Atorvastatin HEC Pharm 40 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

TABLE OF CONTENTS

• I. INTRODUCTION.­.............­.............­.............­.............­.............. Fehler! Textmarke nicht definiert.

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product(s) in the RMS	Atorvastatin HEC Pharm 10 mg; 20 mg; 40 mg; 80 mg Filmtabletten
Name of the drug substance (INN name):	Atorvastatin
Pharmaco-therapeutic group (ATC Code):	C10AA05
Pharmaceutical form(s) and strength(s):	Film-coated tablet
Reference Number(s) for the Decentralised Procedure	DE/H/6498/001–004/DC
Reference Member State:	DE
Member States concerned:	ES, FR, IT, XI
Legal basis of application:	Generic Art 10.1 Dir 2001/83/EC
Marketing Authorisation Holder (name and address)	HEC Pharm GmbH Gabriele-Tergit-Promenade 17 10963 Berlin Deutschland
Names and addresses of all manufacturer(s) responsible for batch release in the EEA	Formula Pharmazeutische und chemische Entwicklungs GmbH Goerzallee 305 b 14167 Berlin Deutschland

I.

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Atorvastatin HEC Pharm 10 mg; 20 mg; 40 mg; 80 mg Filmtabletten, in the treatment of Hyperlcholeste­rolaemia and Prevention of Cardiovascular Disease,

is approved.

II.    EXECUTIVE SUMMARY

• II.1 Problem statement

N/A

• II.2 About the product

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA-reductase inhibitors ATC code: C10AA05.

The targeted indications according to the SmPC are:

Hypercholeste­rolaemia

Atorvastatin HEC Pharm 10 mg, 20 mg ; 40 mg ; 80 mg Filmtabletten is indicated as an adjunct to diet for reduction of elevated total cholesterol (total C), LDL-cholesterol (LDL-C), apolipoprotein B, and triglycerides in adults, adolescents and children aged 10 years or older with primary hypercholeste­rolaemia including familial hypercholeste­rolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia (corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological measures is inadequate.

Atorvastatin HEC Pharm 10 mg, 20 mg ; 40 mg ; 80 mg Filmtabletten is is also indicated to reduce total-C and LDL-C in adults with homozygous familial hypercholeste­rolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

Prevention of cardiovascular disease

Prevention of cardiovascular events in adult patients estimated to have a high risk for a first cardiovascular event, as an adjunct to correction of other risk factors.

Posology

The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.

Renal impairment

No adjustment of dose is required.

Hepatic impairment

Atorvastatin should be used with caution in patients with hepatic impairment. Atorvastatin is contraindicated in patients with active liver disease.

Elderly

Efficacy and safety in patients older than 70 using recommended doses are similar to those seen in

the general population.

Paediatric population

Hypercholeste­rolaemia

Paediatric use should only be carried out by physicians experienced in the treatment of paediatric hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress.

For patients with Heterozygous Familial Hypercholeste­rolemia aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day.

• II.3 General comments on the submitted dossier

The Application is submitted in accordance with Article 10 (1) Directive 2001/83/EC (generic application) as amended. The submitted documentation in relation to the proposed product is of sufficient quality and is consistent with the current EU regulatory requirements from a non-clinical and clinical point of view.

To support the application, the applicant has submitted one bioequivalence study under fasting conditions showing bioequivalence of the test product Atorvastatin 80mg film-coated tablets (the highest strength) with the originator product Lipitor® 80mg film-coated tablets.

With Germany as the Reference Member State in this Decentralized Procedure, HEC Pharm GmbH now applied for the Marketing Authorisations for Atorvastatin HEC Pharm 10 mg; 20 mg; 40 mg; 80 mg Filmtabletten in CMS ES, FR, IT, and UK.

• 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.

For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.

For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. The provided GMP certificate is no longer valid, however this testing site was used for XRD testing of API used to produce commercial batches of the finished product and is no longer relevant for the finished product.

GMP active substance

Regarding the statement on GMP for the active substance a statement/decla­ration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.

GCP

According to the applicant the bioequivalence study and the validation of the methods were conducted in accordance to the principles of GCP and GLP.

GLP

In line with the type of application procedure the Applicant does not submit non-clinical studies.

