Codeine-containing medicines - referral
Current status
Referral
Human
The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) has endorsed by consensus a series of risk-minimisation measures to address safety concerns with codeine-containing medicines when used for the management of pain in children. Codeine is an opioid that is authorised as a painkiller in adults and children. The effect of codeine on pain is due to its conversion into morphine in the patient's body.
This follows a review of these medicines by the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC), which investigated reports of serious and fatal respiratory depression in children after taking codeine for pain relief. Most of the cases occurred after surgical removal of the tonsils or adenoids for obstructive sleep apnoea (frequent interruption of breathing during sleep).
Some of the children who had suffered severe side effects had evidence of being 'ultra-rapid metabolisers' of codeine. In these patients, codeine is converted into morphine in the body at a faster rate than normal, resulting in high levels of morphine in the blood that can cause toxic effects such as respiratory depression.
The PRAC concluded that a number of risk-minimisation measures are necessary to ensure that only children for whom the benefits are greater than the risks are given the medicine for pain relief. The CMDh agreed with the PRAC's conclusions and endorsed the following recommendations:
The risk of side effects with codeine may also apply to adults. Codeine should therefore not be used in people of any age who are known to be ultra-rapid metabolisers nor in breastfeeding mothers (because codeine can pass to the baby through breast milk). The product information for codeine should also include general information for healthcare professionals, patients and carers on the risk of morphine side effects with codeine, and how to recognise their symptoms.
As the PRAC recommendation was endorsed by consensus by the CMDh, it will now be implemented directly by all Member States, according to an agreed timetable.
These recommendations follow a review of available safety and efficacy data on codeine when used for pain relief in children, including pharmacokinetic data, clinical studies, post-marketing data in Europe and other published literature:
Codeine is a widely used opioid medicine for pain relief. It is also used in the treatment of coughs, although this use in not covered by the current review. In the European Union (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 substances such as aspirin or paracetamol.
The effect of codeine on pain is due to its conversion into morphine. Codeine is converted into morphine in the body by an enzyme called CYP2D6. The children who had suffered severe side effects had evidence of being 'CYP2D6 ultra-rapid metabolisers' of codeine. In these patients, codeine is converted into morphine in the body at a faster rate than normal, resulting in high levels of morphine in the blood that can cause toxic effects such as breathing difficulties.
The review was initiated on 3 October 2012, at the request of the United Kingdom medicines agency under Article 31 of Directive 2001/83/EC. After discussions, on 31 October 2012 the scope of the review was extended from post-surgery pain relief in children to pain relief in children.
A review of these data was first conducted by the Pharmacovigilance Risk Assessment Committee (PRAC). As codeine-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 consensus, it will be directly implemented by the Member States.
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.
Description of documents published
Please note that some of the listed documents apply only to certain procedures.
Note that older documents may have different titles.