Pholcodine is an opioid medicine widely present in many over-the-counter cough syrups, for its antitussive activity. Pholcodine is in market since 1950s and the products containing pholcodine are approved for the following conditions:

• Treatment of dry cough (non-productive) in adults and children older than 6 years of age.
• Treatment of symptoms of cold and influenza in combination with other active substances

This products depresses the cough reflex by reducing the nerve signals that are sent to the muscles involved in coughing.

Safety Review & Withdrawal story in concise chronology

Earlier Withdrawals from few EU nations:

• In 1980s & 2007, pholcodine-containing medicines had been withdrawn from the markets in and Norway respectively.
• 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.

Substantiated evidence for the anaphylaxis risk: 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.

Risk Minimization Measure:

Consequently, the French medicines regulatory agency changed the legal status for these medicines in the country from over-the-counter to prescription-only

Article 31-Referral Initiation:

French HA requested the Committee for Medicinal Products for Human Use (CHMP) of EMA 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on whether the marketing authorisations for pholcodine-containing products should be maintained, varied, suspended or withdrawn across the EU. However, upon assessment from Article-31 Referral procedure, CHMP concluded that the existing evidence at that time did not supported the conclusion that the use of pholcodine-containing medicines presents a risk of developing anaphylactic reactions to NMBAs and Benefits of using pholcodine-containing medicines outweighs overall risks. However, CHMP recommended to conduct a post-marketing study (ALPHO) to investigate the causality.

Label Update: In January 2022, a causal link identified between prior use of pholcodine and an increased risk of anaphylaxis (a sudden, severe and life-threatening allergic reaction) during general anesthesia involving neuromuscular blocking agents (NMBAs).

Benefit-Risk Reassessment: PRAC (Pharmacovigilance Risk Assessment Committee), a safety review team from EMA (European Medicines Agency) evaluated all the available safety & benefit information, evidence including the final results of the ALPHO study (recommendation from article-31 referral in 2012), latest post-marketing safety data and information submitted by third parties such as healthcare professionals. The available data confirmed causal link for the occurrence of anaphylactic reaction with the use of pholcodine in the 12 months before general anesthesia with neuromuscular blocking agents.

A decision was made to withdraw pholcodine-containing medicines and therefore no longer be available by prescription or over-the-counter across Europe, considering the below points:

• No effective measures have been identified to minimize this risk
• No specific patient population group identified for whom the benefits of pholcodine outweigh its risks.

Key Information to remind:

• 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 anesthesia with NMBAs have used pholcodine in the previous 12 months, and remain aware of the risk of anaphylactic reactions in these patients.

Decision to withdraw pholcodine-containing medicines also made by TGA in Australia and MHRA- in United Kingdom.

Voluntary ADR reporting:

Every medicinal product has both benefits and risks. Medicines are authorized to market based on the favorable benefit-risk profile anticipated at the time of regulatory approval/entry into market. However, the safety profile of medicine would continuously updates owing to the emerging safety data from the post marketing experience from public. If the rate of reporting of suspected adverse drug reactions (ADR) from public is line with the actual occurrence of ADRs, the time lapse for taking regulatory action can be reduced and thereby improving patient safety.

All health care professionals and consumers of pharmaceutical medicinal products are encouraged to be aware of this fact and observe/monitor for any possible adverse events, reactions, medication errors, or quality complaints of medicinal products and report the same to your respective national health authority.

This would accumulate safety evidence for medicinal products which in turn help health authorities to take regulatory actions at the earliest possibility for a better patient safety and overall public health.