Decentralised Procedure. Public Assessment Report

Transcription

1 Decentralised Procedure Public Assessment Report Acetylcysteine HEXAL 100/200/600 mg effervescent tablets Acetylcysteine Sandoz 200 mg effervescent tablets Acetylcysteine DE/H/3625/ /DC DE/H/3667/001/DC Applicant: Hexal AG Sandoz Pharmaceuticals GmbH Reference Member State DE

2 TABLE OF CONTENTS I INTRODUCTION 4 II EXECUTIVE SUMMARY 4 II.1 ABOUT THE PRODUCT 4 II.2 GENERAL COMMENTS ON THE SUBMITTED DOSSIER 4 II.3 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES 4 III SCIENTIFIC OVERVIEW AND DISCUSSION 5 III.1 QUALITY ASPECTS 5 III.2 NON-CLINICAL ASPECTS 5 III.3 CLINICAL ASPECTS 6 IV BENEFIT RISK ASSESSMENT 7 DE/H/3625/ /DC, DE/H/3667/001/DC Public AR Page 2/7

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS Name of the drug substance (INN name): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number(s) for the Decentralised Procedure Reference Member State: Concerned Member States: Applicant (name and address) Acetylcystein HEXAL 100/200/600 mg Brausetabletten Acetylcystein Sandoz 200 mg Brausetabletten acetylcysteine Cough and cold preparations; Mucolytics (R05CB01) Effervescent tablets 100 / 200 / 600 mg DE/H/3625/ /DC DE/H/3667/001/DC DE BE, BG, EL, IT, LU, PT, RO DK, FI, NO, PL and SE withdrawn Hexal AG Industriestraße Holzkirchen Germany Sandoz Pharmaceuticals GmbH Raiffeisenstraße Holzkirchen Germany DE/H/3625/ /DC, DE/H/3667/001/DC Public AR Page 3/7

4 I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the applications for Acetylcystein HEXAL 100 mg /200 mg/600 mg Brausetabletten and Acetylcystein Sandoz 200 mg Brausetabletten, in in secretolytic therapy in acute and chronic bronchopulmonary diseases accompanied by impaired formation and transport of mucus, are approved. II EXECUTIVE SUMMARY II.1 About the product Acetylcysteine (NAC) is the N-acetyl derivative of the amino acid cysteine. It has been promoted as a mucolytic agent for use in the adjuvant treatment of pulmonary diseases associated with increased viscosity of bronchial secretions. Acetylcysteine exerts its mucolytic action through its free sulfhydryl group, which opens the disulfide bonds and lowers mucus viscosity. This action increases with increasing ph and is most significant at ph 7 to 9. The mucolytic action of acetylcysteine is not affected by the presence of DNA. NAC has been demonstrated to cause a decrease in sputum consistency, to facilitate easier expectoration, and to increase sputum volume. Bronchial mucus is composed of over 95% water; however, the physical characteristics of the mucus are due to glycoproteins. These glycoproteins bind to each other by way of disulfide bonds and give the mucus viscosity. NAC ruptures these disulfide bonds causing depolymerization and a rapid decrease in mucus viscosity. It also produces an irritative bronchorrheic effect on the mucosa, stimulating mucociliary clearance; this irritative effect may cause bronchospasm, thus acetylcysteine is not recommended in asthmatics. The in-vitro ability of NAC to decrease the viscosity of sputum is unchallenged and has been demonstrated in studies using devices designed to objectively evaluate the ability of chemicals to reduce the viscosity of mucopurulent solutions. N-Acetylcysteine's (NAC) action is concentration and ph dependent. A concentration of less than 5% has been found to be little more effective than water or saline. The ph dependency is important with initial application, but within 1 hour there is no large difference between activity at ph 5 and ph 8. It is generally thought that higher ph's are more beneficial. NAC apparently does not influence secretory glands or pulmonary surface activity at normal concentrations. II.2 General comments on the submitted dossier These are article 10(1) generic marketing authorisation applications for Acetylcysteine 100, 200, and 600 mg effervescent tablets. As reference medicinal products which have been authorised for not less than 6/10 years in the EEA, Fluimucil Hustenlöser akut 200 mg; Brausetabletten and Fluimucil Hustenlöser akut 600 mg Brausetabletten, Pierre Fabre Pharma GmbH are declared. The marketing authorisation of these reference products was granted in 1995 in Germany. With Germany as the Reference Member State in this Decentralised Procedure, Hexal AG and Sandoz Pharmaceuticals GmbH are applying for the Marketing Authorisations respectively for Acetylcysteine HEXAL 100 / 200 /600 mg effervescent tablets and Acetylcysteine Sandoz 200 mg effervescent tablets in BE, BG, DK, EL, FI, IT, LU, NO, PL, PT, RO, and SE. However, the applicants decided to withdraw the applications in DK, FI, NO, PL and SE. Acetylcysteine is a well-known substance with a well-established use and an acceptable level of safety and efficacy. The Applicant has not submitted any bioequivalence studies demonstrating that the applied-for products are essentially similar to the authorised reference products. II.3 General comments on compliance with GMP, GLP, GCP and agreed ethical principles For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For each of the manufacturers, satisfactorily manufacturing authorisations and GMP certificates are provided. DE/H/3625/ /DC, DE/H/3667/001/DC Public AR Page 4/7

