Clopidogrel MSN 75 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

PUBLIC ASSESSMENT REPORT

Decentralised Procedure

Clopidogrel Vivanta 75 mg Filmtabletten

Procedure-Number: DE/H/7482/001/DC

Clopidogrel MSN 75 mg Filmtabletten

Procedure-Number: DE/H/7483/001/DC

Active Substance:

Clopidogrel Hydrogen Sulfate

Dosage Form:

Film-coated tablet

Applicant:

Vivanta Generics s.r.o.

Publication:

05.01.2024

This module reflects the scientific discussion for the approval of the above-mentioned procedure. The procedure was finalised on 22.11.2023.

TABLE OF CONTENTS

• II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Clopidogrel Vivanta 75 mg Filmtabletten + Clopidogrel MSN 75 mg Filmtabletten
Name of the drug substance (INN name):	Clopidogrel Hydrogen Sulfate
Pharmaco-therapeutic group (ATC Code):	B01AC04
Pharmaceutical form(s) and strength(s):	75mg, Film-Coated Tablet
Reference Number(s) for the Decentralised Procedure	DE/H/7482+748­3/001/DC
Reference Member State:	DE
Concerned Member States:	BG, ES, IE, HU, NL, PL, RO
Legal basis of application:	Generic Art 10.1 Dir 2001/83/EC
Applicant (name and address)	Vivanta Generics s.r.o. Trtinova 260/1 196 00 Prague, Czechia
Names and addresses of all manufacturer(s) responsible for batch release in the EEA	Pharmadox Healthcare Limited, KW20A Kordin Industrial Park, Paola, PLA3000, Malta MSN Labs Europe Limited, KW20A Corradino Park, Paola, PLA3000, Malta

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Clopidogrel 75 mg Filmtabletten in the treatment of

Secondary prevention of atherothrombotic events

Clopidogrel is indicated in:

• Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.
• Adult patients suffering from acute coronary syndrome:

• – Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).

• – ST segment elevation acute myocardial infarction, in combination with ASA in patients undergoing percutaneous coronary intervention (including patients undergoing a stent placement) or medically treated patients eligible for thrombolytic/fi­brinolytic therapy.

In patients with moderate to high-risk Transient Ischemic Attack (TIA) or minor Ischemic Stroke (IS) Clopidogrel in combination with ASA is indicated in:

• Adult patients with moderate to high-risk TIA (ABCD21 score ≥4) or minor IS (NIHSS2 ≤3) within 24 hours of either the TIA or IS event.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation

In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.

is approved.

II EXECUTIVE SUMMARY

• II.1 Problem statement

For a generic application, this section is not applicable.

• II.2 About the product

As an irreversible P2Y12 receptor antagonist, Clopidogrel irreversibly inhibits ADP-mediated platelet aggregation by blockage of the P2Y12 receptor.

Clopidogrel is classified under platelet aggregation inhibitors excl. heparin (ATC Code: B01AC-04).

Therapeutic indications

Secondary prevention of atherothrombotic events

Clopidogrel is indicated in:

• Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.
• Adult patients suffering from acute coronary syndrome:

• – Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).

• – ST segment elevation acute myocardial infarction, in combination with ASA in patients undergoing percutaneous coronary intervention (including patients undergoing a stent placement) or medically treated patients eligible for thrombolytic/fi­brinolytic therapy.

In patients with moderate to high-risk Transient Ischemic Attack (TIA) or minor Ischemic Stroke (IS) Clopidogrel in combination with ASA is indicated in:

• Adult patients with moderate to high-risk TIA (ABCD21 score ≥4) or minor IS (NIHSS2 ≤3) within

24 hours of either the TIA or IS event.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation

In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.

• II.3 General comments on the submitted dossier

This decentralised application is submitted in accordance with Generic Article 10(1) of directive 2001/83/EC with DE as RMS and with BG, ES, HU, IE, NL, PL and RO as CMS.

The active substance is not considered a new active substance.

The applicant states that the product applied for is a generic version of the originator product Plavix® 75 mg Film Coated Tablets, registered since 15 July 1998, with Sanofi-aventis groupe as marketing authorisation holder (MA-No.: EU/1/98/069/001–002).

To support the application, the applicant has submitted as report one (1) bioequivalence stu­dy:

An open label, randomized, balanced, two-treatment, two-sequence, four-period, single oral dose , crossover, full-replicated , bioequivalence study of Clopidogrel Tablets 75 mg and Plavix® (clopidogrel bisulfate) 75 mg Film Coated Tablets, in healthy, adult, human subjects under fasting conditions.

For a generic application, a PIP is not required.

The applicant has not provided a similarity report. According to the application form and a check of the Community Register of orphan medicinal products, there is no medicinal product designated as an orphan medicinal product for a condition relating to the indication proposed in this application.

The applicant has submitted an RMP for clopidogrel 75 mg.

