Safety Withdrawal Of Pholcodine-containing Cough And Cold Medicines

15th March 2023

Following a comprehensive scientific safety review of the latest available data on the safety of pholcodine, together with advice from the independent Commission on Human Medicines, it has been concluded that the potential risks outweigh the benefits for these products.

The Medicines and Healthcare products Regulatory Agency (MHRA) keeps the safety of medicines under review and acts where necessary to protect patients and the public.

Following a comprehensive scientific safety review of the latest available data on the safety of pholcodine, together with advice from the independent Commission on Human Medicines, it has been concluded that the potential risks outweigh the benefits for these products.

There is already a known link between pholcodine and an increased risk of the very rare event of a severe allergic reaction (anaphylaxis) to muscle relaxants (neuromuscular blocking agents) that are used during general anaesthesia in surgery. In September 2022 the findings of a new study further strengthened the evidence of this link, but the overall risk is very small.

The MHRA advises that pholcodine-containing cough and cold medicines are being removed from the UK market as a precautionary measure.

Dr Alison Cave, MHRA Chief Safety Officer said,

"Safety is our top priority, and we keep the safety of medicines under continual review.

"Following a thorough scientific safety review of all the available evidence on pholcodine, together with advice from the independent Commission on Human Medicines, it has been recommended, as a precautionary measure, that these products should no longer be used.

"If you are taking a cough or cold medicine, check the packaging, label or patient information leaflet to see if pholcodine is a listed ingredient. If it is, and you have any questions, you can talk to your pharmacist who will suggest an alternative medicine.

"If you have an operation scheduled using general anaesthesia, tell your anaesthetist if you think you have used pholcodine, particularly in the past 12 months. The anaesthetist will be well placed to take this into account. Anaesthetists are highly trained in managing anaphylaxis.

"If you want more information or advice, please speak to your pharmacist."

See the MHRA Drug Safety Update

Pholcodine is an opioid medicine that is used to treat a dry cough in adults and children over six years and in combination with other active substances, for the treatment of symptoms of cold and influenza. It works directly in the brain, depressing the cough reflex by reducing the nerve signals that are sent to the muscles involved in coughing.

Neuromuscular blocking agents (NMBAs) are used in general anaesthesia to prevent spontaneous muscle movements and to improve operating conditions.

Cumulative evidence supports an association of pholcodine use with anaphylactic reactions to certain anaesthetic agents. While anaphylaxis has potentially life-threatening consequences, it is a rare event, and the absolute risk remains very small even in association with pholcodine.

The Medicines and Healthcare products Regulatory Agency is responsible for regulating all medicines and medical devices in the UK, by ensuring they work and are acceptably safe. All our work is underpinned by robust and fact-based judgements to ensure that the benefits justify any risks.

The Commission on Human Medicines (CHM) advises ministers and the MHRA on the safety, efficacy and quality of medicines. The CHM is an independent advisory non-departmental public body, sponsored by the Department of Health and Social Care.

Advice for healthcare professionals:
pholcodine-containing cough and cold medicines are being withdrawn from the UK market as a precaution following a review which found that their benefits do not outweigh the increased risk of the very rare event of anaphylaxis to neuromuscular blocking agents (NMBAs) used in general anaesthesia

ask patients scheduled to undergo general anaesthesia involving NMBAs whether they have used pholcodine-containing medicines, particularly in the past 12 months, and maintain awareness about the potential for perianaesthetic anaphylaxis related to NMBAs

do not dispense or sell pholcodine-containing medicines - consider recommending appropriate treatment alternatives for patients who present with a new dry cough or who are currently taking pholcodine

pharmacies should follow the MHRA Class 2 Medicines Recall Notice to quarantine stock of pholcodine-containing medicines and return it to the manufacturer

report suspected adverse drug reactions to the Yellow Card scheme

Advice for healthcare professionals to provide to patients:
pholcodine-containing cough and cold medicines are being withdrawn from sale as a precaution and will no longer be available from pharmacies
if you are taking a cough medicine (including tablets and syrups), check the packaging, label or Patient Information Leaflet to see if pholcodine is a listed ingredient – if it is, and you have any questions, you can talk to your pharmacist who can suggest a different medicine suitable for you
there is evidence that using pholcodine-containing medicines leads to an increased risk of the very rare event of an allergic reaction (anaphylaxis) in patients who receive general anaesthesia involving neuromuscular blocking agents (NMBAs) during surgery
tell your anaesthetist before you have surgery if you have taken pholcodine, particularly in the past 12 months, or think you may have taken a pholcodine-containing product
there is no increased risk of allergic reactions, including anaphylaxis, with other allergens following pholcodine use and the absolute risk in patients who have used pholcodine is very small, but patients should talk to a pharmacist, their GP or their surgical team if they have any questions
Review of pholcodine
Pholcodine is an opioid medicine approved in adults and children older than 6 years of age to treat non-productive (dry) cough and, in combination with other active substances, for the treatment of symptoms of cold and influenza. Previous reviews have examined the link between prior use of pholcodine and an increased risk of anaphylaxis during general anaesthesia involving NMBAs. The potential for cross-reactivity between pholcodine and NMBAs was added to the product information for pholcodine-containing medicines in January 2022.

The MHRA review considered the cumulative safety information, including the results from the recently completed ALPHO study,[footnote 1] which showed that use of pholcodine during the 12 months preceding anaesthesia was significantly associated with an increased risk of perianaesthetic anaphylaxis to NMBAs (adjusted odds ratio = 4.2; 95% CI 2.5 to 6.9). Data on the risk related to the use of pholcodine beyond the period of 12 months was not available from this study, although data from an earlier study in Norway suggest that the very small increased risk may persist for up to 3 years.[footnote 2]

The Commission on Human Medicines (CHM) advised that there is sufficient overall evidence for an association with pholcodine, although the absolute risk of anaphylaxis remains very small in patients who have taken pholcodine. Anaphylaxis following use of NMBAs is roughly estimated as having an overall incidence of fewer than 1 case per 10,000 procedures.[footnote 3] Given the advice of the CHM, and the lack of identifiable effective measures to minimise the increased risk of anaphylactic reactions to NMBAs, pholcodine-containing products are being withdrawn from the market as a precaution.

Pholcodine-containing products have only been available in the UK for purchase in a pharmacy. Pharmacists should provide advice to those who have any concerns about their medicine or would like to seek advice on alternative medicines or management of their symptoms.

The MHRA scientific review took place alongside a review conducted by the European Medicines Agency, which also concluded that the benefits did not outweigh the risks.