Do not prescribe Pholcodine-containing cough syrup:DCGI tells Doctors

This came after the World Health Organization (WHO) alerted about a safety concern that has been identified with Pholcodine containing cough and cold remedies.

According to the advisory doctors and healthcare professionals should advise patients to stop taking Pholcodine containing cough and cold remedies and should suggest an alternative to treat their symptoms. Furthermore, it states to verify whether the patient scheduled to take general anesthetics containing neuromuscular blocking agents (NMBAs) have taken Pholcodine containing cough and cold remedies in previous 12 months and also be aware of anaphylactic reactions in such patients.

Similarly, the advisory warns consumers to be careful in taking Pholcodine containing cough and cold remedies and consult the Doctor or Pharmacist to suggest an alternative treatment.

"In case of patients who are going to take general anesthetics and have taken Pholcodine containing cough and cold remedies in past 12 months should be reported to the Doctor or Healthcare professional prior to the procedure." The advisory was added.

What is Pholcodine?

Pholcodine is an opioid antitussive used to suppress unproductive coughing. The mechanism of action of pholcodine is directly performed in the medulla oblongata. In this site, it exerts analgesic properties on the peripheric reflexogenic receptors. This site is commonly known as the "cough center."

What is pholcodine used for?

Pholcodine is indicated as a cough suppressant for the temporary relief of non-productive dry cough.Cough is the respiratory movement that occurs after an irritation signal is transmitted to the central nervous system and further stimulates the medulla oblongata. This stimulation causes a motor output that is sent through motoneurons to the respiratory muscles. A non-productive cough is a type of cough characterized by the absence of sputum, and it has a large inspiration that will cause continuous coughing.

What does the WHO say?

The World Health Organization (WHO) through its news page had alerted healthcare professionals and regulatory authorities of the risk of anaphylactic reactions in people who have taken Pholcodine containing cough and cold remedies at least 12 months prior to surgical procedures involving the administration of general anesthesia with neuromuscular blocking agents (NMBAs).

The WHO in its alert stated, "The European Medicines Agency (EMA)’s Pharmacovigilance Risk Assessment Committee reviewed all available evidence including post-marketing safety data, information from third parties such as health-care professionals, and final results of a French multicentre case-control study comparing pholcodine exposure within a year before anesthesia between patients with NMBA-related perioperative anaphylactic reactions. The available data showed that the use of pholcodine in the 12 months before general anesthesia with NMBAs is a risk factor for developing an anaphylactic reaction (a sudden, severe, and life-threatening allergic reaction) to NMBAs."

In addition, the WHO added, "As of 29 March 2023, at least three other regulatory authorities had withdrawn prescription and over-the-counter preparations containing pholcodine from their markets: the Therapeutic Goods Administration (TGA), Australia, the Medicines and Healthcare products Regulatory Agency (MHRA), the United Kingdom, and the National Pharmaceutical Regulatory Agency (NPRA), Malaysia."

Study behind issuing alert regarding Pholcodine containing cough and cold remedies

In December 2022, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) had recommended the withdrawal of pholcodine marketing authorisation for all pholcodine-containing products. This recommendation was based on a thorough review of all available evidence, including the final results of the “Allergy to Neuromuscular Blocking Agents and Pholcodine Exposure” (ALPHO) study, post-marketing safety data, and information submitted by healthcare professionals.

Having considered that no suitable risk minimisation measures could be taken to mitigate this risk and that it was not possible to identify a patient population for whom the benefits of pholcodine outweigh its risk, the PRAC concluded a recommendation to withdraw pholcodine from the European market.

Another monocentric case-control study conducted in Western Australia by Sadleir et al. (2021) also identified that both obesity and pholcodine consumption remained as important risk factors for NMBA anaphylaxis after correction of confounding, with pholcodine consumption associated with a very significant risk of anaphylaxis to NMBAs.

The mechanism by which pholcodine exposure triggers the risk of anaphylaxis to NMBA remains elusive.1,7-9 However, the consistent findings from the ALHPO study and the previous Australian study support the pholcodine hypothesis, which proposes that cross-reactivity between substituted ammonium ions present in pholcodine and NMBAs may prime IgE-mediated allergic reactions to NMBAs.

The available data showed that the use of pholcodine in the 12 months before general anaesthesia with NMBAs is a risk factor for developing an anaphylactic reaction to NMBAs.

What does the Indian advisory state?

Following the WHO alert regarding the Pholcodine containing cough and cold remedies, the matter was referred to Subject Expert Committee (Antimicrobial and Antiviral) in a meeting dated 28th June 2023 to seek expert opinion on the safety alert published by WHO on the Prior use of Pholcodine containing cough and cold remedies and risk of perioperative anaphylactic reactions to neuromuscular blocking agents (NMBAs) for any regulatory intervention required on the matter.

After detailed deliberation, the committee advised issuing a warning to consumers, doctors, and other healthcare workers about cough and cold remedies containing pholcodine.

I. To Doctors and healthcare professionals:

1. To advise patients to stop taking Pholcodine containing cough and cold remedies and suggest an alternative to treat their symptoms.

2. To verify whether the patient scheduled to take general anesthetics containing neuromuscular blocking agents (NMBAs) has taken Pholcodine containing cough and cold remedies in the previous 12 months and also be aware of anaphylactic reactions in such patients.

II. To Consumers:

1. To be careful in taking Pholcodine containing cough and cold remedies and consult the Doctor or Pharmacist to suggest an alternative treatment.

2. In case of patients who are going to take general anesthetics and have taken Pholcodine containing cough and cold remedies in the past 12 months should be reported to the Doctor or Healthcare professional prior to the procedure.