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CMDh/223/2005 February 2014 Public Assessment Report Scientific discussion Tezefort 40 mg/10 mg Tezefort 80 mg/5 mg Tezefort 80 mg/10 mg Telmisartan/Amlodipine besylate CZ/H/0253/002-004/DC Date: 29.8.2016 This module reflects the scientific discussion for the approval of Tezefort 40 mg/10 mg (80 mg/5 mg, 80 mg/10 mg). The procedure was finalised at 9.7.2015. I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Tezefort 40 mg/10 mg (80 mg/5 mg, 80 mg/10 mg) tablets, from Zentiva, k.s., U kabelovny 130, 102 37, Praha 10 - Dolní Měcholupy, the Czech Republic. Tezefort is fixed combination product consisting of two well-known active substances with antihypertensive effect: amlodipine besilate and telmisartan. Amlodipine is a calcium antagonist belonging to a class of dihydropyridines and telmisartan is an angiotensin II receptor antagonist. The product is indicated for substitution therapy in adult patients with essential hypertension whose blood pressure is adequately controlled on the combination of amlodipine and telmisartan given concurrently at the same dose level. A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisation has been granted pursuant to Article 10(b) of Directive 2001/83/EC (i.e. a fixed combination application). The concerned member states (CMSs) involved in procedure were: CZ/H/0253/002/DC: PT CZ/H/0253/003-004/DC: BG, EE, LV, PT and SK. In accordance with the type of application and proposed indication the evidence of efficacy/safety of the combination, co-prescription data and proof of bioequivalence with the mono-components have been submitted. In addition to the two bioequivalence studies one interaction study was performed. No further specific clinical studies have been performed and none were required. Bioequivalence was demonstrated for Tezefort 80/10 mg versus the innovator products (single dose products: Micardis 80 mg and Istin10 mg) and biowaiver for Tezefort 80 mg/5 mg was proposed and accepted. The second bioequivalence study confirmed bioequivalence for Tezefort 40/10 mg tablets versus the innovator products (single dose products: Micardis 40 mg and Istin10 mg). The innovator products Micardis 40, 80 mg (Boehringer Ingelheim) have been authorised through a centralised procedure EU/1/98/090. The innovator product Istin 10 mg (Pfizer Manufacturing Deutschland GmbH) is authorised in the Czech Republic since 2001 under the trade name Zorem 10 mg by UK/H/5127/006 procedure. No Paediatric Investigation Plan (PIP) has been submitted and none has been requested. II. QUALITY ASPECTS II.1 Introduction Tezefort 40 mg/10 mg (80 mg/5 mg, 80 mg/10 mg) is presented in the form of uncoated tablets containing 40 mg or 80 mg of telmisartan and 5 or 10 mg of amlodipine. The excipients are sorbitol, sodium hydroxide, povidone 25, cellulose microcrystalline, calcium hydrogen phosphate dihydrate, meglumine and magnesium stearate. The product is packed into blisters made of OPA/Al/PVC/Al. Blisters are placed, together with a package leaflet, into a paper folding box. PAR Scientific discussion 2/13 Compliance with Good Manufacturing Practice The RMS has been assured that acceptable standards of GMP are in place for these product types at site 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. Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer responsible for manufacture of the finished product and batch release situated in the EU. II.2 2.2 Drug Substance Drug substance The active substances are telmisartan and amlodipine besilate. Both of them are described in the Ph.Eur. Telmisartan INN name: Chemical name: Latin name: CAS registry number: Structural Formula Relative molecular mass: Molecular formula: Solubility: Melting point: Hygroscopicity: Optical isomerism: Polymorphism : Telmisartan 4'-[[4 - methyl - 6 - (1 - methyl - 1H- benzimidazol- 2 - yl) 2 - propyl – 1H - benzimidazoI - 1 - yl]methyl]biphenyI - 2 - carboxylic acid Telmisartanum 144701-48-4 514.63 C33H30N4O2 Practically insoluble in water, slightly soluble in methanol, sparingly soluble in methylene chloride. It dissolves in 1M sodium hydroxide. 