Actelsar 80 mg Tabletten

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5 | A-1200 Wien | www.basg.at | www.ages.at

CMDh/223/2005

February 2014

Public Assessment Report

Scientific discussion

Actelsar 20 mg Tabletten

Actelsar 40 mg Tabletten

Actelsar 80 mg Tabletten

Telmisartan

AT/H/0335/001-003/DC

Date: 18.01.2016

This module reflects the scientific discussion for the approval of Actelsar 20 mg

Tabletten, Actelsar 40 mg Tabletten, Actelsar 80 mg Tabletten. The procedure was

finalised at 22.02.2011.

For information on changes after this date please refer to the

module ‘Update’.

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5 | A-1200 Wien | www.basg.at | www.ages.at

I.

INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a

marketing authorisation for Actelsar 20 mg Tabletten, Actelsar 40 mg Tabletten, Actelsar 80

mg Tabletten, from Actavis Group PTC ehf.

The product is indicated for:

Treatment of essential hypertension in adults.

Reduction of cardiovascular morbidity in patients with:

i) manifest atherothrombotic cardiovascular disease (history of coronary heart disease,

stroke, or peripheral arterial disease) or

ii) type 2 diabetes mellitus with documented target organ damage.

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

marketing

authorisation

been

granted

pursuant

Article

10(1)

Directive

2001/83/EC.

Telmisartan is an orally active and specific angiotensin II receptor (type AT

) antagonist.

In human, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked

blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable

up to 48 hours.

II.

QUALITY ASPECTS

II.1

Introduction

Actelsar is a tablet which is presented in a Al/Al blister or a HDPE container.

II.2

Drug Substance

The active substance in Actelsar is telmisartan. The specification of the active substance

meets the current scientific requirements. The adequate quality of the active substance has

been shown by submitting the appropriate control data. The stability of the active substance

has been tested under ICH conditions. The results of the stability studies support the

established retest-period.

II.3

Medicinal Product

Actelsar contains the following excipients:

Magnesium stearate

Croscarmellose sodium

Mannitol (E421)

Povidone (K-29/32)

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5 | A-1200 Wien | www.basg.at | www.ages.at

Potassium Hydroxide

The manufacturers responsible for batch release are:

Actavis hf, Reykjavikurvegur 76-28, 220 Hafnafjördur, Iceland.

Actavis Ltd, BLB 016 Bulebel Industrial Estate, ZTN 3000 Zejtun, Malta.

The development of the product has been sufficiently made and deemed appropriate. The

usage of all the excipients has been described.

The release specification includes the check of all parameters relevant to this pharmaceutical

form. Appropriate data concerning the control of the finished product support the compliance

with the release specifications.

The packaging of the medicinal product complies with the current legal requirements.

Stability studies under ICH conditions have been performed and data presented support the

shelf life claimed in the SmPC, with a shelf life of 24 months when stored in the original

package to protect from light.

The pharmaceutical quality of Actelsar has been adequately shown.

II.4

Discussion on chemical, pharmaceutical and biological aspects

Information on development, manufacture and control of active substance and medicinal

product has been presented in a satisfactory manner. The results of tests carried out indicate

satisfactory consistency and uniformity of important product quality characteristics.

III.

NON-CLINICAL ASPECTS

Pharmacodynamic,

pharmacokinetic

and toxicological

properties of telmisartan

are well

characterized and documented. As telmisartan is widely used and well-known, the applicant

has not provided additional studies and further studies are not required. Overview based on

literature review is, thus, appropriate.

III.1

Ecotoxicity/environmental risk assessment (ERA)

Since Actelsar 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.

IV.

CLINICAL ASPECTS

IV.1

Introduction

This is a generic application, therefore demonstration of therapeutic equivalence is shown by

means of pharmacokinetic bioavailability studies. New clinical studies are neither required

nor submitted. One Bioequivalence study has been submitted.

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5 | A-1200 Wien | www.basg.at | www.ages.at

IV.2

Pharmacokinetics

Three strengths are claimed by the applicant: 20, 40 and 80 mg. Bioequivalence to the brand

leader was tested only with the highest 80 mg strength. Biowaiver is claimed for the lower 40

and 20 mg strengths.

Biowaiver

The following criteria for a biowaiver are fulfilled:

All strengths are manufactured by the same manufacturer using the same process

The qualitative composition of the different strengths is the same

The ratio between amounts of active substance and excipients, is the same for all

strengths

All strengths exhibit similar in vitro dissolution profiles at different pH conditions

The drug in-put is not linear. The BA increases more than proportionally to the dose,

but the BE is investigated at the most sensitive conditions i.e. with the highest 80 mg

strength.

