Decentralised Procedure. Public Assessment Report

Transcription

1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Rivastigmin Tiefenbacher 1.5/ 3/ 4.5/ 6 mg Hartkapseln Niddastig 1.5/ 3/ 4.5/ 6 mg Hartkaspeln Rivastigmine hydrogen tartrate DE/H/ / /DC Applicant: Alfred E. Tiefenbacher GmbH &Co KG STADApharm GmbH Reference Member State DE Date of this report: The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health.

2 TABLE OF CONTENTS I INTRODUCTION 5 II EXECUTIVE SUMMARY 5 II.1 PROBLEM STATEMENT 5 II.2 ABOUT THE PRODUCT 5 II.3 GENERAL COMMENTS ON THE SUBMITTED DOSSIER 5 II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES. 6 III SCIENTIFIC OVERVIEW AND DISCUSSION 6 III.1 QUALITY ASPECTS 6 III.2 NON-CLINICAL ASPECTS 7 III.3 CLINICAL ASPECTS 8 IV BENEFIT RISK ASSESSMENT 9 2/9

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product 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 for the Decentralised Procedure Reference Member State: Member States concerned: Applicant (name and address) Names and addresses of manufacturers responsible for batch release in the EEA Rivastigmin Tiefenbacher 1.5/3/4.5/6 mg Hartkapseln Rivastigmine hydrogen tartrate N06DA03 Capsules, hard; 1.5, 3, 4.5 and 6 mg DE/H/1786/ /DC DE PL Alfred E. Tiefenbacher GmbH & Co. KG Van-der-Smissen-Str. 1, Hamburg, Germany 1. Medinsa S.A. Solana 26, Torrejon de Ardoz, Madrid, Spain 2. Jelfa S.A. Wincentego Pola 21, Jelenia Góra, Poland 3/9

4 Proposed name of the medicinal product 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 for the Decentralised Procedure Niddastig 1.5/3/4.5/6 mg Hartkapseln Rivastigmine hydrogen tartrate N06DA03 Hard Capsules, 1.5 mg, 3 mg, 4.5 mg, 6 mg DE/H/1787/ /DC Reference Member State: Member States concerned: Applicant (name and address) Names and addresses of manufacturers responsible for batch release in the EEA DE AT, BE, DK, ES FI, FR, LU, NL, NO, PL, PT, RO, SE STADApharm GmbH Stadastr. 2-18, Bad Vilbel, Germany STADApharm GmbH Stadastr. 2-18, Bad Vilbel, Germany Aliud Pharma GmbH & Co. KG Gottlieb-Daimler-Str. 19, Laichingen, Germany Centrafarm Services B.V. Nieuwe Donk 9, NL-4879 AC Etten-Leur,The Netherlands Eurogenerics N.V. Heizel Esplanade b22, 1020 Brussel, Belgium Genus Pharmaceuticals Ltd. Benham Valence, Speen, Newbury, Berkshire, RG20 8LU United Kingdom STADA Production Ireland Ltd. Waterford Road, Clonmel, Co. Tipperary, Ireland PharmacCoDane ApS Marielundvej 46 A, 2750 Herlev, Denmark STADA Arzneimittel GmbH Muthgasse 36/2, A-1190 Vienna, Austria Medinsa S.A. Solana 26, Torrejon de Ardoz, Madrid, Spain Jelfa S.A. Wincentego Pola 21, Jelenia Góra, Poland 4/9

