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HALLS DRY COUGH LOZENGES PL 00094/0248 UKPAR TABLE OF CONTENTS Lay Summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 14 Steps taken after authorisation – summary Page 15 Summary of Product Characteristics Page 16 Combined Patient Information Leaflet/ Label Page 19 MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 1- HALLS DRY COUGH LOZENGES PL 00094/0248 LAY SUMMARY The Medicines Healthcare products Regulatory Agency granted Ernest Jackson & Company Limited a Marketing Authorisation (licence) for the medicinal product Halls Dry Cough Lozenges (PL 00094/0248) on 2 August 2012. This pharmacy only medicine (P) and can be purchased at pharmacies under the supervision of a pharmacist. Halls Dry Cough Lozenges contains 7.5 mg of the active ingredient, dextromethorphan hydrobromide per lozenge. Halls Dry Cough Lozenges provides relief from dry coughs. The active ingredient acts as an antitussive (to suppress coughing without drowsiness). No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Halls Dry Cough Lozenges (PL 00094/0248) outweigh the risks; hence a Marketing Authorisation has been granted. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 2- HALLS DRY COUGH LOZENGES PL 00094/0248 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 6 Non-clinical assessment Page 9 Clinical assessment Page 10 Overall conclusions and risk benefit assessment Page 13 MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 3- INTRODUCTION The UK granted a Marketing Authorisation for the medicinal product Halls Dry Cough Lozenges (PL 00094/0248) to Ernest Jackson & Co Ltd on 2 August 2012. This is a pharmacy-only medicine and can be purchased at pharmacies under the supervision of a pharmacist. The product contains the active ingredient, dextromethorphan hydrobromide, which is a cough suppressant; it exerts its antitussive activity by acting on the cough centre of the medulla oblongata. This application was submitted as abridged, bibliographic application according to Article 10a (well-established use) of Directive 2001/83/EC, as amended. No new non-clinical or clinical efficacy studies were necessary for this application, which is acceptable given that this is a bibliographic application for a product containing an active ingredient of well-established use. Bioequivalence studies are not necessary to support this bibliographic application. There are at least three products containing the single active ingredient, dextromethorphan hydrobromide, as an oral solution in the UK: Benylin Dry Coughs (Non-Drowsy), Pfizer Consumer Healthcare, PL 15513/0051, authorised to Pfizer Consumer Healthcare on 16 June 1997; the Marketing Authorisation held by Pfizer Consumer Healthcare was granted following a Change of Ownership Application from Park Davis & Co Limited, Benylin Dry Cough Linctus, PL 00018/0111 and 00018/0111R, authorisations first granted on 13 October 1976 and 27 June 1990, respectively. Dry Cough Syrup, Wrafton Laboratories Limited, PL 12063/0024, authorised to Wrafton Laboratories Limited on 7 March 1997. Nyrolex Dry Cough or Nyrolex for Dry Coughs, The Boots Company PLC, PL 00014/0460, authorised to The Boots Company PLC on 10 January 1995. The MHRA has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture and assembly of these products. Evidence of compliance with GMP has been provided for the named manufacturing and assembly sites. The MHRA considers that the pharmacovigilance system as described by the Marketing Authorisation Holder (MAH) fulfils the requirements and provides adequate evidence that the MAH has the services of a Qualified person (QP) responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. The MAH has provided adequate justification for not providing a Risk Management Plan (RMP). Dextromethorphan hydrobromide is a well-known active drug substance and has been used to treat the symptoms of persistent dry coughs for many years. The safety profile of this product is therefore well-characterised and considered to be acceptable in the patient population in which it is indicated. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 4- No new or unexpected safety concerns arose during review of information provided by the Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Halls Dry Cough Lozenges (PL 00094/0248) outweigh the risks; hence a Marketing Authorisation was granted. