Download Public Assessment Report Scientific discussion Zanacodar Combi

Public Assessment Report
Scientific discussion
Zanacodar Combi 40 mg/12.5 mg,
80 mg/12.5 mg and 80 mg/25 mg tablets
(telmisartan/hydrochlorothiazide)
NL/H/2918/001-003/DC
Date: 7 October 2014
This module reflects the scientific discussion for the approval of Zanacodar Combi 40
mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg tablets. The procedure was finalised on
14 March 2014. For information on changes after this date please refer to the module
‘Update’.
This report includes a summary, on pages 10-12.
I.
INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for Zanacodar Combi 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg
tablets from PharmaSwiss Ceská republika s.r.o.
The product is indicated for treatment of essential hypertension.
The fixed dose combinations of 40 mg telmisartan/12.5 mg hydrochlorothiazide and 80 mg
telmisartan/12.5 mg hydrochlorothiazide are indicated in adults whose blood pressure is not
adequately controlled on telmisartan alone.
The fixed dose combination of 80 mg telmisartan/25 mg hydrochlorothiazide is indicated in adults
whose blood pressure is not adequately controlled on 80 mg/12.5 mg or adults 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 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg tablets, registered
in the EEA since 19 April 2002 by Boehringer Ingelheim through a centralized procedure (MA numbers
EU/1/02/213/001-023).
The concerned member states (CMS) involved in this procedure were Czech Republic, Hungary,
Poland, Slovakia and Slovenia.
The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC.
II.
QUALITY ASPECTS
II.1
Introduction
Zanacodar Combi 40 mg/12.5 mg is a round bilayer tablet with white and yellow color.
Zanacodar Combi 80 mg/12.5 mg is a round bilayer tablet with white and pink color.
Zanacodar Combi 80 mg/25 mg is a round bilayer tablet with white and yellow color.
The tablets are packed in aluminium/aluminium blister packs.
The excipients are: mannitol, povidone K25, crospovidone, magnesium stearate, meglumine, sodium
hydroxide, lactose monohydrate, cellulose microcrystalline, hypromellose, sodium starch glycolate
type A, ferric oxide yellow (E172) (40 mg/12.5 mg and 80 mg/25 mg); ferric oxide red (30E 172) (80
mg/12.5 mg tablet).
The 40 mg/12.5 mg and the 80 mg/25 mg strengths are fully dose proportional. The 80 mg/12.5 mg
bilayer strength differs; the telmisartan layer is proportional with the 80 mg/25 mg strength and the
hydrochlorothiazide layer is proportional with the 40 mg/12.5 mg strength.
II.2
Drug Substances
The active substances are telmisartan and hydrochlorothiazide, established active substances
described in the European Pharmacopoeia (Ph.Eur.*). Telmisartan is a white or slightly yellowish
crystalline powder, which is practically insoluble in water. The polymorphic form of telmisartan is Form
A. Hydrochlorothiazide (HCTZ) is a white to almost white crystalline powder and is slightly soluble in
water.
The CEP procedure is used for all suppliers of the two active substances. 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,
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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 European Pharmacopoeia.
Manufacturing process
CEPs have been submitted; therefore no details on the manufacturing processes have been included.
Quality control of drug substances
For telmisartan the MAH has provided a single compiled drug substance specification for telmisartan
supplied by both suppliers. The specification is in line with the Ph.Eur. with the additional requirements
as stated in the CEPs.
For hydrochlorothiazide Certificates of Suitability of both suppliers confirm that the drug substance is
suitably controlled by the Ph.Eur. monograph for HCTZ.
Stability of drug substances
For telmisartan of one supplier the re-test period of the substance is 3 years with no specific storage
conditions (CEP). In this case, assessment thereof was part of granting the CEP and has been
granted by the EDQM. For telmisartan of the other supplier assessment of stability was not part of
granting the CEP. Therefore separate stability data has been included by the MAH. Results at
accelerated (6 months) and normal (36 months) storage condition show that the substance is stable.
At both storage conditions all tested parameters are staying well within the specification. The
proposed re-test period of 36 months is therefore justified.