5 III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The drug substance is a compendia substance. For each of the suppliers, a CEP is provided. An adequate drug substance specification for the drug product manufacturer which complies with the current monograph of the European Pharmacopoeia and the Certificates of Suitability for each of the suppliers is presented. Batch analysis data obtained by the drug substance suppliers and by the drug product manufacturer are provided which demonstrate the conformity with the Ph. Eur. monograph. A re-test period of 5 years without storage conditions, if stored in double polyethylene bags placed in fibre board drums, or in double PE bags in card board drums, or in double PE bags placed in plastic drum is acceptable, respectively. Drug product (100 and 200 mg) The drug products are effervescent tablets containing 100 and 200 mg Acetylcysteine, and packaged in a thermo-sealed sachet made of polythene/aluminium/paper or in polypropylene tubes with polyethylene stoppers containing desiccant. The 200 mg strength contains a break mark. The excipients are citric acid, anhydrous; sodium hydrogen carbonate; sodium carbonate, anhydrous; sodium citrate; ascorbic acid; mannitol; lactose, anhydrous; saccharin sodium and blackberry flavour. The manufacturing process including flow chart is adequately documented. Adequate process validation data for each of the strengths are provided. Each of the excipients except the flavour complies with respective Ph. Eur. monographs. Information given for the flavour is sufficient. The release and shelf life specifications contain all parameters appropriate for this pharmaceutical form. The limits for the impurities are sufficiently qualified. The analytical control methods are adequately described. The validation of the assay and purity method is in accordance to ICH validation requirements. Batch analysis data are given showing compliance with set specifications. The quality of the packaging material is sufficiently proven. Based on the provided stability data a shelf life of 24 months, if not stored above 25 C, is accepted for product packaged in tubes. For sachets, a shelf life of 36 months, if not stored above 30 C, is accepted. For both strengths, packaged in tubes, the storage precaution Keep the plastic container tightly closed in order to protect from moisture is necessary. Drug product (600 mg) The drug product is an effervescent tablet containing 600 mg Acetylcysteine as drug substance, and packaged in sachets made of polythene/aluminium/paper or polypropylene tubes with polyethylene stoppers containing desiccant. The tablet contains a break mark. The excipients are citric acid, anhydrous; sodium hydrogen carbonate; sodium carbonate, anhydrous; sodium citrate dihydrate; ascorbic acid; mannitol; lactose, anhydrous; saccharin sodium; sodium cyclamate, and blackberry flavour. The manufacturing process including flow chart is adequately documented. Adequate process validation data are provided. Each of the excipients except the flavour complies with respective Ph. Eur. monographs. Information given for the flavour is sufficient. The release and shelf life specifications are considered as appropriate for this pharmaceutical form. The limits for the impurities are sufficiently qualified. The analytical control methods are adequately described. The validation of the assay and purity method is in accordance to ICH validation requirements. Batch analysis data are given showing compliance with set specifications. The quality of the packaging material is sufficiently proven. Based on the stability results of several production batches packaged in the proposed packaging materials for long-time conditions over 36 months, for intermediate conditions over 12 months and for accelerated conditions over 6 months a shelf life of 36 months in both packaging materials is accepted. For product packed in tubes the storage precaution Keep the plastic container tightly closed in order to protect from moisture is necessary. The in-use shelf life of the tubes is 24 months. III.2 Non-clinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of acetylcysteine are well known. DE/H/3625/ /DC, DE/H/3667/001/DC Public AR Page 5/7

