Flupirtine-containing medicinal products - referral

Current status

CMDh final position

Overview

 

Withdrawal of pain medicine flupirtine endorsed

Serious liver problems continued to be reported despite previous restrictions in use

The CMDh¹ has endorsed EMA's recommendation to withdraw the marketing authorisation for the pain medicine flupirtine, because of the risk of serious liver injury. This means that the medicine will no longer be available.

The EMA recommendation was the outcome of a review of flupirtine medicines which was started because liver problems continued to be reported even after measures were introduced in 2013 to manage this risk. These measures had included limiting flupirtine use to no more than 2 weeks in patients with acute pain who could not use other painkillers, and carrying out weekly tests of liver function during treatment.

The review, carried out by EMA's Pharmacovigilance Risk Assessment Committee (PRAC), looked at the available data including studies evaluating whether the 2013 restrictions were followed in clinical practice. It also assessed cases of serious liver damage reported since the 2013 review.

The CMDh agreed with the PRAC conclusion that the restrictions introduced in 2013 have not been sufficiently followed, and cases of serious liver injury, including liver failure, still occurred. In addition, no further measures to increase adherence to the restrictions nor adequately reduce the risk of liver problems could be identified.

The CMDh therefore agreed that patients taking flupirtine-containing medicines continue to be exposed to serious risks which outweigh the benefits of these medicines. In order to protect public health, the CMDh endorsed the PRAC recommendation to withdraw the marketing authorisations of flupirtine-containing medicines.

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¹ The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway.

Information for patients

• Flupirtine-containing medicines have been used to treat acute (short-term) pain for up to two weeks in adults who cannot use other painkillers (such as non-steroidal anti-inflammatory drugs (NSAIDs) and weak opioids).
• These medicines are being taken off the market in the EU because of a risk of serious liver injury.
• Strict measures to try to reduce this risk were introduced in 2013 but have not been put into practice widely enough, and liver injury has continued to be reported. In addition, no further measures to reduce the risk of liver problems could be identified.
• Since 2013, cases of serious liver injury, including 23 cases of acute liver failure (sudden loss of liver function), some of which were fatal or led to transplantation have been reported following flupirtine use².
• Alternative treatment options are available.
• Patients with any questions should speak to their healthcare professional.

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²These cases have been reported in the European database of suspected adverse drug reaction reports (Eudravigilance)between April 2013 and December 2017.

Information for healthcare professionals

• Flupirtine-containing medicines are being taken off the market in the EU because of the risk of serious liver injury.
• Restrictions introduced in 2013, which included limiting flupirtine use to two weeks and regular monitoring of liver function tests, have not been sufficiently followed in clinical practice. While the use of flupirtine-containing products has decreased, the measures implemented have not been effective at minimising the risk.
• In addition, no further measures to increase adherence to the restrictions nor adequately reduce the risk of liver problems could be identified.
• Healthcare professionals should consider alternative treatments for patients.
• Healthcare professionals in the EU countries where flupirtine is marketed will receive a letter with detailed information on the appropriate actions to be taken, including when the medicine will become unavailable.
• Since 2013, cases of serious liver injury, including 23 cases of acute liver failure, some of which were fatal or led to transplantation have been reported following flupirtine use³. The reactions are unpredictable and the exact mechanism by which flupirtine causes liver injury is not known.

Six observational studies showed a lack of compliance with the measures that were introduced to minimise the risk of hepatotoxicity.

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³These cases have been reported in the European database of suspected adverse drug reaction reports (Eudravigilance)between April 2013 and December 2017.

More about the medicine

Flupirtine is a medicine used to treat acute (short-lived) pain for up to 2 weeks, in patients who cannot use other painkillers such as opioids or nonsteroidal anti-inflammatory medicines (NSAIDs). Flupirtine works as a 'selective neuronal potassium channel opener'. This means that it opens specific pores on nerve cells called potassium channels. The opening of these channels reduces the excessive electrical activity that leads to many pain states.

Flupirtine-containing medicines have been authorised since the 1980s and are currently available in the following EU Member States: Estonia, Germany, Latvia, Lithuania, Luxembourg, Poland, Portugal, and Slovakia. They are available under several trade names and in different formulations.

More about the procedure

The review of flupirtine was initiated on 26 October 2017 at the request of Germany, under Article 31 of Directive 2001/83/EC.

The review was first carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. The PRAC recommendations were sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted a position on 21 March 2018. The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway. It is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

Since the CMDh adopted its position by consensus, it will be directly implemented by the Member States where the medicines are authorised, according to an agreed timetable.

Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed

Key facts

About this medicine

• Approved name:
  Flupirtine-containing medicinal products
• International non-proprietary name (INN) or common name:
  flupirtine
• Class:
  Analgesics

About this procedure

• Current status:
  CMDh final position
• Reference number:
  EMEA/H/A-31/1458
• 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.

• Authorisation model:
  Nationally authorised product(s)
• Decision making model:
  PRAC-CMDh

Key dates and outcomes

• Procedure start date:
  26/10/2017
• PRAC recommendation date:
  08/02/2018
• CMDh position date:
  21/03/2018
• Outcome:
  Revocation

All documents

Procedure started

Flupirtine Article-31 referral - Annex I

Reference Number: EMEA/H/A-31/1458

Flupirtine Article-31 referral - PRAC list of questions

Reference Number: EMEA/H/A-31/1458

Flupirtine Article-31 referral - Review started

Reference Number: EMEA/H/A-31/1458

Flupirtine Article-31 referral - Timetable for the procedure

Reference Number: EMEA/H/A-31/1458

Flupirtine Article-31 referral - Notification

Reference Number: EMEA/H/A-31/1458

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Flupirtine Article-31 referral - Assessment report

Reference Number: EMA/166943/2018

PRAC recommends that the marketing authorisation of the painkiller flupirtine be withdrawn

Reference Number: EMA/66114/2018

Position provided by CMDh

Flupirtine Article-31 referral - Annex II

Flupirtine Article-31 referral - Annex I

Flupirtine Article-31 referral - Annex III

Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed

Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed

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.