A multicenter, randomized, parallel group, controlled, double-blind study to evaluate efficacy and safety of pholcodine as antitussive agent vs dextrometorphan in non-productive cough

Start Date06 Aug 2004

Sponsor / Collaborator

Zambon Group SpA

100 Clinical Results associated with Pholcodine

100 Translational Medicine associated with Pholcodine

100 Patents (Medical) associated with Pholcodine

136

Literatures (Medical) associated with Pholcodine

01 Sep 2024·ALLERGOLOGY INTERNATIONAL

Quaternary ammoniums activate human dendritic cells and induce a specific T-cell response in vitro

Article

Author: Peyneau, Marine ; de Chaisemartin, Luc ; Paulet, Virginie ; Noël, Benoît ; Kerdine-Römer, Saadia ; Zeller, Mathilde ; Szely, Natacha ; Pallardy, Marc ; Damiens, Marie-Hélène ; Natsch, Andreas ; Chollet-Martin, Sylvie

BACKGROUND:

In many countries, neuro-muscular blocking agents (NMBAs) are the first cause of perioperative anaphylaxis. Epidemiological studies identified pholcodine, a quaternary ammonium-containing opiate as one of the sensitization sources. However, NMBA anaphylaxis exists in countries where pholcodine was unavailable, prompting the hypothesis of other sensitizing molecules, most likely quaternary ammonium compounds (QACs). Indeed, QACs are commonly used as disinfectants, antiseptics, preservatives, and detergents. Occupational exposure to QACs has been reported as a risk factor for NMBA anaphylaxis, but little is known about the sensitization mechanism and the capacity of these molecules to elicit an immune response. We aimed to establish the immunogenicity of QACs representative of the main existing chemical structures.

METHODS:

We measured the sensitization potential of seven QACs (two polyquaterniums, three alkyl-ammoniums and two aromatic ammoniums) by using two standard dendritic cells (DCs) models (THP-1 cell line and monocyte derived-dendritic cells). The allergenicity of the sensitizing compounds was further tested in heterologous and autologous T-cell-DC co-culture models.

RESULTS:

Amongst the seven molecules tested, four could modulate activation markers on DCs, and thus can be classified as chemical sensitizers (polyquaterniums-7 and -10, ethylhexadecyldimethylammonium and benzethonium). This activation was accompanied by the secretion of pro-inflammatory and maturation cytokines. Furthermore, activation by polyquaternium-7 could induce T-cell proliferation in heterologous and autologous coculture models, demonstrating that this molecule can induce a specific CD4⁺ T cell response.

CONCLUSIONS:

We provide evidence at the cellular level that some QACs can elicit an immune response, which could be in line with the hypothesis of these molecules' role in NMBA sensitization.

01 Jul 2024·SCIENCE OF THE TOTAL ENVIRONMENT

Predicting the new psychoactive substance activity of antitussives and evaluating their ecotoxicity to fish

Article

Author: Chen, Chang-Er ; Long, Xiao-Bing ; Ying, Guang-Guo ; Shi, Wen-Jun ; Xin, Lei

The misuse of antitussives preparations is a continuing problem in the world, and imply that they might have potential new psychoactive substances (NPS) activity. However, few study focus on their ecological toxicity towards fish. In the present study, the machine learning (ML) methods gcForest and random forest (RF) were employed to predict NPS activity in 30 antitussives. The potential toxic target, mode of action (MOA), acute toxicity and chronic toxicity to fish were further investigated. The results showed that both gcForest and RF achieved optimal performance when utilizing combined features of molecular fingerprint (MF) and molecular descriptor (MD), with area under the curve (AUC) = 0.99, accuracy >0.94 and f1 score > 0.94, and were applied to screen the NPS activity in antitussives. A total of 15 antitussives exhibited potential NPS activity, including frequently-used substances like codeine and dextromethorphan. The binding affinity of these antitussives with zebrafish dopamine transporter (zDAT) was high, and even surpassing that of some traditional narcotics and NPS. Some antitussives formed hydrogen bonds or salt bridges with aspartate (Asp) 95, tyrosine (Tyr) 171 of zDAT. For the ecotoxicity, the MOA of these 15 antitussives in fish was predicted as narcosis. The prenoxdiazin, pholcodine, codeine, dextromethorphan and dextrorphan exhibited very toxic/toxic to fish. It was necessary to pay close attention to the ecotoxicity of these antitussives. In this study, the integration of ML, molecular docking and ECOSAR approaches are powerful tools for understanding the toxicity profiles and ecological hazards posed by new pollutants.

