Avatarstad 10 mg Filmtabletten

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Public Assessment Report

Scientific discussion

1) Atorvilbitin 10/20/40/80 mg Filmtabletten

2) Atorvastatin STADA 10/20/40/80 mg Filmtabletten

3) Atornidda 10/20/40/80 mg Filmtabletten

Atorvastatin

1) AT/H/0347/001-004/DC

2) AT/H/0348/001-004/DC

3) AT/H/0349/001-004/DC

This module reflects the scientific discussion for the approval of Atorvilbitin/Atorvastatin

STADA/Atornidda. The procedure was finalised on 27.05.2011. For information on changes

after this date please refer to the module ‘Update’.

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I.

INTRODUCTION

Based on the review of the data and the Applicant’s response to the questions raised by RMS and

CMSs on quality, safety and efficacy, the RMS considers that the application for Atorvilbitin,

Atorvastatin STADA and Atornidda 10 mg/20 mg/40 mg/80 mg film-coated tablets in the treatment of

primary hyperlipidemia and prevention of cardiovascular disease (for exact wording of indications, see

SPC),

is approvable.

II.

EXECUTIVE SUMMARY

II.1

Problem statement

This application through the Decentralised Procedure concerns Atorvastatin 10 mg/20 mg/40 mg/80

mg film-coated tablets. These are a generic version of “Sortis” marketed by Pfizer/Parke Davis. The

originator product was approved in the United Kingdom in 1996, as ”Lipitor” (=Sortis) in its 40mg

strength.

Note: In this Assessment Report, the name Sortis is used.

Through an MR-procedure, Sortis 10, 20 and 40mg tablets were authorized across the EU in 1997,

Sortis 80mg followed in 2002 (DE/H/109/01-04), involving AT, BE, DE, DK, FI, EL, IT, LU, NL, PT,

ES and SE as CMS and DE acting as RMS.

Licensed trade names are: Sortis®, Lipitor®, Zarator®, Liprimar®, Xarator®, Cardyl® and Tahor®

(Pfizer/Parke-Davis).

With Austria as Reference Member State in this Decentralised Procedure, Pharma Resources Dr.

Schluttig GmbH applied for Marketing Authorisation of following products in the listed countries as

shown below:

AT/H/0347/001-004/DC:

001-002: BG

001-003: HU, PL, RO, SI

001-004: BE, CZ, DE, DK, IE, IT, LU, PT, SK

AT/H/0348/001-002/DC: DE, IT

AT/H/0349/001-002/DC: FR

II.2

About the product

Atorvastatin is a synthetic HMG-CoA reductase inhibitor (Statin). Statins revolutionized treatment of

hypercholesterolemia as other lipid lowering agents were either modest in respect of efficacy or

unacceptable in terms of side effects.

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase , the rate-limiting enzyme

that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols including

cholesterol. It also reduces triglyceride levels through an as yet unproven mechanism. Atorvastatin

reduces levels of cholesterol and lipoproteins in plasma by inhibiting of HMG-CoA reductase and by

inhibiting of cholesterol synthesis in liver, and it increases a number of hepatic LDL receptors on the

cellular surface, accelerating thus the absorption and catabolism of LDL. Atorvastatin reduces the

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production of LDL and a number of LDL particles. It also decreases effectively LDL-cholesterol

levels in patients with homozygous familial hypercholesterolemia, which is the population of patients

usually not reacting to hypolipidemic treatment.

It has been demonstrated that reduction of total cholesterol, LDL-cholesterol and triglycerides

decreases the risk of cardiovascular episodes and cardiovascular mortality. Studies following an

influence of atorvastatin on mortality and morbidity have not been established yet.

Currently approved indications:

Atorvastatin is indicated as an adjunct to diet for reduction of elevated total cholesterol, LDL

cholesterol, apolipoprotein B and triglycerides in patients with primary hypercholesterolemia

(including heterozygous, familial hypercholesterolemia) or mixed hyperlipidaemia (Fredrickson

classification, Types IIa and IIb), when response to diet and other nonpharmacological measures is

inadequate.