5 I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Rivastigmin Tiefenbacher 1.5/3/4.5/6 mg hard capsules and Niddastig 1.5/3/4.5/6 mg hard capsules, in the treatment of - Symptomatic treatment of mild to moderately severe Alzheimer s dementia. - Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson s disease. is approved. II EXECUTIVE SUMMARY II.1 Problem statement This decentralised application concerns a generic version of rivastigmine hydrogen tartrate, under the trade names Rivastigmin Tiefenbacher 1.5/ 3/ 4.5/ 6 mg hard capsules and Niddastig 1.5/3/4.5/6 mg hard capsules. In this Assessment Report, the name Rivastigmin Tiefenbacher 1.5/ 3/ 4.5/ 6 mg hard capsules is used. The originator product is EXELON 1.5, 3, 4.5 and 6 mg capsules, hard, by Novartis Europharm Limited, United Kingdom, registered in the European Union since May 12th, DE/H/1786/ /DC With Germany as the Reference Member State in this Decentralised Procedure, Alfred E. Tiefenbacher GmbH & Co. KG, Germany, is applying for the Marketing Authorisations for Rivastigmin Tiefenbacher in PL. DE/H/1787/ /DC With Germany as the Reference Member State in this Decentralised Procedure, STADApharm GmbH, Germany, is applying for the Marketing Authorisations for Rivastigmin Stada in AT, BE, DK, ES FI, FR, LU, NL, NO, PL, PT, RO, SE. II.2 About the product Rivastigmine is a centrally acting reversible inhibitor of acetylcholine- and butyrylcholinesterase of the carbamate type which facilitates cholinergic neurotransmission by increasing the amount of available acetylcholine. Compared to other inhibitors of acetylcholinesterases, like tacrine or donepezil, rivastigmine is characterised by a longer duration of action. Rivastigmine is indicated in symptomatic treatment of mild to moderately severe Alzheimer s dementia and in symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson s disease. II.3 General comments on the submitted dossier The dossier is of generally satisfactory quality. 5/9

6 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. The RMS assures that acceptable standards of GMP are in place for the manufacture and assembly of this product at all proposed manufacturing, packaging and alternative packaging sites for Rivastigmin Tiefenbacher 1.5/3/4.5/6 mg hard capsules and Rivastigmin STADA 1.5/3/4.5/6 mg hard capsules. All manufacturing sites are within the Community. The RMS has accepted copies of current manufacturer authorisations as certification that acceptable standards of GMP are in place at those sites or GMP Certificates both issued by the inspection services of the competent authorities. III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Two Active Substance Master Files (ASMF) for Rivastigmine hydrogen tartrate from two active substance manufacturers are submitted. Rivastigmine hydrogen tartrate is not included in a Pharmacopoeia. The chemical-pharmaceutical documentation and Expert Report in relation to Rivastigmine hydrogen tartrate are of sufficient quality in view of the present European regulatory requirements for both manufacturers. Rivastigmin Interquim: The manufacturing process of Rivastigmine Tartrate used by active substance manufacturer no.1 is an asymmetric process which is based on the chiral pool approach. The manufacturing process starts from a well defined chiral starting material which is successively transformed to give the final drug substance while retaining its defined chirality. The route of synthesis is adequately characterised. The structure of rivastigmine hydrogen tartrate has been confirmed by analytical evidence like elemental analysis and by spectroscopic analyses (IR, 1 H-NMR, 13 C-NMR, MS and XRD). The main impurity originating as by-product and possible hydrolysis product is (3[1(S)-Dimethylamino-ethyl]phenol L- tartrate. The limit for the R Isomer has been set as NMT 0.15%. The control tests and specifications for drug substance product are adequately drawn up. The analytical methods have been sufficiently validated. Batch analysis data of three consecutive commercial batches of rivastigmine hydrogen tartrate have been presented. Stability data are presented for three consecutive commercial scale batches of rivastigmine hydrogen tartrate drug substance manufactured in October 2007 (batch sizes , and kg) at real time (25 C/60 % RH) and accelerated conditions (40 C/75 % RH) for 6 month. The samples were stored in small containers identical to the market container. No significant changes were observed for any of the tested parameters throughout storage. Based on the available data the proposed retest period of 12 month for rivastigmine hydrogen tartrate is acceptable. Rivastigmin Erregiere: The manufacturing process of Rivastigmine Tartrate used by active substance manufacturer no. 2 is a 8 step synthesis starting from 3-hydroxyacetophenone and N,N-dimethylformamide. The resolution of the racemic rivastigmine base is performed by using an optically pure resolving reagent. The route of synthesis is adequately characterised. The structure of rivastigmine hydrogen tartrate has been confirmed by analytical evidence like elemental analysis and by spectroscopic analyses (IR, 1 H-NMR, 13 C-NMR, MS and XRD). The main impurity originating as by-product and possible hydrolysis product is 3-[l dimethylamino)ethyl]phenyl tartrate acid. The limit for the R Isomer has been set as NMT 0.3%. The control tests and specifications for drug substance product are adequately drawn up. The analytical methods have been sufficiently validated. Batch analysis data of three batches of rivastigmine hydrogen tartrate have been presented. Stability data are presented for three consecutive batches of rivastigmine hydrogen tartrate drug substance manufactured in March 2006 (batch sizes 3.20, 4.0 and 4.8 kg) at real time (25 C/60 % RH) for 24 month and accelerated conditions (40 C/75 % RH) for 6 month. The samples were stored in small containers identical to the market container. No significant changes were observed for any of the 6/9

