Pholcodine-containing medicinal products - referral

Current status

European Commission final decision

Overview

Pholcodine medicines withdrawn from EU market

On 1 December 2022, EMA’s safety committee, PRAC, concluded its review of medicines containing pholcodine, which are used in adults and children to treat non-productive (dry) cough and, in combination with other active substances, for the treatment of symptoms of cold and flu, and recommended the revocation of the EU marketing authorisations for these medicines.

During the review, the PRAC evaluated all available evidence including the final results of the ALPHO study,¹ post-marketing safety data and information submitted by third parties such as healthcare professionals. The available data showed that use of pholcodine in the 12 months before general anaesthesia with neuromuscular blocking agents (NMBA) is a risk factor for developing an anaphylactic reaction (a sudden, severe and life-threatening allergic reaction) to NMBAs.

As it was not possible to identify effective measures to minimise this risk, nor to identify a patient population for whom the benefits of pholcodine outweigh its risks, pholcodine-containing medicines are being withdrawn from the EU market and will therefore no longer be available by prescription or over-the-counter.

Healthcare professionals should consider appropriate treatment alternatives and advise patients to stop taking pholcodine-containing medicines. Healthcare professionals should also check whether patients scheduled to undergo general anaesthesia with NMBAs have used pholcodine in the previous 12 months, and remain aware of the risk of anaphylactic reactions in these patients.

The PRAC recommendations were sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh),² which endorsed them and adopted its position on 14 December 2022. As the CMDh position was adopted by majority vote, it was sent to the European Commission, which issued a final legally binding decision applicable in all EU Member States on 6 March 2023.

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¹ Companies marketing pholcodine medicines were requested to conduct the ALPHO study following a previous safety review conducted in 2011.

² The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway.

Information for patients

• A recent study showed that use of pholcodine-containing medicines, which are used to treat dry cough in adults and children, is linked to a risk of anaphylactic reactions (a sudden, severe and life-threatening allergic reaction) to certain medicines called neuromuscular blocking agents (NMBA) that are used in general anaesthesia.
• As no effective measures have been identified to minimise this risk, pholcodine medicines are being withdrawn from the EU market.
• If you are taking pholcodine, talk to your doctor or pharmacist – they will suggest a different treatment.
• If you require general anaesthesia with NMBAs and have taken pholcodine in the past 12 months, talk to your healthcare professional and ask any questions you may have.

Information for healthcare professionals

• Results from the recent ALPHO study show that use of pholcodine during the 12 months preceding anaesthesia is linked to a risk of perianaesthetic anaphylactic reaction related to neuromuscular blocking agents (NMBAs) (OR adjusted=4.2 CI 95% [2.5; 6.9]).
• As no effective measures have been identified to minimise this risk, the marketing authorisations of pholcodine-containing medicines are being revoked in the EU.
• Healthcare professionals should no longer prescribe or dispense pholcodine-containing medicines and should consider appropriate treatment alternatives. Patients should be advised to stop treatment with these medicines.
• For patients scheduled to undergo general anaesthesia with NMBAs, healthcare professionals should check whether patients have used pholcodine-containing medicines in the last 12 months and maintain awareness about potential perianaesthetic anaphylactic reaction related to NMBAs.

A direct healthcare professional communication (DHPC) including the above recommendations will be sent in due course to healthcare professionals prescribing, dispensing or administering these medicines. The DHPC will also be published on a dedicated page on the EMA website.

More about the medicine

Pholcodine is an opioid medicine that is used in adults and children for the treatment of non-productive (dry) cough and, in combination with other active substances, for the treatment of symptoms of cold and flu. 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. In the EU, pholcodine-containing medicines are currently authorised in Belgium, Croatia, France, Ireland, Lithuania, Luxembourg and Slovenia, either subject to medical prescription or as over-the-counter medicines. They often contain pholcodine in combination with other substances and are available as syrups, oral solutions, and capsules under various trade names and as generics. Pholcodine is marketed under various names including Dimetane, Biocalyptol and Broncalene.

More about the procedure

The review of pholcodine was initiated on 1 September 2022 at the request of France, under Article 107i 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. The PRAC recommendations were sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted its position. The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway. It is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

As the CMDh position was adopted by majority vote, it will now be sent to the European Commission, which issued a final legally binding decision applicable in all EU Member States on 6 March 2023.

