Download Public Assessment Report Scientific discussion Telhyd 40 mg/12.5

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Public Assessment Report
Scientific discussion
Telhyd 40 mg/12.5 mg, 80 mg/12.5 mg
and 80 mg/25 mg tablets
(telmisartan and hydrochlorothiazide)
NL/H/3393/001-003/DC
Date: 6 July 2016
This module reflects the scientific discussion for the approval of Telhyd 40 mg/12.5
mg, 80 mg/12.5 mg and 80 mg/25 mg tablets. The procedure was finalised on 3
December 2015. For information on changes after this date please refer to the ‘steps
taken after finalisation’ at the end of this PAR.
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List of abbreviations
ASMF
CEP
CHMP
CMD(h)
CMS
EDMF
EDQM
EEA
ERA
ICH
MAH
Ph.Eur.
PL
RH
RMP
SmPC
TSE
Active Substance Master File
Certificate of Suitability to the monographs of the European Pharmacopoeia
Committee for Medicinal Products for Human Use
Coordination group for Mutual recognition and Decentralised procedure for
human medicinal products
Concerned Member State
European Drug Master File
European Directorate for the Quality of Medicines
European Economic Area
Environmental Risk Assessment
International Conference of Harmonisation
Marketing Authorisation Holder
European Pharmacopoeia
Package Leaflet
Relative Humidity
Risk Management Plan
Summary of Product Characteristics
Transmissible Spongiform Encephalopathy
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INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for Telhyd 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg tablets, from
Apotex Europe B.V.
The products are indicated for treatment of essential hypertension.
Telhyd 40 mg/12.5 mg and Telhyd 80 mg/12.5 mg are indicated in patients whose blood pressure is
not adequately controlled on telmisartan alone.
Telhyd 80 mg/25 mg is indicated in patients whose blood pressure is not adequately controlled on
Telhyd 80 mg/12.5 mg or patients who have been previously stabilised on telmisartan and
hydrochlorothiazide given separately.
A comprehensive description of the indications and posology is given in the SmPC.
This decentralised procedure concerns a generic application claiming essential similarity with the
innovator product Micardis Plus 40/12.5, 80/12.5 and 80/25 mg, tablets which has been registered in
the EEA by Boehringer Ingelheim International GmbH since 19 April 2002 by the centralised
procedure EMEA/H/C/000413.
The concerned member state (CMS) involved in this procedure was Poland.
The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC.
II.
QUALITY ASPECTS
II.1
Introduction
Telhyd 40 mg/12.5 mg and 80 mg/12.5 mg are white and red coloured, two layered, modified capsule
shaped, biconvex uncoated tablets, with “APO” engraved on one side and “40/12.5” or “80/12.5” on
the other side. The white layer may contain red specks and the red layer may contain white specks.
Each tablet contains 40 mg or 80 mg telmisartan and 12.5 mg hydrochlorothiazide.
Telhyd 80 mg/25 mg is a white and yellow coloured, two layered, modified capsule-shaped, biconvex
uncoated tablet, with “APO” engraved on one side and “80/25” on the other side. The white layer may
contain yellow specks and the yellow layer may contain white specks. Each tablet contains 80 mg
telmisartan and 25 mg hydrochlorothiazide.
The tablets are packed in Aluminium-Aluminium blister packs.
The excipients are:
 Isomalt 75:25 (GalenQ 721)
 Mannitol
 Meglumine
 Povidone (K 29/32)
 Potassium hydroxide
 Magnesium stearate
 Microcrystalline cellulose
 Calcium hydrogen phosphate, anhydrous
 Croscarmellose sodium
 Iron oxide red (only Telhyd 40 mg/12.5 mg and 80 mg/12.5 mg tablets)
 Iron oxide yellow (only Telhyd 80 mg/25 mg tablets)
The products are dose proportional.
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Drug Substances
The active substances are telmisartan and hydrochlorothiazide, established active substances that are
both described in the European Pharmacopoeia (Ph.Eur.).
Telmisartan
Telmisartan is a white or slightly yellowish powder. It is practically insoluble in water, sparingly soluble
in strong acid (except insoluble in hydrochloric acid) and soluble in strong bases. Furthermore,
Telmisartan shows polymorphism: two crystalline forms (A and B) and an amorphous form (C) have
been reported. The manufacturing process of telmisartan consistently produces Form A. The
substance is non-hygroscopic.
