C B G

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PUBLIC ASSESSMENT REPORT

of the Medicines Evaluation Board
in the Netherlands

Perindopril tert-butylamine 2 mg Ranbaxy, tablets

Perindopril tert-butylamine 4 mg Ranbaxy, tablets
Perindopril tert-butylamine 8 mg Ranbaxy, tablets
Ranbaxy UK Ltd., United Kingdom

perindopril tert-butylamine
This assessment report is published by the MEB pursuant Article 21 (3) and (4) of Directive 2001/83/EC. The report
comments on the registration dossier that was submitted to the MEB and its fellow –organisations in all concerned EU
member states.
It reflects the scientific conclusion reached by the MEB and all concerned member states at the end of the evaluation
process and provides a summary of the grounds for approval of a marketing authorisation.
This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare
professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the
latter category as the language in this report may be difficult for laymen to understand.

This assessment report shall be updated by a following addendum whenever new information becomes available.

General information on the Public Assessment Reports can be found on the website of the MEB.

To the best of the MEB’s knowledge, this report does not contain any information that should not have been made
available to the public. The MAH has checked this report for the absence of any confidential information.

EU-procedure number: NL/H/0977/001-003/DC

Registration number in the Netherlands: RVG 35208-35210

11 January 2010

Pharmacotherapeutic group: ACE inhibitors, plain

ATC code: C09AA04
Route of administration: oral
Therapeutic indication: hypertension; symptomatic heart failure; stable coronary artery
disease
Prescription status: prescription only
Date of authorisation in NL: 12 September 2008
Concerned Member States: Decentralised procedure with CZ, FI, HU, SK, UK,
Only 4 and 8 mg: BE, EE, LT, LV, PL,
Only 4 mg: ES, IT
Application type/legal basis: Directive 2001/83/EC, Article 10(1) and 10(3)

For product information for healthcare professionals and users, including information on pack sizes and
presentations, see Summary of Product Characteristics (SPC), package leaflet and labelling.

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I INTRODUCTION
Based on the review of the quality, safety and efficacy data, the member states have granted a marketing
authorisation for Perindopril tert-butylamine 2 mg, 4 mg and 8 mg Ranbaxy, tablets from Ranbaxy UK Ltd.
The date of authorisation was on 12 September 2008 in the Netherlands.

The product is indicated for:

• treatment of hypertension
• treatment of symptomatic heart failure
• treatment of stable coronary artery disease; reduction of the risk of cardiac events in patients who
have a history of myocardial infarction and/or revascularisation.

A comprehensive description of the indications and posology is given in the SPC.

Perindopril inhibits the enzyme which converts angiotensin I into angiotensin II (angiotensin-converting
enzyme (ACE)). The converting enzyme or kinase is an exopeptidase which converts angiotensin I into
the vasoconstrictor angiotensin II and degrades the vasodilator bradykinin in to an inactive heptapeptide.
Inhibition of the ACE results in a reduction in the plasma levels of angiotensin II, which leads to an
increase in renin activity in the plasma (as a result of the inhibition of the negative feedback from the renin
release) and a reduction in the secretion of aldosterone. As ACE inactivates bradykinin, the inhibition of
ACE also results in the increased activity of the circulating and local kallikrein-kinin systems (and
consequently also the activation of the prostaglandin system). It is possible that this mechanism
contributes to the antihypertensive activity of the ACE inhibitors and is partly responsible for some of their
side effects (e.g. cough).
Perindopril acts via its active metabolite, perindoprilate. The other metabolites do not show any inhibition
of ACE activity in vitro.

This decentralised procedure concerns a generic application claiming essential similarity with the
innovator products Coversyl 2 mg, 4 mg and 8 mg tablets which have been registered in France by Les
Laboratoires Servier since 22 June 1988. In the Netherlands, Coversyl 2 mg and 4 mg tablets have been
registered since 17 July 1989, and Coversyl 8 mg tablets since 14 April 2003 (NL RVG 13635, 13636 and
27786 respectively). In addition, reference is made to Coversyl authorisations in the individual member
states (reference product).