6 As acetylcysteine is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. The submitted non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is very detailed and is based on an actual comprehensive literature search in relevant data bases. The Non-clinical Overview is considered a sufficient review of the pharmacotoxixcological profile of acetylcysteine and can be accepted. Environmental Risk Assessment (ERA) Since Acetylcysteine 100mg/200mg/600mg effervescent tablet is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.3 Clinical aspects The Applicant has not submitted any bioequivalence studies demonstrating that the applied-for products are essentially similar to the authorised reference products. The applied-for products contain mannitol as a critical excipient, which is absent in the reference product. According the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Cor), mannitol is one of the excipients that might affect bioavailability and it is explicitly stated that excipients that might affect bioavailability should be qualitatively and quantitatively the same in the test product and the reference product. The requirements of the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr.) with regard of the waiver of the bioequivalence studies are satisfied in this case. Even though the applied-for product contains mannitol, the amounts are far below doses that can have a significant impact on the bioavailability of the active substance or on the GI motility. Pharmacokinetics Absorption Absorption of acetylcysteine is rapid following oral administration, but the bioavailability is only 6-10% due to extensive first past metabolism. Oral bioavailability is similar for a single 600-mg dose and three 200-mg doses. Peak plasma levels of acetylcysteine occur approximately one hour following oral administration. Distribution Acetylcysteine may be present in plasma as the parent compound or as various oxidised metabolites such as N-acetylcysteine, N,N-diacetylcysteine, and cysteine either free or bound to plasma proteins by labile disulfide bonds or as a fraction incorporated into protein peptide chains. Following a 100- mg oral dose, 48% was present in lung tissue. Metabolism Acetylcysteine undergoes extensive metabolism in the liver and intestinal wall. Acetylcysteine undergoes rapid deacetylation in vivo to yield cysteine or oxidation to yield diacetylcysteine. Following deacetylation in the liver, it enters the normal metabolic pathway of the amino acid cysteine. An appreciable elevation in total serum sulfhydryl concentration occurs. Elimination Renal Excretion: 22% to 30% Faeces: 3% Total Body Clearance: 6.5 L/hr (healthy subjects). The mean terminal half-life is approximately 6 hours. Pharmacodynamics Acetylcysteine exerts its mucolytic action through its free sulfhydryl group, which opens the disulfide bonds and lowers mucus viscosity. This action increases with increasing ph and is most significant at ph 7 to 9. The mucolytic action of acetylcysteine is not affected by the presence of DNA. N-acetylcysteine has been demonstrated to cause a decrease in sputum consistency, to facilitate easier expectoration, and to increase sputum volume. Bronchial mucus is composed of over 95% water; however, the physical characteristics of the mucus are due to glycoproteins. These glycoproteins bind to each other by way of disulfide bonds and give the mucus viscosity. DE/H/3625/ /DC, DE/H/3667/001/DC Public AR Page 6/7

7 N-acetylcysteine ruptures these disulfide bonds causing depolymerization and a rapid decrease in mucus viscosity. Clinical efficacy In general, Acetylcysteine has a well-recognised efficacy and an acceptable level of safety in the indication and corresponding products have been widely used in many countries. User testing The Applicant submitted a bridging report. In the report it is argued that according to the Guideline on the readability of the labelling and package leaflet of medicinal products for human use, and the CMD(h) Guidance from April 2009 user consultation is not necessary as the Acetylcysteine daughter package inserts: belong to medicines that contain an active substance identical to that of the corresponding medicine of the parent package insert present the key messages in almost identical wording to that used in the previously tested parent package insert use the layout and design of the parent package insert, which is the MAH package insert house style that has been used in many other successfully user tested package inserts build upon the results of the previous successful user test of the parent package insert, which are transferable to the daughter package inserts. Therefore, it can be assumed that patients assess the information contained in the Acetylcysteine daughter package inserts and the previously tested parent package insert equally well, while also being able to comprehend and subsequently act upon the information provided. To conclude, the Acetylcysteine daughter package inserts do not necessitate testing, according to the Guideline on the readability of the labelling and package leaflet of medicinal products for human use and the CMD(h) Guidance from April The RMS accepts this reasoning. Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System and asked the RMS to replace the previously submitted DDPS with the new Summary of Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS accepts this substitution. Risk Management Plan The applicant has not submitted a RMP. The applicant justified the absence of a RMP with the fact that no special important risks or potential risks have been identified which require additional risk minimization activities. It is agreed, that at the moment no RMP is required for this application, as routine pharmacovigilance activities are sufficient. IV BENEFIT RISK ASSESSMENT Acetylcysteine is a well-known substance with a well-established use and an acceptable level of safety and efficacy. The application is approved. For intermediate amendments see current product information. DE/H/3625/ /DC, DE/H/3667/001/DC Public AR Page 7/7