Decentralised Procedure. Public Assessment Report. Memantinhydrochlorid PharOS 10/20 mg Schmelztabletten. Memantine hydrochloride DE/H/3608/ /DC

Transcription

1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Memantinhydrochlorid PharOS 10/20 mg Schmelztabletten Memantine hydrochloride DE/H/3608/ /DC Applicant: PharOS Pharmaceutical Oriented Services Ltd, Greece Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/8 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 /8 Public AR

3 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 ADMINISTRATIVE INFORMATION Memantinhydrochlorid PharOS 10/20 mg Schmelztabletten Memantine hydrochloride N06DX01 Orodispersible tablet DE/H/3608/ /DC DE MT withdrawn PharOs - Pharmaceutical Oriented Services Ltd. Lesvoustr. (end), Thesi Loggos Industrial Zone, Metamorfossi Attikis, Greece Genepharm S.A. 18 km Marathon Avenue, Pallini Attikis, Greece 3/8 Public AR

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Memantinhydrochlorid PharOS 10/20 mg Schmelztabletten, 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 generic versions of memantine hydrochloride, under the trade name Memantinhydrochlorid PharOS 10/20 mg Schmelztabletten. 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/pump actuation, oral solution) by Merz Pharmaceuticals GmbH and H. Lundbeck A/S, respectively, registered simultaneously in the EU via the centralised procedure since 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, PharOS Pharmaceutical Oriented Services Ltd, Greece, is applying for the Marketing Authorisations for Memantinhydrochlorid PharOS 10/20 mg Schmelztabletten in MT as Concerned Member State. However on Day 106 of this procedures, the applicant decided to withdraw the application in Malta. II.2 About the product Memantine hydrochlodride 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 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. 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. 4/8 Public AR

5 The laboratory was GLP-certified by the local authorities. According the Applicant, the bioequivalence study took place under GCP and GLP conditions. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The chemical-pharmaceutical documentation and Quality Overall Summary in relation to product are of sufficient quality in view of the present European regulatory requirements. The control tests and specifications for drug substance product are adequately drawn up. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The active substance general properties are described detailed, the synthesis and reaction pathway is described briefly well. Reprocessing, reworking and batch blending has been declared fully. The micronisation of the active substance neither is part of the manufacturing, nor part of the specification. The elucidation of structure and impurities possible occurring is provided. Analytical methods employed are described in detail, covering procedures, apparatus, sample and standard preparation, relevant sample chromatograms are presented. The methods underwent validation works generally sufficiently. Polymorphism of the substance has been confirmed, as well as the production of definitive Form-I had been demonstrated by analytical measures. Genotoxic discussion has been demonstrated and measures taken were justified. 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. The specification has been set up justified. Batch analyses presently display that the manufacturing process is capable the substance in consistent quality. Reference standards were established after sufficient extensive quality assessment. The container closure system is chosen carefully justified in accordance to the relevant regulations. Data on stability studies at accelerated and intermediate long term conditions confirm product stability. Drug Product The data submitted on the quality of the drug product are acceptable and sufficient to guarantee the quality of memantine orodispersible tablets and reflects well researched and well defined products. 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 plausible. 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 partially guarded by the batch release data of the finished product. The drug product is rather stable. A shelf-life of 18 months is accepted. III.2 Nonclinical aspects The pharmacological and toxicological characteristics of memantine are well known and have been extensively summarised in the non-clinical overview. The proposed SmPC and PL generally reflect the established pharmacological and toxicological characteristics of memantine in an appropriate manner. 5/8 Public AR

6 Environmental Risk Assessment (ERA) Since Memantinhydrochlorid PharOS 10/20 mg Schmelztabletten 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 the application, the applicant has submitted as report one bioequivalence study: Study number: 1458; by Genepharm (Europe) Trading Limited. Title: A Single-Dose, Randomized, Open-Label, Crossover, Pivotal, Comparative Bioavailability Study of Memantine 20 mg Orodispersible Tablets (Genepharm (Europe) Trading Limited) and Ebixa 20 mg Filmcoated Tablets (H. Lundbeck A/S.) in Healthy Male and non-pregnant Female Volunteers under Fasting Conditions. The concentration of memantine was measured in each plasma sample collected over a 72-hour interval after dosing in each period. Pharmacokinetic parameters C max, T max, AUC 0-72 were estimated based on memantine plasma levels for subjects included in the statistical analysis. The clinical conduct of this study (1458) was performed in compliance with Good Clinical Practice (GCP). To establish bioequivalence, the calculated 90% confidence interval for the ratio of geometric means for AUC 0-72 and C max for memantine should fall within 80.00% %. Table 1 and 2 Bioequivalence Analysis Results for Plasma Memantine (Study 1458) Table 3 Confidence Interval of Pharmacokinetic Parameters for Plasma Memantine (Study 1458) 6/8 Public AR

7 The Test/Reference ratio of geometric means and the corresponding 90% confidence interval for the AUC 0-72 and the Cmax parameters were entirely contained within the acceptance range of 80.00% %. Therefore, in this study, bioequivalence was demonstrated between Memantine 20 mg Orodispersible Tablets (Genepharm S.A., Greece) and Ebixa 20 mg Film Coated Tablets (H. Lundbeck A/S, Denmark) in normal, healthy male and non-pregnant female volunteers under fasting conditions. A total of 4 mild AEs were experienced by the subjects after taking the Test product. A total of 5 mild AEs were experienced by the subjects after taking the Reference product. No AEs were experienced by the subjects at post-study. No serious adverse events were reported during the conduct of this study. Both the test product and reference product were well tolerated by all subjects. Pharmacodynamics N/A 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 Memantinhydrochlorid PharOS 10/20 mg Schmelztabletten will be comparable to that of other identical or similar products which are currently licensed and marketed in Europe. User Testing The type of test used for the readability user testing of this PIL was a diagnostic evaluation as based upon authority recommendations as well as the guidance outlined by Articles 59(1) and 59(3) of Council Directive 2001/83/EC, Article 63(2) of Directive 2001/83/EC as amended, the MHRA document Always read the leaflet, Getting the best information with every medicine (2005) and the European Commission document Guideline on the readability of the labelling and package leaflet of medicinal products for human use (2009). The readability user testing of the PIL for Memantine hydrochloride orodispersible tablets was conducted between May 30th, 2012 and June 12th, The package leaflet for Memantine hydrochloride orodispersible tablets has been user tested and achieved a satisfactory result according to the criteria stated above. The 1st round of testing showed that, for each question, 100% of participants were able to find the correct information, and 100% of participants were able to answer the questions correctly. The 2nd round of testing showed that, for each question, 100% of participants were able to find the correct information, and 100% of participants were able to answer the questions correctly. 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 Summary is acceptable. 7/8 Public AR

8 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 accepted. 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. Based on the submitted bioequivalence study Memantine 20 mg Orodispersible Tablets (Genepharm (Europe) Trading Limited) is considered bioequivalent with Ebixa 20 mg filmcoated tablets (H. Lundbeck A/S.). The results of study 1458 with the 20 mg formulation can be extrapolated to the other strength 10mg according to the conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section The application contains an adequate review of published clinical data and the bioequivalence has been shown. The application is approved. 8/8 Public AR