01 Jul 2024·BRITISH JOURNAL OF ANAESTHESIA

Pholcodine and allergy to neuromuscular blocking agents. Comment on Br J Anaesth 2024; 132: 457–60

Letter

Author: Baldo, Brian A

A review.This abstract explores the association between pholcodine use and allergic reactions to neuromuscular blocking agents (NMBAs). Pholcodine, an antitussive commonly used in cough medications, has been implicated in sensitizing individuals to NMBAs, potentially leading to anaphylactic reactions during anesthesia.Recent studies indicate that patients with a history of pholcodine use may exhibit a heightened risk of developing allergies to certain NMBAs, prompting calls for increased awareness and precautionary measures among healthcare providers.Understanding the mechanisms underlying this relationship is crucial for improving patient safety and informing guidelines on the use of pholcodine in populations at risk for allergic reactions to NMBAs.Further research is necessary to establish definitive causality and to explore alternative treatment options for cough management in susceptible individuals.

News (Medical) associated with Pholcodine

02 Dec 2022

·www.ema.europa.eu

Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 28 November - 1 December 2022

EMA recommends withdrawal of pholcodine medicines from EU market EMA’s safety committee, PRAC , has concluded its review of medicines containing pholcodine, which are used in adults and children to treat non-productive (dry) cough and, in combination with other active substances , for the treatment of symptoms of cold and flu, and has recommended the revocation of the EU marketing authorisations for these medicines. During the review, the PRAC evaluated all available evidence including the final results of the ALPHO study, 1 post-marketing safety data and information submitted by third parties such as healthcare professionals. The available data showed that use of pholcodine in the 12 months before general anaesthesia with neuromuscular blocking agents (NMBA) is a risk factor for developing an anaphylactic reaction (a sudden, severe and life-threatening allergic reaction) to NMBAs. As it was not possible to identify effective measures to minimise this risk, nor to identify a patient population for whom the benefits of pholcodine outweigh its risks, pholcodine-containing medicines are being withdrawn from the EU market and will therefore no longer be available by prescription or over the counter. More information is available inEMA’s public health communication . Publication of COVID-19 vaccines safety updates to cease in December 2022 The wide uptake of COVID-19 vaccines has led to a rapid accumulation of extensive safety data from spontaneous reports of suspected side effects. Since the first vaccines were authorised in December 2020, EMA has regularly provided information on the PRAC ’s assessment of these reports, as well as data from other sources, through dedicated monthly safety updates. The majority of the EU population has now received at least one COVID-19 vaccine, and data from clinical trials , other studies and spontaneous reporting have established the safety profile of these vaccines. Therefore, the publication of the monthly updates will cease with the December 2022 issue. As for all medicines authorised in the EU, emerging safety data will continue to be monitored and assessed. From January 2023, relevant changes to the product information of COVID-19 vaccines will be communicated via the PRAC highlights . Dedicated public health communications may also be issued, if needed. Information on the identified side effects for each vaccine is included in the product information , available in all European Union/European Economic Area languages on EMA’s corporate website . High-level information on suspected adverse reaction reports will continue to be updated monthly on EMA’s webpage on COVID-19 vaccines safety . The centralised European database of suspected adverse reactions to medicines - EudraVigilance - will continue to be updated weekly. New safety information for healthcare professionals As part of its advice on safety-related aspects to other EMA committees, the PRAC discussed a