269 °C to 273 °C (DSC) Non-hygroscopic Either a chiral atom or chiral axis or chiral plane do not occur in the molecule of telmisartan, therefore optical isomerism is not applicable. It shows polymorphism Two sources of telmisartan are used, for one of them the applicant uses ASMF procedure, for the second one the CEP procedure is followed. Specification and test methods are in line with Ph.Eur. monograph with additional tests for heavy metals, residual solvents and microbiological quality. Identification of polymorph form is performed. Telmisartan from one source is packed in the duplicate polyethylene bags (LDPE), inserted together with a desiccant into HDPE drum. The proposed re-test period is confirmed by stability data provided.. No significant changes in any parameters were observed. PAR Scientific discussion 3/13 Telmisartan manufactured by the second manufacturer has been assessed by EDQM and Certificate of Suitability has been obtained. The drug substance is tested in line with Ph.Eur. The re-test period is 60 months if stored in double polyethylene bags (outer black) placed in a polyethylene drum. Amlodipine besilate INN name: Chemical Name(s): Chemical Abstracts Service CAS registry number:): Amlodipine Besilate 3- Ethyl 5-methyl (4RS)-2-[(2-aminoethoxy) methyl] - 4-(2-chlorophenyl)-6-methyl- 1, 4 -dihydropyridine3, 5- dicarboxylate benzenesulphonate. 111470-99-6 Structure: Molecular Formula: Molecular Weight: C20H25ClN2O5,C6H6O3S 567.1 Description: Solubility: White or almost white powder Slightly soluble in water, freely soluble in methanol, sparingly soluble in ethanol, slightly soluble in 2propanol. Amlodipine Besilate shows polymorphism/pseudo polymorphism 195ºC-204ºC Non-hygroscopic Amlodipine Besilate has a chiral center. The specific rotation of Amlodipine Besilate is -0.10º to +0.10º (racemate). Polymorphism: Melting range: Hygroscopicity: Specific Optical Rotation: Two sources of amlodipine besilate are used, for both the CEP procedure is followed. The API from both sources is controlled according to the Ph.Eur. The re-test period is supported by stability data provided, the drug substance is stored in double polyethylene bags (outer black) placed in a polyethylene drum. II.3 Medicinal Product Composition The drug products are Telmisartan/Amlodipine uncoated tablets, containing 40 mg/10 mg, 80 mg/5 mg or 80 mg/10 mg telmisartan/amlodipine. The quantitative composition of excipients of the 80 mg/5 mg and the 80 mg/10 mg strength differs only in the amount of microcrystalline cellulose which compensates amount of amlodipine. Telmisartan/Amlodipine 40 mg/10 mg has different quantitative composition (not proportional) to the other strengths. PAR Scientific discussion 4/13 Pharmaceutical development The development of the product has been described, the choice of excipients is justified and their functions explained. Comparison of dissolution profiles with originator has been performed and for telmisartan the requirement for similarity of dissolution profiles in all tested media has been fulfilled. Some differences in the amlodipine dissolution profiles have been found, they have no impact on bioavailability. Manufacturing process Satisfactory batch formulae and description of manufacturing process have been provided. Critical parameters have been identified and tested. The process has been validated for the pilot batches. Excipients The excipients comply with relevant Ph.Eur. monographs, these specifications are acceptable. All excipients are widely used in the pharmaceutical industry. None of them are sourced from animal or human origin, magnesium stearate is of vegetable origin. Quality control of drug product The product specification includes tests for appearance, identification of both drug substances, polymorphism of telmisartan, water content, assay of both drug substances, content uniformity of both drug substances, dissolution of both substances, ethanol content, disintegration, resistance to crushing and microbial quality. The release and shelf life limits are not identical. New purity test method has been developed and validated in order to improve separation of impurities. The analytical methods have been adequately described and validated. Batch analytical data have been provided. Stability of drug product Stability data on the product have been provided at four conditions (Long-term 25 °C/60 %RH, Longterm for zone IVB 30 °C/75 %RH, Intermediate 30 °C/65 %RH, Accelerated40 °C/75 %RH) for two pilot batches (for all three strength). Stability data are available only for six months at all regimes, only for Telmisartan/Amlodipine 80/10 mg for 9 months at all above mentioned conditions (except accelerated). Further stability results up to 18 months in long term conditions are available. Stability data for bulk are available for 6 months. Photostability testing has been performed. Accelerated data show analytical results above the specification limits. Based on the stability results the product is stored at temperature below 25°C in the original package in order to protect from light. Stability data and proposed shelf life is accepted. III. NON-CLINICAL ASPECTS III.1 Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of telmisartan and amlodipine combination are well known. Since these two substances are a widely used, wellknown active substance, no