Atorvastatin is also indicated to reduce total- or LDL-cholesterol in patients suffering from

homozygous familial hypercholesterolemia, either combined with other blood fat lowering actions

(e.g. aphaeresis) or if such treatments are unavailable.

Furthermore, Atorvastatin is indicated for the prevention of cardiovascular events in patients

estimated to have a high risk for a first cardiovascular event (see Section 5.1), as an adjunct to

correction of other risk factors.

Currently approved doses include 10, 20, 40 and 80mg once daily, taken at any time of the day

independent from concomitant intake of meals. The initial daily dosage is 10mg and is to be adjusted

at intervals of 4 weeks and more up to a maximum daily dose of 80mg.

II.3

General comments on the submitted dossier

This application of marketing authorisation on Atorvastatin is based on Article 10(1) of Directive

2001/83/EC as amended (generic application). The originator product on the Austrian market is Sortis

10/20/40/80mg (Pfizer/Parke Davis).

In order to prove essential similarity to the originator product a bioequivalence study with the 80mg

strength was performed against the originator product from the German market (Sortis 80mg,

Goedecke GmbH, Germany).

A biowaiver-justification to extrapolate the results from the BE-study to the 10 and 20 and 40 mg

strengths was provided.

II.4

General comments on compliance with GMP, GLP, GCP and agreed ethical

principles.

The RMS has been assured that acceptable standards of GMP are in place for these product types at all

sites responsible for the manufacture and assembly of this product.

The applicant assures that the submitted bioequivalence study has been conducted according GCP-

and GLP-standards. A GCP-inspection of the analytical study site (Anapharm Europe S.L, Barcelona,

Spain) by the Austrian authority was performed in January 2010. No critical findings were observed.

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III.

QUALITY ASPECTS

III.1

Introduction

Atorvilbitin/Atorvastatin STADA/Atornidda is a film-coated tablet which is presented in an

OPA-Al-

PVC/Al blister

III.2

Drug Substance

The active substance in Atorvilbitin/Atorvastatin STADA/Atornidda is atorvastatin (as atorvastatin

calcium). 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.

III.3

Medicinal Product

Atorvilbitin/Atorvastatin STADA/Atornidda contains the following excipients:

10 mg film-coated tablets:

Tablet core: Lactose monohydrate (92.17 mg); Cellulose, powdered; Hypromellose; Meglumine;

Sodium starch glycolate type A; Magnesium stearate

Film coating: Hypromellose; Povidone; Titanium dioxide (E 171); Propylene glycol

20 mg film-coated tablets:

Tablet core: Lactose monohydrate (184.34 mg); Cellulose, powdered; Hypromellose; Meglumine;

Sodium starch glycolate type A; Magnesium stearate

Film coating: Hypromellose; Povidone; Titanium dioxide (E 171); Propylene glycol

40 mg film-coated tablets:

Tablet core: Lactose monohydrate (368.67 mg); Cellulose, powdered; Hypromellose; Meglumine;

Sodium starch glycolate type A; Magnesium stearate

Film coating: Hypromellose; Povidone; Titanium dioxide (E 171); Propylene glycol

80 mg film-coated tablets:

Tablet core: Lactose monohydrate (737.34 mg); Cellulose, powdered; Hypromellose; Meglumine;

Sodium starch glycolate type A; Magnesium stearate

Film coating: Hypromellose; Povidone; Titanium dioxide (E 171); Propylene glycol

The manufacturers responsible for batch release are

Clonmel Healthcare Ltd., IE – Clonmel, Co. Tipperary

Doppel Farmaceutici S.r.l., I-20089 Quinto de Stampi, Rozanno (MI)

Eurogenerics N.V., B-1020 Brussels

Lamp S. Prospero S.p.A., I-41030 San Prospero (Modena)

PharmaCoDane ApS, DK-2730 Herlev

STADA Arzneimittel AG, DE-61118 Bad Vilbel

ALIUD PHARMA GmbH, Gottlieb-Daimler-Str. 18, 89150 Laichingen

Doppel Farmaceutici S.r.l., I-20089 Quinto de Stampi, Rozanno (MI)

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STADA Arzneimittel AG, DE-61118 Bad Vilbel

Lamp S. Prospero S.p.A., I-41030 San Prospero (Modena)

STADA Arzneimittel GmbH, AT-1190 Wien

STADA Arzneimittel AG, DE-61118 Bad Vilbel

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 below 30°C and stored in the original

package to protect from light.

pharmaceutical

quality

Atorvilbitin/Atorvastatin

STADA/Atornidda

been

adequately

shown.

