Decentralised Procedure. Public Assessment Report. Memantinhydrochlorid Hennig 10/20 mg Filmtabletten Memantine hydrochloride DE/H/3614/ /DC

Transcription

1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Memantinhydrochlorid Hennig 10/20 mg Filmtabletten Memantine hydrochloride DE/H/3614/ /DC Applicant: DiaMed GmbH, Germany Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/7 Public AR

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 Nonclinical aspects... 5 III.3 Clinical aspects... 6 IV. BENEFIT RISK ASSESSMENT /7 Public AR

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) Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA Memantinhydrochlorid Hennig 10/20 mg Filmtabletten Memantine hydrochloride N06DX01 Film coated tablet 10 mg / 20 mg DE/H/3614/ /DC DE withdrawn LU DiaMed GmbH Kaiser-Karl-Ring 4-6, D Münster, Germany Hennig Arzneimittel GmbH & Co. KG Liebigstr. 1-2, Flörsheim am Main Germany 3/7 Public AR

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Memantinhydrochlorid Hennig 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 This decentralised application according to article 10.2b (generic application) concerns a generic version of memantine hydrochloride, under the trade name Memantinhydrochlorid Hennig 10/20 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 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, DiaMed GmbH, Germany, is applying for the Marketing Authorisations for Memantinhydrochlorid Hennig 10/20 mg Filmtabletten in LU. However on Day 106 of this procedure, the applicant decided to withdraw the application in Luxemburg. II.2 About the product Memantine hydrochlodride is a non-competitive, low-affinity antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors that preferentially blocks excessive NMDA receptor activity without disrupting its physiological action. Memantine enters the receptor associated ion channel preferentially when it is excessively open, and its off-rate is relative fast so that it does not accumulate in the channel. Therefore, memantine is a drug that can inhibit the overstimulation of the NMDA receptor and subsequent excitotoxicity without interference with normal synaptic transmission. Memantine is indicated for the treatment of moderate to severe dementia of the Alzheimer s type, at a recommended maximum dose of 20 mg/day. II.3 General comments on the submitted dossier The submitted dossier is of satisfactory quality in line with prevailing European requirements. 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. 4/7 Public AR

5 III. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects The general impression of the documentation is that it has been satisfactorily elaborated and justified in accordance with relevant guidelines. Drug substance Memantine hydrochloride is manufactured by the manufacturer and additionally to Module 3.S an ASMF is submitted. The choice of the starting material is regarded acceptable. The proposed specifications for impurities in the active substance are in accordance with EU/ICH Q6A and Q3A guidelines. The analytical methods for assay, related substances and residual solvents used for the active substance are in general satisfactorily described and validated in accordance with the relevant EU/ICH guidelines on Analytical validation. Reference standards are satisfactorily described, and packaging materials comply with Ph. Eur. and directive 2002/72/EC. A re-test period of 4 years is accepted. Drug product The film coated tablets are formulated with well-known excipients. The pharmaceutical development work is rather short but in accordance with relevant EU-guidelines. Justifications for the choice of dissolution test, manufacturing process and packaging material have been described. The manufacturing process has been satisfactorily described in accordance with the EU guidelines on Manufacture of the finished dosage form. The manufacturing process is conventional using standard techniques. The excipients comply with the current version of the monograph in Ph.Eur. and are tested according to the analytical methods in Ph. Eur. The only excipient stated by applicant derived from animal source is lactose monohydrate. It is confirmed that the preparation of lactose monohydrate is in accordance with the EU regulations. The proposed limits on degradation products are justified according to the EU/ICH Q3B guideline. Other requirements are justified according to relevant EU/ICH guidelines and Ph.Eur. The analytical methods used for the active substance is described and validated in accordance with the relevant EU/ICH guidelines. The experience with the active substance and the data from the stability studies performed with the film coated tablets shows that the chosen standard blister adequately protects the product. The stability studies have been carried out according to relevant EU/ICH stability guidelines. 2 batches have been stored for up to 36 and 6 months (accelerated) at ICH conditions. No changes are observed in the investigated parameters at any condition. Therefore no storage recommendations are needed. A shelf life up to 36 months is accepted. III.2 Nonclinical aspects The pharmacological and toxicological characteristics of memantine are well known and have been adequately presented in the non-clinical overview based on pertinent literature. These characteristics are also appropriately reflected in the corresponding sections of SmPC and PL, respectively, in line with the most recent versions of the product information that have been approved for the reference products Ebixa and Axura. 5/7 Public AR