For hydrochlorothiazide of one supplier the re-test period of the substance is 5 years. Assessment
thereof was part of granting the CEP and has been granted by the EDQM.
For hydrochlorothiazide of the other supplier assessment of stability was not part of granting the CEP.
Therefore separate stability data has been included by the MAH. Following the current guidelines, on
the basis of the submitted 24 months real time data a re-test period of 24 months without specific
storage condition can be granted.
II.3
Medicinal Product
Pharmaceutical development
The aim of the formulation development was to develop a finished product which is equivalent, and as
much similar as possible, to the innovator product Micardis Plus Forte 80 mg/25 mg immediaterelease bilayer tablets which has been authorised by the EMA in 2002. The development of the
product as a bilayer tablet has been described, the choice of excipients is justified and their functions
explained. Manufacturing process development has been adequately described. Comparative
dissolution data support that the test product is essential similar to the reference product. Comparative
dissolution data at pH 1.2, 4.5 and 7.5 have also been provided between the 80/25 mg strength and
the other two strengths in order to support a biowaiver for these strengths. In all cases the dissolution
profiles between the lower dose strength and the 80 mg/25 mg strength were found to be comparable.
In the current Ph.Eur. Monograph of hydrochlorothiazide it is noted that several polymorphic forms
exist. The MAH has demonstrated that the polymorphic form of the drug substance does not change
during tableting and storage.
Manufacturing process
The granules of the telmisartan and HCTZ are manufactured using a wet-granulation process,
followed by calibration. The two granulates are mixed separately with the rest of the excipients. The
final blends of both active substances are compressed into the respective layers. On the basis of the
development studies of the two separate layers a bilayer tablet was manufactured by compressing
tablets in a bilayer tableting machine and subsequently these are packaged in Al/Al-blisters.
Control of excipients
The excipients comply with the European Pharmacopoeia, except for ferric oxide red and yellow,
which comply with USP-NF. These specifications are acceptable.
Quality control of drug product
The product specification includes tests for appearance, water content, identification of both active
ingredients, uniformity of dosage units (content uniformity) of both active ingredients, assay of both
active ingredients, dissolution of both active ingredients, related substances and microbial
contamination. The release and end-of-shelf-life limits are identical.
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The analytical methods have been adequately described. Validation data have been provided for the
water content, dissolution method, impurities method and assay/content uniformity HPLC method.
Batch analysis data have been provided for pilot scale batches on four batches per tablet strength.
Compliance with the proposed release requirements has been demonstrated.
Stability of drug product
Stability data up to 12 months have been provided for all three strengths. The storage conditions were
25°C/60% RH, 30°C/65% RH and 40°C/75% RH . The conditions used in the stability studies are
according to the ICH stability guideline. The batches were stored in Al/Al blisters.
The water content under all three conditions tested shows some variation, however, the values are
well below the limit. The assay values show some variation although this falls within the range of the
analytical variance. Under all three storage conditions no increase is seen in any of the impurities. On
the basis of the currently available data, extrapolation to a shelf-life of 24 months is acceptable.
Results of a photostability studies are not included. However, since the primary package is a Al/Alblister this will adequately protect the drug product against light, and additional studies are not
deemed necessary.
In section 4.2 of the SmPC it is stated that the drug product should be kept in the sealed blister due to
the hygroscopic property of the tablets. Tablets should be taken out of the blister shortly before
administration. This statement was supported by actual data. The precautions for storage in section
6.4 of the SmPC are ‘This medicine does not require any special temperature storage conditions.
Store in the original package in order to protect from moisture and light.’
Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
None of the materials used in the manufacture of telmisartan/hydrochlorothiazide tablets are of animal
or human origin, except for lactose monohydrate. A declaration has been provided stating that this
excipient has been prepared in accordance with the relevant requirements laid down in Note for
Guidance EMEA/410/01 rev 2. All required BSE statements have been presented as well. Magnesium
stearate is of vegetable origin.
