Tetrazepam-containing medicines - referral

Current status

European Commission final decision

Overview

Tetrazepam-containing medicines suspended across the EU

On 24 April 2013, following the recommendation by the Pharmacovigilance Risk Assessment Committee (PRAC), the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) endorsed by majority the PRAC recommendation to suspend the marketing authorisations of tetrazepam-containing medicines across the European Union (EU). The CMDh, a body representing EU Member States, is responsible for ensuring harmonised safety standards for medicines authorised via national marketing-authorisation procedures across the EU.

Tetrazepam, a medicine of the benzodiazepine class, is used in several EU Member States to treat painful contractures (such as in low-back pain and neck pain) and spasticity (excessive stiffness of muscles).

The review of tetrazepam was triggered by the French National Agency for the Safety of Medicine and Health Products (ANSM), following reports of serious skin reactions with this medicine in France. Having assessed all available data on the risk of skin reactions, including post-marketing data in the EU and the published literature, the PRAC concluded that tetrazepam is associated with a low but increased risk of serious skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis and drug-rash-with-eosinophilia-and-systemic-symptoms (DRESS) syndrome) compared with other benzodiazepines. The Committee also noted that, in the light of the risks identified, the available data on the effectiveness of tetrazepam were not sufficiently robust to support its use in the authorised indications.

The CMDh agreed with the PRAC conclusion that the benefits of these medicines do not outweigh their risks, and adopted a final position that the marketing authorisations should be suspended throughout the EU. Because the CMDh took this position by majority it was sent to the European Commission, which endorsed it and adopted a legally binding decision on 29 May 2013.

The suspension of the marketing authorisations can be lifted if the companies that market these medicines provide data identifying a specific group of patients for whom the benefits of tetrazepam-containing medicines outweigh the risks.

Information to patients

• Tetrazepam is a muscle relaxant used in painful conditions such as low-back pain and neck pain as well as spasticity (excessive stiffness of muscles).
• As a result of the risk of unpredictable, serious skin reactions identified, tetrazepam-containing medicines will no longer be available in the EU.
• If you are taking a tetrazepam-containing medicine, you should not suddenly stop taking tetrazepam without your doctor's advice. You should make an appointment with your treating doctor to discuss your treatment. Your doctor may also consider an appropriate alternative treatment for you.

Information to healthcare professionals

• In light of the unfavourable benefit-risk balance, doctors should review their patients' treatment at their next appointment, and may consider an appropriate alternative treatment.
• Pharmacists should refer patients on a new or repeat prescription for tetrazepam to their treating physician.

The CMDh position is based on the PRAC review of all available data on the risk of skin reactions with tetrazepam, including post-marketing data in the EU and the published literature, and the available information on efficacy in licensed indications:

• The review found that half of the reported reactions with tetrazepam are skin disorders, which are sometimes serious, life-threatening or fatal. Serious skin reactions include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme and DRESS syndrome. They are unpredictable and can occur at any stage during treatment, including after short-term treatment, and at recommended doses.
• In the pharmacovigilance database of the originator product, Myolastan, a total of 513 cutaneous (or allergic) reactions were identified. 65 cases of SJS and TEN were reported. Although the majority of cases occurred in patients taking concomitant medications, the causal link with tetrazepam was strong in a high number of cases.
• The risk of skin reaction is higher with tetrazepam than with other benzodiazepines. This is possibly explained by a structural difference between tetrazepam and other benzodiazepines (i.e. the substituted cyclohexenyl ring of tetrazepam).
• Regarding its efficacy, four studies showed no difference between tetrazepam and other active medicines when used for spasticity. The efficacy of tetrazepam for painful contractures is supported mainly by two small double-blind placebo-controlled clinical trials showing limited efficacy.

In view of the serious, potentially fatal, skin reactions and the limited efficacy of tetrazepam, the benefit-risk balance of tetrazepam-containing medicines is considered no longer favourable.

More about the medicine

Tetrazepam belongs to a group of medicines called benzodiazepines. It is taken by mouth to treat painful contractures (sustained shortening of muscle tissue), and spasticity (excessive stiffness of muscles).

Tetrazepam-containing medicines have been approved since the 1960s via national procedures in several EU Member States (Austria, Belgium, Bulgaria, the Czech Republic, France, Germany, Latvia, Lithuania, Luxembourg, Poland, Romania, Slovakia and Spain), and are available on prescription under various trade names, including Epsipam, Miozepam, Musapam, Musaril, Myolastan, Myopam, Panos, Relaxam, Spasmorelax, Tetra-saar, Tetramdura and Tetraratio. The full list is available in annex I under the 'all documents' tab.

Benzodiazepines work by attaching to certain receptors in the brain, thereby increasing the activity of a substance called gamma-aminobutyric acid (GABA). GABA decreases the excitability of many brain cells. By increasing GABA activity, benzodiazepines have a calming effect on various functions of the brain. In particular, tetrazepam is used for its muscle-relaxant effects.

More about the procedure

The review of tetrazepam-containing medicines was initiated in January 2013 at the request of France, under Article 107i of Directive 2001/83/EC, also known as the urgent Union procedure.

The review was first conducted 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. As tetrazepam-containing medicines are all authorised nationally, the PRAC recommendations were sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (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 vote, the CMDh position was sent to the European Commission, which endorsed it and adopted an EU-wide legally binding decision.

Key facts

About this medicine

• Approved name:
  Tetrazepam-containing medicines
• International non-proprietary name (INN) or common name:
  tetrazepam
• Associated names:
  Myolastan and generics
• Class:
  -

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A107i/1352
• 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:
  10/01/2013
• PRAC recommendation date:
  11/04/2013
• CMDh position date:
  24/04/2013
• EC decision date:
  29/05/2013
• Outcome:
  Suspension

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+:
  Tetrazepam-containing medicines - Article-107i procedure - Stakeholder's submission form
• Data submitted should make reference to the Pharmacovigilance Risk Assessment Committee (PRAC) questions:Tetrazepam-containing medicines - Article-107i procedure - PRAC list of questions to be addressed by stakeholders
• The submission of all data should take place by 4 February 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 specific privacy statement for public consultations.

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

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

Tetrazepam-containing medicines - Article-107i procedure - Stakeholder's submission form

Reference Number: EMA/639499/2012

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

Reference Number: EMA/13608/2013

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

Reference Number: EMA/PRAC/15160/2013

Tetrazepam-containing medicines - Article-107i procedure - Review of tetrazepam-containing medicines started

Reference Number: EMEA/H/A-107i/1352

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

Reference Number: EMA/PRAC/15074/2013

Tetrazepam-containing medicines - Article-107i procedure - Notification

Recommendation provided by Pharmacovigilance Risk Assessment Committee

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

Adopted Reference Number: EMA/279100/2013

Tetrazepam-containing medicines Article-107i procedure - PRAC recommends suspension of tetrazepam-containing medicines: Questions and answers

Reference Number: EMA/225675/2013

Position provided by CMDh

Tetrazepam-containing medicines - Article-107i procedure - Tetrazepam-containing medicines suspended across the EU

Adopted Reference Number: EMA/402567/2013 – Rev. 1

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

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

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

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

Adopted

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.