Pholcodine

Source: Wikipedia, the free encyclopedia.

Pholcodine
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityMaximum plasma conc. attained 4-8 hours after oral dose.
Protein binding23.5%
MetabolismLiver
Elimination half-life32-43 hours; volume of distribution is 36-49L/kg.
ExcretionKidney
Identifiers
  • 7,8-Didehydro-4,5α-epoxy-17-methyl-3-[2-(morpholin-4-yl)ethoxy]morphinan-6α-ol
JSmol)
  • O(c5ccc4c1c5O[C@H]3[C@@H](O)\C=C/[C@H]2[C@H](N(C)CC[C@@]123)C4)CCN6CCOCC6
  • InChI=1S/C23H30N2O4/c1-24-7-6-23-16-3-4-18(26)22(23)29-21-19(5-2-15(20(21)23)14-17(16)24)28-13-10-25-8-11-27-12-9-25/h2-5,16-18,22,26H,6-14H2,1H3/t16-,17+,18-,22-,23-/m0/s1
  • Key:GPFAJKDEDBRFOS-FKQDBXSBSA-N

Pholcodine is an

cough suppressant (antitussive). It helps suppress unproductive coughs and also has a mild sedative effect, but has little or no analgesic
effects. It is also known as morpholinylethylmorphine and homocodeine.

Pholcodine is found in certain cough lozenges,[2] and more commonly as an oral solution, typically 5 mg / 5 ml. Adult dosage is 5-10 ml up to 3-4 times daily.[3] Pholcodine now largely replaces the previously more common codeine linctus, as it has a much lower potential for dependence.

Pholcodine has been widely used as an antitussive agent but by 2023 concerns over its association with anaphylaxis in some circumstances meant that it has been withdrawn from sale in many territories. Pholcodine is not prescribed in the United States where it is classed as a Schedule I drug, the most highly controlled drug category.[4]

Following the conclusion of a review of post-marketing safety data by the MHRA, all pholcodine-containing medicines are being recalled and withdrawn from the UK as a precaution.[5] The available data has demonstrated that pholcodine use, particularly in the twelve months before general anesthesia with NMBAs (neuromuscular blocking agents), is a risk factor for developing an anaphylactic reaction to NMBAs. In December 2022, the European Medicines Agency recommended their withdrawal in the EU.[6] As of February 2023, the Australian Therapeutic Goods Administration canceled the registration of pholcodine.[7][8]

Mechanism of action

Pholcodine is readily absorbed from the

hepatic
insufficiency (i.e. liver problems). Its use is therefore contraindicated in patients with liver disease, while care is advised in patients with hepatic impairment.

Metabolism and excretion

Pholcodine is slowly biotransformed in the body via oxidation and conjugation to a series of metabolites that are eliminated primarily in the urine. With an average half-life of approximately 2.3 days, steady-state in someone taking the drug chronically would not be reached for nearly 2 weeks. Nearly one-half of a single dose is eventually excreted as free or conjugated parent drug. The most important urinary metabolite is

urine drug testing program.[9][10]

Side effects

Side effects are rare and may include

respiratory depression have been reported occasionally or after large doses. The primary safety concerns with pholcodine revolve around death during general anaesthesia.[11]

Anaphylaxis during general anaesthesia

Administration of pholcodine causes production of antibodies linked with fatalities during surgery, when essential

neuromuscular blocking agents (NMBAs) are administered to prevent patient movement under general anaesthesia.[12] These antibody levels gradually fall to low levels several years after last dose of pholcodine. However, the presence of these antibodies causes a 300-fold increase in risk of anaphylaxis during anaesthesia.[13]

The link was suspected when neighbouring Norway and Sweden were found to have tenfold differences of surgical anaphylaxis deaths. Sweden had no products approved containing pholcodine, whereas 40% of the population in Norway had consumed the single approved pholcodine product.[13] Norway withdrew pholcodine from the market in 2007, and the prevalence of anti-suxamethonium antibodies fell by over 80% in two years.[14] A corresponding fall in anaesthesia deaths followed.[13]

A similar disparity exists between NMBA anaphylaxis rates in Australia, where pholcodine consumption is high and the US, where pholcodine is banned.[15] In the US, anaphylaxis rates are so low that some anaesthetists question the existence of such reactions to NMBAs.[16] Conversely, Australian anaesthetists have requested a ban on pholcodine[17] due to the high anaphylaxis rate in the country.[18] However, the Therapeutic Goods Administration declined the request in January 2015,[19] pending further reviews to follow. In February 2023, the Therapeutic Goods Administration reversed its previous decision and banned products containing pholcodine.[20]

In contrast, the European Medicines Agency's 2012 "Assessment report for Pholcodine containing medicinal products" concludes this: The Committee considered that evidence of an association between pholcodine use and development of NMBA-related anaphylaxis is circumstantial, not entirely consistent and therefore does not support the conclusion that there is a significant risk of cross-sensitisation to NMBAs and subsequent development of anaphylaxis during surgery.[21]