The Active Substance Master File (ASMF) procedure is used for telmisartan. The main objective of the
ASMF procedure, commonly known as the European Drug Master File (EDMF) procedure, is to allow
valuable confidential intellectual property or ‘know-how’ of the manufacturer of the active substance
(ASM) to be protected, while at the same time allowing the applicant or marketing authorisation holder
(MAH) to take full responsibility for the medicinal product, the quality and quality control of the active
substance. Competent Authorities/EMA thus have access to the complete information that is
necessary to evaluate the suitability of the use of the active substance in the medicinal product.
Manufacturing process
For telmisartan the substance is manufactured in several steps which have been adequately
described. No class 1 organic solvents or heavy metal catalysts are used.
Quality control of drug substance
The drug substance specification of telmisartan is in line with the Ph.Eur. with additional requirements
for polymorphic form, in-house impurities and residual solvents. Batch analytical data demonstrating
compliance with this specification have been provided for three full scaled batches.
Stability of drug substance
Stability data on telmisartan have been provided for six full scaled batches stored at 25°C/60% RH (up
to 48 months) and 40°C/75% RH (6 months). A retest period of 48 months is claimed, which is justified
based on the provided data.
Hydrochlorothiazide
Hydrochlorothiazide is a white crystalline powder. The active substance is slightly soluble in water,
freely soluble in NaOH solution, n-butyl amine and dimethylformamide, sparingly soluble in methanol,
insoluble in ether, chloroform and dilute mineral acids. Hydrochlorothiazide exhibits polymorphism.
The manufacturing process of hydrochlorothiazide consistently produces crystalline polymorph.
The CEP procedure is used for hydrochlorothiazide. Under the official Certification Procedures of the
EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can
apply for a certificate of suitability concerning the control of the chemical purity and microbiological
quality of their substance according to the corresponding specific monograph, or the evaluation of
reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the general
monograph, or both. This procedure is meant to ensure that the quality of substances is guaranteed
and that these substances comply with the Ph.Eur.
Manufacturing process
Assessment of the manufacturing process of hydrochlorothiazide was performed by the EDQM in the
process of granting the CEP, hence no information is included or necessary.
Quality control of drug substance
The drug substance specification of hydrochlorothiazide is in line with the Ph.Eur. except for the tests
for assay and related substances. These tests are performed by in-house analytical procedures. The
assay method has been cross-validated with the Ph.Eur. method. Batch analysis data of three full
scaled batches have been provided.
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Stability of drug substance
Stability data on hydrochlorothiazide have been provided for six full scaled batches stored at
25°C/60% RH (up to 48 months) and 40°C/75% RH (6 months). A retest period of 48 months is
claimed, which is justified based on the provided data.
II.3
Medicinal Product
Pharmaceutical development
The product is an established pharmaceutical form and its development is adequately described in
accordance with the relevant European guidelines. The choice of excipients is justified and their
functions explained. The products have been developed as dose proportional bi-layer tablets. Tablets
are compressed of the two granules (bi-layer). The pharmaceutical development of the product has
been adequately performed.
Two bioequivalence studies have been performed and a biowaiver is requested for the lowest
strength. The composition of the commercial scale batches is identical to those tablets used in the bioequivalence studies. The dissolution studies have not been performed fully according to requirements
of the Note for Guidance (NfG) on Investigation of Bioequivalence regarding rotation speed. However,
the MAH has provided additional data which justify the chosen rotation speed.
Manufacturing process
The granules of the telmisartan-part are manufactured using a wet-granulation process and the
granules of the hydrochlorothiazide are manufactured using a dry-granulation process. Tablets are
compressed as bi-layer tablets. The manufacturing process has been adequately validated according
to relevant European guidelines. Process validation data on the product has been presented for three
smallest commercial scale batches of each strength. The product is manufactured using conventional
manufacturing techniques. Process validation for full scaled batches will be performed post
authorisation.
Control of excipients
The excipients comply with the Ph.Eur. and in-house requirements for the iron oxides. These
specifications are acceptable.
Quality control of drug product
The finished product specifications are adequate to control the relevant parameters for the dosage
form. The specification includes tests for appearance, identification, average weight, dissolution,
uniformity of dosage units, water content, degradation products, assay and microbial limits. Limits in
the specification have been justified and are considered appropriate for adequate quality control of the
product. Satisfactory validation data for the analytical methods have been provided. Batch analytical
data for three small commercial scale batches per strength from the proposed production site have
been provided, demonstrating compliance with the specification.
Stability of drug product
Stability data on the products have been provided for three smallest commercial scale batches stored
at 25°C/60% RH (36 months), 30°C/65% RH (36 months) and 40°C/75% RH (6 months). The
conditions used in the stability studies are according to the ICH stability guideline. The batches were
stored in the proposed package. An increase in degradation products is observed at all conditions.