direct healthcare professional communication (DHPC) containing important information on pholcodine medicines. Pholcodine medicines no longer available in the EU This DHPC will inform healthcare professionals of EMA’s recommendation to revoke the EU marketing authorisation for pholcodine-containing medicines. Healthcare professionals should re-evaluate their patients, consider other treatment alternatives, and advise patients to stop using pholcodine-containing medicinal products . In case of anaesthesia requiring administration of neuromuscular blocking agents (NMBAs), healthcare professionals should check whether patients have used pholcodine-containing medicinal products in the last 12 months and, if so, maintain awareness of potential anaphylactic reactions to NMBAs. The DHPC for pholcodine medicines will be forwarded to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human ( CMDh ). When adopted, the DHPC will be disseminated to healthcare professionals by the marketing authorisation holders , according to an agreed communication plan, and published on the‘ Direct healthcare professional communications ’page and in national registers in EU Member States. 1 Companies marketing pholcodine medicines were requested to conduct the ALPHO study following a previous safety review conducted in 2011. Agenda List item Agenda of the PRAC meeting 28 November - 1 December 2022 (PDF/650.89 KB) (new) Draft First published: 29/11/2022 EMA/PRAC/853738/2022 Corr.1 PRAC statistics: December 2022 Glossary: Safety signal assessments . A safety signal is information which suggests a new potentially causal association, or a new aspect of a known association between a medicine and an adverse event that warrants further investigation. Safety signals are generated from several sources such as spontaneous reports, clinical studies and the scientific literature. More information can be found under ' Signal management '. Periodic safety update reports , abbreviated as PSURs, are reports prepared by the marketing authorisation holder to describe the worldwide safety experience with a medicine in a defined period after its authorisation. PSURs for medicinal products that contain the same active substance or the same combination of active substances but have different marketing authorisations and are authorised in different EU Member States, are jointly assessed in a single assessment procedure. More information can be found under ' Periodic safety update reports: questions and answers '. Risk management plans , abbreviated as RMPs, are detailed descriptions of the activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicines. Companies are required to submit an RMP to EMA when applying for a marketing authorisation . RMPs are continually updated throughout the lifetime of the medicine as new information becomes available. More information is available under 'Risk-management plans '. Post-authorisation safety studies , abbreviated as PASSs, are studies carried out after a medicine has been authorised to obtain further information on its safety, or to measure the effectiveness of risk-management measures. The PRAC assesses the protocols (aspects related to the organisation of a study) and the results of PASSs. More information can be found under ' Post-authorisation safety studies '. Referrals are procedures used to resolve issues such as concerns over the safety or benefit-risk balance of a medicine or a class of medicines. In a referral related to safety of medicines, the PRAC is requested by a Member State or the European Commission to conduct a scientific assessment of a particular medicine or class of medicines on behalf of the EU. More information can be found under referral procedures . Summary safety reports have been introduced as part of the enhanced safety monitoring of COVID-19 vaccines. Marketing authorisation holders are required to submit these reports to EMA, starting on a monthly basis. Their submission complements the submission of PSURs. For more information see EMA’s pharmacovigilance plan for COVID-19 vaccines . Ongoing referrals Procedure Status Update Topiramate – Article-31 referral Under evaluation PRAC continued its assessment

