Tolperisone - referral

Current status

European Commission final decision

Overview

On 21 June 2012, the European Medicines Agency completed a review of the safety and effectiveness of tolperisone. The Agency's Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of tolperisone-containing medicines given orally (by mouth) continue to outweigh their risks, but that their use should be restricted to the treatment of adults with post-stroke spasticity (stiffness). The Committee also recommended that the marketing authorisations for tolperisone-containing medicines given by injection should be revoked throughout the European Union (EU).

After re-examination, the Committee confirmed these recommendations on 18 October 2012.

What is tolperisone?

Tolperisone is a muscle relaxant. Tolperisone-containing medicines have been authorised in several countries in the EU since the 1960s for the treatment of muscle spasms (involuntary contractions) and spasticity caused by different conditions. These include neurological diseases (related to the brain or nerves, such as multiple sclerosis), locomotor diseases (related to the spine and large joints such as the hip), vascular diseases (related to the blood vessels), rehabilitation following surgery, and Little's disease (also known as cerebral palsy, a rare disease where there is damage to parts of the brain that control movement).

The exact way tolperisone works is not known, but it is thought to act in the brain and spinal cord to reduce the nerve impulses that make the muscles contract and become rigid. By reducing these impulses, tolperisone is believed to reduce muscle contraction, helping to relieve the stiffness.

Medicines containing tolperisone are available as tablets or solution for injection in Bulgaria, Cyprus, the Czech Republic, Germany, Hungary, Latvia, Lithuania, Poland, Romania and Slovakia, under various trade names.

Why were tolperisone-containing medicines reviewed?

As tolperisone-containing medicines have been developed by different companies and have been authorised through national procedures in the EU Member States, they are used to treat different conditions in different countries. In Germany, several indications approved in other countries were not authorised because the German medicines agency considered that tolperisone's effectiveness had not been proven in those indications. In addition, numerous reports of hypersensitivity (allergic) reactions to tolperisone had been reported post-marketing in Germany. Consequently, the German medicines agency considered that a full assessment of the benefit-risk balance of tolperisone should be carried out in all approved indications. On 15 July 2011, it asked the CHMP to issue an opinion on whether the marketing authorisations for tolperisone-containing products should be maintained, varied, suspended or withdrawn across the EU.

Which data has the CHMP reviewed?

The CHMP reviewed data on the effectiveness of oral and injectable tolperisone in the different indications, including data from published clinical studies and analyses of various studies provided by the companies that market these medicines. The Committee also reviewed the available post-marketing data on spontaneous reports of side effects.

What are the conclusions of the CHMP?

The CHMP noted that most of the studies with oral tolperisone, performed in the 1960s and 1970s, were of a lower standard than that expected today. The available data to support the use of tolperisone-containing medicines in locomotor diseases, vascular diseases, rehabilitation following surgery and Little's disease are limited and not convincing. Only in the treatment of spasticity caused by neurological diseases was a study considered to be of acceptable quality, showing a moderate improvement of 32% in spasticity with oral tolperisone, compared with a 14% improvement in the placebo (a dummy treatment) group. However, the study only included adults with post-stroke spasticity.

Regarding the safety of tolperisone, the CHMP noted that more than half of the spontaneous reports of side effects with tolperisone were hypersensitivity reactions, while only a small number of hypersensitivity reports had been observed during the clinical trials that supported tolperisone's marketing authorisation. The Committee therefore recommended that the product information should be updated to reflect this risk and include a warning on the signs of hypersensitivity.

Therefore, based on the evaluation of the currently available data and considering that the risk of hypersensitivity reactions is more significant than previously identified, the CHMP concluded that the benefits of oral tolperisone-containing medicines continue to outweigh its risks only when used in the treatment of post-stroke spasticity in adults. In addition, since extremely limited data are available to support the safety and dosing recommendations of injectable tolperisone, the CHMP concluded that the benefits of this formulation do not outweigh the identified risks, and that the marketing authorisations for tolperisone-containing medicines given by injection should be revoked.

The CHMP confirmed the above conclusions after re-examining its opinion. The full changes made to the information to doctors and patients are under the 'All documents' tab.

What are the recommendations for patients?

• Patients should be aware that the benefits of oral tolperisone continue to outweigh its risks only for the treatment of post-stroke spasticity in adults.
• Patients currently using tolperisone for any other indication or using injectable tolperisone should speak to their doctor at their next routine appointment so they can switch to an appropriate alternative treatment.
• Patients should note that symptoms of hypersensitivity can include flushing, rash, severe itching of the skin (with raised lumps), wheezing, difficulty breathing, difficulty in swallowing, fast heartbeat, low blood pressure and fast decrease in blood pressure. Patients should stop taking tolperisone and inform their doctor if they experience any of these symptoms.
• Patients who have any questions should speak to their doctor or pharmacist.

What are the recommendations for prescribers?

• Prescribers are advised that the indication for oral tolperisone has been restricted to the treatment of post-stroke spasticity in adults. Doctors should stop prescribing tolperisone for any other indication.
• Prescribers are advised that injectable tolperisone should no longer be used in the EU.
• Patients should be informed of the possibility of hypersensitivity reactions during treatment with tolperisone. If symptoms of hypersensitivity occur, treatment should be stopped immediately.

The European Commission issued a decision on this opinion on 21 January 2013.

Questions and answers on the review of tolperisone-containing medicines

Reference Number: EMA/673365/2012 Rev.1

Key facts

About this medicine

• Approved name:
  Tolperisone
• International non-proprietary name (INN) or common name:
  tolperisone
• Class:
  -

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1311
• 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:
  18/10/2012
• EC decision date:
  21/01/2013

All documents

Tolperisone: Product information as approved by the CHMP on 19 October 2012 pending endorsement by the European Commission

Opinion provided by Committee for Medicinal Products for human Use

Questions and answers on the review of tolperisone-containing medicines

Reference Number: EMA/673365/2012 Rev.1

European Commission final decision

Assessment report for tolperisone-containing medicinal products

Reference Number: EMA/753061/2012

Tolperisone Article-31 referral - Annex I

Tolperisone Article-31 referral - Annex II

Tolperisone Article-31 referral - Annex III

Tolperisone Article-31 referral - Annex IV

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.