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
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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.
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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
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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
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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
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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’.
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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.
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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.
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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. The control tests and specifications for drug product are adequately drawn up. The proposed shelf-life of 24 months without any special storage condition could be accepted.
III. Non-clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of capecitabine are well known. As capecitabine is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.
IV. Clinical aspects IV.1 Introduction
The applicant has provided documents that set out a detailed description of the system of pharmacovigilance (AET’s DDPS – Version 6 – 01/07/09). A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided.
The RMS considers that the Pharmacovigilance system as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.
The Applicant submitted a statement on the absence of a Risk Management Plan, and indicated that the current application concerns a generic product, for which the active ingredient that has been in use for many years, and has a well-established safety profile.
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PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC Routine pharmacovigilance activities in accordance with EU regulations will be undertaken whilst the product is authorized. As the safety profile of the drug is well-established, a RMP was considered unnecessary.
IV.2 Pharmacokinetics
Capecitabine has almost 100% oral bioavailability and exhibits linear increases in C max and AUC with dosage increases. After 2 doses of 1250 mg/m², the drug undergoes rapid absorption, with peak plasma levels of 3.9 mg/L achieved in 1.5 to 2 hours. In comparison, Cmax for the active metabolite fluorouracil (FU) was lower at 0.66 mg/L with a similar Tmax of 2 hours.
AUC values for the parent drug and active metabolite for the same dosage were 5.96 mg.h/L and 1.34 mg.h/L, respectively. Administration with food decreases the rate of capecitabine absorption, but only results in a minor effect on the AUC of 5’-deoxy-5-fluorouridine (5'- DFUR), and on the AUC of the subsequent metabolite FU.
The pharmacokinetics of capecitabine has been evaluated over a dose range of 502-3514 mg/ m²/ day. The parameters of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR measured on days 1 and 14 were similar. The AUC of FU was 30%-35% higher on day 14. Capecitabine dose reduction decreases systemic exposure to FU more than dose- proportionally, due to non-linear pharmacokinetics for the active metabolite.
No relevant influence of race on the pharmacokinetics of capecitabine, 5’-DFUR, 5’-DFCR or FU was observed. In vitro human plasma studies have determined that capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 54%, 10%, 62% and 10% protein bound, mainly to albumin. About 3% of a dose of capecitabine is excreted in the urine unchanged.
To support the application, the applicant has submitted an adequate single dose bioequivalence study under fed conditions. This comparative bioavailability trial has been performed at ClinTec (India) International Pvt. Ltd. The analytical and biostatistical parts were performed by Sitec Labs Pvt. Limited, India.
This was a multicentric, single-dose, 2-way, cross-over study under fed conditions. The fed conditions are appropriate as per SPC of the reference product, Xeloda. The bioequivalence study is conducted according to the Guideline on the Investigation of Bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1, except for the composition of the meal. A standardized non high-fat meal has been chosen based on the draft Guideline on the Investigation of Bioequivalence at the time of study designing. Although the current Guideline on the Investigation of Bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1 recommends a high-fat meal, it is considered that in this situation a normo-caloric, non high-fat meal is acceptable (cancer patients dealing with reduced appetite). Seventy-three patients with colon, colorectal or breast cancer who were found eligible for the study and compliant with the screening procedures and the inclusion and exclusion criteria were enrolled. The treatment phases were separated by a washout period of at least 7 days.
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PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC The study design, sample size, and statistical methods are appropriate. The 90% confidence intervals of the ratios of geometric means are well in the acceptance range of 80-125% for the primary parameters AUC0-t, AUC0-∞ and Cmax, for capecitabine, 5’DFCR and 5’-DFUR. The sample schedule covers the plasma concentration time curve long enough to provide a reliable estimate of the extent of exposure. AUC0-t covers at least 80% of AUC0-∞ for capecitabine, except in one subject.
Comparative in vitro dissolution profiles in 0.01N HCl, acetate buffer pH 4.5, distilled water and phosphate buffer pH 6.8 of the test and reference 500 mg strengths have been provided and are considered similar.
Originally, the applicant applied for a biowaiver for the 150 mg strength information (extrapolation of the in vivo results obtained with the 500 mg strength). However, due to dissimilar comparative dissolution profiles between both strengths of the test product (which applies also for both strengths of the reference product), the applicant decided to apply for a BCS-based biowaiver for the lower strength. Comparative dissolution profiles in the pH-range 1.0-6.8 and in water (without enzymes) have been provided for three different batches of test and reference products (150 mg strength) and similarity has been observed through the calculation of the f2 values. IV.3 Pharmacodynamics
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Capecitabine is activated via several enzymatic steps. The enzyme involved in the final conversion to 5-FU, thymidine phosphorylase, is found in tumour tissues, but also in normal tissues, in lower levels. Capecitabine is metabolized to the only active compound, FU, via 3 metabolic steps. Once capecitabine is absorbed through the intestine, liver carboxylesterase converts it to 5'-deoxy- 5-fluorocytidine (5'-DFCR). 5'-DFCR is then metabolized to 5'-DFUR by cytidine deaminase, a ubiquitous enzyme with high concentrations in the liver, plasma, and tumor tissue. Finally, 5'-DFUR is converted to the active drug FU by thymidine phosphorylase, found in amounts 3 to 10 times higher in various solid tumors compared with normal adjacent tissue. The localization of this enzyme to the liver and tumor tissue allows for targeted intratumoral release of FU and subsequently less systemic toxicity compared with IV FU. There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of deoxyribonucleic acid (DNA). The incorporation of 5-FU also leads to inhibition of RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may be to create a thymidine deficiency that provokes unbalanced growth and death of a cell. The effects of DNA and RNA deprivation are most marked on those cells which proliferate more rapidly and which metabolise 5-FU at a more rapid rate. IV.4 Clinical efficacy
The SPC claims for the proposed Tifix 150 mg and 500 mg Tablets are identical to those of the innovator product, for which clinical efficacy is well-established. As this application is made under
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PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC Article 10(1) of European Directive 2001/83/EC, as amended, no new efficacy study data are provided.