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 5- PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE DEXTROMETHORPHAN HYDROBROMIDE INN: Chemical name: Dextromethorphan hydrobromide ent-3-Methoxy-17-methylmorphinan hydrobromide monohydrate Structure: Molecular formula: Molecular weight: C18H26BrNO, H2O 370.3 General Properties Description: Almost white, crystalline powder. Solubility: Sparingly soluble in water, freely soluble in alcohol. Dextromethorphan hydrobromide is the subject of a European Pharmacopoeia (Eur Ph.) monograph. Manufacture All aspects of the manufacture and control of the active substance dextromethorphan hydrobromide are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. MEDICINAL PRODUCT Description and Composition The finished product is presented as a lozenge and contains 7.5 mg of dextromethorphan hydrobromide Other ingredients Other ingredients consist of pharmaceutical excipients, sucrose granulated, glucose liquid, blackcurrant flavour, citric acid monohydrate, sucralose, masking flavour, levomenthol and carrot anthocyanin E163 . MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 6- All ingredients comply with their relevant Ph. Eur monographs; with the exception of masking flavour, sucralose, blackcurrant flavour and carrot anthocyanin E163 which show compliance to in-house specifications. Appropriate justification for the inclusion of each excipient has been provided. Satisfactory Certificates of Analysis have been provided for all the excipients. None of the excipients used contain material derived from animal or human origin. Furthermore, no genetically modified organisms are used in the manufacture of any of the excipients. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation studies have been conducted and are accepted. The validation data demonstrated consistency of the manufacturing process. Finished Product Specification Finished product specifications are provided for both release and shelf-life, and are satisfactory; they provide an assurance of the quality and consistency of the finished product. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and adequately validated, as appropriate. Satisfactory batch analysis data are provided and accepted. The data demonstrate that the batches are compliant with the proposed specifications. Certificates of Analysis have been provided for any reference standards used. Container Closure System The finished product is marketed in blister packs composed of white/opaque polyvinylchloride (PVC) coated with polyvinylidene chloride (PVDC) and lidded with aluminium foil. The blister packs are placed into cardboard outer cartons in 6, 8, 10 or 20 lozenges. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. Stability Finished product stability studies have been conducted in accordance with current guidelines and results were within the proposed specification limits. Based on the results, a shelf-life of 24 months has been approved, with the following storage instructions, “Do not store above 25oC”. Expert Report A satisfactory quality overview is provided, and has been prepared by an appropriately qualified expert. The CV of the expert has been supplied. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labelling are pharmaceutically acceptable. Colour mock-ups of the PIL/label have been provided. The labelling is satisfactory and fulfils the statutory requirements for Braille. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 7- The applicant has submitted results of PIL user testing. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to use the information that it contains. MAA Forms The MAA forms are pharmaceutically satisfactory. Conclusion There are no objections to approval of Halls Dry Cough Lozenges from a pharmaceutical point of view. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 8- NON-CLINICAL ASSESSMENT These are abridged applications submitted under Article 10a (well-established use) of Directive 2001/83/EC, as amended, for Halls Dry Cough Lozenges. The pharmacodynamic, pharmacokinetic and toxicological properties of dextromethorphan hydrobromide are well-known. Therefore, no further studies are required and the applicant has provided none. No formal Environmental Risk Assessment has been provided and none was required. The active substance has been used for over 10 years, the use of this product is not expected to increase the overall use of dextromethorphan hydrobromide and so no additional increase in environmental risk has been identified. The SmPCs are satisfactory from a non-clinical viewpoint. There are no objections to the approval of Halls Dry Cough Lozenges from a non-clinical point of view. