Public Assessment Report Decentralised Procedure is Rivastigmine Rosemont 2 mg/ml Oral Solution...

Public Assessment Report

Decentralised Procedure

Rivastigmine Rosemont 2 mg/ml Oral Solution

Procedure No: UK/H/5537/001/DC

UK Licence No: PL 00427/0232

Rosemont Pharmaceuticals Limited

Rivastigmine Rosemont 2 mg/ml Oral Solution UK/H/5537/001/DC

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Lay Summary

Rivastigmine Rosemont 2 mg/ml Oral Solution (rivastigmine hydrogen tartrate)

This is a summary of the public assessment report (PAR) for Rivastigmine Rosemont 2 mg/ml Oral Solution (PL 00427/0232; UK/H/5537/001/DC). It explains how Rivastigmine Rosemont 2 mg/ml Oral Solution was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use Rivastigmine Rosemont 2 mg/ml Oral Solution. For practical information about using Rivastigmine Rosemont 2 mg/ml Oral Solution, patients should read the package leaflet or contact their doctor or pharmacist. What is Rivastigmine Rosemont 2 mg/ml Oral Solution and what is it used for? Rivastigmine Rosemont 2 mg/ml Oral Solution is a ‘generic medicine’. This means that it is similar to a ‘reference medicine’, already authorised in the European Union (EU) called Exelon 2 mg/ml oral solution. Rivastigmine Rosemont 2 mg/ml Oral Solution is used for the treatment of adult patients with mild to moderately severe Alzheimer’s dementia, a progressive brain disorder that gradually affects memory, intellectual ability and behaviour. The oral solution can also be used for the treatment of dementia in adult patients with Parkinson’s disease. How does Rivastigmine Rosemont 2 mg/ml Oral Solution work? Rivastigmine Rosemont 2 mg/ml Oral Solution contains the active substance rivastigmine (as rivastigmine hydrogen tartrate). Rivastigmine belongs to a class of substances called cholinesterase inhibitors. In patients with Alzheimer’s dementia or dementia due to Parkinson’s disease, certain nerve cells die in the brain, resulting in low levels of the neurotransmitter acetylcholine (a substance that allows nerve cells to communicate with each other). Rivastigmine works by blocking the enzymes that break down acetylcholine: acetylcholinesterase and butyrylcholinesterase. By blocking these enzymes, Rivastigmine allows levels of acetylcholine to be increased in the brain, helping to reduce the symptoms of Alzheimer’s disease and dementia associated with Parkinson’s disease. How is Rivastigmine Rosemont 2 mg/ml Oral Solution used? Rivastigmine Rosemont 2 mg/ml Oral Solution should be taken by mouth, using the oral syringe provided to measure the dose. Your doctor will tell you what dose of Rivastigmine Rosemont 2 mg/ml Oral Solution to take. Treatment usually starts with a low dose and the doctor will then slowly increase the dose, depending on the patient’s response to treatment. The highest dose that should be taken is 6 mg twice a day. Please read Section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, and the duration of treatment. The medicine can only be obtained with a prescription.


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How has Rivastigmine Rosemont 2 mg/ml Oral Solution been studied? No additional studies were needed as Rivastigmine Rosemont 2 mg/ml Oral Solution is a generic medicine that is taken orally, as a solution, and contains the same active substance, in the same concentration, as the reference medicine Exelon 2 mg/ml oral solution. What are the possible side effects of Rivastigmine Rosemont 2 mg/ml Oral Solution? Because Rivastigmine Rosemont 2 mg/ml Oral Solution is a generic medicine its benefits and possible side effects are taken as being the same as the reference medicine. For information about side effects that may occur with using Rivastigmine Rosemont 2 mg/ml Oral Solution, please refer to the package leaflet or the Summary of Product Characteristics (SmPC) available on the Medicines and Healthcare products Regulatory Agency website. Why is Rivastigmine Rosemont 2 mg/ml Oral Solution approved? It was concluded that, in accordance with EU requirements, Rivastigmine Rosemont 2 mg/ml Oral Solution has been shown to have comparable quality and to be comparable to Exelon 2 mg/ml oral solution. Therefore, the view was that, as for Exelon 2 mg/ml oral solution, the benefits outweigh the identified risks and it was recommended that Rivastigmine Rosemont 2 mg/ml Oral Solution can be approved for use. What measures are being taken to ensure the safe and effective use of Rivastigmine Rosemont 2 mg/ml Oral Solution? A Risk Management Plan (RMP) has been developed to ensure that Rivastigmine Rosemont 2 mg/ml Oral Solution is used as safely as possible. Based on this plan, safety information has been included in the SmPC and the package leaflet for this product, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients and healthcare professionals will be monitored and reviewed continuously as well.

Other information about Rivastigmine Rosemont 2 mg/ml Oral Solution France, Germany and the UK agreed to grant a marketing authorisation for Rivastigmine Rosemont 2 mg/ml Oral Solution on 23 December 2014. The marketing authorisation in the UK was granted to Rosemont Pharmaceuticals Limited on 21 January 2015. The full PAR for Rivastigmine Rosemont 2 mg/ml Oral Solution follows this summary. For more information about treatment with Rivastigmine Rosemont 2 mg/ml Oral Solution, read the package leaflet or contact your doctor or pharmacist. This summary was last updated in April 2015.