II.4
Discussion on chemical, pharmaceutical and biological aspects
Based on the submitted dossier, the member states consider that Zanacodar Combi tablets has a
proven chemical-pharmaceutical 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 Zanacodar Combi 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 tot 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.
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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 a bioequivalence study, which is discussed
below.
IV.2
Pharmacokinetics
The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product
Zanacodar Combi 80 mg/25 mg (PharmaSwiss Ceská republika s.r.o., CZ) is compared with the
pharmacokinetic profile of the reference product Micardis Plus 80 mg/25 mg tablets (Boehringer
Ingelheim International GmbH & Binger, Germany).
The choice of the reference products in the bioequivalence study is justified, as these have been
registered through a centralised procedure. The formula and preparation of the bioequivalence batch
is identical to the formula proposed for marketing.
Biowaiver
According to the CPMP guideline “Note for guidance on the investigation of bioavailability and
bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr**), a bioequivalence study investigating only
one tablet strength is acceptable, as the following conditions are fulfilled:
 The pharmaceutical products are manufactured by the same manufacturer and process
 The qualitative composition of the different strengths is the same.
 The composition of the strengths is quantitatively proportional.
 The dissolution profiles should be similar under identical conditions for the additional strengths
and the strength of the batch used in the bioequivalence study
The 40 mg/12.5 mg and the 80 mg/25 mg strengths are fully dose proportional. For the 80 mg/12.5 mg
bilayer strength the telmisartan layer is proportional with the 80 mg/25 mg strength and the
hydrochlorothiazide layer is proportional with the 40 mg/12.5 mg strength. The biowaiver for
Zanacodar Combi 40 mg/12.5 mg and 80 mg/12.5 mg tablets can be granted.
Bioequivalence study
Design
A single-dose, randomised, four-period, two-treatment, two-sequence, replicate crossover
bioequivalence study was carried out under fasted conditions in 42 healthy male subjects, aged 19-52
years. Each subject received a single dose (80 mg/25 mg) of one of the 2 telmisartan/
hydrochlorothiazide formulations. A single dose was administered orally to each subject in each period
with 240 ml of water after an overnight fast. The subjects fasted from 10 hours prior to drug
administration and until 4 hours following drug administration. Subjects were randomly assigned to
one of the two dosing sequences TRTR or RTRT (T=test, R=reference). The dosing periods were
seperated by a wash-out period of 14 days.
Blood samples were collected pre-dose and at 0.167, 0.333, 0.5, 0.667, 0.833, 1, 1.25, 1.5, 1.75, 2,
2.5, 3, 4, 5, 6, 8, 14, 24, 36, 48 and 72 hours after administration of the products.
The design of the study is acceptable. The sampling schedule is sufficient to characterize the Cmax of
both analytes adequately and sufficiently long to characterise the absorption and elimination of
telmisartan and hydrochlorothiazide appropriately. As telmisartan/HCTZ can be taken with or without
food, the demonstration of in vivo bioequivalence under fasting conditions is adequate.
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. The wider acceptance criterion for Cmax of telmisartan to a
maximum range of 69.84-143.19% is justified as the intra-subject variability for Cmax of the reference
product is > 30%,
Results
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Forty subjects completed all four periods of the study. Two subjects discontinued during the study: one
subject was dismissed due to weakness and vomiting in period one and the other subject withdrew
consent during period two. Since this subject completed period 1 and period 2 of the study, he was
included in the analysis. Therefore forty-one subjects are included in the pharmacokinetic and
statistical analysis.
The mean values of telmisartan pharmacokinetic parameters are presented below. A=test,
B=reference.
