Flupirtine-containing medicines - referral

Current status

European Commission final decision

Overview

 

Restrictions in the use of flupirtine-containing medicines

On 26 June 2013, the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) endorsed by majority new recommendations to restrict the use of oral flupirtine medicines and suppositories. These medicines should only be used for treating acute (short-term) pain in adults who cannot use other painkillers, such as non-steroidal anti-inflammatory drug (NSAIDs) and weak opioids, and treatment should not last longer than 2 weeks.

In addition, patients' liver function should be checked after each full week of treatment and treatment should be stopped if the patient has any signs of liver problems. Flupirtine must also not be used in patients with pre-existing liver disease or alcohol abuse problems or in patients taking other medicines known to cause liver problems.

The recommendations follow a review by the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) which looked into reported liver problems with flupirtine, ranging from high liver-enzyme levels to liver failure. The PRAC evaluated the available data on liver safety, noting that there were no cases of liver failure or liver transplantation reported in patients who took the medicine for 2 weeks or less. The PRAC also reviewed the available data on the benefits of flupirtine and concluded that, while there were data from studies in the treatment of acute pain, there were insufficient data to support its use in the treatment of long-term pain.

In addition to oral medicines and suppositories, this review also covered injectable flupirtine medicines which were being given as a single injection for pain following surgery. The PRAC concluded that the benefits of injectable flupirtine continue to outweigh their risks when used in this way. Doctors using the injectable flupirtine should also follow relevant advice to minimise risk to patients.

The CMDh agreed with the PRAC's conclusions and endorsed the PRAC's recommendations on the use of flupirtine-containing medicines. The CMDh position was sent to the European Commission, which endorsed it and adopted a final legally binding decision valid throughout the EU on 5 September 2013.

Information to patients

• Oral flupirtine medicines and suppositories should only be used to treat acute (short-term) pain in adults who cannot use other painkillers (such as NSAIDs and weak opioids). If you are taking flupirtine, your treatment should not last longer than 2 weeks.
• You should not take flupiritine as a long-term treatment for chronic pain. If you have been taking flupirtine for longer than 2 weeks you will need to get your treatment reviewed by your doctor or pharmacists.
• Because flupirtine may have effects on the liver in some patients, your doctor will test your liver function during treatment and stop treatment if there are any signs of liver problems.
• If you are being treated with flupirtine and have any questions or concerns about your treatment, speak to your doctor or pharmacist.

Information to healthcare professionals

A review of the safety data from the EU adverse reaction database revealed 330 cases of adverse liver events suspected to be linked to flupirtine. The events ranged from asymptomatic increases in liver enzymes to liver failure. No cases of liver failure or liver transplantation were reported in patients who took the medicine for 2 weeks or less.

With regard to the evidence of efficacy, the review highlighted a lack of sufficient data on the benefits of flupirtine in chronic pain. In particular, there was a lack of efficacy data on the use of flupirtine for longer than 8 weeks.

Based on the findings of this review, healthcare professionals in the EU are advised of the following updated recommendations:

• Oral flupirtine medicines and suppositories should only be used to treat adults with acute pain and only if treatment with other painkillers (such as NSAIDs and weak opioids) is contraindicated.
• The duration of treatment with flupirtine should not exceed 2 weeks and patients' liver function should be checked after each full week of treatment.
• Treatment must be stopped in any patient with abnormal liver function tests results or symptoms of liver disease.
• Flupirtine must not be used in patients with pre-existing liver disease or alcohol abuse problems or in patients taking other medicines known to cause liver problems.
• Healthcare professionals should review the treatment of patients taking flupirtine taking into account the recommendations above.

More about the medicine

Flupirtine is a non-opioid painkiller that has been used to treat pain, such as pain associated with muscle tension, cancer pain, menstrual pain and pain following orthopaedic surgery or injuries.

Flupirtine-containing medicines have been authorised since the 1980s and are currently available in the following EU Member States: Bulgaria, Estonia, Germany, Hungary, Italy, Latvia, Lithuania, Poland, Portugal, Romania and Slovakia.

Flupirtine is available as 100-mg immediate-release capsules, 400-mg extended-release tablets, 75-mg and 150-mg suppositories and as a solution for injection (100 mg). The 100-mg immediate-release capsules are available in the 11 EU Member States listed above. The other dosages and pharmaceutical forms are only available in Germany.

Flupirtine was first introduced as an alternative painkiller to opioids and NSAIDs. Subsequently, multiple other actions such as muscle relaxation were identified. Flupirtine works as a 'selective neuronal-potassium-channel opener'. This means that it opens specific pores on the surface of nerve cells called potassium channels. The opening of these channels reduces the excessive electrical activity that leads to many pain states.

More about the procedure

The review of flupirtine-containing medicines was initiated in March 2013 at the request of Germany, under Article 107i of Directive 2001/83/EC. It followed the procedural steps laid out in Article 107i of Directive 2001/83, also known as the urgent Union procedure.