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TABLE OF CONTENTS

I Introduction Page 5 II Quality aspects Page 7 III Non-clinical aspects Page 9 IV Clinical aspects Page 9 V User consultation Page 14 VI Overall conclusion, benefit/risk assessment

and recommendation Page 14

Table of content of the PAR update for

MRP and DCP

Page 16


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I Introduction Based on the review of the data on quality, safety and efficacy, the Member States have granted a marketing authorisation (MA) for the medicinal product Rivastigmine Rosemont 2 mg/ml Oral Solution. The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and France and Germany as Concerned Member States (CMSs). Rivastigmine Rosemont 2 mg/ml Oral Solution is a prescription-only medicine (POM), indicated for the:

- Symptomatic treatment of mild to moderately severe Alzheimer’s dementia, and - Symptomatic treatment of mild to moderately severe dementia in patients with

idiopathic Parkinson’s disease. This application was made under Article 10(1) of Directive 2001/83/EC, as amended, claiming to be a generic medicinal product. The reference medicinal product, which has been authorised in accordance with Community provisions in force for not less than 10 years in the European Economic Area, is Exelon 2mg/ml oral solution; this reference product was authorised to Novartis Europharm Limited on 12 May 1998 via a Centralised procedure (EU/1/98/066/013, EU/1/98/066/018). The medicinal product contains the active substance rivastigmine (as rivastigmine hydrogen tartrate). 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. It is a semi-synthetic derivative of physostigmine and has been used in the treatment of Alzheimer’s in capsule and liquid formulations since 1997. In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated with Parkinson's disease. Rivastigmine has demonstrated significant treatment effects on cognitive (thinking and memory), functional (activities of daily living) and behavioural problems commonly associated with Alzheimer’s and Parkinson's disease dementias and has been used in more than 6 million patients worldwide. No new non-clinical or clinical data were submitted, which is acceptable given that the application is for an oral solution which is a generic medicinal product of an originator product that has been licensed for over 10 years. Since Rivastigmine Rosemont 2mg/ml oral solution 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. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture and assembly of this product.


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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. A Risk Management Plan (RMP) and a summary of the pharmacovigilance system have been provided with this application and are satisfactory. The RMS and CMSs considered that the application could be approved at the end of procedure (Day 210) on 23 December 2014. The marketing authorisation in the UK was granted to Rosemont Pharmaceuticals Limited on 21 January 2015.


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II Quality aspects II.1 Introduction The application is submitted according to Article 10(1) of Directive 2001/83/EC, as amended referring to Exelon 2mg/ml oral solution, (MA holder: Novartis Europharm Limited; EU/H/1/98/066/013, EU/H/1/98/066/018), as the reference medicinal product. This is acceptable. The product is formulated as a clear yellow oral solution containing the active substance rivastigmine (as rivastigmine hydrogen tartrate) at a concentration of 2 mg/ml. The excipients present are sodium benzoate (E211), citric acid monohydrate (E330), sodium citrate (E311), quinoline yellow (E104) and purified water. The oral solution is presented as a 120 ml volume in an amber (type III glass) bottle with a high density polyethylene (HDPE), expanded polyethylene (EPE) - wadded, child resistant closure. The product is supplied with a 0.25 ml graduated, 3 ml capacity polypropylene oral dosing syringe, and low density polyethylene bottle adaptor. II.2 Drug Substance Rivastigmine hydrogen tartrate rINN: Rivastigimine hydrogen tartrate Chemical Name: 3-[(1S)-1-(Dimethylamino)ethyl]phenyl ethyl(methyl)carbamate

hydrogen (2R,3R)-2,3-dihydroxybutanedioate Structure:

Molecular formula: C18H28N2O8 Molecular weight: 400.4 Appearance: White or almost white powder, very hygroscopic, crystalline or fine

crystalline powder Solubility: Very soluble in water, soluble in methanol, very slightly soluble in

ethyl acetate. Rivastigmine hydrogen tartrate is the subject of a European Pharmacopoeia monograph. An Active Substance Master File (ASMF) has been provided by the active substance manufacturer, covering the manufacture and control of the active substance rivastigmine hydrogen tartrate. Synthesis of the drug substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents and these are supported by relevant certificates of analysis.

