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Unfavourable benefit-risk balance of codeine linctus: reclassification to Prescription Only Medicine

The MHRA has recently announced that codeine linctus has been reclassified from a pharmacy medicine to a prescription-only medicine due to the risk of dependence, addiction and overdose.1 In this blog we explain the significance of this decision in terms of risk management and risk minimisation.

Codeine linctus (oral codeine solution) has been used for many years as a cough medicine and is currently authorised in the UK for treating dry cough in adults and children aged 12 years and over without breathing difficulties. Codeine is an opioid and is acknowledged to be addictive. There is little evidence for the efficacy of codeine for short-term cough, but opioids have been shown to be effective in treatment of chronic cough (cough lasting over 8 weeks).2

The MHRA has been monitoring for evidence of addiction to codeine for several years, which has previously led to regulatory action to improve product information and labelling. However in recent years there had been increasing awareness of recreational use of codeine linctus for its opioid effects, with the consequent potential for addiction and overdose. In particular, there was concern over the use of codeine linctus with promethazine to make a recreational drink, which has been popularised on social media.

The Commission on Human Medicines (CHM) advised that codeine linctus should be reclassified as Prescription Only Medicine (POM) in October 2022.3 Subsequently the MHRA set up a public consultation on the proposed reclassification, which closed in August 2023.4 Following the CHM advice and the results of the public consultation, the MHRA announced the immediate reclassification of codeine linctus to POM in February 2024.

Weighing up risks and benefits

The key objective of risk management is to ensure the benefits of a medicinal product justify the risks.5

The benefits of codeine linctus are modest for treatment of cough, with its limited antitussive effect being restricted to chronic cough.

The risks of codeine linctus relate to its addictive opioid qualities. Consumption of a recreational drink containing codeine linctus has become more widespread, particularly among young adults. Such illicit use of codeine is of particular concern because the dose of codeine in the drink can vary widely, meaning that users are more likely to experience overdose. Symptoms of overdose, including loss of consciousness and respiratory suppression, can be intensified by concomitant use of alcohol and other medication. The active dose of codeine can vary widely amongst users due to polymorphism in cytochrome P450 2D6, the enzyme responsible for conversion of the codeine prodrug into morphine. Thus users of codeine, whether illicit or not, can easily underdose or overdose depending on whether they are fast- or slow metabolisers. Codeine linctus has been easily available via high street or online pharmacies for many years.

Accordingly it is clear that the benefits of codeine linctus are outweighed by the risks and it is necessary to reduce the risks in order to protect public safety.

Updating risk minimisation measures for codeine linctus

It had become clear that existing routine risk minimisation measures were in adequate. Therefore in order to reduce the risks associated with codeine linctus, further routine risk minimisation measures were required:

  • A reminder that codeine linctus is only approved to treat chronic cough.
  • Restrict availability of codeine linctus to prescription only, following consultation with a GP, thereby reducing ease of access and decreasing the possibility of recreational and illicit use.
  • Urge patients with chronic cough that lasts over 8 weeks to consult their GP.  This provides the opportunity for the GP to investigate and treat possible underlying causes for the chronic cough and refer the patient for further medical assessments if required. It also allows the patient to be provided with a prescription for codeine linctus if appropriate.
  • Advise prescribers to read the Summary of Product Characteristics and patients to read the Patient Information Leaflet to ensure that they are aware of the potential for addiction.

There are few alternatives to treat dry cough that are supported by robust evidence of effectiveness. Thus it is important for codeine linctus to remain available to patients, but limited to prescribing under medical supervision.

As both the evidence of harm and evidence of limited benefit of codeine linctus have been available for many years it is not clear why the reclassification has been delayed until now. Regulatory authorities should consider a more timely response to drug safety issues that are supported by high quality evidence and have a significant impact on public health.

References

  1. Codeine linctus (codeine oral solutions): reclassification to prescription-only medicine, MHRA, 20 February 2024: https://www.gov.uk/drug-safety-update/codeine-linctus-codeine-oral-solutions-reclassification-to-prescription-only-medicine Accessed 8 March 2024
  2. Morice A, Kardos P. Comprehensive evidence based review on European antitussives. BMJ Open Resp Res 2016;3:e000137. doi:10.1136/bmjresp-2016- 000137
  3. Codeine linctus (codeine oral solutions): Proposal to reclassify to prescription only. Public Assessment Report. MHRA February 2024: https://assets.publishing.service.gov.uk/media/65d33fc20f4eb1ec90a98147/PAR_-_codeine_linctus.pdf Accessed 18 March 2024
  4. MHRA Public consultation on the proposal to make Codeine Linctus available as a prescription-only medicine (POM), 20 February 2024: https://www.gov.uk/government/consultations/mhra-public-consultation-on-the-proposal-to-make-codeine-linctus-available-as-a-prescription-only-medicine-pom Accessed 18 March 2024
  5. European Medicines Agency, Guideline on good pharmacovigilance practices (GVP) Module V (Rev 2), 2017: https://www.ema.europa.eu/en/documents/scientificguideline/guideline-good-pharmacovigilance-practices-module-v-risk-managementsystems-rev-2_en.pdf Accessed 18 March 2024