Results remain within specification limits up to 24 months at long-term and intermediate conditions
and 6 months accelerated conditions. The only change that was observed in photo stability studies
was the appearance of ‘open’ tablets.
The proposed shelf-life period of 24 months can be granted. No specific storage restriction is required
regarding temperature, but the product should be ‘stored in original packaging in order to protect from
moisture and light’.
Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
There are no substances of ruminant animal origin present in the product nor have any been used in
the manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded.
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Discussion on chemical, pharmaceutical and biological aspects
Based on the submitted dossier, the member states consider that Telhyd has a proven chemicalpharmaceutical quality. Sufficient controls have been laid down for the active substance and finished
product.
No post-approval commitments were made.
III.
III.1
NON-CLINICAL ASPECTS
Ecotoxicity/environmental risk assessment (ERA)
Since Telhyd 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.2
Discussion on the non-clinical aspects
This product is a generic formulation of Micardis Plus which is available on the European market.
Reference is made to the preclinical data obtained with the innovator product. A non-clinical overview
on the pharmacology, pharmacokinetics and toxicology has been provided, which is based on up-todate and adequate scientific literature. The overview justifies why there is no need to generate
additional non-clinical pharmacology, pharmacokinetics and toxicology data. Therefore, the member
states agreed that no further non-clinical studies are required.
IV.
IV.1
CLINICAL ASPECTS
Introduction
Telmisartan and hydrochlorothiazide are well-known active substances with established efficacy and
tolerability. A clinical overview has been provided, which is based on scientific literature. The overview
justifies why there is no need to generate additional clinical data. Therefore, the member states
agreed that no further clinical studies are required.
For this generic application, the MAH has submitted two bioequivalence studies with the 80 mg/12.5
mg and 80 mg/25 mg formulation and requested a biowaiver for the 40 mg/12.5 mg formulation. The
bioequivalence studies and biowaiver are discussed below.
IV.2
Pharmacokinetics
Bioequivalence studies
The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product
Telhyd 80 mg/12.5 mg tablets (Apotex Europe B.V., NL) is compared with the pharmacokinetic profile
of reference product; Micardis Plus 80 mg/12.5 mg tablets (Boehringer Ingelheim International GmbH,
Germany).
In addition, a second bioequivalence study was conducted in which the pharmacokinetic profile of the
test product Telhyd 80 mg/25 mg tablets (Apotex Europe B.V., NL) is compared with the
pharmacokinetic profile of reference product; Micardis Plus 80 mg/25 mg (Boehringer Ingelheim
International GmbH, Germany).
The choice of the reference product
The choice of the reference products in the bioequivalence studies has been justified. It was a three
period study in which two reference products were used, MicardisPlus from Germany and Australia.
As only the data of the reference product registered in Germany will be used for the evaluation of
bioequivalence, the issues related to the product from Australia will not be reported here.
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The formula and preparation of the bioequivalence batch is identical to the formula proposed for
marketing.
Analytical/statistical methods
The analytical method has been adequately validated and is considered acceptable for analysis of the
plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical
evaluation are considered acceptable.
Biowaiver
The MAH applied for a biowaiver for the telmisartan/hydrochlorothiazide 40 mg/12.5 mg strength in
comparison with the 80 mg/12.5 mg strength. The tablets are dose proportional with the exemption of
the amount of hydrochlorothiazide. But as this amount is less than 5% of the total weight of the 40
mg/12.5 mg tablet (440 mg), this is considered acceptable according the current guideline.
Comparative dissolution of telmisartan/hydrochlorothiazide 80 mg/12.5 mg and 80 mg/25 mg is
shown. The biowaiver is therefore accepted.
Bioequivalence study I – 80 mg/25 mg tablets
Design
A comparative, randomised, single dose, three-way cross-over bioequivalence study was carried out
under fasted conditions in 119 healthy non smoking male subjects, aged 18 - 45 years. Each subject
received a single dose (80 mg/25 mg) of one of the 2 formulations. The tablet was orally administered
with 240 ml water after an overnight fast of 10 hours. There were 3 dosing periods, separated by a
washout period of 2 weeks.
Blood samples for telmisartan determination were collected pre-dose and at 0.25, 0.33, 0.5, 0.67,
0.83, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 9, 12, 16, 24, 36, 48, 60 and 72 hours after administration of the
products. Blood samples for hydrochlorothiazide determination were taken pre-dose and at 0.5, 0.75,
1, 1.33, 1.67, 2, 2.5, 3, 4, 5, 6, 8, 12, 18, 24, 32, 40 and 48 hours after administration of the products.
