Codeine-containing medicinal products for the treatment of cough or cold in paediatric patients - referral

Current status

CMDh final position

Overview

Codeine not to be used in children below 12 years for cough and cold

The CMDh¹ has agreed by consensus new measures to minimise the risk of serious side effects, including breathing problems, with codeine-containing medicines when used for cough and cold in children. As a result of these new measures:

• Use of codeine for cough and cold is now contraindicated in children below 12 years. This means it must not be used in this patient group.
• Use of codeine for cough and cold is not recommended in children and adolescents between 12 and 18 years who have breathing problems.

The effects of codeine are due to its conversion into morphine in the body. Some people convert codeine to morphine at a faster rate than normal, resulting in high levels of morphine in their blood. High levels of morphine can lead to serious effects, such as breathing difficulties.

The new measures follow a review by EMA's Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC considered that, although morphine-induced side effects may occur in patients of all ages, the way codeine is converted into morphine in children below 12 years is more variable and unpredictable, making this population at special risk of such side effects. In addition, children who already have problems with their breathing may be more susceptible to respiratory problems due to codeine. The PRAC also noted that cough and cold are generally self-limiting conditions and the evidence that codeine is effective at treating cough in children is limited.

In addition to the new measures for children, codeine must also not be used in people of any age who are known to convert codeine into morphine at a faster rate than normal ('ultra-rapid metabolisers') nor in breastfeeding mothers, as codeine can harm the baby because it passes into breast milk.

This review comes after a previous review of codeine for pain relief in children, which resulted in several restrictions being introduced in order to ensure that the medicine was used as safely as possible. As it was realised that similar considerations could apply to the use of codeine for cough and cold in children, a second EU-wide review of such use was started. The restrictions for codeine for cough and cold are largely in line with the previous recommendations for codeine when used for pain relief.

As the CMDh has now agreed the PRAC measures by consensus, the measures will be directly implemented by the Member States where the medicines are authorised, according to an agreed timetable.

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¹ The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway.

Information for patients

• Following an EU-wide review of codeine when used for cough and cold, changes have been made to the way the medicine is used to ensure that the benefits continue to outweigh the risks in children and adolescents.
• Codeine-containing medicines for cough and cold must not be used in children below 12 years of age because of the risk of serious side effects, including breathing problems.
• In children and adolescents between 12 and 18 years who have problems with their breathing, codeine is not recommended as this population may be more susceptible to breathing problems due to codeine.
• Patients of all ages who are known to be 'ultra-rapid metabolisers', which means that they convert codeine into morphine very rapidly, must not use codeine for cough and cold as they are more at risk of serious side effects with codeine.
• Mothers who are breastfeeding must not take codeine as codeine can harm the baby because it passes into breast milk.
• Parents and caregivers who notice any of the following symptoms in a patient given codeine should stop giving the medicine and seek medical attention immediately: slow or shallow breathing, confusion, sleepiness, small pupils, feeling or being sick, constipation and lack of appetite.
• If you or your child are being treated with codeine and have any questions or concerns about your treatment, speak to your doctor or pharmacist.

Information for healthcare professionals

• Codeine for cough and cold is now contraindicated in children below 12 years, and not recommended in children between 12 and 18 years with compromised respiratory function.
• Codeine is also contraindicated in women during breastfeeding and patients known to be CYP2D6 ultra-rapid metabolisers.

These new measures follow a review of available safety and efficacy data on codeine when used for cough and cold, including data from clinical studies, observational studies and meta-analyses, post-marketing data in Europe and other published literature on the use of codeine in children.

In total, 14 cases of codeine intoxication in children (aged from 17 days to 6 years) related to the treatment of cough and respiratory infection were identified in the published literature, four of which had a fatal outcome.

The available data indicate that the way codeine is converted into morphine in children below 12 years is more variable and unpredictable, making this population at special risk of morphine-induced side effects. In addition, the evidence that codeine is effective at treating cough in children is limited and international guidelines emphasise that cough associated with viral infections may be satisfactorily managed with fluids and increased ambient humidity; in the case of chronic cough, treatment should be directed at the underlying disease.

More about the medicine

Codeine is an opioid medicine that is converted into morphine in the body. It is widely used for pain relief and for the treatment of the symptoms of coughs and colds. In the EU, codeine-containing medicines have been approved via national procedures, and are available either on prescription or over the counter in the different Member States. Codeine is marketed as a single-ingredient medicine or in combination with other active substances.

More about the procedure

The review of codeine when used for cough and cold in children was initiated in April 2014 at the request of the German medicines agency (BfArM), under Article 31 of Directive 2001/83/EC.

The review was carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), EMA's Committee responsible for the evaluation of safety issues for human medicines, which has made a set of recommendations. As codeine-containing medicines are all authorised nationally, the PRAC recommendations were forwarded to the CMDh for its position. The CMDh is a body representing EU Member States as well as Iceland, Lichtenstein and Norway, and is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

On 22 April 2015 the CMDh adopted its position by consensus, so the measures recommended by the PRAC will be directly implemented by the Member States where the medicines are authorised, according to an agreed timetable.

Codeine Article-31 referral - Codeine not to be used in children below 12 years for cough and cold

Adopted

Key facts

About this medicine

• Approved name:
  Codeine-containing medicinal products for the treatment of cough or cold in paediatric patients

About this procedure

• Current status:
  CMDh final position
• Reference number:
  EMEA/H/A-31/1394
• 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:
  12/03/2015
• CMDh position date:
  22/04/2015
• Outcome:
  Variation

All documents

Procedure started

Codeine Article-31 referral - Timetable for the procedure

Reference Number: EMA/PRAC/180087/2014

Codeine Article-31 referral - Notification

Codeine Article-31 referral - PRAC list of questions

Reference Number: EMA/PRAC/180085/2014

Codeine Article-31 referral - Review started

Reference Number: EMA/209409/2014

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Codeine Article-31 referral - PRAC assessment report

AdoptedReference Number: EMA/235820/2015

Codeine Article-31 referral - PRAC recommends restrictions on the use of codeine for cough and cold in children

AdoptedReference Number: EMA/163792/2015

Position provided by CMDh

Codeine Article-31 referral - Annex II

Codeine Article-31 referral - Annex IV

Codeine Article-31 referral - Codeine not to be used in children below 12 years for cough and cold

Adopted

Codeine Article-31 referral - Annex III

Codeine Article-31 referral - Annex I

Reference Number: EMA/713187/2012

Codeine Article-31 referral - Codeine not to be used in children below 12 years for cough and cold

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.