Health Sciences Authority (HSA) announces that all pholcodine-containing medicines have been withdrawn in Singapore with effect from 22 Jun 2023. HSA had, in consultation with its Product Vigilance Advisory Committee, concluded that the benefit of pholcodine for the symptomatic relief of non-productive cough did not outweigh the potential increased risk of perioperative anaphylaxis (POA) with neuromuscular blocking agents (NMBAs). The product registrant had cancelled the registrations for all pholcodine-containing products in Singapore and ceased their supply to pharmacies, clinics and healthcare institutions in Jun 2023.
Since data from a post-authorisation study showed that the use of pholcodine during the 12 months preceding anaesthesia was associated with an increased risk of POA with NMBAs, the risk period is considered relatively long. Therefore, anaesthesiologists and anaesthetists are advised to ask patients who are scheduled to undergo general anaesthesia with NMBAs, whether they have used pholcodine, particularly in the past 12 months, and to maintain clinical vigilance for potential NMBA-related POA in their patients.
The Allergy to Neuromuscular Blocking Agents and Pholcodine Exposure (ALPHO) study was a post-authorisation safety study imposed by the European Medicines Agency (EMA) on pholcodine-containing products to investigate the possibility of an association between pholcodine use and NMBA-related anaphylaxis. It was a multicentre case-control study comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related POA (cases) and control patients with uneventful anaesthesia. Each case was matched to two controls by age, sex, type of NMBA, geographic area and anaesthesia period. A total of 167 NMBA-related POA cases were matched with 334 control patients. Overall, 47% of cases and 20% of controls reported the use of pholcodine in the year preceding the anaesthesia index (p<0.001). The multivariable analysis showed that pholcodine consumption was associated with NMBA-related POA with an adjusted odds ratio of 4.2 (95% confidence interval 2.3-7.0).
Pholcodine is suspected to cross-sensitise individuals to NMBAs by inducing the production of immunoglobulin E (IgE) antibodies, thereby increasing their susceptibility to develop POA to NMBAs. Although the underlying pathogenic mechanisms have yet to be elucidated, the IgE binding epitopes on both pholcodine and NMBAs contain quaternary ammonium. The ALPHO study found the positive predictive value for specific IgE antibodies to pholcodine and quaternary ammonium to be very low (up to only 5.3%), suggesting that only a small proportion of patients (~ 5 out of 100) who have IgE antibodies to pholcodine/quaternary ammonium will develop POA to NMBAs. This precludes the use of these biomarkers to identify pholcodine-exposed patients who are at high risk of developing POA to NMBAs.
Several regulatory agencies, including the EMA, Australia Therapeutic Goods Administration, United Kingdom Medicines and Healthcare Products Regulatory Agency, Malaysia National Pharmaceutical Regulatory Agency and Hong Kong Department of Health, have announced the withdrawal of pholcodine-containing products in their jurisdictions. These actions were taken following their review of the ALPHO study results and other available information.
HSA’s assessment took into consideration the findings from the ALPHO study, use of pholcodine in the local context, availability of therapeutic alternatives, expert opinions of local healthcare professionals and the regulatory actions taken by the international health regulatory authorities.
POA is a potentially life-threatening systemic hypersensitivity reaction that typically manifests abruptly after induction of anaesthesia, with severe symptoms that require immediate diagnosis and treatment. The local incidence of POA is considered to be rare and ranges from 1 to 4 in 10,000, with NMBAs identified as the causative agent for up to half of these cases. The clinical presentation of POA can vary across patients depending on the triggering agent, underlying comorbidities and concomitant use of other drugs. Hence, the outcome of any NMBA-related POA is dependent on the timeliness and effectiveness of the recognition and management of the anaphylaxis.
The overall absolute risk of pholcodine-associated POA with NMBAs was assessed to be very small given the rare NMBA-specific incidence of POA reported locally and that the risk applies to a small subset of patients with prior exposure to pholcodine who are subjected to an NMBA during the perioperative period. However, there are no effective risk mitigation measures that can reduce the risk of pholcodine-associated POA with NMBAs in individual patients. There are no biomarkers or tests that can predict which pholcodine-exposed patients will develop POA to NMBAs, and it may not be possible to accurately obtain history of pholcodine use due to poor patient recollection or in situations of emergency surgeries. There is also uncertainty of a longer risk period beyond 12 months.
To date, HSA has not received any local reports of POA to NMBAs associated with prior pholcodine use, although the possibility of under reporting of cases cannot be ruled out.
Considering the serious and life-threatening nature of POA, the clinical necessity of using NMBAs during anaesthesia, the non-serious and self-limiting nature of non-productive coughs, as well as the availability of therapeutic alternatives, HSA concluded that the benefit of pholcodine did not outweigh its associated risk of cross-sensitisation and POA to NMBAs.
Please refer to the following website in HSA for details:
http://www.hsa.gov.sg/announcements/safety-alert/reminder-on-the-risk-of-pholcodine-associated-perioperative-anaphylaxis-with-neuromuscular-blocking-agents
In Hong Kong, there are 27 registered pharmaceutical products containing pholcodine. All products are pharmacy-only medicines. So far, the Department of Health (DH) has received one case of adverse drug reaction related to pholcodine, but this case was not related to anaphylaxis. Related news was previously issued by various overseas drug regulatory authorities, and was posted on the Drug Office website since 19 Feb 2011, with the latest update posted on 23 Jun 2023. Letters to inform local healthcare professionals were issued by the DH on 1 Mar 2023.
In Apr 2023 and Jul 2023, the Registration Committee of the Pharmacy and Poisons Board discussed the matter, and decided to de-register pharmaceutical products containing pholcodine with effect from 1 Jan 2024 because the benefits of the products no longer outweigh their risks. A press statement was issued on 7 Jul 2023. The DH issued letters to healthcare professionals and pharmaceutical traders to inform them of the Committee's decision, and to advise healthcare professionals to arrange suitable alternative treatments for their patients on the same date.
Ends/Friday, Sep 22, 2023
Issued at HKT 15:00
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