6 Environmental Risk Assessment (ERA) Since Memantinhydrochlorid Hennig 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 The generic formulations of the medicinal products applied for authorisation on the base of the presented documentation fulfil the requirements of the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98, Rev. 1, 2010): - The medicinal products are manufactured by the same manufacturer and the same process. - The active substance memantine is linear over the therapeutic range. An exemption from in vivo bioavailability studies according the BCS-based biowaiver approach is requested for memantine in accordance with the recommendations given in Appendix III of the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98, Rev. 1, 2010). Memantine hydrochloride - is highly soluble in water - is rapidly and almost completely absorbed following oral ingestion - demonstrates dose linearity in the therapeutic range - demonstrates dose-proportional pharmacokinetics with steady state in serum levels occurring within 24 to 48 hours after initiation of therapy - is manufactured by the use of excipients are not suspect of having any relevant impact on bioavailability Memantine is classified as a highly permeable drug according to the BCS guidance. Memantine hydrochloride is a rapidly dissolving drug. Memantine shows linear and dose proportional kinetics. The pharmacokinetic parameters were found to be proportional in the dose range of 5 mg respectively 10 mg to 40 mg for single doses respectively multiple doses. In a study of single-dose and multipledose memantine in healthy Chinese volunteers pharmacokinetic profiles were characterized. Linear pharmacokinetics was found at doses from 5 mg to 20 mg. The multiple-dose pharmacokinetic parameters were nearly similar compared with the single-dose administration. Food had no effect on the rate and extent of absorption of memantine HCl following administration of 2x 10 mg memantine HCl film-coated tablets. Memantine can be dosed without regard to food. The pharmacokinetic parameters following administration of memantine tablets under fasting and fed conditions are tabulated in the following table. Table 1 Pharmacokinetic parameters of memantine following administration of 2 x 10 mg memantine tablets under fasting and fed conditions in healthy male and female subjects 6/7 Public AR

7 Pharmacodynamics N/A Clinical efficacy N/A Clinical safety N/A User testing In order to meet the requirements of Directive 2004/27/EC, an adequate bridging report was provided (complete report see module 1.3.4) that compares the current package leaflets (PLs) of Ebixa 10 mg, 20 mg film-coated tablets i.e. Parent PLs, and the proposed PLs of Memantine hydrochloride (HCl) 10 mg, 20 mg film-coated tablets, i.e. Daughter PLs, in order to present and evaluate the differences between the originator PLs and proposed PLs for Memantine HCl 10 mg and 20 mg film-coated tablets. The proposed PLs of Memantine HCl 10 mg and 20 mg film-coated tablets do not substantially differ from the parent PL and are considered readable and acceptable to the patient. Pharmacovigilance system Description of Pharmacovigilance System The applicant has provided documents that set out a detailed description of the Hennig system of pharmacovigilance (Version 03 dated 16 November 2011). A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided. The Pharmacovigilance system as described by the applicant fulfils the requirements as described in Volume 9A of the Rules Governing Medicinal Products in the European Union and provides adequate evidence that the applicant has the services of a qualified person 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. Risk Management Plan Memantine hydrochloride is not a new active substance as it has been on the market for more than 10 years at the time of submission (l st registration date via Centralised Procedure was 15/05/2002 in the European Community under the product name Ebixa ), it is not a similar biological product and it does not concern a significant change in a marketing authorisation. No safety concerns requiring additional risk minimisation activities with respect to the reference medicinal product are known to the Applicant. Considering all of the above, a Risk Management Plan is therefore not considered necessary and the justification for not submitting one is acceptable. IV. BENEFIT RISK ASSESSMENT It can be concluded from the available clinical data and the nature and incidence of adverse events, that memantine hydrochloride is a safe and effective drug for the treatment of mild to moderate Alzheimer s disease. By respecting the long-year therapeutical experience (more than 30 years), the contraindications, warnings and precautions, the use of memantine in the proposed dosages is medically justified because the benefit/risk-ratio is clearly in favour of the drug. The application is approved. 7/7 Public AR