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Appropriate proof-of-structure data have been supplied for the active pharmaceutical ingredient. All potential known impurities have been identified and characterised. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Satisfactory certificates of analysis have been provided for all working standards. Batch analysis data are provided and comply with the proposed specification. Suitable specifications have been provided for all packaging used to contain the active substance. The primary packaging has been shown to comply with current guidelines concerning contact with food. Appropriate stability data have been generated supporting a suitable retest period when stored in the proposed packaging. II.3 Medicinal Product Pharmaceutical development Formulation development was based on the reference product, and brand leader, Exelon 2 mg/ml oral solution, and the development of a generic product. The choice of excipients is justified and their functions explained. Satisfactory comparative assay and impurity data between Rivastigmine Rosemont 2 mg/ml Oral Solution and the reference product, Exelon 2 mg/ml oral solution, has been provided that show both products are comparable. All the excipients used in the manufacture of the proposed formulation, with the exception of quinoline yellow, comply with their respective European Pharmacopoeia monographs. Quinoline yellow is controlled by a suitable in house specification and complies with Commission Directive (EU) No 231/2012 as amended, which lays down specific purity criteria concerning colours for use in foodstuffs. Satisfactory certificates of analysis have been provided for all excipients showing compliance with their proposed specifications. None of the excipients used contain material of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these excipients.

Manufacture of the product A satisfactory batch formula has been provided for the manufacture of the finished product, together with an appropriate account of the manufacturing process. The manufacturing process has been validated with three production scale batches and results are satisfactory. Finished Product Specification The finished product specification is satisfactory. Test methods have been described that have been adequately validated, as appropriate. Batch data have been provided from three


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batches that comply with the release specification. Certificates of analysis have been provided for all working standards used. Stability of the product Stability studies were performed in accordance with current guidelines on batches of the finished product, packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 18 months unopened and 1 month once opened, with special storage conditions of “Do not store above 30°C” and “Do not refrigerate or freeze”. Suitable post approval stability commitments have been provided. II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of a marketing authorisation is recommended. III Non-clinical aspects The pharmacodynamic, pharmacokinetic and toxicological properties of rivastigmine hydrogen tartrate are well-established. As rivastigmine hydrogen tartrate is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. An overview based on a literature review is, thus, appropriate. The applicant’s overview has been written by an appropriately qualified person and is adequate. Suitable justification has been provided for non-submission of an Environmental Risk Assessment (ERA). As the application is for a generic version of an already authorised product, it is not expected that environmental exposure will increase following approval of the marketing authorisation for the proposed product. IV Clinical aspects IV.1 Introduction No new clinical data have been submitted for this application. The applicant’s clinical overview on the clinical pharmacology, efficacy and safety of the product has been written by an appropriately qualified person and is adequate. The applicant has applied for a bioequivalence waiver according to the CPMP guideline “Note for guidance on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**) on the grounds that the test product, Rivastigmine Rosemont 2mg/ml oral solution, is in aqueous oral solution at the time of administration and contains the active substance in the same concentration as the approved reference medicinal product, Exelon 2 mg/ml oral solution. The excipients used in the generic product are well-established and qualitatively the same as that of the reference product. Based on the data submitted Rivastigmine 2 mg/ml oral solution can be considered bioequivalent to the reference product Exelon 2 mg/ml oral solution. IV.2 Pharmacokinetics In line with the CPMP guideline on the “Note for guidance on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**) the test product is to be administered as an aqueous oral solution containing the same active substance concentration as the approved reference medicinal product. No bioequivalence data have been submitted


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with this application and none were required. IV.3 Pharmacodynamics No new pharmacodynamic data are required for this application and none have been submitted. IV.4 Clinical efficacy No new efficacy data were submitted with this application and none were required. IV.5 Clinical safety No new safety data were submitted with this application and none were required. IV.6 Risk Management Plan (RMP) The marketing authorisation holder has submitted an RMP, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Rivastigmine Rosemont 2 mg/ml Oral Solution. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below:


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Summary table of risk management measures All medicines have a Summary of Product Characteristics (SmPC), which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet. The measures in these documents are known as routine risk minimisation measures. IV.7 Discussion on the clinical aspects The grant of a marketing authorisation is recommended for this application. V User consultation A user consultation with target patient groups on the package leaflet has been performed on the basis of a bridging report making reference to the content of Exelon 2 mg/ml oral solution (MA Holder: Novartis Europharm Limited; EU/1/98/066/013, EU/1/98/066/018) and the format of Perizam 2 mg/ml Oral Suspension (MA Holder: Rosemont Pharmaceuticals; PL 00427/0228). The bridging report submitted by the applicant is acceptable. VI Overall conclusion, benefit/risk assessment and recommendation The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. The application includes an adequate review of published non-clinical and clinical data concerning the efficacy and safety of rivastigmine. The test product Rivastigmine Rosemont 2 mg/ml Oral Solution can be considered bioequivalent with the reference product Exelon 2 mg/ml oral solution. The benefit/risk assessment is, therefore, considered to be positive. The Summary of Product Characteristics (SmPC), package leaflet and labelling are satisfactory, in line with current guidelines and consistent with the reference product. In accordance with Directive 2012/84/EU, the current approved UK versions of the SmPC and package leaflet for this product is available on the MHRA website. The currently approved carton and label is listed below:


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Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II variations, PSURs, commitments)

Scope Procedure

number Product information affected

Date of start of the procedure

Date of end of procedure

Approval/ non approval

Assessment report attached Y/N (version)

Public Assessment Report Decentralised Procedure is Rivastigmine Rosemont 2 mg/ml Oral Solution...

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