Pholcodine medicines withdrawn from EU market

Reference Number: EMA/126062/2023

Key facts

About this medicine

• Approved name:
  Pholcodine-containing medicinal products
• International non-proprietary name (INN) or common name:
  pholcodine
• Class:
  Cough and cold preparations

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-107i/1521
• Type:
  Article 107i procedures

  This type of procedure is triggered when a Member State or the European Commission consider that urgent action is necessary because of a safety issue. Situations that fall under this procedure include consideration for suspension or revocation of the marketing authorisation for a medicine, the prohibition of supply of a medicine or major changes to the marketing authorisation such as deletion of indications, reduction of the recommended dose or new contraindications. The procedure is also applicable in case of a safety issue with a class of medicines.

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

Key dates and outcomes

• Procedure start date:
  01/09/2022
• PRAC recommendation date:
  01/12/2022
• CMDh position date:
  14/12/2022
• EC decision date:
  06/03/2023
• Outcome:
  Revocation

Data submission

The Agency invites all stakeholders (e.g. healthcare professionals, patients' organisations, the general public) to submit data relevant to this procedure. This is in accordance with Article 107j(1) of Directive 2001/83/EC.

The following requirements apply for data to be considered:

• Submissions must be accompanied by the submission form below, with all fields completed. This form needs to be opened with a PDF reader. EMA advises to save the document first, and then open with a PDF reader, such as Acrobat Reader:

  Pholcodine-containing medicinal products Article-107i referral - Stakeholders submission form

• Data submitted should make reference to the Pharmacovigilance Risk Assessment Committee (PRAC) questions:

  Pholcodine-containing medicinal products Article-107i referral - List of questions to stakeholders

• The submission of all data should take place by 26 September 2022. 

Submitting data

Send the completed form electronically to the stakeholders' submission inbox ([e-mail]). Specify the name of the medicine in the subject line of the e-mail.

The size of the submission file should not exceed 25 MB. If your attempt to send your data package to the dedicated e-mail address is unsuccessful, please use alternative submission means.

It is of the utmost importance that data are provided promptly, to avoid undermining the safety review. Due to the urgent nature of the procedure, you are strongly advised to submit your data in English.

Protection of personal data

Personal data submitted are subject to data-protection rules as established by Regulation (EC) 45/2001. They will be treated in accordance with the European Medicines Agency’s privacy statement public and targeted consultations.

Treatment and publication of data

Data submitted will be received and recorded by the Agency.

The Agency will prepare a list of all submissions received, which will be published as an annex to the PRAC assessment report for transparency purposes and public awareness.

Please note that all data submitted in the context of this procedure may be shared and disclosed in the public domain.

All documents

Procedure started

Pholcodine-containing medicinal products Article-107i referral - Rationale for triggering

Pholcodine-containing medicinal products Article-107i referral - List of questions to marketing authorisation holder(s)

Reference Number: EMA/PRAC/704708/2022

Pholcodine-containing medicinal products Article-107i referral - List of questions to stakeholders

Reference Number: EMAP/PRAC/709548/2022

Pholcodine-containing medicinal products Article-107i referral - Stakeholders submission form

Pholcodine-containing medicinal products Article-107i referral - Timetable for the procedure

Reference Number: EMA/PRAC/704846/2022

Pholcodine-containing medicinal products Article-107i referral - Annex I

Draft Reference Number: EMA/722200/2022 Rev. 1

Pholcodine-containing medicinal products Article-107i referral - Notification

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Pholcodine-containing medicinal products Article-107i referral - EMA recommends withdrawal of pholcodine medicines from EU market

Reference Number: EMA/906150/2022

Position provided by CMDh

EMA recommends withdrawal of pholcodine medicines from EU market

Reference Number: EMA/906150/2022

European Commission final decision

Pholcodine-containing medicinal products Article-107i referral - Annex II

Pholcodine-containing medicinal products Article-107i referral - Annex I

Pholcodine-containing medicinal products Article-107i referral - Divergent positions to CMDh position

Adopted

Pholcodine-containing medicinal products Article-107i referral - Assessment report

Adopted Reference Number: EMA/950036/2022

Pholcodine medicines withdrawn from EU market

Reference Number: EMA/126062/2023

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.