Table 1. Telmisartan primary pharmacokinetic parameters
Means
90% CI
Contrast
Ratio
Parameter
TRT Arithmetic
CV%
Geometric
lower
upper
Based on Measured Data
A1
1865.61
82
1441.71
A2
1886.87
80
AUC0-72
A vs. B
98.15
94.33
102.12
(ng.h/mL) B1
1907.53
82
1468.90
B2
1895.53
76
A1
307.36
96
238.85
A2
313.96
90
Cmax
A vs. B
89.66
82.39
97.58
(ng/mL)
B1
348.27
82
266.39
B2
323.14
83
Analyte: (A1 & B1: n = 41 / A2 & B2: n = 40 (Replicate Measures)) *ln-transformed values
intra-sub
CV(%)
A: 15
B: 16
A: 27
B:37
For the test formulation the tmax was 2.21 ± 0.62 hours and for the reference formulation the tmax was
1.03 ± 0.48 hours. A significant treatment effect was detected by ANOVA for Cmax (p=0.0348)
parameter. The 90% confidence interval of the test to reference ratio is entirely contained within the
80.00-125.00% bioequivalence range even when the protocol mentioned wider acceptance range.
ANOVA did not detect any significant differences in AUC0-72 parameter.
The mean values of hydrochlorothiazide pharmacokinetic parameters are presented in table 2.
Table 2. Hydrochlorothiazide primary pharmacokinetic parameters
Means
Contrast
Parameter
TRT Arithmetic
CV%
Geometric
Based on Measured Data
A1
1125.778
18
1100.984
A2
1113.842
17
AUC0-t
A vs. B
(ngh/mL)
B1
1150.885
17
1132.663
B2
1153.749
19
A1
172.759
24
168.800
A2
174.100
20
Cmax
A vs. B
(ng/mL)
B1
184.341
21
180.806
B2
186.225
22
Analyte: (A1 & B1: n = 41 / A2 & B2: n = 40 (Replicate Measures))
Ratio
90% CI
lower
upper
intra-sub
CV(%)
A: 8
97.20
95.37
99.07
B: 7
A: 17
93.36
89.64
97.24
B:15
Within-Subject-within-Reference CV% (15.51%) is lower than 30%. Therefore the standard bioequivalence acceptance range should be used: 80 - 125 %.
A significant treatment effect was detected by ANOVA for AUCt (p=0.0151) and Cmax (p=0.0060)
parameters. The 90% confidence interval of the test to reference ratio is entirely contained within the
80-125% bioequivalence range.
Bioequivalence between the test and reference product has been shown appropriately. The 90%
confidence interval of the test to reference ratio is entirely within the 80 - 125% bio-equivalence range
for both active substances.
Safety
Subjects were administered a single dose of the study medications 14 days apart, in four study
periods. There were 65 adverse events (Aes) involving 18 subjects in the study of which 63 were of
mild intensity and two were of severe intensity. No serious AEs were reported during the conduct of
this study.
The MEB has been assured that the bioequivalence study has 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).
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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 Zanacodar Combi tablets.
Summary table of safety concerns as approved in RMP
Sepsis
Important identified risks
Renal dysfunction as consequence of
dual RAAS blockade
Foetotoxicity
Hypoglycaemia
Important potential risks
Increase of hepatic-related adverse
reactions in the Japanese population
Rhabdomyolysis
Interstitial lung diseases
Severe cutaneous reactions
Suicide/self-injury
Malignancies
Important missing information
Pregnancy
Lactation
Children and adolescents below 18 years
old
The member states agree that routine pharmacovigilance and routine risk minimisation activities 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 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg tablets. No new clinical
studies were conducted. The MAH demonstrated through a bioequivalence study 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
The package leaflet (PL) 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 test consisted of a pilot test with
4 participants, followed by two rounds with 10 participants each. Inclusion and exclusion criteria were
well described. The developed questionnaire contained 16 questions specific to
telmisartan/hydrochlorothiazide tablets and 3 questions specific to the format of the PL.
There were sufficient questions about the critical sections and the areas concerning traceability,
comprehensibility and applicability were sufficiently covered. The results showed that all questions met
the passing criteria in the first and second round. The readability test has been sufficiently performed.
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VI.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Zanacodar Combi 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 40 mg/12.5 mg, 80 mg/12.5 mg and 80
mg/25 mg 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 Zanacodar Combi with the reference product, and have therefore
granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome
on 14 March 2014
There were no post-approval commitments made during the procedure.