Bioequivalence study

Test product: Telmisartan 80 mg tablets

Reference product: Micardis 80 mg tablets, Boehringer Ingelheim GmbH

study

designed

according

open-label,

randomised,

single-dose,

2-way

crossover, 2-sequence classical scheme.

Healthy non-smoking adult female and male volunteers were enrolled. In each period,

subjects were housed before dosing until after the 24-hour post-dose events. Subjects were

required to return to the clinical facility the 36, 48, 72, 96, and 120-hour blood draws.

On the morning of Day 1, in each period, subjects received a single oral 80 mg dose, after an

overnight fast, with 240 ml of water. Doses were separated by a 14-day washout period.

A total of 25 blood samples were collected in each period at pre-dose (2 samples) 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, 8, 12, 24, 36, 48, 72, 96, and

120 hours post-dose.

Pharmacokinetic Variables

Relevant PK parameters of telmisartan were estimated. The pharmacokinetic parameters

0-t,

0-inf

and t

were either observed or calculated. AUC was calculated by the

trapezoidal rule. C

and t

were directly estimated from the individual concentrations

versus time profiles.

Bioequivalence Criteria:

Bioequivalence could be concluded if the 90 % CI of the ratio of the least square means of the

test to reference products is within 80-125 % for AUC and 75-133 % for C

No statement is made for t

Results:

Table 1.

Pharmacokinetic

parameters

(non-transformed

values;

arithmetic

mean ± SD, t

max

median, range): Single Telmisartan 80 mg oral dose

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5 | A-1200 Wien | www.basg.at | www.ages.at

Treatment

AUC

0-t

xg/ml/h

AUC

0-∞

xg/ml/h

C

max

xg/ml

t

max

h

Test

1537.90

(2034.16)

1865.50

(2581.17)

266.13

(327.49)

1.00

[0.50-5.00]

Reference

1535.62

(2057.61)

1920.03

(2462.45)

311.86

(416.17)

0.84

(0.33-4.00)

*Ratio (90% CI)

[94;107]%

100 %

[91; 104]%

97 %

[76;95]%

85 %

AUC

0-t

Area under the plasma concentration curve from administration to last observed

concentration at time t.

0-72h

be reported instead of AUC

, in studies with sampling period of

72 h, and where the concentration

at 72 h is quantifiable. Only for immediate release products

AUC

0-∞

Area under the plasma concentration curve extrapolated to infinite time.

0-∞

does not need to be reported when

0-72h

is reported instead of

C

max

Maximum plasma concentration

t

max

Time until Cmax is reached

*ln-transformed values

The conventional CI for Log transformed AUC

, AUC

are within the (80;125)% acceptance

range.

No significant difference in t

was evidenced by the non parametric test.

A statistically significant difference between the Test and Reference is observed with C

The point estimate for the ratio is 0.85 and the 90% CI is not included in the standard

[80;125]% acceptance range. The applicant claimed that the acceptance range should be

widened and set to [75;133]%. This claim is extensively justified in the study protocol.

Conclusion on bioequivalence studies:

Based

submitted

bioequivalence

study,

Actelsar

Tabletten

considered

bioequivalent with Micardis 80 mg tablets.

The results of the bioequivalence study with the 80 mg formulation can be extrapolated to the

other strengths 20 mg and 40 mg, according to conditions in Guideline on the Investigation of

Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6.

The justification for BCS (Biopharmaceutics Classification System) - based biowaiver can be

accepted.

IV.3

Pharmacodynamics

Pharmacodynamic

properties of telmisartan

are well characterized

and documented. As

telmisartan is widely used and well-known, the applicant has not provided additional studies

and further studies are not required.

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5 | A-1200 Wien | www.basg.at | www.ages.at

IV.4

Clinical efficacy and safety

Efficacy and safety of telmisartan in the proposed indications are known and assessed as

being scientifically based considering recent knowledge, guidelines, and recommendations.

The safety profile of the test product is comparable with the safety profile of the reference

product.

IV.5

Risk Management Plan

No Risk Management Plan (RMP) is in place for Actelsar.

Marketing authorisation was granted before the new pharmacovigilance legislation came into

force. Therefore it is accepted that the marketing authorisation holder did not submit a RMP.

IV.6

Discussion on the clinical aspects

The dossier contains an adequate review of published clinical data and bioequivalence has

been shown for the 80 mg formulation. For the 20 mg and 40 mg formulations a biowaver can

be granted.