further studies are provided. Therefore, overview based on literature review is appropriate. III.2 Ecotoxicity/environmental risk assessment (ERA) Tezefort 40/10mg, 80/5 mg and 80/10 mg tablets do not contain or consist of any components which result in additional hazard to the environment during storage, distribution, use and disposal. PAR Scientific discussion 5/13 Since the product is intended as a substitution therapy for patients already controlled on mono-components given concurrently, increased environmental risk is not expected. The product is intended for substituting parts of the prescriptions of the currently marketed innovator’s single component products. Consequently no changes with regards to environmental risks which are not already known are to be expected. The ERA is therefore not deemed necessary. IV. CLINICAL ASPECTS IV.1 Pharmacokinetics Pharmacokinetic profiles of telmisartan and amlodipine are well known and the applicant has not provided any new own studies and none are deemed necessary. Pharmacokinetics drug-drug interactions The Applicant has conducted one own PK interaction study between amlodipine and telmisartan. This interaction study proved that there is no potential for interactions between telmisartan and amlodipine. Furthermore, the applicant has submitted two bioequivalence studies comparing the use of two strengths of Tezefort 40/10 mg and 80/10 mg to innovator products Micardis 40 mg, Micardis 80 mg and Istin 10 mg: STUDY TLAL-BESD-01-ZNV/12 This was a single-dose, block randomized, three-period, three-sequence, single-centre, partially replicate design bioequivalence study designed to evaluate the comparative bioavailability of telmisartan 80 mg and amlodipine 10 mg in healthy male and female subjects under fasting conditions. The products compared were as follows: Test product TELMISARTAN/AMLODIPINE 80/10 mg tablets ZENTIVA k.s., Czech Republic Batch size: 100 000 tablets Reference products: Micardis 80 mg Tabletten Boehringer Ingelheim, GmbH, Germany Istin 10 mg Tablets; Pfizer Limited, United Kingdom Telmisartan was analysed in plasma via a validated HPLC MS/MS method with an assay range of 1-1000 ng/mL. Amlodipine was analysed in plasma via a validated HPLC MS/MS method with an assay range of 15-15000 pg/ml. The 90 % confidence intervals for the ratio test/reference of Cmax, AUCt were within the prespecified bioequivalence acceptance limits of 80 - 125 %. PAR Scientific discussion 6/13 Results for telmisartan: Results for amlodipine: PAR Scientific discussion 7/13 Both products were well tolerated. No serious adverse events or deaths were reported during this study. No subject was withdrawn from the study for safety reasons. STUDY TLAL-BESD-02-ZVN/12 This was a single-dose, block randomized, three-period, three-sequence, single-centre, partially replicate design bioequivalence study designed to evaluate the comparative bioavailability of telmisartan and amlodipine in healthy male and female subjects under fasting conditions. Test product TELMISARTAN/AMLODIPINE 40/10 mg, tablets ZENTIVA k.s., the Czech Republic Batch size: 100 000 tablets Reference products Micardis 40 mg, tabletten Boehringer Ingelheim Istin 10 mg, tablets Pfizer Limited, United Kingdom Telmisartan was analysed in plasma via a validated HPLC MS/MS method with an assay range of 1-1000 ng/mL. Amlodipine was analysed in plasma via a validated HPLC MS/MS method with an assay PAR Scientific discussion 8/13 range of 15-15000 pg/ml. The 90 % confidence intervals for the ratio test/reference of Cmax, AUCt were within the prespecified bioequivalence acceptance limits of 80 - 125 %. Results for telmisartan: Results for amlodipine: PAR Scientific discussion 9/13 Both products were well tolerated. No serious adverse events or deaths were reported during this study. No subject was withdrawn from the study for safety reasons. Conclusion on bioequivalence study Bioequivalence was demonstrated for Tezefort 80/10 mg versus the innovator products (single dose products: Micardis 80 mg and Istin 10 mg) and Tezefort 40/10 mg tablets versus the innovator products (single dose products: Micardis 40 mg and Istin 10 mg). Biowaiver was granted for Tezefort 80 mg/5 mg strength. The RMS has been assured that the bioequivalence studies were conducted in accordance with the protocol and other pertinent requirements of GCP/GLP. IV.2 Pharmacodynamics Pharmadodynamic profiles of telmisartan and amlodipine are well known. The applicant has not provided any new own PD studies and none are deemed necessary. IV.3 Clinical efficacy The clinical efficacy of telmisartan and amlodipine used as monocomponents was well established in a large number of clinical trials. No new efficacy data were submitted by