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 9- CLINICAL ASSESSMENT Clinical Background Dextromethorphan hydrobromide is a centrally acting antitussive and at therapeutic doses does not cause depression of respiration. It is a synthetic phenanthrene derivative of opium and the synthetic dextroisomer of codeine. Although structurally related to morphine, dextromethorphan hydrobromide has no analgesic properties. Dextromethorphan hydrobromide exerts a sedative effect on the central nervous system. Dextromethorphan hydrobromide is used for the relief of non-productive cough. Indications For the relief of persistent dry coughs. The above stated therapeutic indication is essentially the same as that for other products containing dextromethorphan hydrobromide as a single active substance in the UK; the following therapeutic indications are stated in the authorisations for three products. PL 15513/0051 – Benylin Dry Coughs (Non-Drowsy) – Pfizer Consumer Healthcare …is indicated as an antitussive, for the relief of persistent, dry, irritating cough. PL 12063/0024 – Dry Cough Syrup – Wrafton Laboratories Limited To soothe and control dry coughs. PL 00014/0460 – Nyrolex Dry Cough or Nyrolex for Dry Coughs – The Boots Company PLC For short-term use in the relief of dry, ticklish, unproductive coughs. PL 00165/0151 – Robitussin Soft Pastilles for Dry Cough – Wyeth Consumer Healthcare For the relief of persistent dry irritant coughs. In conclusion the requested therapeutic indication would be acceptable for use in the UK. Dose and Dose Regimen Adults the Elderly and Children over 12 years: 2 lozenges (15mg) 3 to 4 times daily. Children 6 to 12 years: 1 lozenge (7.5 mg) 3 to 4 times daily. Children under 6 years: Not recommended. Suck each lozenge until dissolved. Do not take more than 4 doses in 24 hours. The posology is in line with other products containing dextromethorphan hydrobromide. The product is intended for supply through pharmacies only (P). Paediatric Development Programme The Applicant is not seeking authorisation in children under 6 and therefore a clinical programme or bibliographic review is not presented in support of use in this age group. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 10 - CLINICAL PHARMACOLOGY PHARMACOKINETICS Introduction and overview Dextromethorphan hydrobromide is well absorbed from the gut following oral administration. It is metabolised in the liver and excreted in the urine as unchanged dextromethorphan and dimethylated metabolites including dextrorphan. Bioequivalence No bioequivalence studies have been submitted as this is a bibliographical application. Overall conclusions on pharmacokinetics The dose of the active proposed is in-line with other products containing dextromethhorphan hydrobromide and therefore acceptable. PHARMACODYNAMICS Introduction Dextromethorphan hydrobromide is a centrally acting cough suppressant. Overall conclusions on pharmacodynamics No new data have been submitted and none was required for an application of this type; this is satisfactory. CLINICAL EFFICACY The applicant has presented no new data and none are required for an application of this type. A thorough literature review of controlled studies versus placebo or other antitussive medications has been conducted. A coherent review of all relevant published literature has been presented. Overall conclusions on clinical efficacy The active, dextromethorphan hydrobromide, has a well established efficacy profile which has been adequately reviewed by the Clinical Expert. CLINICAL SAFETY The clinical expert presents an overview of the safety of dextromethorphan hydrobromide and discusses cases of abuse. The Applicant lists adverse events reported in Martindale Pharmacopoeia and these include dizziness and gastrointestinal upset. Excitation, confusion and respiratory depression may occur following overdose. Information from the Toxic Exposure Surveillance System suggests that abuse ore misuse of dextromethorphan in 13-19 year olds has increased by more than 300% in the 3-year period from January 2000 to November 2003. There is little published evidence regarding the extent of dextromethorphan abuse in the UK. The clinical expert concludes that this should be closely monitored and that warnings not to exceed the maximum recommended MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 11 - daily dose and taking the medicine for prolonged periods may lead to addiction should be included in the SPC. Use in Pregnancy The Applicant states that out of 300 women who are known to have taken dextromethorphan hydrobromide during pregnancy there have been no reports of fetal malformations. The SPC recommends that although dextromethorphan has been in widespread use for many years caution should be exercised by balancing the potential benefit of treatment against any possible hazards. Dextromethorphan has been used in man since 1954 and would appear to be well tolerated when used in the recommended dose. The most common adverse effects during normal use are dizzy states and gastrointestinal disorders. When administered in high dose the most common adverse effects were drowsiness and sleep. At very high dose/in overdose drowsiness or even coma, respiratory depression and convulsions may occur. Misuse and abuse of dextromethorphan hydrobromide is well documented and appropriate warnings have been included in the SPC. Overall conclusions on clinical safety The above safety aspects as well as use in pregnancy and information about overdose has also been summarised by the Clinical Expert and all these aspects are adequately addressed in the proposed product literature which is consistent with similar products currently licensed in the UK. Expert Report A satisfactory clinical overview is provided, and has been prepared by an appropriately qualified physician. The curriculum vita of the expert has been provided. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPC and the combined label/PIL are acceptable from a clinical perspective, and consistent with those for the reference product. The labelling is acceptable and in line with current requirements. MAA (Marketing Authorisation Application) form The MAA form is satisfactory. Conclusion There are no objections to the approval of Halls Dry Cough Lozenges from a clinical point of view. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 12 - OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Halls Dry Cough Lozenges are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for an application of this type. EFFICACY No new data are submitted and none are required for applications of this type. The published literature supports the efficacy of this product in the proposed indications. The efficacy of dextromethorphan hydrobromide is well-known. The presented evidence for well-established use of the active substance is sufficient. The literature review identifies no new safety issues or concerns. The safety profile of dextromethorphan hydrobromide is well-known. No new or unexpected safety concerns arose from this application. PRODUCT LITERATURE The SmPC, PIL and labelling are satisfactory. The approved labelling artwork complies with statutory requirements. In line with current legislation, the name of the product appears in Braille on the outer packaging. The applicant has stated that all relevant patient information is to be displayed on the outer carton as there are no plans to produce a leaflet for this product. This approach has been used for other OTC products of a similar nature and is therefore deemed acceptable. A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to similar product- Halls Chesty Cough Lozenges (PL 00094/0247). The bridging report submitted by the applicant has been found acceptable. RISK BENEFIT ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Dextromethorphan hydrobromide is an active substance of wellknown safety and efficacy and has been used for a number of decades in the EC. Extensive clinical experience with dextromethorphan hydrobromide is considered to have demonstrated the therapeutic value of the active substance. The benefit/risk ratio is therefore considered to be positive. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 13 - HALLS DRY COUGH LOZENGES PL 00094/0248 STEPS TAKEN FOR ASSESMENT 1 The MHRA received the marketing authorisation application on 13 March 2006. 2 Following standard checks and communication with the applicant the MHRA considered the application valid on 23 March 2006. 3 Following assessment of the applications the MHRA requested further information relating to the quality dossiers on 28 July 2006, 19 November 2009 and 19 January 2011 and information relating to the clinical dossiers on 26 February 2007. The applicant responded to the MHRA’s requests, providing further information on the quality dossier on 6 November 2006, 27 September 2010 and 12 April 2011 further information on the clinical dossier on 10 May 2007. 4 5 The applications were determined on 2 August 2012. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 14 - HALLS DRY COUGH LOZENGES PL 00094/0248 STEPS TAKEN AFTER AUTHORISATION - SUMMARY Date Application submitted type Scope Outcome MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 15 - HALLS DRY COUGH LOZENGES PL 00094/0248 SUMMARY OF PRODUCT CHARACTERISTICS The UK Summary of Product Characteristics (SmPC) for Halls Dry Cough Lozenges is as follows: 1 NAME OF THE MEDICINAL PRODUCT Halls Dry Cough Lozenges 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Dextromethorphan hydrobromide Ph.Eur. 7.5mg per lozenge. For full list of excipients, see section 6.1 3 PHARMACEUTICAL FORM Lozenge 4 4.1 CLINICAL PARTICULARS Therapeutic indications For the relief of persistent dry coughs. 4.2 Posology and method of administration Adults the Elderly and Children over 12 years: 2 lozenges (15mg) 3 to 4 times daily. Children 6 to 12 years: 1 lozenge (7.5 mg) 3 to 4 times daily. Children under 6 years: Not recommended. Suck each lozenge until dissolved. Do not take more than 4 doses in 24 hours. For oral use. 4.3 Contraindications Hypersensitivity to any of the ingredients. In patients at risk of developing respiratory failure, for example, during an acute asthmatic attack or in patients with Chronic Obstructive Pulmonary Disease (COPD). 