The design of the study is acceptable considering the absorption rate and half-lives. Also the washout
period is acceptable. As this product can be taken without reference to food intake, a study under
fasting conditions is justified.
Results
Out of the 119 subjects that participated:
 101 subjects completed all three periods.
 10 subjects completed two periods, and received 1 x test and 1x reference product
 111 subjects were included in the pharmacokinetic analysis for the test formulation
 A total of 107 subject received 1x test and 1x German reference product, and were included in the
pharmacokinetic analysis for the (European) reference product.
Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of telmisartan under fasted conditions.
Treatment
AUC0-t
AUC0-∞
Cmax
tmax
ng.h/ml
ng.h/ml
ng/ml
h
h
Test – n=111
2170 ± 1427
2311 ± 1581
312 ± 183
17.1 ± 5.1
Reference –
n=107
*Ratio
(90% CI)
CV (%)
2245 ± 1475
2438 ± 1666
349 ± 215
17.4 ± 5.2
0.97
(0.95 - 1.00)
11.7
0.97
(0.95 - 1.00)
12.5
0.89
(0.83 - 0.95)
32.3
1.0
(0.5 - 4.0)
1.0
(0.25 - 4.0)
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--
AUC0-∞
AUC0-t
Cmax
tmax
t1/2
CV
area under the plasma concentration-time curve from time zero to infinity
area under the plasma concentration-time curve from time zero to t hours
maximum plasma concentration
time for maximum concentration
half-life
coefficient of variation
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*ln-transformed values
Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of hydrochlorothiazide under fasted conditions.
Treatment
AUC0-t
AUC0-∞
Cmax
tmax
µg/ml/h
µg/ml/h
µg/ml
h
t1/2
h
Test – n=111
1173 ± 260
1219 ± 268
165 ± 52.6
11.0 ± 1.9
Reference –
n=107
*Ratio
(90% CI)
CV (%)
1180 ± 1244
1226 ± 253
170 ± 53.1
0.99
(0.95 - 1.02)
14.0
0.99
(0.96 - 1.02)
13.4
0.95
(0.91 - 0.99)
18.4
1.67
(0.75 - 5.0)
0.67
(0.75 - 4.0)
---
--
11.0 ± 1.5
--
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax
maximum plasma concentration
tmax
time for maximum concentration
t1/2
half-life
CV
coefficient of variation
*ln-transformed values
Safety
There were no serious adverse events. Fifteen subjects in the test group experienced 16 mild adverse
events; 11 subjects in the reference 1 group experienced 15 mild adverse events and 9 subjects
experienced 11 mild adverse events in the reference 2 group. These comprised a range of minor
symptoms or out of range laboratory values; there were no discernible differences in the nature or
frequency of these between the test and reference formulations.
Bioequivalence study II – 80 mg/12.5 mg tablets
Design
A comparative, randomised, single dose, three-way cross-over bioequivalence study was carried out
under fasted conditions in 120 healthy non smoking male subjects, aged 18 - 45 years. Each subject
received a single dose (80 mg/12.5 mg) of one of the 2 formulations. The tablet was orally
administered with 240 ml water after an overnight fast of 10 hours. There were 3 dosing periods,
separated by a washout period of 2 weeks.
Blood samples for telmisartan determination were collected pre-dose and at 0.25, 0.33, 0.5, 0.67,
0.83, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 9, 12, 16, 24, 36, 48, 60 and 72 hours after administration of the
products. Blood samples for hydrochlorothiazide determination were collected pre-dose and at 0.5,
0.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, 5, 6, 8, 12, 18, 24, 32, 40 and 48 hours after administration of the
products.
The design of the study is acceptable considering the absorption rate and half-lives. Also the washout
period is acceptable. As this product can be taken without reference to food intake, a study under
fasting conditions is justified.
Results
Results
Out of the 120 subjects that participated:
 88 subjects completed all three periods.
 102 subjects completed two periods, and received 1 x test and 1x reference product
 A total of 96 subject received 1x test and 1x German reference product, and were included in the
pharmacokinetic analysis for the (European) reference product.
Table 4. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of telmisartan under fasted conditions.