A review of these data was first conducted by the PRAC. The PRAC recommendations were sent to the CMDh, which adopted a final position. The CMDh, a body representing EU Member States, is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

As the CMDh position was adopted by majority it was sent to the European Commission, which endorsed it and adopted a final legally binding decision valid throughout the EU.

Flupirtine-containing medicines Article-107i procedure - Restrictions in the use of flupirtine-containing medicines

Reference Number: EMA/563900/2013

Key facts

About this medicine

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

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-107i/1363
• Type:
  Article 107i procedures

  This type of procedure is triggered when a Member State or the European Commission consider that urgent action is necessary because of a safety issue. Situations that fall under this procedure include consideration for suspension or revocation of the marketing authorisation for a medicine, the prohibition of supply of a medicine or major changes to the marketing authorisation such as deletion of indications, reduction of the recommended dose or new contraindications. The procedure is also applicable in case of a safety issue with a class of medicines.

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

Key dates and outcomes

• Procedure start date:
  07/03/2013
• PRAC recommendation date:
  13/06/2013
• CHMP opinion date:
  26/06/2013
• EC decision date:
  05/09/2013
• Outcome:
  Risk minimisation measures

Data submission

The Agency invites all stakeholders (e.g. healthcare professionals, patients' organisations and the general public) to submit data relevant to this procedure. This is in accordance with Article 107j(1) of Directive 2001/83/EC.

The following requirements apply for data to be considered:

• Submissions must be accompanied by the submission form below, with all fields completed. The form must be used with Adobe Reader X+ or Adobe Acrobat X+:
  Flupirtine-containing medicines Article-107i procedure - Stakeholders' submission form

• Data submitted should make reference to the Pharmacovigilance Risk Assessment Committee (PRAC) questions:
  Flupirtine-containing medicines Article-107i procedure - PRAC list of questions to be addressed by the stakeholders

• The submission of all data should take place by 8 April 2013.

Submitting data

Send the completed form electronically to the stakeholders' submission inbox ([e-mail]). Specify the name of the medicine in the subject line of the e-mail.

The size of the submission file should not exceed 25 MB. If your attempt to send your data package to the dedicated e-mail address is unsuccessful, please use alternative submission means.

It is of the utmost importance that data are provided promptly, to avoid undermining the safety review. Due to the urgent nature of the procedure, you are strongly advised to submit your data in English.

Protection of personal data

Personal data submitted are subject to data-protection rules as established by Regulation (EC) 45/2001. They will be treated in accordance with the

.

 

Treatment and publication of data

Data submitted will be received and recorded by the Agency.

The Agency will prepare a list of all submissions received, which will be published as an annex to the PRAC assessment report for transparency purposes and public awareness.

Please note that all data submitted in the context of this procedure may be shared and disclosed in the public domain.

All documents

Procedure started

Flupirtine-containing medicines Article-107i procedure - PRAC list of questions to be addressed by the stakeholders

AdoptedReference Number: EMA/PRAC/144072/2013

Flupirtine-containing medicines Article-107i procedure - PRAC list of questions to be addressed by the marketing-authorisation holders

AdoptedReference Number: EMA/PRAC/137417/2013

Flupirtine-containing medicines Article-107i procedure - Timetable for the procedure

AdoptedReference Number: EMA/PRAC/137732/2013

Flupirtine-containing medicines Article-107i procedure - Notification

Adopted

Flupirtine-containing medicines Article-107i procedure - Stakeholders' submission form

AdoptedReference Number: EMA/639499/2012

Flupirtine-containing medicines Article-107i procedure - Review started

AdoptedReference Number: EMA/139661/2013

Flupirtine-containing medicines Article-107i procedure - Annex I

AdoptedReference Number: EMA/147828/2013

Flupirtine-containing medicines Article-107i procedure - Rationale for triggering

Adopted

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Flupirtine-containing medicines Article-107i procedure - PRAC assessment report

AdoptedReference Number: EMA/404308/2013

Flupirtine-containing medicines Article-107i procedure - PRAC recommends restricting the use of flupirtine-containing medicines

Reference Number: EMA/362055/2013

Position provided by CMDh

Flupirtine-containing medicines Article-107i procedure - Annex I

Flupirtine-containing medicines Article-107i procedure - Annex IV

Flupirtine-containing medicines Article-107i procedure - Annex III

Flupirtine-containing medicines Article-107i procedure - Annex II

Flupirtine-containing medicines Article-107i procedure - Divergent positions to CMDh position

Flupirtine-containing medicines Article-107i procedure - Restrictions in the use of flupirtine-containing medicines - CMDh endorses PRAC recommendation

Reference Number: EMA/384191/2013

European Commission final decision

Flupirtine-containing medicines Article-107i procedure - Restrictions in the use of flupirtine-containing medicines

Reference Number: EMA/563900/2013

Flupirtine-containing medicines Article-107i procedure - Restrictions in the use of flupirtine-containing medicines

Reference Number: EMA/563900/2013

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.