The marketing authorisation is granted based on article 10(1) of Directive 2001/83/EC. In Hungary and
Finland the marketing authorisation for the 2 mg tablet is granted according to Article 10(3) of Directive
2001/83/EC, hybrid application, as the 2 mg product is not authorised in these member states. The
reference product is the 4 mg strength.

This type of application refers to information that is contained in the pharmacological-toxicological and
clinical part of the dossier of the authorisation of the reference product. A reference product is a medicinal
product authorised and marketed on the basis of a full dossier, i.e. including chemical, biological,
pharmaceutical, pharmacological-toxicological and clinical data. This information is not fully available in
the public domain. Authorisations for generic products are therefore linked to the ‘original’ authorised
medicinal product, which is legally allowed once the data protection time of the dossier of the reference
product has expired. For this kind of application, it has to be demonstrated that the pharmacokinetic profile
of the product is similar to the pharmacokinetic profile of the reference product. To this end the MAH has
submitted two bioequivalence studies in which the pharmacokinetic profile of the product is compared with
the pharmacokinetic profile of the reference product. For one study the reference product was Coversyl 4
mg tablets, and for the other study Coversyl 8 mg tablets. Both reference products were registered in
France. A bioequivalence study is the widely accepted means of demonstrating that difference of use of
different excipients and different methods of manufacture have no influence on efficacy and safety. These
generic products can be used instead of their reference products.

No new pre-clinical and clinical studies were conducted, which is acceptable for this abridged application.
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No scientific advice has been given to the MAH with respect to these products, and no paediatric
development programme has been submitted, as this is not required for a generic application.

II SCIENTIFIC OVERVIEW AND DISCUSSION

II.1 Quality aspects

Compliance with Good Manufacturing Practice

The MEB has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for
these product types at all sites responsible for the manufacturing of the active substance as well as for the
manufacturing and assembly of this product prior to granting its national authorisation.

Active substance
The active substance is perindopril tert-butylamine, an established active substance described in the
European Pharmacopoeia (Ph.Eur.*). The active substance is freely soluble in water.

The CEP procedure is used for the active substance. 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 suitablity 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 new 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.

Quality control of drug substance

The chemical-pharmaceutical documentation on the active substance is of sufficient quality in view of the
present European regulatory requirements. The MAH has submitted a copy of a valid CEP for the active
substance perindopril tert-butylamine. The control tests and specifications for the drug substance are
adequately drawn up. Batch analytical data demonstrating compliance with the drug substance
specification have been provided.

Stability
The active substance is stable for 24 months when stored under the stated conditions. Assessment
thereof was part of granting the CEP and has been granted by the EDQM.

* Ph.Eur. is an official handbook (pharmacopoeia) in which methods of analysis with specifications for
substances are laid down by the authorities of the EU.

Medicinal Product

Composition
Perindopril tert-butylamine 2 mg Ranbaxy contains as active substance 2 mg of perindopril tert-
butylamine, corresponding to 1.669 mg perindopril, and is a light pink to pink coloured capsule shaped
tablet debossed with ‘P9’ on one side and a deep breakline on the other side.

Perindopril tert-butylamine 4 mg Ranbaxy contains as active substance 4 mg of perindopril tert-

butylamine, corresponding to 3.338 mg perindopril, and is a white to off-white capsule shaped tablet
debossed with ‘P5’ on one side and a deep breakline on other side.

Perindopril tert-butylamine 8 mg Ranbaxy contains as active substance 8 mg of perindopril tert-

butylamine, corresponding to 6.676 mg perindopril, and is a white to off white coloured capsule shaped
tablet debossed with ‘P’ and ‘6’ on either side of the breakline on one side and a breakline on the other
side.

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The tablets are packed in a transparent PVC/Aluminium foil blister or in an opaque cold form/Aluminium
foil blister.

The excipients are: lactose monohydrate, microcrystalline cellulose (E460), magnesium stearate (E470b),
colloidal anhydrous silica (E551); 2 mg only: red ferric oxide (E172).

