Decentralised Procedure. Public Assessment Report. Memantin Orion 10/20 mg Filmtabletten. Memantine hydrochloride DE/H/3653/ /DC

Transcription

1 Decentralised Procedure Public Assessment Report Memantin Orion 10/20 mg Filmtabletten Memantine hydrochloride DE/H/3653/ /DC Applicant: Orion Corporation, Finland 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.1Quality aspects... 5 III.2Non-clinical aspects... 5 III.3Clinical aspects... 5 IV. BENEFIT RISK ASSESSMENT... 7 Memantin Orion, DE/H/3653/ /DC Public AR Page 2/7

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 Orion 10/20 mg Filmtabletten Memantine hydrochloride N06DX01 Film coated tablet 10/20 mg DE/H/3653/ /DC DE CZ, DK, EE, FI, HU, LT; LV, NO, PL, SE, SK Orion Corporation Orionintie 1, FI_02200 Espoo, Finland Memantin Orion, DE/H/3653/ /DC Public AR Page 3/7

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Memantin Orion 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 concerns a generic version of Memantine hydrochlodride, under the trade names Memantin Orion 10/20 mg Filmtabletten. In this Assessment Report, the name Memantine is used. The reference product is Ebixa 10/20 mg film-coated tablet by H. Lundbeck A/S, Denmark, registered since 15 May 2002 via the Centralized Procedure. In the same period a second application was assessed and approved for Merz Pharmaceuticals GmbH, Germany, on 17 May 2002 with the product name Axura. With Germany as the Reference Member State in this Decentralized Procedure, Orion Corporation, Finland is applying for the Marketing Authorisations for Memantine in CZ, DK, EE, FI, HU, LT, LV, NO, PL, SE, and SK. II.2 About the product Memantine hydrochloride is an N-methyl-D-aspartate (NMDA) receptor antagonist, it preferentially blocks the excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity open-channel blocker. 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 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 in Module 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, close-out letters or exchange of information 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 studies took place under GCP and GLP conditions. Memantin Orion, DE/H/3653/ /DC Public AR Page 4/7

5 III. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance Memantine hydrochloride is not described in the current European Pharmacopoeia. The drug substance data is provided in the form of an Active Substance Master File. Letter of access as well as the applicant s parts are included in the dossier. The complete ASMF has been submitted directly to BfArM by the ASMF-holder. The chemical-pharmaceutical documentation and Quality Overall Summary 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. The control tests and specifications for drug substance product are adequately drawn up. The analytical methods have been sufficiently validated. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The retest period of five years is 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. Memantine film coated tablets are a straightforward product. The dissolution profile is very fast reflecting the high solubility of the drug substance and the performance of the dosage form which is an immediate release tablet with non functional coating. The only non standard issue is the fact is that memantine bears no chromophores, what requires a derivatision step to make analyte detectable for UV-spectromteric methods. 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 but could be partially tightened based upon batch release and stability results of the finished product. The drug product is rather stable and stability data justify a shelf-life of 48 months. III.2 Non-clinical 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. The characteristics of memantine are also reflected in the corresponding sections of SmPC and PL, respectively, and are fully harmonised with the originator Ebixa. Environmental Risk Assessment (ERA) Since Memantin Orion 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. Justification of the absence of an ERA was provided by the applicant. III.3 Clinical aspects Pharmacokinetics To support this application, the applicant has submitted as report two bioequivalence studies. Memantin Orion, DE/H/3653/ /DC Public AR Page 5/7

6 Both studies were randomized, open-label, two treatment, two period, two sequence, single dose, crossover bioquivalence studies under fasting conditions. In Study 1836/09 Memantine Hydrochloride 10 mg tablets (test formulation, i.e. the intended 10 mg tablets) were compared to Ebixa 10 mg tablets of Lundbeck, Germany (reference formulation). In Study 1837/09 Memantine Hydrochloride 20 mg tablets (test formulation, i.e. the intended 20 mg tablets) were compared to Ebixa 20 mg tablets of Lundbeck, Germany (reference formulation). The mean pharmacokinetic characteristics of Memantine after treatment with Test and Rererence products were as follows: Study No 1836/09: Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median, range) Treatment AUC 0-72 C max h *ng/ml ng/ml Test (±91.026) (±2.795) Reference (±83.875) (±2.242) *Ratio (90% CI) t max h (±2.051) (±2.342) *ln-transformed values Study No 1837/09: Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median, range) Treatment AUC 0-72 C max h *ng/ml ng/ml Test (± ) (±3.311) Reference (± ) (±3.866) *Ratio (90% CI) t max h (±1.977) (±1.495) *ln-transformed values The 90% confidence intervals for the 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 submitted bioequivalence studies show that the intended Memantine 10 mg tablets are bioequivalent with Ebixa 10 mg and that the intended Memantine 20 mg tablets are bioequivalent with Ebixa 20 mg. 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 Orion, DE/H/3653/ /DC Public AR Page 6/7

7 Clinical safety No new data were submitted. It is considered that the safety profile of the intended Memantin tablets will be comparable to that of other identical or similar products which are currently licensed and marketed in Europe. User Testing In the first as well as in the second round a satisfactory test outcome was reached for each question, thus the condition 90% of all participants are able to find the information requested within the PIL and 90% of all participants can show that they understand and can act upon it is fulfilled. This readability testing indicates that the applied PL of Memantine hydrochloride containing tablets is easy to understand and written in a comprehensible manner. The leaflet is readable and the users are able to act on the information that it contains. No changes of the PL were required. Pharmacovigilance system Description of Pharmacovigilance System The applicant has provided documents that set out a detailed description of the Orion system of pharmacovigilance (Version 4.0 dated 21 July 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 (lst 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 Based on the submitted bioequivalence studies the intended Memantine tablets are considered bioequivalent with Ebixa 10 mg and 20 mg tablets, respectively. The application contains an adequate review of published clinical data and the bioequivalence has been shown. The PI has been updated in accordance with the PI of the reference product (Ebixa) and is acceptable. The application is approved. For intermediate amendments see current product information. Memantin Orion, DE/H/3653/ /DC Public AR Page 7/7