Decentralised Procedure. Public Assessment Report. Memantin Pharmascope 10 / 20 mg Filmtabletten Memantine hydrochloride DE/H/3673/ /DC

Transcription

1 Decentralised Procedure Public Assessment Report Memantin Pharmascope 10 / 20 mg Filmtabletten Memantine hydrochloride DE/H/3673/ /DC Applicant: Pharmascope Limited, Ireland; DAWA Limited, United Kindom; Sopharma AD, Bulgaria Reference member state: DE

2 TABLE OF CONTENTS I. INTRODUCTION... 4 II. EXECUTIVE SUMMARY... 4 II.1 Problem statement... 4 II.2 About the product... 4 II.3 General comments on the submitted dossier... 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.. 4 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 4 III.1 Quality aspects... 4 III.2 Non-clinical aspects... 5 III.3 Clinical aspects... 5 IV. BENEFIT RISK ASSESSMENT... 8 Memantin Pharmascope, DE/H/3673/ /DC Public AR Page 2/8

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product(s) 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: Member States concerned: Applicant (name and address) Memantin Pharmascope 10 / 20 mg Filmtabletten Memantine hydrochloride N06DX01 Film-coated tablets ; 10 / 20 mg DE/H/3673/ /DC DE BG, FR, NL, RO, SE, UK Pharmascope Limited Unit 2, Ashbourne Manufacturing Park, Ashbourne, Co. Meath, Ireland For BG only: Sopharma AD 16 Iliensko Shosse Str., 1220-Sofia, Bulgaria For UK only: DAWA Limited 5, SandridgeClose, Harrow, HA1 IXD, United Kingdom Memantin Pharmascope, DE/H/3673/ /DC Public AR Page 3/8

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Memantin Pharmascope 10 / 20 mg Filmtabletten in the treatment of patients with moderate to severe Alzheimer s disease, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement N/A II.2 About the product This decentralised application according to article 10.2b (generic application) concerns generic versions of memantine hydrochloride, under the trade name Memantin Pharmascope 10 / 20mg Filmtabletten. In this Assessment Report, the name memantine is used. The originator products are Axura and Ebixa (5/10/15/20 mg film-coated tablets and 5 mg drops/oral solution) by Merz Pharmaceuticals GmbH and H. Lundbeck A/S, respectively, registered simultaneously in the EU via the centralised procedure since 15 th May 2002 for the treatment of patients with moderate to severe Alzheimer s disease. In the US, the FDA approved memantine for a similar indication in 2003 (Namenda ). With Germany as the Reference Member State in this Decentralized Procedure / Mutual Recognition Procedure, Pharmascope Ltd., Ireland is applying for the Marketing Authorisations for Memantin Pharmascope 10 / 20 mg Filmtabletten in BG, FR, NL, RO, SE, UK for DE/H/3673/001/DC and in FR, NL, RO, SE, UK for DE/H/3673/002DC. Memantine is a non-competitive NMDA glutamate receptor antagonist. The excessive release of glutamate is claimed to be associated with neurodegeneration in acute and chronic disorders of the central nervous system such as hypoxia, ischaemia, stroke and Alzheimer s disease. II.3 General comments on the submitted dossier This application concerns an abridged application, according to article 10.2(b) so called generic application. The grounds and evidence used for demonstrating that the intended medicinal product is essentially similar to the reference medicinal product are appropriately outlined. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. The GCP inspection was successfully concluded. The triggered GCP inspection focussed on the compliance of the BE-trial MEMA-1K with international recognised ethical and scientific standards, the verification of the clinical and bioanalytical data reported in the MAH for Memantine HCl tablets 20 mg of Pharmascope Ltd (procedure DE/H/3673/ /DC) and the QMS established. The trial was conducted and the data were generated in compliance with ICH-GCP and other applicable regulations. For the finished product manufacturer and the drug substance manufacturer valid GMP certificate have been provided. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance Data are provided in the ASMF format. The active substance general properties are described detailed, the synthesis and reaction pathway is described briefly. The elucidation of structure and impurities possible occurring is provided. The impurity profile has been discussed. Analytical methods employed are described in detail covering procedures, apparatus, sample and standard preparation, relevant sample chromatograms are presented. In general the methods underwent validation work sufficiently. An adequate genotoxic discussion has been provided. Residual solvents probably present have been examined and relevant measures are implemented, respectively where not present in the active substance the specification has been adjusted. Memantin Pharmascope, DE/H/3673/ /DC Public AR Page 4/8