• 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 Seite 6 von 10 place at those non-Community sites.

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.

Clinical GCP/GLP:

According to the applicant, the bioequivalence study was performed according to GCP and GLP standards. The assessment did not reveal concerns that might trigger an inspection.

• III SCIENTIFIC OVERVIEW AND DISCUSSION

• III.1 Quality aspects

Drug substance

The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Clopidogrel 75 mg Filmtabletten are of sufficient quality in view of the present European regulatory requirements.

A current EDQM certificate of suitability (CEP) has been provided for the drug substance clarifying that the drug substance can be controlled adequately by the respective monograph of Ph. Eur.

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

Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period is justified.

Drug Product

The development of the product has been described, the choice of excipients is justified and their functions explained. The batch of the test product used in the bioequivalence study has been manufactured using the composition provided in the dossier, manufacturing process provided in the dossier as well.

Similarity of dissolution profiles to those of the reference medicinal product could not be demonstrated. The results of the bioequivalence study overrule the in vitro results.

EU-GMP has been certified for the drug product manufacturer.

Excipients used for the manufacture of the drug product formulation do not contain materials that are of animal or human origin and are not in contact with materials of animal or human origin during their manufacture with the exception of the film-coating containing lactose, whose TSE risk is negligible in accordance with EMA/410/01-Rev 3.

The provided nitrosamine risk assessment is acceptable.

The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on three batches. The batch analysis results show that the finished products meet the specifications proposed.

Clopidogrel film-coated tablets are packaged in Alu/Alu blister packs.

The conditions used in the stability studies are according to the ICH stability guideline. Relevant data has been presented.

Seite 7 von 10 The proposed shelf life of 24 months for the drug product is considered acceptable. This medicinal product does not require any special storage conditions.

• III.2 Non clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of clopidogrel are well known. As clopidogrel is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.

Environmental Risk Assessment (ERA)

Since Clopidogrel Vivanta 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

To support the application, the applicant has submitted as report one bioequivalence stu­dy:

An open label, randomized, balanced, two-treatment, two-sequence, four-period, single oral dose , crossover, full-replicated , bioequivalence study of Clopidogrel Tablets 75 mg and Plavix® (clopidogrel bisulfate) 75 mg Film Coated Tablets in healthy, adult, human subjects under fasting conditions.

The general design of the submitted bioequivalence study is considered appropriate for demonstration of bioequivalence of immediate release tablets of 75 mg test and 75 mg reference product. It corresponds to the requirements of the EU bioequivalence guideline (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**).

Results of the clinical studies:

Study (75 mg, fasted)

Table 1. Pharmacoki­netic parameters for Clopidogrel (non-transformed values; arithmetic mean ± SD, t max median, range) (n= 40 (for Test 1, Reference 1 and 2); n=39 (for Test 2 due to SUB 13 dropout))

Treatment	AUC0–24 h ng/ml
Test 1 (Periods 1+2)	2.647 ± 2.304	2.875 ± 2.336	2.115 ± 2.012	0.83 (0.33 – 2.50)
Reference 1 (Periods 1+2)	2.648 ± 2.157	2.829 ± 2.190	1.903 ± 1.459	0.77 (0.33 – 2.00)
Test 2 (Periods 3+4)	2.619 ± 1.666	2.771 ± 1.6888	2.114 ± 1.444	0.67 (0.33 – 2.50)
Reference 2 (Periods 3+4)	2.807 ± 2.434	3.069 ± 2.477	2.354 ± 1.866	0.67 (0.17 – 1.67)

*Ratio (90% CI) Test / Reference	98.26 (90.77 – 106.37)	---	96.33 (87.32 – 106.28)	---
AUC 0–24 Area under the plasma concentration curve from administration to last observed concentration at 24 h post-dose. AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. C max Maximum plasma concentration t max Time until Cmax is reached

*ln-transformed values; for Cmax ISCV of Reference was found 47.18%CV, therefore acceptance for 90% Confidence Interval was widened to 71.12 – 140.60.

Based on the submitted bioequivalence study (Clopidogrel, 75 mg, fasted), the test product Clopidogrel 75 mg film coated Tablets can be considered bioequivalent with the reference product Plavix® (clopidogrel) film coated Tablets 75 mg (Lot No 8A730, Sanofi Clir SNC, France.).

Additional Data:

Comparative dissolution profiles of Plavix® (Clopidogrel) 75 mg film-coated tablets vs. Clopidogrel 75 mg film-coated tablets were performed in diffferent media in the pH range from 1 to 6.8..

Pharmacodynamics

No data were submitted. No data are demanded.

Clinical efficacy

No data were submitted. No data are demanded.

Clinical safety

There were no reports of death, serious or unexpected adverse events.

No new safety information emerged during the study.

Summary Pharmacovigilance system

The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Pro­posed Future Seite 9 von 10 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 Module 1.8.2 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.