III.  SCIENTIFIC OVERVIEW AND DISCUSSION

• III.1 Quality aspects

Drug substance

Atorvastatin calcium trihydrate is a well-known API described in a Ph.Eur. monograph. A CEP has been provided to document the quality.

The control tests and specifications for drug substance product are adequately drawn up.

The re-test period of 5 years if stored in a polyethylene bag, in a laminated aluminium bag, placed in a polyethylene drum has been confirmed on the CEP.

Drug Product

The development of the product has been described, the choice of excipients is justified and their functions explained. A strength biowaiver is claimed and adequately justified.

The product specifications cover appropriate parameters for this dosage form. Justifications have been provided to omit tests for microbial purity, crystal form, elemental impurities and enantiomeric purity. The applicant has also provided a statement regarding absence of a risk for nitrosamine presence. Validations of the analytical methods have been presented. Batch analysis has been performed on 3 batches of each strength. The batch analysis results show that the finished products meet the specifications proposed.

Hold times have been defined surpassing 30 days, however the applicant has confirmed that the start of shelf life is taken from the date that the active ingredient is first mixed with other ingredients.

The proposed shelf life of 24 months requires further justification, i.e. qualification of the proposed limits for identified, specified impurities.

Currently a shelf life of 12 months is justified.

• III.2 Non-clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of atorvastatin are well known. As atorvastatin is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.

The non-clinical overview is dated November 2019. Report refers to 59 publications up to year 2019.

The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology was initially not fully adequate. In response to a request to include and assess information regarding excipients and impurities of the medicinal product under review the Applicant added references to the dossier. Excipients used and impurities reported finally do not raise concerns.

Environmental Risk Assessment (ERA)

Since Atorvastatin HEC Pharm xx mg Filmtabletten is a generic product, it will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

• III.3 Clinical aspects

Pharmacokinetics

This application concerns 4 strengths i.e 10, 20, 40 and 80 mg film-coated tablets.

To support the application, the applicant has submitted as report one single dose bioequivalence study under fasting conditions ( Study 1 ) with the 80 mg tablet which is acceptable for this immediate release tablet formulation.

Study Study 1 was a was an open label, balanced, randomized, two-treatment, four period, two-sequence, single oral dose, full replicate, bioequivalence study of Atorvastatin HEC 80mg Film-coated Tablets of HEC Pharm GmbH with Sortis® 80mg Filmtabletten Atorvastatin of PFIZER PHARMA PFE GmbH in normal, healthy, adult, human subjects under fasting conditions.

The tablets were administered with 240 ml of drinking water after an overnight fast. A washout of 15 days was kept between each consecutive dosing period.

The primary variables for conclusion of bioequivalence were AUC0-t and Cmax for atorvastatin. Criteria for conclusion of bioequivalence for atorvastatin was defined that the 90% CI for the test/reference LSM ratio of the log-transformed AUC0-t and Cmax should be between 80–125% if the within-subject coefficient of variation of the reference product (CVWR) is ≤ 30% for Cmax. If intrasubject co-efficient of variation of reference formulation for Cmax is greater than 30%, acceptance range for 90% confidence interval was widened, corresponding to maximum intra-subject variability of 50% for reference formulation in accordance to EMEA guidance.

For atorvastatin the within-subject-reference CV% for Cmax was greater than 30% and therefore the widened acceptance range of 74.28% – 134.62% was used as predefined in the study protocol.

The results show that the 90% confidence interval for the ln-transformed of atorvastatin AUCt, AUC0-t and Cmax were within the 80.00–125.00% acceptance criteria. Therefore, the Atorvastatin 80 mg film-coated tablets can be considered bioequivalent to the reference product Sortis® 80 mg Filmtabletten (atorvastatin) (PFIZER PHARMA PFE GmbH) from the German market.

Table III3.1. Pharma­cokinetic data for Atorvastatin in Study 1

Pharmacokinetic parameter	2 Arithmetic Means (±SD)
	Test product (T)	Reference Product ®
16ATN-0682
AUCo-t (hi.ng mLi	235.118 ±136.9772	239 912 ±160.9387
AtC«-x(hr.ngmL)	240.860 ±137.1772	245 841 ±162.7233
C„„(ng?mL)	64.149 ± 36.0299	62 985 ± 51.6217
Tmax 1 (hr)	0.750 (0.33 – 4.00)	0.750 (0.33 – 4.00)

1 Median (Min. Max)

2 Arithmetic Means (±SD) may be substituted by Geometrie Mean (±CV %)

Table III3.2. Bioequ­ivalence evaluation of Atorvastatin in Study 1

Pharmacokinetic parameter	Geometric Mean Ratio (T R) (%)	90% C onfidence Intermls (TrsR) (%)	CV%’(%)
16-MN-0682
t max	104.48	97.01 – 112.53	31 30
AUCjo-t)	99 44	94.87 – 104.23	18.90

Estimated from the Residual Mean Squares. For replicate design studies report the wit hin-subject CV% using only the reference product data.