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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
Summary Public Assessment Report
Generics
Zanacodar Combi 40 mg/12.5 mg,
80 mg/12.5 mg and 80 mg/25 mg tablets
telmisartan and hydrochlorothiazide
NL/H/2918/001-003/DC
Date: 7 October 2014
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Summary Public Assessment Report
Generics
Zanacodar Combi 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg tablets
Active substances: telmisartan and hydrochlorothiazide
This is a summary of the public assessment report (PAR) for Zanacodar Combi. It explains how this
medicine was assessed and its authorisation recommended as well as its conditions of use. It is not
intended to provide practical advice on how to use this medicine.
For practical information about using this medicine, patients should read the package leaflet or contact
their doctor or pharmacist.
What is Zanacodar Combi and what is it used for?
Zanacodar Combi is a ‘generic medicine’. This means that it is similar to a ‘reference medicine’
already authorised in the European Union (EU) called MicardisPlus 40 mg/12.5 mg, 80 mg/12.5 mg
and 80 mg/25 mg tablets
This medicine is used in adult patients who have essential hypertension (high blood pressure) that is
not adequately controlled by telmisartan alone or who have been previously stabilised on telmisartan
and hydrochlorothiazide given separately. ‘Essential’ means that the hypertension has no obvious
cause.
How does this medicine work?
Zanacodar Combi contains two active substances, telmisartan and hydrochlorothiazide. Telmisartan is
an ‘angiotensin-II-receptor antagonist’, which means that it blocks the action of a hormone in the body
called angiotensin II. Angiotensin II is a powerful vasoconstrictor (a substance that narrows blood
vessels). By blocking the receptors to which angiotensin II normally attaches, telmisartan stops the
hormone having an effect, allowing the blood vessels to widen.
Hydrochlorothiazide is a diuretic (a ‘water pill’), which is another type of treatment for hypertension. It
works by increasing urine output, reducing the amount of fluid in the blood and reducing the blood
pressure.
The combination of the two active substances has an additive effect, reducing the blood pressure
more than either medicine alone. By lowering the blood pressure, the risks associated with high blood
pressure, such as having a stroke, are reduced.
How is this medicine used?
The medicine can only be obtained with a prescription. The usual dose is one tablet a day. The tablets
should be taken around the same time each day, with or without food. The tablets should be
swallowed with some water or other non-alcoholic drink.
Please read section 3 of the PL for detailed information on dosing recommendations, the route of
administration, and the duration of treatment.
How has this medicine been studied?
Because Zanacodar Combi is a generic medicine, studies in patients have been limited to tests to
determine that it is bioequivalent to the reference medicine, MicardisPlus. Two medicines are
bioequivalent when they produce the same levels of the active substance in the body.
What are the possible side effects of this medicine?
Because Zanacodar Combi is a generic medicine and is bioequivalent to the reference medicine, its
benefits and risks are taken as being the same as MicardisPlus.
Why is this medicine approved?
It was concluded that, in accordance with EU requirements, Zanacodar Combi has been shown to
have comparable quality and to be bioequivalent to MicardisPlus. Therefore, the Medicines Evaluation
Board of the Netherlands decided that, as for the reference medicine, the benefits are greater than its
risk and recommended that it can be approved for use.
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What measures are being taken to ensure the safe and effective use of this medicine?
A risk management plan has been developed to ensure that this medicine is used as safely as
possible. Based on this plan, safety information has been included in the summary of product
characteristics and the package leaflet for Zanacodar Combi, including the appropriate precautions to
be followed by healthcare professionals and patients.
Known side effects are continuously monitored. Furthermore new safety signals reported by
patients/healthcare professionals will be monitored/reviewed continuously as well.
Other information about this medicine
The marketing authorisation for Zanacodar Combi 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg
tablets was granted on 27 May 2014.
The full PAR for this medicine can be found on the website http://mri.medagencies.org/Human.
For more information about treatment with Zanacodar Combi, read the package leaflet
(http://mri.medagencies.org/download/NL_H_2918_001_FinalPL.pdf) or contact your doctor or
pharmacist.
This summary was last updated in October 2014.
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