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Public Assessment Report Public Assessment Report Tifix 150mg and 500mg film-coated tablets Capecitabine BE/H/195/01-02/DC BE licence no: BE423552-BE423561 Applicant: Alfred E. Tiefenbacher, Germany Date: 27-04-2012 Toepassingsdatum : 15-09-10 Page 1 of 17 Blz. 1 van 17 This assessment report is published by the Federal Agency for Medicines and Health Products following Article 21 (3) and (4) of Directive 2001/83/EC, amended by Directive 2004/27/EC and Article 25 paragraph 4 of Directive 2001/82/EC as amended by 2004/28/EC. The report comments on the registration dossier that was submitted to the Federal Agency for Medicines and Health Products and its fellow organisations in all concerned EU member states. It reflects the scientific conclusion reached by the Federal Agency for Medicines and Health Products and all concerned member states at the end of the evaluation process and provides a summary of the grounds for approval of a marketing authorisation. This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the latter category as the language in this report may be difficult for laymen to understand. This assessment report shall be updated by a following addendum whenever new information becomes available. To the best of the Federal Agency for Medicines and Health Products’ knowledge, this report does not contain any information that should not have been made available to the public. The Marketing Autorisation Holder has checked this report for the absence of any confidential information. Toepassingsdatum : 15-09-10 Page 2 of 17 Blz. 2 van 17 PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC TABLE OF CONTENTS Chapter 1: Administrative Information Page 4 Chapter 2: Scientific Discussion Page 5 1. Introduction 2. Quality aspects 3. Non-clinical aspects 4. Clinical aspects 5. Overall conclusion, benefit/risk assessment and recommendation Chapter 3: Steps taken after the initial procedure – update Page 15 Toepassingsdatum : 15-09-10 Page 3 of 17 Blz. 3 van 17 PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC ADMINISTRATIVE INFORMATION Name of the medicinal product Tifix INN (or common name) of the active Capecitabine substance(s) Pharmaco-therapeutic Group Cytostatic (antimetabolite) and ATC Code L01BC06 Pharmaceuticals form(s) film-coated tablets Strength(s) 150mg and 500mg Target Species NA Indications indicated for the adjuvant treatment of patients following surgery of stage III (Dukes’ stage C) colon cancer for the treatment of metastatic colorectal cancer for first-line treatment of advanced gastric cancer in combination with a platinum based regimen in combination with docetaxel for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline. as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and ananthracyclinecontaining chemotherapy regimen or for whom further anthracycline therapy is not indicated. Type of application DCP - Know Active substance - Abridged Legal Basis Generics (article 10(1) of Directive 2001/83/EC) Type of active substance chemical substance Prescription status Prescription only Reference number for the procedure BE/H/195/01-02/DC Reference Member State BE Concerned Member State DE, FR Marketing Authorisation Holder Alfred E.Tiefenbacher GmbH & Co. KG Van-der-Smissen-Strasse,1 22767Hamburg Germany Toepassingsdatum : 15-09-10 Page 4 of 17 Blz. 4 van 17 PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC Public Assessment Report SCIENTIFIC DISCUSSION Tifix 150mg and 500mg film-coated tablets Capecitabine Page 5 of 17 PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC This module reflects the scientific discussion for the approval of Tifix. The procedure was finalised at 27/04/2012 For information on changes after this date please refer to the module ‘Update’. Page 6 of 17 PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC I. Introduction This application is being made according to Article 28 of Directive 2001/83/EC as amended, granted by the Belgian Health Authorities on 04/07/2012 (MA number: BE423552-BE423561). This application concerns a abridged application, submitted according to Article 10 (1) Directive 2001/83/EC as amended. This type of application refers to information that is contained in the dossier of the authorisation of the reference product. A reference product is a medicinal product authorised and marketed on the basis of a full dossier, i.e. including chemical, biological, pharmaceutical, pharmacological- toxicological and clinical data. This information is not fully available in the public domain. Authorisations for generic products are therefore linked to the ‘original’ authorised medicinal product, which is legally allowed once the data protection time of the dossier of the reference product has expired. For this kind of applications, it has to be demonstrated that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of the reference product. To this end a bio-equivalence study has to be submitted. A bioequivalence study is the widely accepted means of demonstrating that the therapeutic equivalence and the use of different excipients and different methods of manufacture has no influence on efficacy and safety. A generic product can be used instead of its innovator product. No new pre-clinical and clinical studies were conducted, which is acceptable for this abridged application. This generic application concerns a decentralised procedure, with Belgium as Reference Member State and Germany and France as concerned member states. With respect to the legal basis in the RMS and the CMSs, the application for all strengths has been made according to article 10.1 of Directive 2001/83/EC, as amended. Essential similarity is claimed with the innovator product Xeloda® 150 mg and 500 mg tablets marketed by Roche Registration Limited, centrally registered since 2 February 2001 via the EU Centralised Authorisation EU/1/00/163/001-002. The medicinal product under assessment contains the same active substance qualitatively and quantitatively and has the same pharmaceutical form (film-coated tablets). The applicant has submitted one bioequivalence study comparing a single dose of 4 tablets of Capecitabine 500 mg from Cipla Limited, India and single dose of 4 tablets of Xeloda® 500 mg from Roche Ltd., UK under fed conditions. Since Capecitabine is cytotoxic in nature, the study has been conducted in patients with colon, colorectal or breast cancer, because using healthy normal volunteers would have not been appropriate. A single dose bioequivalence study is sufficient since the application concerns an immediate release formulation. Steady state studies are not indicated as no accumulation is expected, and bioavailability is not affected by repeated doses. This comparative bioavailability trial has been performed by the ClinTec (India) International Pvt. Ltd from October 2009-October 2010. Page 7 of 17 PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC Tifix is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes’ stage C) colon cancer for the treatment of metastatic colorectal cancer for first-line treatment of advanced gastric cancer in combination with a platinum based regimen in combination with docetaxel for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline. as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and ananthracyclinecontaining chemotherapy regimen or for whom further anthracycline therapy is not indicated. II. Quality aspects II.1 Introduction Tifix film-coated tablets are pink colored, capsule shaped, biconvex, debossed with “150” or “500”on one side and plain on the other side. The excipients are lactose monohydrate, microcrystalline cellulose, hypromellose 6 cps, croscarmellose Sodium and magnesium stearate. The tablets are packed into PVC/PVDC-Aluminium blisters. 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. II.2 Drug Substance Tifix is an orally administered antimetabolite, belonging to the fluoropyrimidine carbamate class. It is a precursor, that is enzymatically converted into the cytotoxic moiety 5-fluorouracil (5-FU). The active ingredient capecitabine used is not subject to a monograph in the Ph. Eur. but it is in the United States Pharmacopoeia (USP). The specification set for the API used in Tifix, 150 and 500 mg film-coated tablets, is based on the USP monograph. In addition, impurity limits are tighter controlled and a limit for total impurities, particle size and residual solvents according to ICH are included. Stability studies have been performed with the drug substance. No significant changes in any parameter were observed. The proposed retest period of 24 months is justified. Page 8 of 17 PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC II.3 Medicinal Product The development of the product has been described appropriately, the choice of excipients is justified and their functions explained. The manufacturing process is described appropriately and validated well. The excipients are well-known for film-coated tablets. The film-coating is performed using a commercial Opadry pink mixture. The product specifications cover appropriate parameters for this dosage form, although some impurity limits could be tightened. Validations of the analytical methods have been presented. Batch analysis has been performed on sufficient batches. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline.
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