7 tested parameters throughout storage. Based on the available data the proposed retest period of 36 month for rivastigmine hydrogen tartrate is acceptable. Forced degradation studies with rivastigmine hydrogen tartrate were performed by both manufacturers by treatment with heat, under acidic and alkaline conditions, under oxidizing conditions as well as under light stress conditions. The results indicate that the assay and chromatographic purity method are stability indicating. Drug Product The development of the product 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 data from three batches of each capsule strength with batch size of capsules are provided. 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. Stability results under long term conditions up to 24 month and under accelerated conditions up to six month of two batches of each strength with the drug substance from active substance manufacturer no.2 and one batch (1.5 mg and 6 mg strength) with drug substance from a third active manufacturer which is not included in the dossier have been presented. The batches were manufactured by AET and packed in Alu/Alu blisters. Additionally, stability results under long term and accelerated conditions for 6 month and under intermediate conditions up to 3 month of batches manufactured by Medsina (1.5 mg and 6 mg strength) with the drug substance from active substance manufacturer no.1 have been provided. One batch is packed in Alu/Alu blisters and the other one in PVC/PVdC blisters. All results comply with the specifications. Results of photostability studies which indicate that Rivastigmine capsules have satisfactory stability when direct exposed to light have been presented. Results of bulk stability studies on two batches of each strength packed in HDPE containers stored for six month has been presented. No changes were observed. On the basis of the presented results a shelf-life of 36 months is proposed for Rivastigmine capsules 1.5/3/4.5/6 mg packed in Alu/Alu blisters. The proposed shelf-life without storage precautions is regarded acceptable. A shelf-life of 6 months is accepted for Rivastigmine capsules 1.5/3/4.5/6 mg packed in PVC/PVdC blisters with the storage condition Do not store above 30 C. The capsules can be stored in bulk (HDPE containers) for a period of six months. III.2 Non-clinical aspects Pharmacology Rivastigmine is a centrally acting, non-competitive inhibitor of acetylcholine- and butyrylcholinesterase. It interferes with degradation of acetylcholine by these enzymes thereby facilitating cholinergic neurotransmission. Rivastigmine shows greater selectivity for the hippocampus and cortex areas of the brain than for the striatum or brainstem and is also less active in the heart and skeletal muscle. In addition, rivastigmine has no affinity for dopaminergic, opioid, muscarinic, nicotinic and α- and β-adrenergic receptors. This specificity suggests a lower propensity of this drug to cause severe side effects like respiratory paralysis and was confirmed in safety pharmacological investigations in rodents, where rivastigmine dose-dependently increased central effects like tremor and hypothermia with no influence on peripheral salivation and lacrimation. However, effects on respiration were observed in toxicity studies in dogs (see below). In several preclinical models of Alzheimer s disease rivastigmine ameliorated learning deficits and memory impairments and conferred neuroprotection after transient cerebral ischemia. 7/9

