Flupirtine-containing medicinal products

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Summary


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.


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.

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.


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.

Name Language First published Last updated
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed BG = bălgarski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed ES = español 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed CS = čeština 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed DA = dansk 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed DE = Deutsch 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed ET = eesti keel 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed EL = elliniká 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed EN = English 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed FR = français 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed IT = italiano 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed LV = latviešu valoda 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed LT = lietuvių kalba 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HU = magyar 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed MT = Malti 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed NL = Nederlands 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed PL = polski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed PT = português 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed RO = română 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed SK = slovenčina 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed SL = slovenščina 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed FI = suomi 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed SV = svenska 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  

Key facts

About this medicine

Approved nameFlupirtine-containing medicinal products
International non-proprietary name (INN) or common name

flupirtine

Associated names-
ClassAnalgesics

About this procedure

Current statusPosition provided by CMDh
Reference numberEMEA/H/A-31/1458
TypeArticle 31 referrals

This type of referral is triggered when the interest of the Community is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Decision making modelPRAC-CMDh
Authorisation modelNationally authorised product(s)

Key dates and outcomes

Procedure start date26/10/2017
PRAC recommendation date08/02/2018
CHMP opinion/CMDh position date21/03/2018
OutcomeRevocation

All documents

Procedure started

Name Language First published Last updated
Flupirtine Article-31 referral - PRAC list of questions HR = Hrvatski 2017-10-27  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2017-10-27 2017-12-04
Flupirtine Article-31 referral - Timetable for the procedure HR = Hrvatski 2017-10-27  
Flupirtine Article-31 referral - Review started HR = Hrvatski 2017-10-27  
Flupirtine Article-31 referral - Notification HR = Hrvatski 2017-10-27  

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Name Language First published Last updated
Flupirtine Article-31 referral - Assessment report HR = Hrvatski 2018-03-28  
PRAC recommends that the marketing authorisation of the painkiller flupirtine be withdrawn HR = Hrvatski 2018-02-09  

Position provided by CMDh

Name Language First published Last updated
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Withdrawal of pain medicine flupirtine endorsed HR = Hrvatski 2018-03-23  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex III HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex II HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  
Flupirtine Article-31 referral - Annex I HR = Hrvatski 2018-05-04  

Document description:

  • Annex I - List of the medicines affected by the referral
  • Annex II - Scientific conclusions of the Committee for Medicinal Products for Human Use (CHMP) or Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh)
  • Annex III - Changes to the summary of product characteristics, labelling or package leaflet - available when the CHMP or CMDh recommends changes to the product information. Also includes conditions for lifting of suspensions, if applicable
  • Annex IV - Conditions of the marketing authorisation - available when the CHMP or CMDh recommends other measures to be taken for the marketing authorisation such as safety measures or additional studies
  • Notification - A letter from a Member State, the European Commission or a marketing-authorisation holder requesting the initiation of a referral procedure
  • Rationale for triggering - Background provided by the party triggering the referral explaining the issues leading to the initiation of the procedure
  • PRAC list of questions - Questions agreed by the PRAC requesting further information to evaluate the issues identified
  • PRAC timetable - Timeframe agreed by the PRAC to receive information, assess the issues and adopt a recommendation
  • PRAC / CHMP / CMDh assessment report - The assessment and conclusions of the PRAC and CHMP or CMDh on the issues investigated

Current status:
Position provided by CMDh