Lorazepam Macure 4 mg/ml, solution for injection - referral

Current status

European Commission final decision

Overview

On 27 June 2024, the European Medicines Agency (EMA) completed a review of Lorazepam Macure following disagreement among EU Member States about an application to update the medicine’s product information to include the control of status epilepticus (epileptic seizure lasting longer than 5 minutes or recurrent seizures without recovery in between) in adults, adolescents and children from 1 month old.

The Agency agreed that this use can be added to the product information in the Member States of the EU where the medicine is authorised. However, the product information should include information to minimise the potential risk of toxicity in young children linked to the combined use of three alcohol-based excipients. 

What is Lorazepam Macure?

Lorazepam Macure, a medicine of the benzodiazepine class, is used in several EU countries as a sedative before surgery or extensive physical examinations. It is also used to relieve severe fear or tension in people who cannot swallow tablets.

Lorazepam Macure contains the active substance lorazepam and is a generic medicine. A generic medicine contains the same active substance and works in the same way as a reference medicine authorised in the EU. The reference medicine for Lorazepam Macure is called Xilmac.

Lorazepam Macure is authorised in Austria, Belgium, Denmark, Finland, Germany, Ireland, Italy, the Netherlands, Norway, Slovenia and Sweden.

The company that markets Lorazepam Macure is Macure Pharma ApS.

Why was Lorazepam Macure reviewed?

Lorazepam Macure was authorised in the EU via national procedures.

In June 2022, Macure Pharma ApS submitted an application to the Dutch medicines agency as part of a mutual recognition procedure to update the product information for Lorazepam Macure in line with that of the reference medicine Xilmac. The update involved the addition of a new use to control status epilepticus in adults, adolescents, children and infants from 1 month of age.

The company wanted this update to be recognised in all the other Member States where the medicine is authorised. However, the Member States were not able to reach an agreement and the matter was therefore referred to EMA for arbitration on 1 February 2024.

The Swedish medicines agency had concerns about the measures in place to minimise the risks associated with the medicine in infants below 5 years of age. They considered that the product information for Lorazepam Macure should be updated to better highlight and minimise the risk of accumulation of three alcohol-based excipients (benzyl alcohol, propylene glycol and polyethylene glycol) in these infants. 

What is the outcome of the review?

The Agency recommended approving the update to the product information of Lorazepam Macure to add the control of status epilepticus in adults, adolescents, children and infants from 1 month of age. However, the product information should also provide additional information about the potential risk of toxicity in young children exposed to the combination of benzyl alcohol, propylene glycol and polyethylene glycol. In particular, the product information will underline that the medicine must not be given to newborn infants to control status epilepticus. It will also include a warning on the risk of cumulative exposure in children under 5 years with the combined use of the three alcohol excipients and advice not to repeat the maximum dose within 24 hours in these children.

More about the procedure

The review of Lorazepam Macure was initiated on 22 February 2024 at the request of the Netherlands under Article 13 of Regulation (EC) No 1234/2008.

The review was carried out by EMA’s Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use.

The European Commission issued an EU-wide legally binding decision to implement these changes on 29 August 2024.

Lorazepam Macure - Article 13 referral - Control of status epilepticus to be added to product information

Reference Number: EMA/415192/2024

Key facts

About this medicine

• Approved name:
  Lorazepam Macure 4 mg/ml, solution for injection
• International non-proprietary name (INN) or common name:
  lorazepam

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-13/1536
• Type:
  Article 13 referrals

  This type of referral is triggered for a medicine that has been authorised by mutual recognition or via the decentralised procedure when there is disagreement between Member States on a variation (type II), on the grounds of a potential serious risk to public health.

• Authorisation model:
  Nationally authorised product(s)
• Decision making model:
  CHMP-EC

Key dates and outcomes

• Procedure start date:
  22/02/2024
• CHMP opinion date:
  27/06/2024
• EC decision date:
  29/08/2024

All documents

Opinion provided by Committee for Medicinal Products for human Use

Lorazepam Macure - Article 13 referral - Product Information as approved by the CHMP on 27 June 2024, pending endorsement by the European Commission

European Commission final decision

Lorazepam Macure - Article 13 referral - Annex III

Lorazepam Macure - Article 13 referral - Annex II

Lorazepam Macure - Article 13 referral - Annex I

Lorazepam Macure - Article 13 referral - Assessment report

AdoptedReference Number: EMA/390606/202

Lorazepam Macure - Article 13 referral - Control of status epilepticus to be added to product information

Reference Number: EMA/415192/2024

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.