Download I. Introduction

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.
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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.
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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.
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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.
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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 %.
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Results for telmisartan:
Results for amlodipine:
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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
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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:
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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.
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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.
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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.
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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.
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