The 4 mg and the 8 mg formulation are fully dose proportional; the 2 mg tablet contains the same amount
of excipients as the 4 mg formulation with a minor difference in lactose to compensate for the difference in
the content of the active substance.

Pharmaceutical development
The development of the product has been described, the choice of excipients is adequately justified and
their functions explained. The excipients and packaging are usual for this type of dosage form. The
dissolution profiles show that the test products and the reference products dissolve fast at three different
pH conditions. The profiles are similar for all tablets strengths and are equivalent to the reference product.
The pharmaceutical development of the product has been adequately performed.

Manufacturing process
The manufacturing process consists of blending the ingredients of the tablet core and granulating by
compaction. The manufacturing process has been adequately validated according to relevant European
guidelines. Process validation data on the product have been presented for 2 pilot scaled batches of 2 mg
tablets and 2 batches of a common blend for 4 or 8 mg tablets. The tabletting process is comparable for
all strengths. The provided data are therefore deemed sufficient. The product is manufactured using
conventional manufacturing techniques. Process validation for full scaled batches will be performed post
authorisation.

Excipients
The excipients comply with Ph.Eur. These specifications are acceptable.

Quality control of drug product

The product specification includes tests for appearance, identity, assay, degradation, dissolution,
disintegration, microbial limits, water, and uniformity of dosage units. For water content, related
substances and assay separate shelf-life requirements have been set. The proposed limits are
acceptable.
The analytical methods have been adequately described and validated. Batch analytical data from the
proposed production site have been provided on 2 pilot scaled batches of each strength, demonstrating
compliance with the release specification.
The product specifications cover appropriate parameters for this dosage form. Validations of the analytical
methods have been presented. Batch analysis have been performed on 2 batches of each tablet strength.
The available batch analysis results show that the tablets meet the proposed specifications.

Stability tests on the finished product

Stability data on the product have been provided on 2 pilot scaled batches of each strength stored at
25°C/60% RH (18 months) and 30°C/65% RH (12 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
PVC/Al blisters and in OPA-Al-PVC/ Al blisters as proposed for marketing.
The available results are sufficient to grant the claimed shelf-life of 18 months, stored below 25°C, for the
tablets packaged in PVC/Al blisters and in OPA-Al-PVC/ Al blisters.
Photostability studies show that the product is not sensitive to light. The substance and the product are
however sensitive to moisture. The proposed storage conditions ‘Store in the original packaging for
protection against moisture’ are therefore acceptable.

Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
For lactose and magnesium stearate, scientific data and/or Certificates of suitability issued by the EDQM
have been provided and compliance with the Note for Guidance on Minimising the Risk of Transmitting
Animal Spongiform Encephalopathy Agents via medicinal products has been satisfactorily demonstrated.
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II.2 Non clinical aspects

This products are generic formulations of Coversyl 2 mg, 4 mg and 8 mg tablets, which are available on
the European market. No new preclinical data have been submitted, and therefore the application has not
undergone preclinical assessment. This is acceptable for this type of application.

Environmental risk assessment

The product is intended as a substitute for other identical products on the market. The approval of this
product will not result in an increase in the total quantity of perindopril tert-butylamine released into the
environment. It does not contain any component, which results in an additional hazard to the environment
during storage, distribution, use and disposal.

II.3 Clinical aspects

Perindopril tert-butylamine is a well-known active substance with established efficacy and tolerability.

For this generic application, the MAH has submitted a bioequivalence study in which the pharmacokinetic
profile of the test product Perindopril tert-butylamine 4 mg Ranbaxy is compared with the pharmacokinetic
profile of the reference product Coversyl 4 mg tablets.

The choice of the reference product

The choice of the reference product in the bioequivalence study has been justified by comparison of
dissolution results of reference products in different member states.

The formula and preparation of the bioequivalence batch is identical to the formula proposed for
marketing.