Biowaiver

The dissolution data showed that the 10, 20, 40 and 80 mg (biobatch) formulations have comparable dissolution at pH 1, pH 4.5 and pH 6.8. Considering that the formulations are dose proportional, are manufactured by the same manufacturing process and the linear pharmacokinetics, the requirements for the biowaiver for additional strengths according to the guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **) have been fulfilled.

Major objections and other concerns raised by CMS ES concerning the dissolution data in regard of the used paddle speed of 75 rpm instead of 50 rpm, the sampling time points and not achieving sink conditions have been sufficiently solved by the applicant.

Analytical Methods

The analytical part of the study was conducted at Veeda Clinical Research Pvt. Ltd., India

Plasma concentrations of atorvastatin, o-hydroxy atorvastatin and p-hydroxy atorvastatin were determined using an automated liquid-liquid extraction procedure and LC-MS/MS method with atorvastatin-d5 used as internal standard.

A calibration curve extending over the range from 0.200ng/mL to 200.000 ng/mL with a LLOQ of 0.200 ng/mL (-2.5% accuracy, 3.59% precision) was used in subject sample analysis of atorvastatin. The concentrations of the standards for atorvastatin, was calculated using linear regression analysis with a weighting factor of 1/concentration2, for each analyte.

Dilution of samples by a factor 10 did not affect the accuracy and precision.

The stability results, whole blood (10h at ambient temperature), plasma long term stability (108 days at –20°C), autosampler stability (91h at 5±3°C) and 5 freeze/thaw cycles stability at –20±5°C showed that the analyte is stable under these conditions.

Longest storage period for atorvastatin in study 1 was 108 Days at –20±5°C and –78±8°C.

Pharmacodynamics / Clinical efficacy / Clinical safety

The Clinical Overview on the rationale, clinical pharmacology, efficacy and safety is considered sufficient in view of the indications presently sought.

No new studies on pharmacodynamics, clinical efficacy or clinical safety have been submitted, which is appropriate for a generic application under Article 10(1).

Summary Pharmacovigilance system

The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Pro­posed Future MAH's Pharmaco­vigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS/Rapporteur considers the Summary acceptable.

Risk Management Plan

The MAA 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 the medicinal product(s) applied for authorisation.

Safety specification

According to the Applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product/similar products which is acceptable.

Pharmacovigilance Plan

Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.

Risk minimisation measures

Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.

Summary of the RMP

The submitted Risk Management Plan is considered acceptable.

After approval the MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in the dossier of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• – At the request of the RMS;

• – Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

Periodic Safety Update Report (PSUR)

With regard to PSUR submission, the MAH should take the following into account:

• PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c (7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR.
• For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list.
• For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

IV. BENEFIT RISK ASSESSMENT

Clinical

Based on the submitted bioequivalence study under fasting conditions the Atorvastatin 80 mg film-coated tablets (Sunshine Lake Pharma Co., Ltd., China) can be considered bioequivalent to the reference product Sortis® 80 mg Filmtabletten (atorvastatin) (PFIZER PHARMA PFE GmbH) from the German market. The results obtained for the 80 mg film-coated tablet can be extrapolated to the 10, 20, and 40 mg film-coated tablets as the criteria for biowaiving additional strengths are fulfilled. Major Objections and Other Concerns that have been raised on D100 and D145 have been sufficiently solved by the Applicant.

Approval is recommended from a clinical point of view.

Nonclinical: There is no objection against granting of Marketing Authorization for the product under review.

Quality: Approvable is recommended from a quality point of view.

The application is approved. For intermediate amendments, see the current product information.

Atorvastatin HEC Pharm 10 mg, 20 mg ; 40 mg ; 80 mg Filmtabletten

DE/H/6498/001–004/DC Public Assessment Report

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