Pholcodine

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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At the time of the review, pholcodine-containing medicines had been withdrawn from the markets in Sweden (in the 1980s) and Norway (in 2007).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.

Name Language First published Last updated
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine BG = bălgarski 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine ES = español 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine CS = čeština 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine DA = dansk 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine DE = Deutsch 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine ET = eesti keel 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine EL = elliniká 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine EN = English 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine FR = français 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine IT = italiano 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine LV = latviešu valoda 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine LT = lietuvių kalba 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine HU = magyar 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine MT = Malti 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine NL = Nederlands 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine PL = polski 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine PT = português 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine RO = română 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine SK = slovenčina 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine SL = slovenščina 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine FI = suomi 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine SV = svenska 2011-11-18  

Key facts

Approved namePholcodine
International non-proprietary name (INN) or common name

Pholcodine

Associated names
Class
Reference numberEMEA/H/A-31/1292
TypeArticle 31 referrals

This type of referral is triggered when the interest of the Community is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

StatusEuropean Commission final decision
Opinion date15/12/2011

All documents

Name Language First published Last updated
Pholcodine - Article 31 referral - Assessment report (English only) 2012-03-28  
Pholcodine - Article 31 referral - Annex I BG = bălgarski 2012-03-28  
Pholcodine - Article 31 referral - Annex I ES = español 2012-03-28  
Pholcodine - Article 31 referral - Annex I CS = čeština 2012-03-28  
Pholcodine - Article 31 referral - Annex I DA = dansk 2012-03-28  
Pholcodine - Article 31 referral - Annex I DE = Deutsch 2012-03-28  
Pholcodine - Article 31 referral - Annex I ET = eesti keel 2012-03-28  
Pholcodine - Article 31 referral - Annex I EL = elliniká 2012-03-28  
Pholcodine - Article 31 referral - Annex I EN = English 2012-03-28  
Pholcodine - Article 31 referral - Annex I FR = français 2012-03-28  
Pholcodine - Article 31 referral - Annex I IT = italiano 2012-03-28  
Pholcodine - Article 31 referral - Annex I LV = latviešu valoda 2012-03-28  
Pholcodine - Article 31 referral - Annex I LT = lietuvių kalba 2012-03-28  
Pholcodine - Article 31 referral - Annex I HU = magyar 2012-03-28  
Pholcodine - Article 31 referral - Annex I MT = Malti 2012-03-28  
Pholcodine - Article 31 referral - Annex I NL = Nederlands 2012-03-28  
Pholcodine - Article 31 referral - Annex I PL = polski 2012-03-28  
Pholcodine - Article 31 referral - Annex I PT = português 2012-03-28  
Pholcodine - Article 31 referral - Annex I RO = română 2012-03-28  
Pholcodine - Article 31 referral - Annex I SK = slovenčina 2012-03-28  
Pholcodine - Article 31 referral - Annex I SL = slovenščina 2012-03-28  
Pholcodine - Article 31 referral - Annex I FI = suomi 2012-03-28  
Pholcodine - Article 31 referral - Annex I SV = svenska 2012-03-28  
Pholcodine - Article 31 referral - Annex II BG = bălgarski 2012-03-28  
Pholcodine - Article 31 referral - Annex II ES = español 2012-03-28  
Pholcodine - Article 31 referral - Annex II CS = čeština 2012-03-28  
Pholcodine - Article 31 referral - Annex II DA = dansk 2012-03-28  
Pholcodine - Article 31 referral - Annex II DE = Deutsch 2012-03-28  
Pholcodine - Article 31 referral - Annex II ET = eesti keel 2012-03-28  
Pholcodine - Article 31 referral - Annex II EL = elliniká 2012-03-28  
Pholcodine - Article 31 referral - Annex II EN = English 2012-03-28  
Pholcodine - Article 31 referral - Annex II FR = français 2012-03-28  
Pholcodine - Article 31 referral - Annex II IT = italiano 2012-03-28  
Pholcodine - Article 31 referral - Annex II LV = latviešu valoda 2012-03-28  