Bioequivalence study with 4 mg

Design
An open label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover
bioequivalence study was carried out under fasted conditions in 32 healthy male Asian subjects, aged 20-
37 years. Each subject received a single dose (4 mg) of one of the 2 perindopril tert-butylamine
formulations. The tablet was orally administered with 240 ml water. There were 2 dosing periods,
separated by a washout period of at least 5 weeks.

Blood samples were collected pre-dose and at 0.17, 0.33, 0.5, 0.58, 0.67, 0.83, 1, 1.25, 1.5, 2, 2.5, 3, 3.5,
4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 16, 24, 48, 72, 120, 168, 216, 264, 312 and 360 hours after
administration of the products.

Analytical/statistical methods
A high performance liquid chromatography mass spectrometric method (LCMS/MS) for the simultaneous
determination of parent perindopril and its active metabolite perindoprilat in human plasma was developed
and validated using ramipril and ramiprilat as internal standards. The bioanalytical methods have been
validated.
Analysis of variance (ANOVA) has been performed on pharmacokinetic parameters (Cmax, AUC0-t and
AUC0-∞ for log (natural)- transformed data using appropriate procedure of SAS system. The 90%
confidence intervals for the ratios of Cmax, AUC0-t and AUC0-∞ have been calculated. The mixed effect
ANOVA model included sequence, formulation (treatment) and period as fixed effects and subject nested
within sequence as a random effect.

Results
Out of the 32 included subjects, 26 subjects completed both periods of the study. A total of 6 subjects
were withdrawn from the study for the following reasons:

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• One subject was withdrawn from the study in Period I due to an adverse event of acarodermatitis
(infected scabies).
• One subject was withdrawn from the study in Period I due to an adverse event of pyrexia.
• One subject was withdrawn from the study in Period II due to inadequate cooperation.
• One subject was withdrawn from the study in Period II due to an adverse event of furuncle over left
cheek.
• One subject was withdrawn from the study in Period II due to an adverse event of vomiting.
• One subject was withdrawn from the study prior to Period II due to an adverse event of skin injury,
experienced during the washout of Period I.

Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax

(median, range)) of perindopril under fasted conditions.

Treatment AUC0-t AUC0-∞ Cmax tmax t1/2

N=26 μg.h/l μg.h/l μg/l h h
Test 61 ± 15 61 ± 15 59 ± 15 0.58 0.78 ± 0.13
(0.33-1.33)

Reference 58 ± 14 59 ± 14 56 ± 14 0.58 0.78 ± 0.14

(0.50-1.33)
*Ratio (90% 1.05 1.05 1.05 - -
CI) (1.00-1.10) (1.00-1.09) (0.98-1.13)

CV (%) 9.9 9.7 14.3 - -

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
*ln-transformed values

Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax

(median, range)) of perindoprilat under fasted conditions.

Treatment AUC0-t AUC0-∞ Cmax tmax t1/2

N=26 μg.h/l μg.h/l μg/l h h
Test 303 ± 104 445 ± 163 6.0 ± 2.7 6.5 175 ± 88
(0.67-16.0)

Reference 299 ± 112 450 ± 176 6.1 ± 3.2 7.0 186 ± 95

(0.83-16.0)
*Ratio (90% 1.05 1.02 1.02 - -
CI) (0.97-1.15) (0.94-1.11) (0.91-1.14)

CV (%) 18.5 17.9 24.4 - -

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
*ln-transformed values

The 90% confidence intervals calculated for AUC0-t, AUC0-∞ and Cmax are in agreement with those
calculated by the MAH and are within the bioequivalence acceptance range of 0.80 – 1.25. The

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extrapolation of the AUC of perindoprilat was more than 20% caused by the long half-life of perindoprilat
of approximately 180 hours, which is according to literature. However, as sampling for perindoprilat took
place for 360 hours the truncated AUC is sufficient. Based on the pharmacokinetic parameters of
perindopril supported by the data of perindoprilat under fasted conditions, it can be concluded that
Perindopril tert-butylamine 4 mg Ranbaxy and Coversyl 4 mg tablets are bioequivalent with respect to rate
and extent of absorption, and fulfil the bioequivalence requirements outlined in the relevant CHMP Note
for Guidance. It is advice also for the innovator that peridopril should be used before the meals. Therefore
no food interaction study is necessary.

