Decentralised Procedure. Public Assessment Report. Memantinhydrochlorid Alchemia 5/10/15/20 mg Filmtabletten. Memantine hydrochloride

Transcription

1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Memantinhydrochlorid Alchemia 5/10/15/20 mg Filmtabletten Memantine hydrochloride DE/H/3663/ /DC Applicant: Alchemia Limited 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 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 Alchemia 5/10/15/20 mg Filmtabletten Memantine hydrochloride N06DX01 Film coated tablet ; 5/10/15/20 mg DE/H/3663/ /DC DE IS Alchemia Limited 5th Floor, 86 Jermyn Street, UK-London, SW1Y 6AW, United Kingdom Actavis Ltd. BLB016, Bulebel Industrial Estate Zejtun ZTN 3000, Malta Actavis hf. Reykjavikurvegur 78, IS- 220 Hafnarfjörður, Iceland 3/8 Public AR

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Memantinhydrochlorid Alchemia 5/10/15/20 mg Filmtabletten in the treatment of patients with moderate to severe Alzheimer s disease, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement For generic application this section is not applicable. 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 This decentralised application concerns a generic version of memantine hydrochlodride, under Memantinhydrochlorid Alchemia 5/10/15/20 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, Alchemia Limited is applying for the Marketing Authorisations for Memantine Alchemia and IS. 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. 4/8 Public AR

5 III. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects 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 5 years has been set. 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 filmcoated tablets are a straigtforward 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 non eligible for direct UV-spectromteric methods. The applicant has chosen to perform the assay and dissolution with refractomety detection. 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. The drug product showed some degradation trends, in particular under intermediate storage conditions, but stays within the proposed limits for assay and impurities. The stability data justify the shelf-life of 24 months if stored below 25 C. III.2 Nonclinical aspects The pharmacological and toxicological characteristics of memantine are well known and have been superficially presented in the non-clinical overview based on pertinent literature. The applicant provided an adequate discussion on impurities in the nonclinical overview. The 0.5% and 0.2% limits for specified and unspecified impurities respectively, correspond to the qualification and identification thresholds in Note for Guidance CPMP/ICH/2738/99 on Impurities in New Drug Products. The instructions on use of the active substance during pregnancy and lactation and the preclinical safety data contained in the proposed SmPC and PL, respectively, have been harmonised with the most recent version of the texts approved for the reference product Ebixa (EMEA/H/C/ IB/0074/G) and are therefore considered adequate. 5/8 Public AR

6 Environmental Risk Assessment (ERA) Since Memantinhydrochlorid Alchemia 5/10/15/20 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 this application, the applicant has submitted one bioequivalence study: A randomized, Open Label, Two Treatment, Two Period, Two Sequence, Single Dose, Crossover, Bioequivalence Study of Memantine Hydrochloride 20 mg Film Coated Tablets of Actavis Group PTC ehf, Iceland and Ebixa (Memantine Hydrochloride) 20 mg Film Coated Tablets of Lundbeck A/S, Denmark, in healthy adult subjects, under fasting conditions, study code 1985/09. The aim of this study was to investigate the relative bioavailability of a new generic tablet of MEMANTINE 20 mg film-coated tablets (test preparation) manufactured by Actavis Group PTC ehf and to compare it to EBIXA 20 mg film-coated tablets (reference preparation) marketed by LUNDBECK A/S, Denmark. Results: Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max median, range) Treatment AUC 0-72 ng/ml/h AUC 0- ng/ml/h Test ± ± ±1.72 Reference ± ± ±1.68 *Ratio (90% CI) ( ) ( ) AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC 0-72h can be reported instead of AUC 0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0- Area under the plasma concentration curve extrapolated to infinite time. AUC 0- does not need to be reported when AUC 0-72h is reported instead of AUC 0- t C max t max Maximum plasma concentration Time until Cmax is reached *ln-transformed values The 90% confidence intervals for the geometric mean ratios of Test to Reference formulations for AUC O-72 and C max were within the bioequivalence acceptance range of 80 to 125%. According to the guidelines the bioequivalence study was performed with the highest strength. The choice of Ebixa 20 mg film-coated-tablets by H. Lundbeck A/S, from the Denmark market is acceptable as well. A justification for a biowaiver was provided for the 5,10 and 15 mg strength according to the relevant Guideline and is accepted. C max ng/ml t max h 6/8 Public AR

7 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 Alchemia film-coated 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 and second round of testing all 10 (100%) participants traced correct sections and answered correctly all 17 questions. In the qualitative evaluation some questions were located with little difficulties, they were classified as easy instead of very easy. But in the qualitative evaluation of understanding all questions were graded as very easy. Summarizing the quantitative evaluation in both rounds all questions met the success criteria of 90% of the participants being able to locate the requested information, and of those, 90% being able to give the correct answer, to indicate that they understood the information presented. Thus these results are in line with the Guideline on the Readability of the Labelling and Package Leaflet of Medicinal Products for Human Use. In the readability testing no conclusive trends could be found across testing where participants failed to locate or understand a given point but were rather only isolated incidents. Summarizing the results of the readability testing the package leaflet can be judged as understandable and comprehensive. In the additional questions the participants gave a positive feed back of the package leaflet s quality. Based on the results of this user testing the User Test is approvable. Pharmacovigilance system Description of Pharmacovigilance System The applicant Alchemia Ltd. has provided documents that set out a detailed description of the Alchemia Ltd. system of pharmacovigilance (Version 1.03 dated 01 July 2011, contains the Panacea Pharma Projects Ltd. (PPP) system DDPS Version 3 dated 01 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. 7/8 Public AR

8 IV. BENEFIT RISK ASSESSMENT Based on the submitted bioequivalence study Memantine Alchemia 20 mg film-coated tablets are considered bioequivalent with Ebixa 20 mg film-coated tablets. The results of study 1985/09 with Memantine 20 mg formulation CAN be extrapolated to the strength 5, 10, 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. 8/8 Public AR