Pholcodine - Article 31 referral - Annex II LT = lietuvių kalba 2012-03-28  
Pholcodine - Article 31 referral - Annex II HU = magyar 2012-03-28  
Pholcodine - Article 31 referral - Annex II MT = Malti 2012-03-28  
Pholcodine - Article 31 referral - Annex II NL = Nederlands 2012-03-28  
Pholcodine - Article 31 referral - Annex II PL = polski 2012-03-28  
Pholcodine - Article 31 referral - Annex II PT = português 2012-03-28  
Pholcodine - Article 31 referral - Annex II RO = română 2012-03-28  
Pholcodine - Article 31 referral - Annex II SK = slovenčina 2012-03-28  
Pholcodine - Article 31 referral - Annex II SL = slovenščina 2012-03-28  
Pholcodine - Article 31 referral - Annex II FI = suomi 2012-03-28  
Pholcodine - Article 31 referral - Annex II SV = svenska 2012-03-28  
Pholcodine - Article 31 referral - Annex III BG = bălgarski 2012-03-28  
Pholcodine - Article 31 referral - Annex III ES = español 2012-03-28  
Pholcodine - Article 31 referral - Annex III CS = čeština 2012-03-28  
Pholcodine - Article 31 referral - Annex III DA = dansk 2012-03-28  
Pholcodine - Article 31 referral - Annex III DE = Deutsch 2012-03-28  
Pholcodine - Article 31 referral - Annex III ET = eesti keel 2012-03-28  
Pholcodine - Article 31 referral - Annex III EL = elliniká 2012-03-28  
Pholcodine - Article 31 referral - Annex III EN = English 2012-03-28  
Pholcodine - Article 31 referral - Annex III FR = français 2012-03-28  
Pholcodine - Article 31 referral - Annex III IT = italiano 2012-03-28  
Pholcodine - Article 31 referral - Annex III LV = latviešu valoda 2012-03-28  
Pholcodine - Article 31 referral - Annex III LT = lietuvių kalba 2012-03-28  
Pholcodine - Article 31 referral - Annex III HU = magyar 2012-03-28  
Pholcodine - Article 31 referral - Annex III MT = Malti 2012-03-28  
Pholcodine - Article 31 referral - Annex III NL = Nederlands 2012-03-28  
Pholcodine - Article 31 referral - Annex III PL = polski 2012-03-28  
Pholcodine - Article 31 referral - Annex III PT = português 2012-03-28  
Pholcodine - Article 31 referral - Annex III RO = română 2012-03-28  
Pholcodine - Article 31 referral - Annex III SK = slovenčina 2012-03-28  
Pholcodine - Article 31 referral - Annex III SL = slovenščina 2012-03-28  
Pholcodine - Article 31 referral - Annex III FI = suomi 2012-03-28  
Pholcodine - Article 31 referral - Annex III SV = svenska 2012-03-28  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine BG = bălgarski 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine ES = español 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine CS = čeština 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine DA = dansk 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine DE = Deutsch 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine ET = eesti keel 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine EL = elliniká 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine EN = English 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine FR = français 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine IT = italiano 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine LV = latviešu valoda 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine LT = lietuvių kalba 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine HU = magyar 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine MT = Malti 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine NL = Nederlands 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine PL = polski 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine PT = português 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine RO = română 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine SK = slovenčina 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine SL = slovenščina 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine FI = suomi 2011-11-18  
Questions and answers on the review of the marketing authorisations for medicines containing pholcodine SV = svenska 2011-11-18  

Document description

  • Questions and answers (Q&A) - easy-to-understand summary of key issues and Committee conclusions
  • Summary of Opinion - contains the CHMP opinion of the referred medicine(s)
  • List of the medicines affected by the referral (Annex I)
  • Scientific conclusions of the Committee (Annex II)

The following two documents are sometimes available:

  • Changes to the summary of product characteristics, labeling or package leaflet (also known as Annex III) - available when changes have been recommended by the Committee
  • Conditions of the marketing authorisation (also known as Annex IV) - available when the Committee recommends measures to be taken for the marketing authorisation(s) such as safety measures or extra studies

Current status:
European Commission final decision

More information on pholcodine