Extrapolation to other strengths

The Perindopril tert-butylamine tablets fulfil the conditions for waiver of bioequivalence studies with 2 mg
and 8 mg strengths of the product:
• The qualitative composition of the different strengths is the same (except for 2 mg where ferric oxide
(red) is used as colorant).
• The excipients included in the composition of the formulation are well established and no interaction
with the pharmacokinetics of the active substance is expected.
• The 4 mg and 8 mg Perindopril tert-butylamine tablets are “scale up - scale down” of the same
formulation (the ratio of active ingredient to excipients is the same in both strengths). The 2 mg and 4
mg strengths are ‘look alike’ formulations, i.e, the ratio between the amounts of excipients (except
diluent and colourant) is similar for both the strengths (the amount active ingredient differs,
compensated by the amount of lactose, for the rest all amounts of excipients are equal).
• The therapeutic doses of perindopril show a linear and dose-proportional kinetic behaviour following
both single oral dosing and at steady state during a once a day multiple dosing regimen.
• The dissolution profiles are similar. The in vitro test of dissolution characteristics demonstrates that
dissolution profiles of the MAH’s perindopril tert-butylamine tablets and those of the Innovator’s in
different member states are very similar.
• The results of comparative in vitro dissolution studies exhibit that the rate and extent of % drug
dissolved from the MAH’s and Innovator’s formulations are comparable.

However, the ratio between the amounts of active substance and excipients is not the same for the 2 mg
and 4 mg tablets. Furthermore, in both tablets the concentration of the active substance is not less than
5%, which is a requirement for the “look alike” approach according to the CHMP NfG on Investigation of
Bioavailability and Bioequivalence (2001). However, based on the good solubility properties of the
perindopril tablets and that perindopril is well and quickly absorbed, it is expected that the deviation from
the guideline has no influence on the bioavailability/bioequivalence of the various perindopril strengths
presented in this application. The results of the bioequivalence study performed with the 4 mg strength
therefore apply also to the 2 mg strength.

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).

Discussion on bioequivalence
One of the CMS’s could not agree with the extrapolation of the results from the bioequivalence study with
the 4 mg strength in support of the application for the 8 mg strength. According to this member state,
evidence of bioequivalence of the 8 mg product has not been provided and the safety/efficacy of the 8 mg
product has not been demonstrated.
This issue could not be resolved during the initial procedure, and therefore a CMD(h) referral was started
for the 8 mg strength. The rationale provided by the CMS for referral was as follows:
The linearity/non-linearity of perindopril is not straightforward and the free:bound fraction increases with
increasing the dose. If there is bioinequivalence, it is more likely to be shown with the higher dose (8 mg
versus 4 mg), where the sensitivity to detect a difference between formulations may be greater.
As regards CHMP Note for Guidance (NfG), the arguments related to safety, pharmacokinetic and
analytical grounds need to be addressed to the particular dose chosen for the bioequivalence study and
not in general. There are no apparent safety or analytical issues with perindopril 8 mg being used in

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bioequivalence study. For reasons given above, 8 mg might be more likely to detect any difference
between these formulations and should have been the dose selected for the study.

CMD(h) referral
During the CMD(h) referral procedure, the MAH submitted a protocol of a bioequivalence study with
Perindopril tert-butylamine 8 mg Ranbaxy tablets. In addition, a renewed literature overview was given,
demonstrating that although perindopril dose linearity is not straightforward, due to a saturable protein /
ACE binding, this is not translated into an observed nonlinearity in a clinical study setting. Concentration
dependent perindoprilat protein binding, mainly to ACE, is only about 20% estimated from the 8 mg dose,
which explains why despite a theoretical ceiling in perindopril protein binding dose linear pharmacokinetics
are observed in the clinical dose range. The choice of the 4 mg dose-strength for the bioequivalence study
would then be justified on the CHMP NfG requirements, safety and analytical considerations.
Despite these justifications, consensus could not be reached on the main question whether the results
from the bioequivalence study with the 4 mg strength could be extrapolated to the 8 mg in support of the
application for the 8 mg strength. As the MAH had already started a bioequivalence study with the 8 mg
strength, it was decided to await the results.

