Decentralised Procedure Public Assessment Report Tolcapon
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Decentralised Procedure Public Assessment Report Tolcapon-neuraxpharm 100 mg Filmtabletten Tolcapone DE/H/4644/001/DC Applicant: neuraxpharm Arzneimittel GmbH, Germany Reference Member State DE 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........ 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION.................................................................... 5 III.1 Quality aspects ....................................................................................................................... 5 III.2 Non-clinical aspects ................................................................................................................ 5 III.3 Clinical aspects....................................................................................................................... 6 IV. BENEFIT RISK ASSESSMENT............................................................................................ 8 Tolcapon-neuraxpharm, DE/H/4644/001/DC Public AR Page 2/8 ADMINISTRATIVE INFORMATION Proposed name of the medicinal Tolcapon-neuraxpharm 100 mg Filmtabletten product(s) in the RMS Name of the drug substance (INN Tolcapone name): Pharmaco-therapeutic group N04BX01 (ATC Code): Pharmaceutical form(s) and Film-coated tablet; 100 mg strength(s): Reference Number(s) for the DE/H/4644/001/DC Decentralised Procedure Reference Member State: DE Concerned Member States: LU withdrawn Applicant (name and address) neuraxpharm Arzneimittel GmbH Elisabeth-Selbert-Str. 23, 40764 Langenfeld, Germany Tolcapon-neuraxpharm, DE/H/4644/001/DC Public AR Page 3/8 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for “Tolcapon- neuraxpharm 100 mg Filmtabletten”, with the following indication: in combination with levodopa/benserazide or levodopa/carbidopa for use in patients with levodopa-responsive idiopathic Parkinson’s disease and motor fluctuations, who failed to respond to or are intolerant of other catechol-O-methyltransferase COMT inhibitors (see section 5.1). Because of the risk of potentially fatal, acute liver injury, “Tolcapon-neuraxpharm 100 mg Filmtabletten” should not be considered as a first-line adjunct therapy to levodopa/benserazide or levodopa/carbidopa (see sections 4.4 and 4.8). Since “Tolcapon-neuraxpharm 100 mg Filmtabletten” should be used only in combination with levodopa/benserazide and levodopa/carbidopa, the prescribing information for these levodopa preparations is also applicable to their concomitant use with “Tolcapon-neuraxpharm 100 mg Filmtabletten”, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement N/A II.2 About the product Tolcapone is an orally active, selective and reversible catechol-O-methyltransferase (COMT) inhibitor. Administered concomitantly with levodopa and an aromatic amino acid decarboxylase inhibitor, it leads to more stable plasma levels of levodopa by reducing metabolism of levodopa to 3-methoxy-4-hydroxy-L- phenylalanine (3-OMD). Tolcapone is indicated second line in combination with levodopa/benserazide or levodopa/carbidopa for use in patients with levodopa-responsive idiopathic Parkinson’s disease and motor fluctuations. Because of the risk of fatal liver injury, Tolcapone may not be used as a first-line adjunct therapy to levodopa/benserazide or levodopa/carbidopa. Due to liver toxicity tolcapone has been withdrawn from many countries. The drug is available in the Czech Republic, New Zealand, Poland, Slovakia, Switzerland and the US under restrictive labelling. The CPMP completed a review of available evidence, and made the following recommendations for changes to the product information for tolcapone and conditions for use of the agent: more stringent monitoring of liver function and closer attention to signs of underlying liver disease; contraindication in patients with severe dyskinesia or a previous history of neuroleptic malignant syndrome symptom complex, traumatic rhabdomyolysis or hyperthermia; prescribing only by physicians experienced in the management of advanced Parkinson's disease. The product information for tolcapone has been revised accordingly, with the use of the agent restricted to the treatment of patients who have failed to respond to, or who are intolerant of, other catechol-O-methyltransferase inhibitors. II.3 General comments on the submitted dossier This decentralised application concerns a generic version of Tolcapone, under Tolcapon-neuraxpharm 100 mg Filmtabletten trade name. With Germany as the Reference Member State in this Decentralized Procedure, neuraxpharm Arzneimittel GmbH, Germany is applying for the Marketing Authorisations for Tolcapon-neuraxpharm 100 mg Filmtabletten in Germany and Luxemburg. However, the applicant decided to withdraw the application in Luxemburg. This application of Tolcapone 100 mg film-coated tablets is a "generic application", legally based on Article 10 (1) of Directive 2001/83/EC as amended. Tolcapon-neuraxpharm, DE/H/4644/001/DC Public AR Page 4/8 It can be considered pharmaceutically equivalent to Tasmar, marketing authorization holder Meda AB. The European Commission granted a marketing authorization valid throughout the European Union of Tasmar on August 1997 (EMEA-agency number: EMEA/H/C/000132). The products have the same active ingredient, the same pharmaceutical forms, strengths and routes of administration. In this application CHMP guidance documents were followed, no Scientific Advice was given. 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. Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The chemical-pharmaceutical documentation and Quality Overall Summary in relation to product name 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, however require some clarification. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed, except for water content. The proposed retest period of 24 months is justified. 18 month data have been provided and no clear trends were detectable. Drug Product The pharmaceutical development is limited but acceptable for straightforward standard dosage form. 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 guarded by batch release data of the finished product. The stability testing data cover a time period of 12 months. Based on the provided data a shelf life of 24 months is accepted. III.2 Non-clinical aspects The pharmacological and toxicological characteristics of tolcapone are well established and have been satisfactorily summarised based on publicly available information in Module 2.4. This document also confirms that the excipients used in the drug product are well established. By reference to pertinent sections of Module 3, Module 2.4 clarifies that the inherent impurity profile of the drug substance and drug product complies with prevailing ICH and European requirements (CPMP/SWP/5199/02, EMA/CHMP/ICH/82260/2006; Guideline ICH Q3A and Guideline ICH Q3B). Tolcapon-neuraxpharm, DE/H/4644/001/DC Public AR Page 5/8 Thus, further toxicological qualification measures are not required. The pharmacological and toxicological properties of tolcapone are appropriately reflected in the