In September 2022, the European Medicines Agency (EMA) started reviewing its position[22] at the request of the French ANSM, which withdrew all pholcodine-containing medicines[23] after preliminary results from a local study showed an increased risk of anaphylaxis after pholcodine use.[24] The EMA review concluded on 14 December 2022 with the recommendation that pholcodine be withdrawn from the EU market.[25] This decision was ratified by the European Commission in March 2023.[26] The UK government recalled all products containing pholcodine in March 2023.[27]

References

  1. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 3 August 2023.
  2. ^ "Potter's Pholcodine cough pastilles". Lloyds Pharmacy. Archived from the original on 29 February 2020. Retrieved 29 February 2020.
  3. ^ British National Formulary 54. London: BMJ Publishing Group Ltd., RPS Publishing. 2007. p. 175.
  4. ^ "Legislation - Controlled Substances". U.S. Food and Drug Administration (FDA). 11 June 2009. Archived from the original on 4 February 2016.
  5. ^ "Pholcodine-containing cough and cold medicines: withdrawal from UK market as a precautionary measure". GOV.UK. 23 March 2023. Archived from the original on 11 November 2023. Retrieved 11 November 2023.
  6. ^ "EMA recommends withdrawal of pholcodine medicines from EU market". European Medicines Agency (EMA). 2 December 2022. Archived from the original on 8 February 2024. Retrieved 8 February 2024.
  7. ^ "Pholcodine". Therapeutic Goods Administration (TGA). 28 February 2023. Archived from the original on 18 May 2024. Retrieved 18 May 2024.
  8. ^ "About pholcodine cough medicines cancelled by the TGA and recalled from pharmacies for safety reasons". Therapeutic Goods Administration (TGA). 1 March 2023. Archived from the original on 18 May 2024. Retrieved 18 May 2024.
  9. S2CID 5935454
    .
  10. ^ Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1258–1260.
  11. ^ Andalo D (17 January 2015). "Anaesthetists campaign for pholcodine cough medicines to become prescription-only products". The Pharmaceutical Journal. Royal Pharmaceutical Society. Archived from the original on 17 September 2016. Retrieved 17 September 2016.
  12. PMID 19563989
    .
  13. ^
    PMID 23283141
    .
  14. S2CID 21048759
    .
  15. PMID 23335568
    .
  16. PMID 15041566
    .
  17. doi:10.18773/austprescr.2014.032
    .
  18. PMID 24809013
    .
  19. ^ Medew J (5 January 2015). "Cough medicine alert over surgery". The Age. Archived from the original on 7 January 2015. Retrieved 5 January 2015.
  20. ^ "Pholcodine cough medicines cancelled by the TGA and recalled from pharmacies for safety reasons". Therapeutic Goods Administration. Archived from the original on 28 February 2023. Retrieved 28 February 2023.
  21. ^ "Assessment report for Pholcodine containing medicinal products" (PDF). European Medicines Agency. 17 February 2012. Archived from the original (PDF) on 16 December 2017. Retrieved 24 March 2017.
  22. ^ "Review of pholcodine medicines started". European Medicines Agency. 9 February 2022. Archived from the original on 13 October 2022. Retrieved 13 October 2022.
  23. ^ "Pholcodine: Suspension des autorisations de mise sur le marché et retrait de toutes les boîtes de sirop contenant de la pholcodine en raison d'un risque d'allergie croisée avec les curares" [Pholcodine: Suspension of marketing authorizations and withdrawal of all boxes of syrup containing pholcodine due to a risk of cross allergy with curares]. Agence nationale de sécurité du médicament et des produits de santé (ANSM) [National Agency for the Safety of Medicines and Health Products] (in French). Archived from the original on 13 October 2022. Retrieved 13 October 2022.
  24. ^ "Rationale for the Triggering of Procedure Under Article 107i of Directive 2001/83/EE on Pholcodine" (PDF). French Competent Authority (ANSM - French National Agency for Medicines and Health Products Safety) Agence nationale de sécurité du médicament et des produits de santé. August 2022. Archived (PDF) from the original on 12 October 2022. Retrieved 13 October 2022.
  25. ^ "EMA recommends withdrawal of pholcodine medicines from EU market". European Medicines Agency. 1 December 2022. Archived from the original on 20 December 2022. Retrieved 20 December 2022.
  26. ^ "Pholcodine medicines withdrawn from EU market" (PDF). European Medicines Agency. 6 March 2023. Archived (PDF) from the original on 5 April 2023. Retrieved 3 July 2023.
  27. ^ Medicines and Healthcare products Regulatory Agency (14 March 2023). "Class 2 Medicines Recall: Various Marketing Authorisation Holders, pholcodine-containing products, EL (23)A/09". Archived from the original on 14 March 2023. Retrieved 14 March 2023.
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