III.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.

IV.

NON-CLINICAL ASPECTS

Pharmacodynamic, pharmacokinetic and toxicological properties of atorvastatin are well known. As

atorvastatin is a widely used, well-known active substance, further studies were not required and the

applicant provides none, except for qualification studies regarding impurities of the active substance..

The tests did not show any evidence of genotoxic or mutagenic activity. The additionally performed

bacterial mutation tests with the required amount of impurities revealed also no mutagenic/genotoxic

activity.

Environmental risk assessment

This product is intended to substitute for other identical products on the market. The approval of this

product does not result in an increase of the total quantity of atorvastatin released into the

environment. It does not contain any component which would result in an additional hazard to the

environment during storage, distribution, use and disposal.

V.

CLINICAL ASPECTS

Pharmacokinetics

Absorption:

Atorvastatin is rapidly absorbed after oral administration, maximum plasma concentrations (C

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occur within 1 to 2 hours. The low absolute bioavailability of atorvastatin parent drug of

approximately 12% -14% is due to presystemic clearance in the gastrointestinal mucosa and/or first-

pass metabolism in the liver, its primary site of action. The systemic availability of HMG-CoA

reductase inhibitory activity is approximately 30%. Although food decreases rate and extent (C

AUC) of drug absorption by approximately 25% and 9% respectively, LDL-C reduction is similar

whether atorvastatin is given with or without food.

Following evening drug administration atorvastatin plasma concentrations are 30% lower for C

AUC when compared with morning drug administration. However, LDL-C reduction is the same

regardless of the time of day of administration.

Extent of absorption increases in proportion to atorvastatin dose. Dose dependent reductions in LDL

cholesterol levels ranging from 41% to 61% have been reported for the dose range of 10 to 80 mg/dl.

Grapefruit juice in large amounts has been shown to interfere with the metabolism of atorvastatin,

causing increases in C

and AUC.

Distribution:

Mean volume of distribution is approximately 381 litres. Protein binding is very high (> 98%).

Metabolism:

Atorvastatin undergoes extensive hepatic and/or extra-hepatic metabolism. Atorvastatin is metabolized

by cytochrome P450 3A4 to ortho (= 2-OH)- and para-(= 4-OH)hydroxylated derivates and various

beta-oxidation products. Atorvastatin and its 2-OH- and 4-OH- metabolites were found to have equal

inhibitory effects on HMG-CoA reductase in vitro. The active metabolites are responsible for

approximately 70% of the inhibition of HMG-CoA reductase. Atorvastatin is extensively metabolized

in the gut wall and liver, at least in part by the CYP3A4 enzymes. The 2-OH- and 4-OH-atorvastatin

metabolites have HMG-CoA reductase inhibitory activity equal to that of Atorvastatin. Approximately

70% of atorvastatin’s pharmacological activity is attributed to active metabolites.

However, the 4-OH-metabolite has much lower concentrations and may not contribute significantly to

the drug activity.

Therefore, additional to the plasma concentrations of atorvastatin, concentrations of the active

metabolite ortho-hydroxyatorvastatin (2-OH-Atorvastatin) were measured.

Excretion:

Following hepatic/extrahepatic metabolism, atorvastatin is primarily eliminated in bile although

atorvastatin doesn’t show significant enterohepatic recirculation.

Elimination half-life is approximately 14 hours however due to the contribution of active metabolites

the inhibitory activity for HMG-CoA reductase is approximately 20 – 30 hours.

V.1

Pharmacodynamics

Pharmacodynamic studies are not presented and not required.

V.2

Clinical safety

No new data/studies were submitted. For a generic product however this is considered acceptable.