Bioequivalence study with 8 mg

Design
An open label, balanced, randomized, two treatment, two-period, two-sequence, single dose, crossover
bioequivalence study was carried out under fasted conditions in 26 healthy male Asian subjects, aged 21-
32 years. The study was carried out with Perindopril tert-butylamine 8 mg Ranbaxy tablets and the
reference product Coversyl 8 mg tablets from the French market. The test product is identical to the
product to be marketed. The generic product has the same qualitative composition as the originator
product with regard to the active ingredient. Each subject received a single dose (8 mg) of one of the 2
perindopril tert-butylamine formulations. The tablet was orally administered with 240 ml water. There were
2 dosing periods, separated by a washout period of at least 35 days.

Blood samples were collected pre-dose and at 0.083, 0.167, 0.25, 0.333, 0.417, 0.5, 0.583, 0.667, 0.75,
0.833, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48 and 72 hours after administration of the
products.

Analytical/statistical methods
A high performance liquid chromatography mass spectrometric method (LCMS/MS) for the simultaneous
determination of the parent perindopril and the active metabolite perindoprilat in human plasma was
developed and validated using ramipril and ramiprilat as internal standards.
Analysis of variance (ANOVA) has been performed on pharmacokinetic parameters (Cmax, AUC0-t and
AUC0-∞ for log (natural)- transformed data using appropriate procedure of SAS system. The 90%
confidence intervals for the ratios of Cmax, AUC0-t and AUC0-∞ have been calculated. The mixed effect
ANOVA model included sequence, formulation (treatment) and period as fixed effects and subject nested
within sequence as a random effect.

Results
All 26 subjects completed the study and were eligible for pharmacokinetic analysis.

Table 3. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax

(median, range)) of perindopril under fasted conditions.

Treatment AUC0-t AUC0-∞ Cmax tmax t1/2

N=26 μg.h/l μg.h/l μg/l h h
Test 94 ± 21 95 ± 21 98 ± 32 0.58 0.78 ± 0.22
(0.33-1.25)

Reference 92 ± 26 92 ± 26 96 ± 26 0.58 0.78 ± 0.15

(0.25-1.00)

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*Ratio (90% 1.03 1.03 1.00 - -

CI) (0.96-1.11) (0.96-1.11) (0.90-1.11)

CV (%) 16 16 22 - -

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
*ln-transformed values

Table 4. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax

(median, range)) of perindoprilat under fasted conditions.

Treatment AUC0-t AUC0-∞ Cmax tmax t1/2

N=26 μg.h/l μg.h/l μg/l h h
Test 233 ± 34 - 12 ± 4 6.0 -
(4.0-10.0)

Reference 222 ± 52 - 11 ± 5 6.0 -

(4.0-12.0)
*Ratio (90% 1.07 - 1.10 - -
CI) (1.01-1.12) (1.00-1.20)

CV (%) 10 - 19 - -

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
*ln-transformed values

The 90% confidence intervals calculated for AUC0-t, AUC0-∞ and Cmax of perindopril and AUC0-t and Cmax of
perindoprilat are in agreement with those calculated by the MAH and are within the bioequivalence
acceptance range of 0.80 – 1.25. It is acceptable that for the metabolite only the AUC0-t is reported,
because of the long half-life of perindoprilat (approximately 180 hours) and as after 72 hours absorption is
assumed to be complete. Based on the pharmacokinetic parameters of perindopril supported by the data
of perindoprilat under fasted conditions, it can be concluded that Perindopril tert-butylamine 8 mg
Ranbaxy and Coversyl 8 mg tablets are bioequivalent with respect to rate and extent of absorption, and
fulfil the bioequivalence requirements outlined in the relevant CHMP Note for Guidance.

