Decentralised Procedure. Public Assessment Report. Memantin AbZ 10 mg/20 mg Filmtabletten ; Starterpack

Transcription

1 Decentralised Procedure Public Assessment Report Memantin AbZ 10 mg/20 mg Filmtabletten ; Starterpack Memantin-ratiopharm Starterpackung 5 mg /10 mg /15 mg /20 mg Filmtabletten ;10 mg/20 mg Filmtabletten Memantine hydrochloride DE/H/ / /DC Applicant: TEVA Pharma B.V., The Netherlands 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... 5 III.1 Quality aspects... 5 III.2 Non-clinical aspects... 5 III.3 Clinical aspects... 5 IV. BENEFIT RISK ASSESSMENT... 9 Memantin-ratiopharm DE/H/ / /DC 2/9 Public AR

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product(s) in the RMS INN (or common name) of the active substance(s): 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 AbZ 10 mg/20 mg Filmtabletten ; Starterpack Memantin-HCl-ratiopharm Starterpackung 5 mg/10 mg/15 mg/ 20 mg Filmtabletten ; 10 mg/20 mg Filmtabletten Memantine hydrochloride N06DX01 Film coated tablets, 10,20 mg ; Starterpack DE/H/3496/ /DC DE/H/3542/ /DC DE DE/H/3496/ /DC: BE, DK, EL, ES, FR, HU, IE, IT, MT, NL, PL, PT, RO, SE, SI, UK FI withdrawn DE/H/3542/ /DC: ES, LU TEVA Pharma B.V. Computerweg 10, NL-5342DR Utrecht, The Netherlands Memantin-ratiopharm DE/H/ / /DC 3/9 Public AR

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Memantin AbZ 10 mg/20 mg Filmtabletten ; Starterpack ; Memantin-HCl-ratiopharm Starterpackung 5 mg/10 mg/15 mg/ 20 mg Filmtabletten ; 10 mg/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(1) (generic application) concerns generic versions of memantine hydrochloride, under the trade name Memantin AbZ 10 mg/20 mg Filmtabletten ; Starterpack ; Memantin-HCl-ratiopharm Starterpackung 5 mg/10 mg/15 mg/ 20 mg Filmtabletten ; 10 mg/20 mg 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) 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 Procedure, Teva Pharmae B.V., The Netherlands is applying for the Marketing Authorisations for Memantin AbZ 10 mg/20 mg Filmtabletten ; Starterpack ; Memantin-HCl-ratiopharm Starterpackung 5 mg/10 mg/15 mg/ 20 mg Filmtabletten ; 10 mg/20 mg Filmtabletten in BE, DK, EL, ES, FI, FR, HU, IE, IT, MT, NL, PL, PT, RO, SE, SI, UK for DE/H/3496/ /DC and in ES and LU for DE/H/3542/ /DC. However, the applicant in DE/H/3496/ /DC decided to withdraw the application in FI. 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 RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. 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 manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non- Community sites. According the Applicant, the bioequivalence study took place under GCP and GLP conditions Memantin-ratiopharm DE/H/ / /DC 4/9 Public AR

5 III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance Memantine hydrochloride is not described in the current European Pharmacopoeia. An Active Substance Master File (ASMF) for Memantine hydrochloride from the active substance manufacturer is submitted. Letter of access as well as the applicant part is included in the dossier. The complete ASMF has been submitted directly to BfArM by the ASMF-holder. The chemical-pharmaceutical documentation and Expert Report in relation to Memantine hydrochloride are of sufficient quality in view of the present European regulatory requirements. The structure of Memantine hydrochloride has been confirmed by analytical evidence like elemental analysis and spectroscopic analyses (IR, 1 H- NMR, 13 C-NMR, MS). The control tests and specifications for drug substance product are adequately drawn up. The analytical methods have been sufficiently validated. Sufficient batch analysis data for industrial batches have been presented. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period for drug substance is justified. Drug Product The development of the products has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on two pilot scale batches of each strength. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. Results of stability studies for 6 months are available for batches stored both at long term and accelerated storage conditions. A shelf-life of 24 months for each strength of Memantine HCl 5 mg, 10 mg, 15 mg and 20 mg Tablets, packaged in transparent PVC/PVdC/ aluminium blisters, transparent PVC/PE/PVdC/aluminium blisters and aluminium -aluminium blisters and in bottles is accepted. 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 AbZ 10 mg/20 mg Filmtabletten ; Starterpack ; Memantin-HCl-ratiopharm Starterpackung 5 mg/10 mg/15 mg/ 20 mg Filmtabletten ; 10 mg/20 mg Filmtabletten 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 Pharmacokinetics To support this application, the applicant has submitted as report one bioequivalence study. In order to show the essential similarity with the original product Ebixa (H. Lundbeck-A/S, Denmark) the applicant conducted a bioequivalence study of the test product Memantine hydrochloride with the reference product Ebixa (H. Lundbeck-A/S, Denmark) in the dose of 20 mg in fasting subjects: Randomized, open-label, 2-way crossover, bioequivalence study of memantine hydrochloride 20mg tablet and Ebixa (reference) following a single 20mg dose in healthy subjects under fasting conditions. Memantin-ratiopharm DE/H/ / /DC 5/9 Public AR

