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

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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Number(s) for the DE/H/4644/001/DC Decentralised Procedure Reference Member State: DE Concerned Member States: LU withdrawn Applicant (name and address) neuraxpharm Arzneimittel GmbH Elisabeth-Selbert-Str. 23, 40764 Langenfeld, Germany

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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.

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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).

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Thus, further toxicological qualification measures are not required. The pharmacological and toxicological properties of tolcapone are appropriately reflected in the proposed SmPC and PL, which have been completely harmonised with the currently approved versions of the reference product “Tasmar” (EMEA/H/C/000132-IA/0053).

Environmental Risk Assessment (ERA) Since “Tolcapon-neuraxpharm 100 mg Filmtabletten” 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.

III.3 Clinical aspects In support of this application one bioequivalence study number 188-13-GLP has been provided:

A randomized, open-label, balanced, two-treatment, two-period, two-sequence, single-dose, two-way crossover oral bioequivalence study of Tolcapone tablets 100 mg and Tasmar (Tolcapone) 100 mg film- coated tablets in 40 healthy, adult, human subjects under fasting conditions

The study has been operated in India and conducted in accordance with ethical principles outlined in the Declaration of Helsinki and ICH – GCP guidelines. Satisfactorily inspection data of the involved clinical and analytical agencies have been provided.

The clinical part of the study started on 04 May 2015 and was completed on 13 May 2015. Drug administration of tolcapone tablets was between 05 May 2015 and 12 May 2015. The origin of the reference product used is agreed.

Analysis of tolcapone was performed using a validated analytical method. 40 healthy, male, Asian subjects were enrolled in the study, 4 of these dropped out due to personal reasons (3 subjects) and adverse events (1 subject), thus 36 subjects were included in the pharmacokinetic evaluation.

In study no 188-13-GLP the 90% CI for the ratio of the test and reference product of the primary variables Cmax and AUC0-t fell within the acceptance criteria of 80.00-125.00%. There were no important differences in safety between test and reference products but the study was not powered to detect such differences.

Based on the submitted bioequivalence study 188-13-GLP Tolcapone 100 mg Filmtabletten are considered bioequivalent with the originator Tasmar 100 mg Filmtabletten.

Condition of biowaiver of strength is not concerned in this application, because this application only deals with one strength.

SmPC provided is in line with that one of the originator product Tasmar 100 mg film-coated tablets referred to in this generic application.

Pharmacodynamics No additional studies have been provided.

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Legal Status Medicinal product is subject to medical prescription.

User Testing User testing of Tolcapon-neuraxpharm 100 mg Filmtabletten was conducted in October 2015 in London, England. The participants included were adequate in view of age, gender and education. The prepared questions sufficiently cover the main safety issues of PIL. The methodology of user testing was adequate and results well documented.

The 1st and 2nd round of testing showed that, for each question, 100% of participants were able to find the correct information, and 100% of participants were able to answer the questions correctly. No changes were necessary after the preliminary and the 1st round of testing. The results of the interview showed that the PL of Tolcapon-neuraxpharm 100 mg Filmtabletten could be rated as readable and comprehensible according to the requirements of the European Commission document “Guideline on the readability of the labelling and package leaflet of medicinal products for human use” (2009). With this user test readability and comprehensibility of PIL of Tolcapon-neuraxpharm 100 mg Filmtabletten was shown.

Summary Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan The MAH has submitted a risk management plan, 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 Tolcapon neuraxpharm.

The MAH presented the following summary of safety concerns.

Summary of safety concerns Important identified risks  Serious potentially fatal hepatic events  Neuroleptic malignant syndrome  Impulse control disorders  Dyskinesia

Important potential risks  Drug interactions with significant clinical consequences

including sudden onset sleep Missing information  Use in pregnant and lactating women

The Applicant did not propose additional risk minimisation measures, which is endorsed. Currently routine risk minimisation measures are considered sufficient to address the risks of the medicinal product in the proposed indication(s).

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An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account: • PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. • For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. • For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

IV. BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data. Based on the submitted bioequivalence study Tolcapon-neuraxpharm 100 mg Filmtabletten are considered bioequivalent with Tasmar 100 mg Filmtabletten. This application only refers to one strength of Tolcapon- neuraxpharm, thus waiving in vivo data to other strengths is not of relevance in this application. The application is approved. For intermediate amendments see current product information.

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