CMD(h) conclusion
Bioequivalence has been demonstrated for the 8 mg product. Therefore, agreement could be reached and
the 8 mg strength was found approvable.

Risk management plan

Perindopril tert-butylamine was first approved in 1988, and there is now more than 10 years post-
authorisation experience with the active substance. The safety profile of perindopril tert-butylamine can be
considered to be well established and no product specific pharmacovigilance issues were identified pre- or
postauthorisation which are not adequately covered by the current SPC. Additional risk minimisation
activities have not been identified for the reference medicinal product. The MAH has a pharmacovigilance
system at their disposal, which is based on the current European legislation. Routine pharmacovigilance
activities are sufficient to identify actual or potential risks and a detailed European Risk Management Plan
is not necessary for this product.
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Product information

Readability test
The package leaflet has been evaluated via a user consultation study in accordance with the requirements
of Articles 59(3) and 61(1) of Directive 2001/83/EC. A preliminary test was performed with 2 participants,
which led to some revisions to the leaflet e.g. addition of examples of ACE inhibitors in section 1 and
several changes in section 2 ‘Do not take Perindopril tablets if any of the following apply to you’.
Subsequently a test with 10 participants was performed. This led to the following main results:
- The correct section was traced to answer the question on average 98.75% of the time.
- A similar result was achieved that, on average, each question was answered correctly 98.13% of
the time.
Due to the high score no changes to the leaflet have been done. A second round with an additional 10
participants gave a similar outcome and also after this round the leaflet has not been modified.
The readability test itself and the evaluation report are of acceptable quality. There were sufficient
questions about the critical sections. The conclusions are clear, concise and clearly presented.
Furthermore, the following areas have been sufficiently covered: traceability, comprehensibility and
applicability.

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III OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT

Perindopril tert-butylamine 2 mg, 4 mg and 8 mg Ranbaxy, tablets have a proven chemical-
pharmaceutical quality and are generic forms of Coversyl 2 mg, 4 mg and 8 mg tablets. Coversyl tablets is
a well-known medicinal product with an established favourable efficacy and safety profile.

The MAH has provided written confirmation that systems and services are in place to ensure compliance
with their pharmacovigilance obligations.

The SPC, package leaflet and labelling are in the agreed templates and are in agreement with other
perindopril tert-butylamine containing products.

The Board followed the advice of the assessors.

Agreement between member states was reached during a written procedure on the 2 mg and 4 mg
tablets. Bioequivalence was shown to be in compliance with the requirements of European guidance
documents.
Regarding the 8 mg tablets, an unresolved issue remained regarding demonstration of bioequivalence.
Therefore, a CMD(h) referral was started. Agreement could still not be reached on whether the 4 mg
bioequivalence results could be extrapolated to the 8 mg strength. Subsequently, the MAH submitted a
newly performed bioequivalence study with the 8 mg tablet, demonstrating bioequivalence. Herewith
agreement could be reached, and the issue regarding bioequivalence was resolved.

The member states, on the basis of the data submitted, considered that essential similarity has been
demonstrated for Perindopril tert-butylamine 2 mg, 4 mg and 8 mg Ranbaxy, tablets with the reference
product, and have therefore granted a marketing authorisation. The decentralised procedure was finished
on 23 January 2008 for the 2 mg and 4 mg strengths, and on 1 May 2008 for the 8 mg product. Perindopril
tert-butylamine 2 mg, 4 mg and 8 mg Ranbaxy, tablets were authorised in the Netherlands on 12
September 2008.

The PSUR submission cycle is 3 years. The first PSUR will cover the period from January 2008 to
January 2011.

The date for the first renewal will be: 23 January 2013

There were no post-approval commitments made during the procedure.