5 The specification has been set up justified. Reference standards for the active substance were established after sufficient extensive quality assessment. The container closure system is justified in accordance to the relevant regulations. Stability studies at accelerated and long term are and the proposed re-test period of 12 months and 48 month at standard conditions, respectively is considered justified. Drug Product The ingredients, the manufacturing process and the in-process controls of the drug product correspond to the current standard of pharmaceutical technology and are suitable to guarantee an appropriate product quality. The description of the analytical test methods is adequate. The validation results are sufficient. All relevant quality criteria are specified in accordance with internationally acknowledged pharmacopoeias. The specified limits are in line with the requirements of the CHMP Guidelines and are guarded by the finished product. The stability testing data showing no significant trends. Based on the provided data yet a shelf life of 36 month is justified by extrapolation. The photostability has been investigated and the results show that the primary container adequately protects the dosage form. In use stability data are provided and support shelf life after first opening of 75 days. III.2 Non-clinical aspects Memantine is a substance with well-known pharmacodynamic, pharmacokinetic and toxicological properties. Although the non-clinical overview hardly meets the expectations on a generic application for marketing authorisation, no new information is available which would, from a pre-clinical perspective, change the general positive benefit/risk assessment of the product. The instructions regarding the use of the active substance during pregnancy and lactation and preclinical safety data contained in the proposed SmPC and PL, respectively, essentially reflect the texts that were approved for the originator product Ebixa. Environmental Risk Assessment (ERA) Since Memantin Pharmascope 10 / 20 mg Filmtabletten are 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 Pharmacokinetics To support the application, the applicant has submitted as report one bioequivalence study (MEM A- 1K ). The relative bioavailability for Memantine Hydrochloride 20 mg Film-coated Tablets has been compared to the EU marketed product Ebixa 20mg Tablets in an open-label balanced randomised two treatment, two-period, two-sequence, single dose, crossover bioequivalence study in healthy adult human subjects under fasting conditions undertaken at the Micro Therapeutic Research Labs Private Limited facility at No.6, Kamarajar Salai, Selaiyur, East Tambaram, Chennai , Tamil Nadu, India. The concentration of Memantine in plasma samples were analyzed using validated bio analytical methods. Pharmacokinetic and statistical analyses were performed on obtained drug concentration data. The results for the relative bioavailabilities between the Memantine Hydrochloride 20 mg Filmcoated Tablets and the Ebixa 20mg tablets administered under fasting conditions are summarized below in Tables 1-2. Memantin Pharmascope, DE/H/3673/ /DC Public AR Page 5/8

6 Table 1: Pharmacokinetic data for Memantine in MEMA-1K Table 2: Bioequivalence evaluation of Memantine in MEMA-1K For Memantine, the 90% confidence interval of the relative mean C max and AUC 0-72 hr of the test to reference formulation for Ln-transformed data should be within % % to establish bioequivalence. The results of bioequivalence study (Project No.: MEMA-1K ) performed with the 20 mg formulation can be extrapolated to the lower strength (10mg), according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section Pharmacodynamics No new pharmacodynamic studies were conducted and reference was made to literature data which is acceptable. Clinical efficacy The efficacy of memantine in moderate to severe Alzheimer s disease has been well documented in literature. The applicant provided an adequate overview of recent publications. No new data were submitted. Clinical safety No new data were submitted. It is considered that the safety profile of Memantin hydrochloride 10/20 mg Filmtabletten/Memantin Pharmascope will be comparable to that of other identical to similar products which are currently licensed and marketed in Europe. Memantin Pharmascope, DE/H/3673/ /DC Public AR Page 6/8

7 User Testing It was declared that, following Directive 2001/83/EC, articles 59(3) and 61(1) as amended by Directive 2004/27/EC, the readability of the Patient Information Leaflet for the medicinal product Memantine Hydrochloride 10 mg Film-coated Tablets referenced below was assessed to ensure potential users could locate, understand and appropriately act upon the information contained in the leaflet. A summary of the test details and outcome are presented with the package leaflet that incorporates any changes resulting from assessment. All 15 questions succeeded in reaching the benchmark pass criteria of 90% or more. In all cases 90% of volunteers were able to find the information and in all cases, 100% of these individuals were deemed able to understand the information. The patient information leaflet for Memantine Hydrochloride 10 mg Film-coated Tablets has shown herein to be highly accessible to its potential users. In both rounds of testing all questions successfully passed the test criteria. As the leaflet passed in both rounds and only very minor changes were made, further rounds of testing are not deemed necessary. Following the performance of readability testing of 20 (24 including pilot) volunteers from the general population, it is concluded that the final Patient Information Leaflet for Memantine Hydrochloride 10 mg Film-coated Tablets contains the required information for the user that is locatable by 90% of volunteers and comprehensible by 90% of those volunteers. All information within the Patient Information Leaflet was compiled in accordance with EMEA/QRD/ version 3. Summary Pharmacovigilance system The Applicant/Proposed Future MAH has submitted signed Summary of the Applicant's/Proposed Future MAH's 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 considers the Summary acceptable. Risk Management Plan Memantin Pharmascope, DE/H/3673/ /DC Public AR Page 7/8

8 All three Applicants provided RMPs with the same safety specifications.no additional pharmacovigilance or risk minimisation measures are proposed which is endorsed. The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time. Periodic Safety Update Report (PSUR) For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. IV. BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data regarding pharmacology, efficacy and safety. Based on the statistical results obtained, Memantine Hydrochloride Tablets 20 mg as manufactured by Sharon Bio-Medicine Limited, India and EBIXA (Memantine Hydrochloride) Tablets 20 mg of H. Lundbeck A/S Ottiliavej 9, DK-2500 Valby Denmark are found to be bioequivalent in healthy, adult, human subjects under fasting conditions. The results of bioequivalence study (Project No.: MEMA-1K ) performed with the 20 mg formulation can be extrapolated to the lower strength (10mg), according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section The application is approved. For intermediate amendments see current product information. Memantin Pharmascope, DE/H/3673/ /DC Public AR Page 8/8