Netherlands and the United Kingdom.

Why was orlistat reviewed?

Since 2001, it has been recognised that some patients taking orlistat could experience very rare liver-related side effects. This risk has been closely monitored by the CHMP and measures to manage the known risks were put in place. The product information for orlistat-containing medicines lists hepatitis, cholelithiasis (gall stones) and a change in liver enzyme levels as potential liver-related side effects.

Xenical and Alli are together estimated to have been used by over 53 million people worldwide, with over 20 million in the EU. Since authorisation, there have been some reports of severe liver problems in users of these medicines. Recent safety monitoring showed that from August 2009 to January 2011, four cases of severe liver injury were reported in patients using Xenical where the role of orlistat could not be excluded, including one fatal case of liver failure and one case leading to liver transplantation. Overall, from 1997 to January 2011, 21 cases of severe liver toxicity were reported where Xenical was considered a possible cause, although other factors that could have caused the liver injury were present. There were 9 reports of liver failure in people using Alli since it was marketed in May 2007 until January 2011, although in some cases there were other possible explanations and in some cases there was insufficient information to assess the cause.

Therefore, the CHMP considered it necessary to assess whether the evidence gathered over time on the risk of severe liver problems had altered the benefit-risk balance of orlistat-containing medicines. Consequently, the European Commission asked the CHMP to issue an opinion on orlistat and on whether the marketing authorisation for orlistat-containing medicines should be maintained, varied, suspended or withdrawn across the EU.

Which data has the CHMP reviewed?

The CHMP reviewed the available data on the risk of liver injury and other side effects with orlistat, including post-marketing surveillance, data from the studies supporting the marketing authorisations and population-based studies in the published literature. The Committee also reviewed information requested from the companies that market orlistat-containing medicines, including the estimated number of people using these medicines and an analysis of the observed number of reports of severe liver problems compared with the expected background rate of liver problems in these people.

What are the conclusions of the CHMP?

The CHMP considered that there was no strong evidence that orlistat increased the risk of severe liver injury, and there was no known mechanism by which orlistat was expected to cause liver disorders. The Committee concluded that the number of reported severe liver reactions in orlistat users was low and below the background rate expected in these people, given the large number of users. A pattern was not seen in the type of liver problems reported, and in most cases there were other factors which were likely to increase the risk of liver injury such as existing health problems or the use of other medicines. The CHMP also noted that published population-based studies suggest that obesity may be associated with a higher risk of liver disease. The Committee considered that while there may be very rare cases of serious liver injury for which orlistat cannot be excluded as a possible cause, the cases do not provide good evidence of a causal link.

Based on the evaluation of the currently available data and the scientific discussion within the Committee, the CHMP concluded that the benefits of orlistat continue to outweigh its risks, and therefore recommended that the marketing authorisations be maintained for orlistat-containing medicines. It noted that the product information for Xenical already listed 'hepatitis that may be serious' as a side effect of unknown frequency, and recommended that the product information for all orlistat-containing medicines should be harmonised to include this information. The product information for Alli, which currently lists 'hepatitis', will be updated accordingly. The Committee also agreed on minor amendments to the package leaflet for all orlistat-containing medicines to ensure they give the same information, including a description of the symptoms of hepatitis to alert patients to these symptoms.

The amended information to doctors and patients are detailed under the 'All documents' tab.

What are the recommendations for patients and prescribers?

• Patients and prescribers are reminded that the benefits of orlistat-containing medicines continue to outweigh the risks. These medicines should continue to be used as before.
• Patients and prescribers should be aware that certain liver-related problems, including very rare serious reactions such as hepatitis, have been reported and are listed in the product information for orlistat-containing medicines as possible side effects. There remains no clear evidence that orlistat causes these reactions.
• Patients should note that symptoms of hepatitis can include yellowing skin and eyes, itching, dark coloured urine, stomach pain and liver tenderness (indicated by pain under the front of the rib cage), sometimes with a loss of appetite. Patients should stop taking orlistat and inform their doctor if they experience any of these symptoms.
• Patients who have any questions should speak to their doctor or pharmacist at a routine appointment.

The European Commission issued a decision for orlistat Article 31 on 24 April 2012.

Questions and answers on the review of orlistat-containing medicines

Adopted Reference Number: EMA/CHMP/113837/2012 Rev.1

Key facts

About this medicine

• Approved name:
  Orlistat
• International non-proprietary name (INN) or common name:
  orlistat
• Class:
  -

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1318
• 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:
  16/02/2012
• EC decision date:
  24/04/2012

All documents

Orlistat - Article 31 referral - Annex III

European Commission final decision

Orlistat - Article 31 referral - Annex I

Orlistat - Article 31 referral - Assessment report for orlistat-containing medicinal products

Adopted Reference Number: EMA/276546/2012

Orlistat - Article 31 referral - Annex II

Questions and answers on the review of orlistat-containing medicines

Adopted Reference Number: EMA/CHMP/113837/2012 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.