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List of abbreviations
ASMF Active Substance Master File
ATC Anatomical Therapeutic Chemical classification
AUC Area Under the Curve
BP British Pharmacopoeia
CEP Certificate of Suitability to the monographs of the European Pharmacopoeia
CHMP Committee for Medicinal Products for Human Use
CI Confidence Interval
Cmax Maximum plasma concentration
CMD(h) Coordination group for Mutual recognition and Decentralised procedure for
human medicinal products
CV Coefficient of Variation
EDMF European Drug Master File
EDQM European Directorate for the Quality of Medicines
EU European Union
GCP Good Clinical Practice
GLP Good Laboratory Practice
GMP Good Manufacturing Practice
ICH International Conference of Harmonisation
MAH Marketing Authorisation Holder
MEB Medicines Evaluation Board in the Netherlands
NfG Note for Guidance
OTC Over The Counter (to be supplied without prescription)
PAR Public Assessment Report
Ph.Eur. European Pharmacopoeia
PIL Package Leaflet
PSUR Periodic Safety Update Report
SD Standard Deviation
SPC Summary of Product Characteristics
t½ Half-life
tmax Time for maximum concentration
TSE Transmissible Spongiform Encephalopathy
USP Pharmacopoeia in the United States

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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY

Scope Procedure Type of Date of start Date of Approval/ Assessment
number modification of the end of the non report
procedure procedure approval attached
Insertion of text in section 5.1 of NL/H/0977/ II 2-9-2008 1-11-2008 Approval Y, Annex I
SmPC after Heart Failure Indication 001-002
/II/001
Change in batch size of the NL/H/0977/ IA 23-7-2008 6-8-2008 Approval N
finished product; up to 10-fold 002/IA/002
compared to the original batch size
approved at the grant of the
marketing authorisation

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ANNEX I – Type II variation NL/H/0977/001-002/II/001

INTRODUCTION
The MAH proposes two type II variations to include the results of the EUROPE study in the SPC.
Perindopril is indicated for the treatment of essential hypertension, symptomatic heart failure and
reduction of the risk of cardiac events in stable coronary artery disease.
The Netherlands is the RMS in this procedure with the following CMSs: BE, CZ, EE, ES, FI, HU, IT, LT,
LV, PL, SK, UK.

ASSESSMENT
The MAH proposes to implement a text in section 5.1 of the SPC. This variation considers adjustment of
the SPC in section 5.1 after Heart Failure indication to include the results of the EUROPE study.
The following text has been added:

Patients with stable coronary artery disease

The EUROPA study was a multicentre, international, randomised, double-blind, placebo-controlled clinical
trial lasting 4 years.
Twelve thousand two hundred and eighteen (12218) patients aged over 18 were randomised to
perindopril 8 mg (n=6110) or placebo (n=6108).
The trial population had evidence of coronary artery disease with no evidence of clinical signs of heart
failure.
Overall, 90% of the patients had a previous myocardial infarction and/or revascularisation.
Most of the patients received the study medication on top of conventional therapy including plalelet
inhibitors, lipid lowering agents and beta-blockers.
The main efficacy criterion was the composite of cardiovascular mortality, non fatal myocardial infarction
and/or cardiac arrest with successful resuscitation. The treatment with perindopril 8 mg once daily resulted
in a significant absolute reduction in the primary endpoint of 1.9% (relative risk reduction of 20%, 95%CI
[9.4; 28.6] – p<0.001). In patients with a history of myocardial infarction and/or revascularisation, an
absolute reduction of 2.2% corresponding to a RRR of 22.4% (95%CI [12.0; 31.6] – p<0.001) in the
primary endpoint was observed by comparison to placebo.

The text proposal is in harmonisation with the text in the SPC of the innovators product. Furthermore, the
text has already been implemented in the SPC of Perindopril tert-butylamine 8 mg Ranbaxy
(NL/H/0977/003/MR) during the CMD(h) referral procedure of this strength. The variation at issue has
been submitted to include the same text in the SPC of the other strengths (2 and 4 mg) and for the
registration (NL/H/0978).

CONCLUSION
The variations were mutually recognised and ended positively on 1 November (day 60 of the procedure).

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