6 The objective of this study was to compare the rate and extent of absorption of memantine 20mg tablet (test), versus Ebixa 20mg tablet administered as 1 x 20 mg tablet under fasting conditions. The mean pharmacokinetic characteristics of Memantine after treatment with Test and Reference products were as follows: Table 1 Pharmacokinetic parameters The 90% confidence intervals for the geometric mean ratios of Test to Reference formulations for AUC O-t and C max were within the bioequivalence acceptance range of 80 to 125%. The results of the bioequivalence study are indicative of bioequivalence between Test and Reference product. The bioequivalence study has been performed with the highest of four strengths. The results of study with 20 mg formulation can be extrapolated to the lower strengths (5, 10 and 15mg), 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. Memantin-ratiopharm DE/H/ / /DC 6/9 Public AR

7 Clinical safety No new data were submitted. It is considered that the safety profile of Memantin AbZ 10 mg/20 mg Filmtabletten ; Starterpack ; Memantin-HCl-ratiopharm Starterpackung 5 mg/10 mg/15 mg/ 20 mg Filmtabletten will be comparable to that of other identical or similar products which are currently licensed and marketed in Europe. User Testing The PL for Memantine TEVA 5 mg + 10 mg + 15 mg + 20 mg film-coated tablets initiation pack (Daughter PL) is justified to be supported by the user test conducted on the PL for Memantine hydrochloride 10 mg/ml oral solution (Parent PL for Content) PL for the following reasons. The products: have identical active ingredients and indications have closely similar key issues for safe use potential users are the same target population have the same complexity of the message and language Memantine hydrochloride 10 mg/ml oral solution (Parent PL for Content) is considered to be the parent PL for Memantine TEVA 5 mg + 10 mg + 15 mg + 20 mg film-coated tablets initiation pack (Daughter PL). Memantine hydrochloride 10 mg/ml oral solution (Parent PL for Content) is considered to be the parent PL for Memantine TEVA 5 mg + 10 mg + 15 mg + 20 mg film-coated tablets initiation pack (Daughter PL) as the text from the previously tested version of the PL was used wherever possible and the only notable differences are in the administration, due to the different pharmaceutical forms, and would not be expected to influence readability. Therefore, it is concluded the testing on the PL for Memantine hydrochloride 10 mg/ml oral solution (Parent PL for Content) should support the Memantine TEVA 5 mg + 10 mg + 15 mg + 20 mg film-coated tablets initiation pack (Daughter PL). The terminology used for both PLs is closely similar. The PL for Memantine TEVA 5 mg + 10 mg + 15 mg + 20 mg film-coated tablets initiation pack (Daughter PIL) is justified to be supported for format by the user test conducted on the PL for Lansoprazole 15 mg and 30 mg gastro-resistant capsules (Parent PL for Format) for the following reasons. The Mock Ups both: use TEVA livery style have the same use of white space and line spacing have closely similar headings and similar subheadings use the same font type and size. Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a 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. Memantin-ratiopharm DE/H/ / /DC 7/9 Public AR

8 Risk Management Plan Summary of safety concerns and planned pharmacovigilance actions Summary of safety concerns Important identified risks Important potential risks Important missing information Hepatic disorders Off-label use Prostate cancer Use in pregnant women Safety concern Routine risk minimisation measures Additional risk minimisation measures Hepatic disorders Use of memantine in patients with hepatic impairment has been sufficiently described in section 4.2 of the SmPC and hepatobiliary disorders are listed in section 4.8 of the SmPC and in PL. As stated by SmPC, no dose adjustment is needed in patients with mild or moderate hepatic impaired function. However, since no data on the use of memantine in patients with severe hepatic impairment are available, administration of memantine is not recommended in patients with severe hepatic impairment. Elevated liver function test and hepatitis have been reported in patients treated with memantine. Not applicable Off-label use Therapeutic indication is clearly stated in section 4.1, as well as posology and method of administration in section 4.2 of the SmPC and in PL. As required in the SmPC, this medicinal product should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer s dementia. Not applicable Prostate cancer In the absence of specific safety signals relating to prostate cancer, the applicant does not propose any risk minimization activities at this time. Not applicable Memantin-ratiopharm DE/H/ / /DC 8/9 Public AR

9 Use in pregnant women Memantine should not be used during pregnancy Not applicable unless clearly necessary (SPC, section 4.6 and PL). SmPC Section 5.3 sumarises data from animal studies. As required in the SmPC, this medicinal product should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer s dementia. Justification for routine PV: Routine pharmacovigilance is considered to be sufficient to manage the important identified and potential risks and missing information associated with the use of Memantine hydrochloride tablets. IV. BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data regarding pharmacology, efficacy and safety. Bioequivalence of Memantin AbZ 10 mg/20 mg Filmtabletten ; Starterpack ; Memantin-HCl-ratiopharm Starterpackung 5 mg/10 mg/15 mg/ 20 mg Filmtabletten with Ebixa 20 mg.has been shown. The results of bioequivalence study performed with the 20 mg formulation can be extrapolated to the lower strengths (5, 10 and 15 mg), 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-ratiopharm DE/H/ / /DC 9/9 Public AR