Pholcodine - referral

Current status

European Commission final decision

Overview

The European Medicines Agency has completed a review of the safety and effectiveness of pholcodine, following concerns that its use may put people at risk of developing anaphylactic (severe allergic) reactions to neuromuscular blocking agents used during surgery. The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the existing evidence of the risk is weak, and that the benefits of pholcodinecontinue to outweigh its risks. Therefore, it recommended that all marketing authorisations for medicines containing pholcodine should be maintained throughout the European Union (EU).

What is pholcodine?

Pholcodine is an opioid medicine that is used for the treatment of non-productive (dry) cough in children and adults. It works directly in the brain, depressing the cough reflex by reducing the nerve signals that are sent to the muscles involved in coughing.

Pholcodine has been used as a cough suppressant since the 1950s. Pholcodine-containing medicines are currently approved in the EU in Belgium, France, Ireland, Lithuania, Luxembourg, Malta, Slovenia, Spain and the United Kingdom, either subject to medical prescription or as over-the-counter medicines. They may be available as syrups, oral solutions, suppositories, tablets and capsules under various trade names and as generics.

Why was pholcodine reviewed?

At the time of the review, pholcodine-containing medicines had been withdrawn from the markets in Sweden (in the 1980s) and Norway (in 2007). In 2009, a study was published indicating that the reduction in pholcodine consumption in these countries was associated with a decrease in reports of anaphylactic reactions to neuromuscular blocking agents (NMBAs). NMBAs are used in emergency hospital procedures to prevent spontaneous muscle movements during surgery. Further publications in 2010 and 2011 from the same authors supported the hypothesis that pholcodine use may increase the likelihood of patients having an anaphylactic reaction if they are exposed to an NMBA. In France, data from spontaneous reports also suggested a 25% increase in anaphylactic reactions to NMBAs coinciding with a 9% increase in pholcodine use.

Consequently, the French medicines regulatory agency changed the prescription status for these medicines in France from over-the-counter to prescription-only, and asked the CHMP to carry out a full assessment of the benefit-risk balance of pholcodine and to issue an opinion on whether the marketing authorisations for pholcodine-containing products should be maintained, varied, suspended or withdrawn across the EU.

Which data has the CHMP reviewed?

The CHMP reviewed all the available data on the effects of pholcodine as a cough suppressant. To assess its safety, the Committee reviewed the results from preclinical and clinical studies, post-marketing data, epidemiological studies and data from the published literature. A group of experts in immunology and anaesthesia was also convened to provide advice.

What are the conclusions of the CHMP?

Regarding pholcodine's benefits, the CHMP noted that there is a large body of data demonstrating the effectiveness of opioids in the management of non-productive cough and that pholcodine has been in use for several decades. Regarding pholcodine's safety, the majority of adverse effects reported with pholcodine are those commonly seen with opioid medicines.

The hypothesis that pholcodine use could trigger anaphylactic reactions to NMBAs is based on the body producing antibodies against pholcodine, which eventually trigger reactions to NMBAs ('cross-sensitisation'). The CHMP considered that, although this is biologically plausible, the available data are weak and not fully consistent. The Committee noted that the study in Sweden and Norway looked at changes in reporting rates of adverse reactions to NMBAs following the withdrawal of these medicines, without convincingly establishing a causal link with pholcodine use. Cross-sensitisation has also been observed in countries where pholcodine is not on the market, suggesting that other substances may also trigger cross-sensitisation and that the observed changes in reporting rates may be explained by other factors. Therefore, the CHMP concluded that the existing evidence does not support the conclusion that the use of pholcodine-containing medicines presents a risk of developing anaphylactic reactions to NMBAs. The Committee nevertheless recommended that a new post-marketing study investigating the possibility of an association between pholcodine and anaphylactic reactions to NMBAs should be carried out.

Based on the evaluation of the currently available data and the scientific discussion within the Committee, the CHMP concluded that the benefits of pholcodine-containing medicines continue to outweigh their risks, and therefore recommended that all marketing authorisations for these medicines should be maintained.

What are the recommendations for patients and healthcare professionals?

• Patients and healthcare professionals are reminded that the benefits of pholcodine continue to outweigh its risks for the treatment of non-productive cough. No new risks have been identified with pholcodine.
• Patients taking pholcodine-containing medicines can continue to do so, and should contact their doctor or pharmacist if they have any questions about their treatment.

The European Commission issued a decision on 17 February 2012.

Questions and answers on the review of the marketing authorisations for medicines containing pholcodine

AdoptedReference Number: EMA/890819/2011Summary:

The European Medicines Agency has completed a review of the safety and effectiveness of pholcodine, following concerns that its use may put people at risk of developing anaphylactic (severe allergic) reactions to neuromuscular blocking agents used during surgery.

Key facts

About this medicine

• Approved name:
  Pholcodine
• International non-proprietary name (INN) or common name:
  pholcodine

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1292
• 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:
  15/12/2011
• EC decision date:
  17/02/2012

All documents

Pholcodine - Article 31 referral - Assessment report

Pholcodine - Article 31 referral - Annex I

Pholcodine - Article 31 referral - Annex II

Pholcodine - Article 31 referral - Annex III

Questions and answers on the review of the marketing authorisations for medicines containing pholcodine

AdoptedReference Number: EMA/890819/2011Summary:

The European Medicines Agency has completed a review of the safety and effectiveness of pholcodine, following concerns that its use may put people at risk of developing anaphylactic (severe allergic) reactions to neuromuscular blocking agents used during surgery.

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.