V.

USER CONSULTATION

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. The language used for the

purpose of user testing the PIL was English.

The results show that the package leaflet meets the criteria for readability as set out in the

Guideline on the readability of the label and package leaflet of medicinal products for human

use.

VI.

OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

Bioequivalence of Actelsar 80 mg Tabletten with the reference product Micardis 80 mg

tablets, Boehringer Ingelheim, has been shown. Additionally, a biowaver has been granted for

Actelsar 20 mg Tabletten and Actelsar 40 mg Tabletten.

The pharmaceutical quality of Actelsar has been adequately shown and no new non-clinical or

clinical concerns have been identified.

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5 | A-1200 Wien | www.basg.at | www.ages.at

Public Assessment Report

Update

Actelsar 20 mg Tabletten

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5 | A-1200 Wien | www.basg.at | www.ages.at

Actelsar 40 mg Tabletten

Actelsar 80 mg Tabletten

Telmisartan

This module reflects the procedural steps and scientific information after the finalisation

of the initial procedure.

PAR Scientific discussion

9/10

Scope

Procedure number

Product Information

affected

Date of start of the

procedure

Date of end of

procedure

Approval/

non approval

Assessment report

attached

B.II.d).1. z) Other variation Microbiological quality validation

AT/H/0335/001-

003/IB/001

15.12.2011

20.02.2012

Approved

B.III.1.a). 1 New certificate from an already approved

manufacturer

AT/H/0335/001-

003/IA/002

15.12.2011

04.01.2012

Positive

Grouped variations: DMF updated,

- Starting material redefined

- Tightening of specification limits

- Addition of a new specification parameter to the specification

with its corresponding test method

- Extension or introduction of a re-test period/storage period

supported by real time data

AT/H/0335/001-

003/IB/003/G

15.12.2011

20.02.2012

Approved

C.I.2. a) Implementation of change(s) for which no new

additional data are submitted by the MAH CHMP adopted

safety variations for originator Micardis

AT/H/0335/001-

003/IB/004

04.12.2012

20.02.2012

Approved

C.I.2. a) Implementation of change(s) for which no new

additional data are submitted by the MAH Update of product

information according to European Public Assessment Report

for Telmisartan Actavis

AT/H/0335/001-

003/IB/005

04.12.2012

10.01.2013

Approved

Administrative change: Withdrawal of 20 mg strengths in HU

21.12.2012

Approved

Administrative change: Withdrawal of 20,40,80 mg strengths

in IE

29.04.2013

Approved

B.II.f).1.b). 1 As packaged for sale (supported by real time

data) 24->36 months

AT/H/0335/001-

003/IB/006

25.07.2013

27.08.2013

Approved

Administrative change: Withdrawal of 40 mg and 80 mg

strengths in SK

15.04.2014

Approved

B.II.b).4. a) Up to 10-fold compared to the originally approved

batch size

AT/H/0335/001-

002/IA/007

12.05.2014

16.05.2014

Positive

C.I.1. a) The medicinal product is covered by the defined

scope of the procedure C.I.2. a) Implementation of change(s)

for which no new additional data is required to be submitted

by the MAH

Article 31 for RAS

- Safety update in line with originator

AT/H/0335/001-

003/IB/008/G

04.08.2014

22.01.2015

Approved

PAR Scientific discussion

10/10

Administrative change: Withdrawal of 40 mg and 80 mg

strengths in HU

29.08.2014

Approved

A.7. Deletion of manufacturing sites for an active substance,

intermediate or finished product, packaging site, manufacturer

responsible for batch release, site where batch control takes

place, or supplier of a starting material, reagent or excipient

(when mentioned in the dossier)* B.III.1.a). 2 Updated

certificate from an already approved manufacturer

AT/H/0335/001-

003/IA/009/G

05.11.2015

04.12.2015

Positive

Renewal

AT/H/0335/001-

003/R/001

04.02.2016

14.10.206

Approved

A.7. Deletion of manufacturing sites for an active substance,

intermediate or finished product, packaging site, manufacturer

responsible for batch release, site where batch control takes

place, or supplier of a starting material, reagent or excipient

(when mentioned in the dossier)*

AT/H/0335/001-

003/IA/010

18.12.2016

17.01.2017

Positive

C.I.8. a) Introduction of a summary of pharmacovigilance

system, changes in QPPV (including contact details) and/or

changes in the Pharmacovigilance System Master File (PSMF)

location

AT/H/0335/001-

003/IA/011/G

30.03.2017