Ambroxol and bromhexine-containing medicines - referral

Current status

European Commission final decision

Overview

 

Ambroxol and bromhexine expectorants: safety information to be updated

Risk of allergy and skin reactions to be included in the product information

The CMDh¹ has endorsed by majority vote recommendations to update the product information for ambroxol- and bromhexine-containing medicines with information about the small risk of severe allergic reactions and severe cutaneous adverse reactions (SCARs). The medicines are widely available in the EU for use as expectorants (to help clear mucus from the airways).

The recommendations were originally made by EMA's Pharmacovigilance Risk Assessment Committee (PRAC), which confirmed the previously known risk of allergic reactions and also identified a small risk of SCARs, a group of skin conditions which include erythema multiforme and Stevens-Johnson syndrome.

As a result, SCARs are now to be listed as side effects in the product information for these medicines, and patients are to stop treatment immediately if symptoms of SCARs occur. Reports of severe allergic reactions and SCARs in patients taking the medicines are rare, and the frequencies of these side effects are unknown.

In making the recommendations, the PRAC evaluated available data on ambroxol and bromhexine, including reports of severe allergic reactions or SCARs.

As the CMDh position was adopted by majority vote, the CMDh position will now be sent to the European Commission, which will take an EU-wide legally binding decision.

Information to patients

• There is a small risk of allergy and skin reactions with ambroxol and bromhexine used as expectorants to clear mucus in the airways.
• If you experience skin reactions such as skin swellings or rash, stop treatment immediately and contact your doctor.
• If you are taking ambroxol or bromhexine and have any questions or concerns speak to your doctor of pharmacist.

Information to healthcare professionals

• Anaphylactic reactions and severe cutaneous adverse reactions (SCARs), including erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis and acute generalised exanthematous pustulosis, have been reported in patients receiving ambroxol.
• As ambroxol is a metabolite of bromhexine, the risk of anaphylactic and severe cutaneous reactions is considered to apply also to bromhexine.
• The risk of anaphylactic reactions and SCARs with ambroxol or bromhexine is low. Frequencies of these side effects are unknown.
• Advise your patients that they should stop treatment immediately if symptoms of progressive skin rash occur.

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¹ The CMDh is a medicines regulatory body representing the European Union (EU) Member States.

Information to patients

• There is a small risk of allergy and skin reactions with ambroxol and bromhexine used as expectorants to clear mucus in the airways.
• If you experience skin reactions such as skin swellings or rash, stop treatment immediately and contact your doctor.
• If you are taking ambroxol or bromhexine and have any questions or concerns speak to your doctor of pharmacist.

Information to healthcare professionals

• Anaphylactic reactions and severe cutaneous adverse reactions (SCARs), including erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis and acute generalised exanthematous pustulosis, have been reported in patients receiving ambroxol.
• As ambroxol is a metabolite of bromhexine, the risk of anaphylactic and severe cutaneous reactions is considered to apply also to bromhexine.
• The risk of anaphylactic reactions and SCARs with ambroxol or bromhexine is low. Frequencies of these side effects are unknown.
• Advise your patients that they should stop treatment immediately if symptoms of progressive skin rash occur.

More about the medicines

Ambroxol and bromhexine are mainly used by mouth as expectorants to help make the mucus thinner and therefore easier to be cleared away in patients with short- or long-term diseases of the lungs or airways.

For ambroxol, lozenge formulations are also available to relieve sore throat. Ambroxol formulations for injection are also used in premature and newborn babies to treat respiratory distress syndrome, a condition in which the baby's lungs are too immature for the baby to breathe properly. Some of these injectable formulations are also used to increase lung development before birth. Injectable formulations are also used to prevent and treat lung complications following surgery.

Ambroxol- and bromhexine-containing medicines are marketed as single products or as fixed combination products with various other active ingredients. The majority of these medicines are available over the counter, whereas some are prescription-only medicines, depending on the condition to be treated and how the treatment is given.

As these medicines have been authorised via national procedures, approved uses are not the same in all EU countries.

Ambroxol and bromhexine medicines have been authorised in: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain and Sweden.

More about the procedure

The review of ambroxol and bromhexine was initiated on 4 April 2014 at the request of Belgium, under Article 31 of Directive 2001/83/EC.

The review was 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. As ambroxol- and bromhexine-containing medicines are all authorised nationally, the PRAC recommendation was forwarded to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), for a position. The CMDh is a regulatory body representing EU Member States, and is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

The CMDh position was agreed by majority vote, and will now be sent to the European Commission for the adoption of an EU-wide legally binding decision.

Ambroxol and bromhexine Article-31 referral - Ambroxol and bromhexine expectorants: safety information to be updated

AdoptedReference Number: EMA/130676/2015

Key facts

About this medicine

• Approved name:
  Ambroxol and bromhexine-containing medicines
• International non-proprietary name (INN) or common name:
  • ambroxol
  • bromhexine
• Class:
  -

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1397
• 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.

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

Key dates and outcomes

• Procedure start date:
  10/04/2014
• PRAC recommendation date:
  10/09/2015
• CMDh position date:
  18/11/2015
• EC decision date:
  14/01/2016
• Outcome:
  Variation

All documents

Procedure started

Ambroxol and bromhexine Article-31 referral - Review started

Reference Number: EMA/203011/2014 corr. 1

Ambroxol and bromhexine Article-31 referral - Notification

Ambroxol and bromhexine Article-31 referral - Timetable for the procedure

Reference Number: EMA/PRAC/189079/2014

Ambroxol and bromhexine Article-31 referral - Annex I

Reference Number: EMA/223489/2014 – corr.1

Ambroxol and bromhexine Article-31 referral - PRAC list of questions

Reference Number: EMA/PRAC/189078/2014

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Ambroxol and bromhexine Article-31 referral - PRAC assessment report

AdoptedReference Number: EMA/PRAC/133132/2015

Ambroxol and bromhexine Article-31 referral - PRAC considers risk of severe allergic reactions with ambroxol- and bromhexine-containing medicines to be small

Reference Number: EMA/796499/2014

Position provided by CMDh

Ambroxol and bromhexine Article-31 referral - Ambroxol and bromhexine expectorants: safety information to be updated

AdoptedReference Number: EMA/130676/2015

Ambroxol and bromhexine Article-31 referral - Ambroxol and bromhexine expectorants: safety information to be updated

AdoptedReference Number: EMA/130676/2015

European Commission final decision

Ambroxol and bromhexine Article-31 referral - Divergent opinion (Belgium, Luxembourg)

Ambroxol and bromhexine Article-31 referral - Annex II

Ambroxol and bromhexine Article-31 referral - Divergent opinion (Croatia)

Ambroxol and bromhexine Article-31 referral - Divergent opinion (Portugal, Czech Republic)

Ambroxol and bromhexine Article-31 referral - Divergent opinion (France)

Ambroxol and bromhexine Article-31 referral - Divergent opinion (Italy)

Ambroxol and bromhexine Article-31 referral - Divergent opinion (Germany, Hungary, Latvia)

Ambroxol and bromhexine Article-31 referral - Divergent opinion (Netherlands)

Ambroxol and bromhexine Article-31 referral - Annex III

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.