Vaccine

02 Dec 2022

·www.ema.europa.eu

EMA recommends withdrawal of pholcodine medicines from EU market

EMA’s safety committee, PRAC , has concluded its review of medicines containing pholcodine, which are used in adults and children to treat non-productive (dry) cough and, in combination with other active substances , for the treatment of symptoms of cold and flu, and has recommended the revocation of the EU marketing authorisations for these medicines. During the review, the PRAC evaluated all available evidence including the final results of the ALPHO study, 1 post-marketing safety data and information submitted by third parties such as healthcare professionals. The available data showed that use of pholcodine in the 12 months before general anaesthesia with neuromuscular blocking agents (NMBA) is a risk factor for developing an anaphylactic reaction (a sudden, severe and life-threatening allergic reaction) to NMBAs. As it was not possible to identify effective measures to minimise this risk, nor to identify a patient population for whom the benefits of pholcodine outweigh its risks, pholcodine-containing medicines are being withdrawn from the EU market and will therefore no longer be available by prescription or over-the-counter. 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 anaesthesia with NMBAs have used pholcodine in the previous 12 months, and remain aware of the risk of anaphylactic reactions in these patients. The PRAC recommendations will now be sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human ( CMDh ) 2 for consideration at its next meeting in December 2022. Information for patients A recent study showed that use of pholcodine-containing medicines, which are used to treat dry cough in adults and children, is linked to a risk of anaphylactic reactions (a sudden, severe and life-threatening allergic reaction) to certain medicines called neuromuscular blocking agents (NMBA) that are used in general anaesthesia. As no effective measures have been identified to minimise this risk, pholcodine medicines are being withdrawn from the EU market. If you are taking pholcodine, talk to your doctor or pharmacist – they will suggest a different treatment. If you require general anaesthesia with NMBAs and have taken pholcodine in the past 12 months, talk to your healthcare professional and ask any questions you may have. Information for healthcare professionals Results from the recent ALPHO study show that use of pholcodine during the 12 months preceding anaesthesia is linked to a risk of perianaesthetic anaphylactic reaction related to neuromuscular blocking agents (NMBAs) (OR adjusted=4.2 CI 95% [2.5; 6.9]). As no effective measures have been identified to minimise this risk, the marketing authorisations of pholcodine-containing medicines are being revoked in the EU. Healthcare professionals should no longer prescribe or dispense pholcodine-containing medicines and should consider appropriate treatment alternatives. Patients should be advised to stop treatment with these medicines. For patients scheduled to undergo general anaesthesia with NMBAs, healthcare professionals should check whether patients have used pholcodine-containing medicines in the last 12 months and maintain awareness about potential perianaesthetic anaphylactic reaction related to NMBAs. A direct healthcare professional communication (DHPC) including the above recommendations will be sent in due course to healthcare professionals prescribing, dispensing or administering these medicines. The DHPC will also be published on a dedicated page on the EMA website. More about the medicine Pholcodine is an opioid medicine that is used in adults and children for the treatment of non-productive (dry) cough and, in combination with other active substances , for the treatment of symptoms of cold and flu. It works directly in the brain, depressing the cough reflex by reducing the nerve signals that are sent to the muscles involved in coughing. Pholcodine has been used as a cough suppressant since the 1950s. In the EU, pholcodine-containing medicines are currently authorised in Belgium, Croatia, France, Ireland, Lithuania, Luxembourg and Slovenia, either subject to medical prescription or as over-the-counter medicines. They often contain pholcodine in combination with other substances and are available as syrups, oral solutions, and capsules under various trade names and as generics. Pholcodine is marketed under various names including Dimetane, Biocalyptol and Broncalene. More about the procedure The review of pholcodine was initiated on 1 September 2022 at the request of France, under Article 107i of Directive 2001/83/EC . The review has been carried out by the Pharmacovigilance Risk Assessment Committee ( PRAC ), the Committee responsible for the evaluation of safety issues for human medicines, which has made a set of recommendations. The PRAC recommendations will now be sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human ( CMDh ), which will adopt a position. The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway. It is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU. 1 Companies marketing pholcodine medicines were requested to conduct the ALPHO study following a previous safety review conducted in 2011. 2 The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway.

Drug Approval

02 Sep 2022

·www.ema.europa.eu

Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 29 August – 1 September 2022