Treatment
AUC0-t
AUC0-∞
Cmax
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t1/2
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N=96-102
Test – n=96
Reference –
n=102
*Ratio
(90% CI)
CV (%)
AUC0-∞
AUC0-t
Cmax
tmax
t1/2
CV
B
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ng.h/ml
ng.h/ml
ng/ml
h
h
2261 ± 1252
2398 ± 1392
354 ± 179
1.0
(0.5 - 4.0)
17.1 ± 5.9
2243 ± 1251
2386 ± 1360
378 ± 201
16.6 ± 4.5
1.0
(0.96 - 1.03)
15.3
1.0
(0.96 - 1.02)
12.6
0.95
(0.88 - 1.03)
34.7
1.0
(0.33 - 3.0)
---
--
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--
area under the plasma concentration-time curve from time zero to infinity
area under the plasma concentration-time curve from time zero to t hours
maximum plasma concentration
time for maximum concentration
half-life
coefficient of variation
*ln-transformed values
Table 4. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of hydrochlorothiazide under fasted conditions.
Treatment
N=96-102
Test – n=96
Reference –
n=102
*Ratio
(90% CI)
CV (%)
AUC0-t
AUC0-∞
Cmax
tmax
µg/ml/h
µg/ml/h
µg/ml
h
t1/2
h
604 ± 145
633 ± 153
87.8 ± 20.9
10.5 ± 1.5
591 ± 138
619 ± 146
90.3 ± 23.6
1.02
(0.99 - 1.06)
12.6
1.02
(1.00 - 1.06)
12.2
098
(0.94 - 1.02)
16.5
1.6
(0.75 - 5.0)
1.6
(0.75 - 3.0)
---
--
10.4 ± 1.6
--
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax
maximum plasma concentration
tmax
time for maximum concentration
t1/2
half-life
CV
coefficient of variation
*ln-transformed values
Safety
A total of 9 mild adverse events occurred in 8 subjects after they received the test preparation. A total
of 16 mild adverse events occurred in 14 subjects and 1 moderate adverse event occurred in 1 subject
after they received the reference preparation. No difference was observed between test and reference
product in safety.
Conclusion on bioequivalence studies
The 90% confidence intervals calculated for AUC0-t, AUC0-∞ and Cmax are within the bioequivalence
acceptance range of 0.80 – 1.25. Based on the submitted bioequivalence studies Telhyd 80 mg/25 mg
and 80 mg/12.5 mg tablets are considered bioequivalent with the corresponding Micardis Plus tablets.
The high rate of drop outs in these studies can be mainly attributed to study subjects not showing up
for subsequent period check in and missing of ambulatory visits. The MEB has been assured that the
bioequivalence studies have been conducted in accordance with acceptable standards of Good
Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives
2004/9/EC and 2004/10/EC).
IV.3
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 Telhyd.
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Summary table of safety concerns as approved in RMP:
Important identified risks
Important potential risks
Missing information


Sepsis
Renal dysfunction as consequence of dual RAAS
blockade
 Foetotoxicity
 Hypoglycaemia
 Increase of hepatic related adverse reactions in the
Japanese population
 Rhabdomyolysis
 Interstitial lung disease
 Severe cutaneous reactions
 Suicide/self-injury
 malignancies
Not applicable
The member states agreed that routine pharmacovigilance activities and routine risk minimisation
measures are sufficient for the risks and areas of missing information.
IV.4
Discussion on the clinical aspects
For this authorisation, reference is made to the clinical studies and experience with the innovator
product Micardis Plus. No new clinical studies were conducted. The MAH demonstrated through
bioequivalence studies that the pharmacokinetic profile of the product is similar to the pharmacokinetic
profile of this reference product. Risk management is adequately addressed. This generic medicinal
product can be used instead of the reference product.
V.
USER CONSULTATION
A user consultation with target patient groups on the package leaflet (PL) has been performed on the
basis of a bridging report making reference to Micardis Plus tablets. The bridging report submitted by
the MAH has been found acceptable.
VI.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Telhyd 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg tablets have a proven chemicalpharmaceutical quality and are generic forms of Micardis Plus tablets. Micardis Plus is a well-known
medicinal product with an established favourable efficacy and safety profile.
Bioequivalence has been shown to be in compliance with the requirements of European guidance
documents.
The Board followed the advice of the assessors.
There was no discussion in the CMD(h). Agreement between member states was reached during a
written procedure. The member states, on the basis of the data submitted, considered that essential
similarity has been demonstrated for Telhyd with the reference product, and have therefore granted a
marketing authorisation. The decentralised procedure was finalised with a positive outcome on 3
December 2015.
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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE – SUMMARY
Scope
Procedure
number
Type of
modification
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Date of start
of the
procedure
Date of
end of the
procedure
Approval/
non
approval
Assessment
report
attached