8 Pharmacokinetics Rivastigmine is quickly and almost completely absorbed following oral administration. Maximum plasma concentrations are reached after 0.25 to 1.7 h. Oral bioavailability is variable and is highest in dogs and lowest in rats (43 % vs. 3 %, respectively). It tends to increase with dose due to a saturable first-pass metabolism. In humans, the bioavailability is about 36 %. Rivastigmine shows fast distribution into tissues reaching highest levels in liver, kidney and salivary glands. Moreover, the substance readily penetrates the brain, crosses the placenta and also distributes into milk. Rivastigmine is rapidly cleared in all species (approximately 12 l/h) with a terminal half-life of less than 1 h. The metabolic pattern is qualitatively similar across species and involves decarbamylation, sulphate conjugation and N-demethylation. The metabolites have very little inhibitory activity against acetylcholinesterase and are at least tenfold less potent than the parent compound. Renal elimination of rivastigmine dominates and is nearly completed within 24 h after drug administration. Toxicology Effects of rivastigmine in toxicology studies were mainly associated with an exaggerated pharmacological action of the drug, i.e. excessive cholinergic stimulation. No target organ toxicity was identified after repetitive dosing in mice (13 weeks), rats (up to 52 weeks), mini pigs (4 weeks), dogs (up to 52 weeks) and monkeys (2 weeks), but gastrointestinal (e.g. diarrhoea) and respiratory effects were prominent in dogs. The NOAEL in rodents and dogs was around 0.11 mg/kg, i.e. less than the maximum recommended human dose. Rivastigmine is considered to have no genotoxic and carcinogenic potential. Nevertheless, it should be noted that a slight increase in chromosomal aberrations were found at high concentrations in the human lymphocyte test and that the exposure to rivastigmine was lower in carcinogenicity studies in rodents compared to the intended human exposure. Rivastigmine prolonged the gestation time, but did not affect fertility or embryo-foetal development in rats and rabbits, except at maternally toxic doses where increased embryonic resorptions, postimplantation losses, neonatal mortality and reduced postnatal body weights were detected. Altogether, rivastigmine is a substance with well-known pharmacodynamic, pharmacokinetic and toxicological properties. From a preclinical point of view, no new information is available which would change the positive risk/benefit assessment of the product. The applicant harmonised the instructions for drug use during pregnancy and lactation of SPC and PL in line with the originator product Exelon. Hence, there are no non-clinical objections against approval of Rivastigmin Tiefenbacher 1.5/ 3/ 4.5/ 6 mg hard capsules and Rivastigmin Stada 1.5/3/4.5/6 mg hard capsules. III.3 Clinical aspects Pharmacokinetics To support the application, the applicant has submitted two bioequivalence studies (with rivastigmine 1.5mg and 6 mg capsules): A) Open label, two way, crossover, block randomised, single dose bioequivalence study of Rivastigmine 1.5 mg hard capsules (test formulation) vs. equal dose of a marketed formulation in healthy male and female subjects under fed conditions Study No: RIV-BESD-04-TIE/07 Investigators: I. Mihetiu M.D. and M. Creteanu M.D. Study centre(s): Sf. Ioan Cel Nou Emergency Hospital, 1 December 1981 Avenue 21, 5800 Suceava, Romania B) Open label, two way, crossover, block randomised, single dose bioequivalence study of Rivastigmine 6.0 mg hard capsules (test formulation) vs. equal dose of a marketed formulation in healthy male and female subjects under fed conditions - Study No: RIV-BESD-05-TIE/07 Investigators: I. Mihetiu M.D. and M. Creteanu M.D. Study centre(s): Sf. Ioan Cel Nou Emergency Hospital, 1 December 1981 Avenue 21, 5800 Suceava, Romania 8/9

9 Study results indicated the investigated products (1.5 mg resp. 6mg rivastigmine) to be bioequivalent to the reference products. The 90% confidence intervals for test/reference ratios of AUC 0-t, AUC 0- and C max were completely within the acceptance range of %. Based on the submitted bioequivalence studies (with rivastigmine 1.5 gm resp. 6 mg) and the perceived pharmacokinetic parameters of rivastigmine, the reference products and test products are bioequivalent. The results of the BE-studies could be extrapolated to the other strengths applied for. Pharmacovigilance system DE/H/1786/ /DC Pharmacovigilance system Alfred E. Tiefenbacher, Version 04 effective as of 1 December 2007 incl. Appendices 1-8, Description of Pharmacovigilance System The applicant has provided documents that set out a detailed description of the system of pharmacovigilance. 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 RMS considers that 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. DE/H/1787/ /DC Pharmacovigilance system of STADA Arzneimittel AG, Version 03 dated 02 July 2008 Description of Pharmacovigilance System The applicant has provided documents that set out a detailed description of the system of pharmacovigilance (Version 03 dated 02 July 2008). 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 RMS considers that 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. IV BENEFIT RISK ASSESSMENT Based on the submitted bioequivalence studies (with rivastigmine 1.5 mg resp. 6 mg) and the perceived pharmacokinetic parameters of rivastigmine, the reference products and test products are bioequivalent. The results of the BE-studies could be extrapolated to the other strengths applied for, i.e. 3 mg resp.4.5 mg strength. The applications are approved. 9/9