V.3

Discussion on the clinical aspects

For generic applications of this nature, the need for repetitive tests on animals and humans is to be

avoided. The applicant submitted a bioequivalence study to prove essential similarity of the test

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formulation Atorvastatin 80 mg film-coated tablets (STADA Arzneimittel AG, Germany) and the

reference formulation Sortis 80mg (Goedecke GmbH, Germany).

Bioequivalence Study

The bioequivalence study was carried out at Anapharm, Québec, Canada in 2009. The objective of

this study was to assess bioequivalence between the test formulation Atorvastatin 80 mg film-coated

tablets (STADA Arzneimittel AG, Germany) and the reference formulation Sortis 80mg (Goedecke

GmbH, Germany).

Therefore a single-dose, single centre, open-label, randomised, 2-way crossover design in

84 male patients under fasting conditions was chosen.

4 Subjects discontinued the study prematurely for personal reasons.

One subject had to be excluded from analysis due to abnormal values (N=79).

Nevertheless, the study report contains an additional summary of the results for atorvastatin and ortho-

hydroxy-atorvastatin, when the subject is included (N=80).

Even in this case (N=80), AUC and Cmax fit within the protocol-defined limits.

According to the study protocol, bioequivalence was to be accepted if the 90% geometric confidence

intervals of the ratio of least-squares means of the test to reference product of ln-transformed AUC0-t

were within the acceptance range of 80% to 125% and if the 90% geometric confidence intervals of

the ratio of least-squares means of the test to reference product of ln-transformed Cmax were within

the acceptance range of 75% to 133% for atorvastatin. Data from the metabolite ortho-hydroxy-

atorvastatin were to be reported and presented as supportive data. Parametric ANOVA was used for

the calculations of AUC and Cmax, nonparametric Wilcoxon’s Test was performed on Tmax.

Widening of the confidence interval for Cmax to 75-133% was predefined and justified in the protocol

with regard to efficacy and safety concerns as stated in the NfG on the Investigation of Bioavailability

and Bioequivalence (CPMP/EWP/QWP/1401/98).

The results of the bioequivalence study are in conformity with the bioequivalence criteria defined in

the protocol. Even when the outlier is included, the confidence intervals fit within the predefined

limits.

Based on the results of the bioequivalence study, the test product atorvastation 80mg film-coated

tablet and the reference product Sortis 80mg film-coated tablet can be considered as bioequivalent.

VI.

OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

Based on the results of the bioequivalence study performed with the 80mg strength, the Test and the

Reference product can be regarded as bioequivalent.

The results can also be extrapolated to the remaining strengths, as the biowaiver-requirements of the

guideline (CPMP/EWP/QWP/1401/98; 26 July 2001) are fulfilled.

pharmaceutical

quality

Atorvilbitin/Atorvastatin

STADA/Atornidda

been

adequately

shown.

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User consultation

The submitted User-Test is acceptable.

package

leaflet

been

evaluated

user

consultation

study

accordance

with

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.

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

initial procedure.

Scope

Procedure number

Product Information affected

Date of start of the procedure

The synthesis route has been

changed. This basic route DMF

will replace the approved DMF.

AT/H/0347-9/001-004/II/006

02.03.2012

Date of end of

procedure

Approval/

non approval

Assessment report

attached

31.08.2012

Approved

Scope

Procedure number

Product Information affected

Date of start of the procedure

Widening the limit of

specification for sulphated ash

in cellactose

AT/H/0347-9/001-

004/II/009,009,008

15.06.2012

Date of end of

procedure

Approval/

non approval

Assessment report

attached

15.09.2012

Approved

Scope

Procedure number

Product Information affected

Date of start of the procedure

Substantial changes in RP.

AT/H/0347-9/001-

004/II/015,012,011

08.08.2014

Date of end of

procedure

Approval/

non approval

Assessment report

attached

05.02.2016

Withdrawn

Scope

Procedure number

Product Information affected

Date of start of the procedure

Renewal of MA

AT/H/0347-9/001-004/R/001

09.12.2016

Date of end of

procedure

Approval/

non approval

Assessment report

attached

31.03.2017

Approved