Medicines Healthcare Products Regulatory Agency
Advice for healthcare professionals:
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pholcodine-containing cough and cold medicines are being withdrawn from the UK market as a precaution following a review which found that their benefits do not outweigh the increased risk of the very rare event of anaphylaxis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
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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
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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
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pharmacies should follow the MHRA Class 2 Medicines Recall Notice to quarantine stock of pholcodine-containing medicines and return it to the manufacturer
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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- pholcodine-containing cough and cold medicines are being withdrawn from sale as a precaution and will no longer be available from pharmacies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.
Report suspected adverse drug reactions
Please continue to report suspected adverse drug reactions via the Yellow Card scheme.
Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:
- the Yellow Card website
- the Yellow Card app; download from the Apple App Store or Google Play Store
- some clinical IT systems for healthcare professionals (EMIS, SystmOne, Vision, MiDatabank, and Ulysses)
When reporting, please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.
Article citation: Drug Safety Update volume 16, issue 8: March 2023: 1. This article has been issued ahead of the rest of the March 2023 issue.
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ClinicalTrials.Gov. Allergy to Neuromuscular Blocking Agents and Pholcodine Exposure (ALPHO) study protocol. Accessed March 2023.?
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Florvaag E and others. IgE-sensitization to the cough suppressant pholcodine and the effects of its withdrawal from the Norwegian market IgE-sensitization to the cough suppressant pholcodine and the effects of its withdrawal from the Norwegian market. Allergy 2011; 66: 955960.?
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Anaesthesia, Surgery and Life-Threatening Allergic Reactions. Report and findings of the Royal College of Anaesthetists 6th National Audit Project: Perioperative Anaphylaxis. Published May 2018. Accessed March 2023.?