European Medicines Agency Evaluation of Medicines for Human Use ASSESSMENT REPORT FOR authorised Rivastigmine Teva International Non proprietary Name: rivastigmine longer no Procedure No. EMEA/H/C/001044 Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted. product Medicinal 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 85 45 E-mail: [email protected] http://www.emea.europa.eu European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged. TABLE OF CONTENTS 1. BACKGROUND INFORMATION ON THE PROCEDURE ........................................... 3 1.1 Submission of the dossier ........................................................................................................ 3 1.2 Steps taken for the assessment of the product.......................................................................... 4 2. SCIENTIFIC DISCUSSION................................................................................................. 5 2.1 Introduction.............................................................................................................................. 5 2.2 Quality aspects......................................................................................................................... 5 2.3 Non-Clinical aspects ................................................................................................................ 8 2.4 Clinical Aspects ....................................................................................................................... 8 2.5 Pharmacovigilance................................................................................................................. 14 2.6 Overall conclusions, benefit/risk assessment and recommendation ...................................... 15 authorised longer no product Medicinal Rivastigmine Teva Page 2/16 1. BACKGROUND INFORMATION ON THE PROCEDURE 1.1 Submission of the dossier The applicant Teva Pharma B.V submitted on 03 July 2008 an application for Marketing Authorisation to the European Medicines Agency (EMEA) for Rivastigmine Teva, in accordance with the centralised procedure falling within the scope of the Annex to Regulation (EC) 726/2004 under Article 3 (3) – ‘Generic of a Centrally authorised product’. The application legal basis refers to Article 10(1) at the time of the opinion. The chosen reference product is: ■ Reference medicinal product which is or has been authorised in accordance with the community provisions in force for not less than 6/10 years in the EEA: . Product name, strength, pharmaceutical form: Exelon 1.5mg hard capsules, Exelon 3mg hard capsules, Exelon 4.5mg hard capsules, Exelon 6mg hard capsules . Marketing authorisation holder: Novartis Europharm Limited . First authorisation: 12/05/98 . Member State (EEA)/Community: EU registration authorised ■ Reference medicinal product authorised in the Community/Member State where the application is made: . Product name, strength, pharmaceutical form: Exelon 1.5mg hard capsules, Exelon 3mg hard capsules, Exelon 4.5mg hard capsules, Exelon 6mg hard capsules . Marketing authorisation holder: Novartis Europharm Limited . Marketing authorisation number(s): EU/1/98/066/001-3, longerEU/1/98/066/004-6, EU/1/98/066/007-9, EU/1/98/066/010-12, EU/1/98/066/014-16, EU/1/98/066/017. ■ Medicinal Product used for bioequivalence studyno (where applicable) . Product name, strength, pharmaceutical form: Exelon 1.5 mg hard capsules, Exelon 6 mg hard capsules . Marketing authorisation holder: Novartis Europharm Limited . Member State of source: UK Rapporteur : Dr. Broich Pharmacovigilance Rapporteur product: Dr. Demolis Scientific Advice: The applicant did not seek scientific advice at the CHMP. Licensing status: The product was not licensed in any country at the time of submission of the application. Medicinal Rivastigmine Teva Page 3/16 1.2 Steps taken for the assessment of the product The application was received by the EMEA on 03 July 2008. The procedure started on 23 July 2008. The Rapporteur's first Assessment Report was circulated to all CHMP members on 10 October 2008. During the meeting on 17 - 20 November 2008, the CHMP agreed on the consolidated List of Questions to be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 20 November 2008. The applicant submitted the responses to the CHMP consolidated List of Questions on 18 December 2008. The Rapporteur circulated the Joint Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 30 January 2009. During the meeting on 16 – 19 February 2009, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a Marketing Authorisation to Rivastigmine Teva on 19 February 2009. The applicant provided the letter of undertaking on the follow-up measures to be fulfilled post-authorisation on 10 February 2009. authorised longer no product Medicinal Rivastigmine Teva Page 4/16 2. SCIENTIFIC DISCUSSION 2.1 Introduction Rivastigmine Teva 1.5 mg, 3 mg, 4.5 mg, 6 mg hard capsules is a generic medicinal product containing rivastigmine hydrogen tartrate as the active substance. The reference product Exelon 1.5 mg, 3 mg, 4.5 mg and 6 mg hard capsules has been centrally authorised on 12 May 1998. Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer’s disease and Parkinson’s disease. Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer’s disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated authorisedby rivastigmine was similar to that of AChE. The safety and efficacy of rivastigmine has been demonstrated in randomised, placebo-controlled trials in patients with Alzheimer’s disease. A summary of these studies may be found in the EPAR of Exelon. The indication proposed for Rivastigmine Teva is the samelonger as for the authorized Reference medicinal product Exelon. Rivastigmine Teva is indicated for the treatment ofno mild to moderately severe Alzheimer’s dementia and treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s disease. Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient. product 2.2 Quality aspects Introduction Rivastigmine Teva is presented as hard gelatin capsules containing 2.4 mg, 4.8 mg, 7.2 mg and 9.6 mg of rivastigmine hydrogen tartrate as active substance, corresponding respectively to 1.5 mg, 3 mg, 4.5 mg and 6 mg of rivastigmine. The other ingredients are microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, magnesium stearate, purified water, gelatin capsules and ImprintingMedicinal Inks (shellac glaze-45% in ethanol, iron oxide black, N-butyl alcohol, Isopropyl alcohol, propylene glycol, ammonium hydroxide). The hard gelatin capsules are marketed in blister (PVC/alu) packed in cartons or in bottles (HDPE) with a white polypropylene cap. It was verified that the pack sizes are consistent with the posology and treatment duration as approved in the summary of product characteristics. Rivastigmine Teva Page 5/16 Active substance The drug substance is Rivastigmine hydrogen tartrate and its chemical name is (S)-N-ethyl-3- [1- (dimethyl amino) ethyl] - N-methyl phenyl carbamate hydrogen tartrate according to the IUPAC nomenclature. Rivastigmine hydrogen tartrate white to off-white fine crystalline powder, very hygroscopic and deliquescent. According the information described in the literature this active substance is very soluble in water, in ethanol and acetonitrile, slightly soluble in n-octanol and slightly soluble in ethyl acetate. It was noticed that rivastigmine hydrogen tartrate has one chiral centre. Therefore, it is optically active. Manufacture Rivastigmine hydrogen tartrate is synthesised in three reactions steps. The manufacturing process has been adequately described. Critical parameters have been identified and adequate in-process controls included. Specifications for starting materials, reagents, and solvents have been provided. Adequate control of critical steps and intermediates has been presented. The active substance is purified by filtration. The purified active substance is finally packed in a double polythene bag enclosed within a triple laminated high barrier bag, which is