4.4 Special warnings and precautions for use Do not exceed the maximum recommended daily dose. . Prolonged use of dextromethorphan may lead to addiction. Use with caution in patients taking monoamine oxidase inhibitors or within 14 days of stopping such treatment. Use with caution in patients with .hepatic impairment. Contains 2.4g sucrose and glucose per lozenge. This should be taken into account in patients with diabetes mellitus. Unsuitable in fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency. Use with caution in patients with a history of asthma. As there are no specific studies of dextromethorphan hydrobromide in patients with renal impairment caution should be exercised if this drug is prescribed to patients with any degree of renal impairment. Keep all medicines out of reach of children. If symptoms persist consult your doctor or pharmacist. MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 16 - 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of a dextromethorphan containing product and monoamine oxidase inhibitors can occasionally result in symptoms such as hyperpyrexia, hallucinations, gross excitation or coma. Toxicity may occur if dextromethorphan is taken with SSRIs or other medicines which increase synaptic levels of serotonin. Accumulation of dextromethorphan may occur if Halls Dry Cough Lozenges are taken with medicines which inhibit cytochrome P450 2D6. The concomitant ingestion of alcohol may increase the sedative effect of centrally acting atitussives. 4.6 Fertility, pregnancy and lactation There is no or inadequate evidence of the safety of dextromethorphan in human pregnancy therefore dextromethorphan should not be used in pregnancy unless the potential benefit to the mother will exceed all possible risks to the foetus or neonate, consult a doctor or pharmacist before using Halls Dry Cough Lozenges during this period. It is not known whether dextromethorphan or any of its metabolites are excreted in the human milk. 4.7 Effects on ability to drive and use machines This medicinal product may have some influence on the ability to drive and use machines. This product may cause drowsiness or dizziness and patients experiencing these effects should not drive or operate machinery. 4.8 Undesirable effects Occasionally dizziness, nausea, vomiting, allergic skin reactions or gastro-intestinal disturbance may occur but these are rare. 4.9 Overdose Overdosage may lead to nausea, vomiting, abdominal discomfort, drowsiness, dizziness, excitation, mental confusion, hallucinations, respiratory depression, hypotension and ataxia. Treatment should consist of gastric lavage and general supportive measures. Activated charcoal may be of use if given within one hour of the overdose. 5 5.1 PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties ATC code R05DA09; Opium Alkaloids and Derivatives Dextromethorphan hydrobromide is a cough suppressant, it exerts its antitussive activity by acting on the cough centre of the medulla oblongata. 5.2 Pharmacokinetic properties Dextromethorphan hydrobromide is well absorbed from the gut following oral administration. It is metabolised in the liver and excreted in the urine as unchanged dextromethorphan and dimethylated metabolites including dextrorphan. 5.3 Preclinical safety data None stated. 6 6.1 PHARMACEUTICAL PARTICULARS List of excipients Sucrose Granulated Glucose Liquid Blackcurrant flavour (contains propylene glycol and nature-identical flavouring substances) Citric acid monohydrate Sucralose Masking flavour (contains propylene glycol) Levomenthol Carrot anthocyanin E163 (contains anthocyanin extract in water and citric acid) MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 17 - 6.2 Incompatibilities Not applicable. 6.3 Shelf life 24 months. 6.4 Special precautions for storage Do not store above 25oC. Store in the original package. 6.5 Nature and contents of container Blister packs of 250m white/opaque PVC coated with 60 gsm PVDC lidded with 20m hard temper aluminium foil contained in an outer carton. Pack sizes are 6, 8,10 lozenges (1blister strip) or 20 lozenges ( 2 blister strips) in a carton. 6.6 Special precautions for disposal No special requirements 7 MARKETING AUTHORISATION HOLDER Ernest Jackson & Co Ltd 29 High Street, Crediton, Devon EX17 3AP United Kingdom 8 MARKETING AUTHORISATION NUMBER(S) PL 00094/0248 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE 02/08/2012 10 DATE OF REVISION OF THE TEXT 02/08/2012 MHRA-UKPAR – Halls Dry Cough Lozenges AUTHORISATION PL 00094/0248 - 18 - HALLS DRY COUGH LOZENGES PL 00094/0248 PATIENT INFORMATION LEAFLET /LABEL MHRA-UKPAR – Halls Dry Cough Lozenges PL 00094/0248 - 19 -