the applicant and none are deemed necessary since the efficacy and clinical benefit of combined use of telmisartan and amlodipine was adequately discussed and justified by the Applicant in the clinical overview – demonstration is based on literature references. PAR Scientific discussion 10/13 Studies Fogari et al.2011 and Ohishi et al. 2013, co-prescription data and interaction study are considered as crucial in evaluation of telmisartan/amlodipine fixed dose combination efficacy. Furthermore, two supportive studies Ma et al. 2012 and Lu et al. 2012 were submitted. In overall, the RMS is of the opinion that data submitted and discussed in the clinical overview are sufficient for justification of clinical efficacy of fixed dose combination of telmisartan and amlodipine in the proposed indication. IV.4 Clinical safety With the exception of the data generated during the bioequivalence and interaction studies no new safety data were submitted and none were required for these applications. No new or unexpected safety issues were raised by the bioequivalence data or the interaction study. IV.5 Risk Management Plan The MAH has submitted RMP No. 08/14 version 1.0 dated 04.03.2014 as required for MAA under Article 10(b) of Directive 2001/83/EC. Summary of the safety concerns and proposed risk minimisation measures are stated in the table below: RMS considers that the RMP of Tezefort is approvable. Pharmacovigilance system The MAH has submitted a signed Summary of the Applicant's and 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. Periodic Safety Update Report (PSUR) The requirements for submission of periodic safety update reports (PSURs) for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines webportal. PAR Scientific discussion 11/13 IV.6 Discussion on the clinical aspects The application was supported by demonstration of efficacy and safety by literature references, submitted co-prescription data, two bioequivalence studies and one interaction study. Bioequivalence was demonstrated for Tezefort 80/10 mg versus the innovator products (single dose products: Micardis 80 mg and Istin10 mg) and biowaiver for Tezefort 80 mg/5 mg was proposed and accepted. The second bioequivalence study confirmed bioequivalence for Tezefort 40/10 mg tablets versus the innovator products (single dose products: Micardis 40 mg and Istin10 mg). No further specific clinical studies have been performed and none were required. Risk management was adequately addressed. V. USER CONSULTATION The readability user testing was performed between November 21th, 2013 and November 27th, 2013 in Cambridge, England. The test was performed in accordance with the requirements of the guidance for readability testing as outlined by European Council and MHRA guidance. The final leaflet is considered readable, with patients/users being able to act properly upon the information that it contains. PAR Scientific discussion 12/13 VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Based on the review of the data on quality, safety and efficacy, the risk-benefit ratio for the application for Tezefort as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of amlodipine and telmisartan given concurrently at the same dose level is considered positive. With the exception of the data generated during the bioequivalence and interaction studies no new safety data were submitted and none were required for these applications. The SmPC, PIL and labelling are satisfactory. Agreement between Member States was reached during the procedure. There was no discussion in the CMDh. The decentralised procedure was finalised with a positive outcome on 9.7.2015. No conditions pursuant to Article 21a or 22 of Directive 2001/83/EC have been made during the procedure. The following post-approval commitments regarding quality have been made during the procedure: 1. The stability studies on the pilot batches will continue to firmly establish the shelf life. 2. The first three production scale batches manufactured post approval packed in the packaging proposed for marketing will be placed on long term stability studies through the proposed shelf life and on accelerated studies for 6 months. 3. Microbiological purity will be tested at release and at the end of shelf life. 4. Comparative dissolution profiles will be determined on the first three production batches of three drug product strengths. 5. The full process validation studies will be carried out on the first three production batches of each strength and evaluated in the validation report. The validation will be finished before the drug product is placed on the market. Process validation will be repeated every time the production is scale up to a new batch size. PAR Scientific discussion 13/13