Tifix has shown varying degrees of efficacy with acceptable tolerability in numerous cancers including prostate, renal cell, ovarian, and pancreatic, with the largest amount of evidence in metastatic breast and colorectal cancer.
Tifix is an effective and well-tolerated first-line chemotherapy regimen for patients with advanced gastric cancer.
In patients with pretreated advanced breast cancer, Tifix is effective as monotherapy and also in combination with other agents. Efficacy has also been demonstrated with Tifix monotherapy and combination therapy in previously untreated patients in preliminary trials. In conclusion, Tifix, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens.
Tifix monotherapy is effective and well tolerated in all line settings of chemotherapy in patients with metastatic or advanced breast cancer, and is suitable for outpatient therapy.
On the basis of published clinical studies, meta-analyses and review articles, it can be concluded that Tifix has proven clinical efficacy in the treatment of patients following surgery of stage III colon cancer, treatment of metastatic colorectal cancer, as first-line treatment of advanced gastric cancer in combination with a platinum-based regimen; and in combination with docetaxel for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy.
The RMS considers that efficacy has clearly been shown for the brand product Xeloda. And recent literature data are supporting the efficacy of Tifix when used for the listed indications. IV.5 Clinical safety
The most common dose-limiting adverse effects associated with Tifix monotherapy are hyperbilirubinemia, diarrhea, and hand-foot syndrome. Myelosuppression, fatigue and weakness, abdominal pain, and nausea have also been reported. Compared with bolus FU/LV, Tifix was associated with more hand-foot syndrome but less stomatitis, alopecia, neutropenia requiring medical management, diarrhea, and nausea. Tifix has been reported to increase serum phenytoin levels and the international normalized ratio in patients receiving concomitant phenytoin and warfarin, respectively. Tifix has been well-tolerated among elderly patients, treatment-related deaths in these elderly populations have been rare.
V. Overall conclusion, benefit/risk assessment and recommendation
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PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC
The efficacy of capecitabine has been shown for Xeloda and is in addition confirmed by recent literature data. The applicant’s conclusion that «in view of the established use of Capecitabine 150 mg and 500 mg tablets for the intended indications and the essential similarity to the innovator product, a favorable risk/benefit ratio can be expected when the proposed product is used in accordance with the instructions in the Summary of Product Characteristics» is endorsed.
Bioequivalence
Study design, analytical methodology and statistical evaluation of the provided relevant bioequivalence study (BE study n° PRC/CRD/33/08) for capecitabine 500 mg film-coated tablets are carried out in accordance with the Guideline on the Investigation of Bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1.
The 90 % confidence interval calculated for AUC0-t, AUC0-∞ and Cmax, for capecitabine, 5’DFCR and 5’-DFUR consistently fall within the 80 – 125 % acceptance range after single dose administration. Test and reference formulations can be considered as bioequivalent with respect to rate and extent of absorption with regard to demonstrated bioequivalence of the sole 500 mg film-coated tablets formulation. A marketing authorisation could be recommended for the 500 mg film-coated tablets.
For the 150 mg strength, all conditions for the BCS-based biowaiver have been fulfilled and, as such, a marketing authorisation could also be recommended for the 150 mg film-coated tablets.
Periodic Safety Update Report (PSUR)
Considering the fact that this medicinal product concerns a generic version of the originator product of Xeloda® (produced by Roche Registration Limited), the applicant has applied for a PSUR submission scheme of 3-years PSUR Cycle instead of the 6-months cycle during the first 2 years and yearly PSURs during the following three years before renewal in each Concerned Member State. The applicant confirmed to monitor and cumulatively review all adverse events in the PSUR and to inform the authorities in case of significant change in the benefit/risk ratio.
With regard to PSUR submission, the Applicant/MAH should take into account the following:
• In accordance with the revised legislation on pharmacovigilance (Directive 2010/84/EU), the list of European Union Reference Dates (the EURD list) of PSURs has been established and published by EMA. Marketing authorisation holders shall continuously check the EMA 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.”
European harmonised birth date is 30/04/1998 Date for first renewal date is 27/04/2017
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PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC
User consultation for medicinal products for human use
1) The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was English. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.
The PIL for Tifix 500 mg film-coated tablets as the product with the highest concentration of active substance has been chosen as parent PIL to be tested in the readability user test. The Tifix 500 mg film-coated tablets leaflet and the Tifix 150 mg film-coated tablets PIL (daughter) are identical in text, structure and layout. They only differ in the concentration of the active substance. A readability testing can be applied also to medicinal products marketed with different product names provided that a comparable wording and layout is used. Due to the similarity of the two PILs, the navigation and find ability of information can be also considered as comparable for the patient. In conclusion, the daughter PIL may be able to rely on testing applied to the parent PIL and the PIL Tifix 150 mg film-coated tablets need not be tested separately.
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PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC
Public Assessment Report
UPDATE
Tifix 150mg and 500mg film-coated tablets Capecitabine
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PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC
This module reflects the procedural steps and scientific information after the finalisation of the initial procedure.
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PAR Tifix 150mg and 500mg film-coated tablets BE/H/195/01-02/DC
Scope Procedure number Product infomation Date of start of the Date of end of Approval/ Assessment report attached affected procedure procedure non approval < Type II analytical or clinical procedure; renewal; < sections of SmPC and
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