PRAC starts review of topiramate use in pregnancy and women of childbearing potential EMA’s safety committee ( PRAC ) has started a review of topiramate and the risk of neurodevelopmental disorders in children whose mothers were taking topiramate during pregnancy. Topiramate is a medicine used in the European Union (EU) for the treatment of epilepsy, prevention of migraine and, in some countries, in combination with phentermine for body weight reduction. Use of topiramate in pregnant women is known to increase the risk of birth defects. Women with epilepsy who are being treated with topiramate for their seizures are advised to avoid becoming pregnant, and to consult their doctor for advice if they wish to become pregnant. Topiramate must not be used to prevent migraine or control body weight in pregnant women and in women of childbearing potential (women able to have children) who are not using highly effective birth control methods (contraception). The review was triggered by a recent study 1 which suggested a possible increase in the risk of neurodevelopmental disorders, in particular autism spectrum disorders and intellectual disability, in children whose mothers were taking topiramate during pregnancy. The PRAC started reviewing the study results as part of a safety signal assessment in July 2022. The committee will now conduct an in-depth review of the available data on the benefits and risks of topiramate use in pregnant women and women of childbearing potential in the approved indications . The committee will look in particular at the current risk minimisation measures and consider the need for additional measures to minimise the risks of topiramate use in these women. While the review is ongoing, topiramate should continue to be used according to the authorised product information . Women should discuss any questions or concerns about their topiramate treatment with their doctor or pharmacist. Patients should not stop antiepileptic treatment before speaking with their doctor. EMA will communicatethe PRAC ’s recommendation once the review has concluded. More information is available in EMA’s public health communication . PRAC : Review of pholcodine medicines started EMA has started a review of medicines that contain pholcodine following concerns that their use may put people at risk of developing anaphylactic reactions (a sudden, severe and life-threatening allergic reaction) to certain medicines called neuromuscular blocking agents (NMBA). Pholcodine is used to treat non-productive (dry) cough in adults and children and NMBAs are used in general anaesthesia to prevent spontaneous muscle movements to improve operating conditions. The review was requested by the French medicines agency (ANSM) following preliminary results of a study carried out in France 2 . The results of the study suggested that taking pholcodine up to 12 months before general anaesthesia may increase the risk of having an NMBA-related anaphylactic reaction. Based on these results ANSM is considering, as a precautionary measure, to suspend the use of pholcodine-containing medicines in France. The PRAC will now review the results of the ALPHO study together with all available data and assess their impact on the benefit-risk balance of pholcodine-containing medicines and issue a recommendation on whether their marketing authorisations should be maintained, varied, suspended or withdrawn across the EU. More information is available in EMA’s public health communication . 1 Bjørk M, Zoega H, Leinonen MK, et al. Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability. JAMA Neurol. Published online May 31, 2022. doi:10.1001/jamaneurol.2022.1269. 2 Allergy to Neuromuscular Blocking Agents and Pholcodine Exposure (ALPHO) https://clinicaltrials.gov/ct2/show/NCT02250729 Agenda List item Agenda - PRAC draft agenda of meeting 29 August - 1 September 2022 (PDF/753.64 KB) (new) Draft First published: 29/08/2022 EMA/PRAC/626661/2022 PRAC statistics: September 2022 List item PRAC statistics: September 2022 (PDF/542.91 KB) (new) First published: 02/09/2022 Glossary: Safety signal assessments . A safety signal is information which suggests a new potentially causal association, or a new aspect of a known association between a medicine and an adverse event that warrants further investigation. Safety signals are generated from several sources such as spontaneous reports, clinical studies and the scientific literature. More information can be found under ' Signal management '. Periodic safety update reports , abbreviated as PSURs, are reports prepared by the marketing authorisation holder to describe the worldwide safety experience with a medicine in a defined period after its authorisation. PSURs for medicinal products that contain the same active substance or the same combination of active substances but have different marketing authorisations and are authorised in different EU Member States, are jointly assessed in a single assessment procedure. More information can be found under ' Periodic safety update reports: questions and answers '. Risk management plans , abbreviated as RMPs, are detailed descriptions of the activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicines. Companies are required to submit an RMP to EMA when applying for a marketing authorisation . RMPs are continually updated throughout the lifetime of the medicine as new information becomes available. More information is available under 'Risk-management plans '. Post-authorisation safety studies , abbreviated as PASSs, are studies carried out after a medicine has been authorised to obtain further information on its safety, or to measure the effectiveness of risk-management measures. The PRAC assesses the protocols (aspects related to the organisation of a study) and the results of PASSs. More information can be found under ' Post-authorisation safety studies '. Referrals are procedures used to resolve issues such as concerns over the safety or benefit-risk balance of a medicine or a class of medicines. In a referral related to safety of medicines, the PRAC is requested by a Member State or the European Commission to conduct a scientific assessment of a particular medicine or class of medicines on behalf of the EU. More information can be found under referral procedures . Summary safety reports have been introduced as part of the enhanced safety monitoring of COVID-19 vaccines. Marketing authorisation holders are required to submit these reports to EMA, starting on a monthly basis. Their submission complements the submission of PSURs. For more information see EMA’s pharmacovigilance plan for COVID-19 vaccines . Ongoing referrals Procedure Status Update Janus Kinase inhibitors (JAKi) – Article 20 Referral Under evaluation PRAC continued its assessment Terlipressin-containing medicinal products Under evaluation PRAC continued its assessment Amfepramone-containing medicinal products Under re-evaluation PRAC started re-examination

Vaccine

100 Deals associated with Pholcodine

External Link

KEGG	Wiki	ATC	Drug Bank
D07385	Pholcodine	R05DA08	DB09209

R&D Status

10 top approved records.

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Indication	Country/Location	Organization	Date
Cough	EU	-	01 Jan 1950
Cough	IS	-	01 Jan 1950
Cough	LI	-	01 Jan 1950
Cough	NO	-	01 Jan 1950

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