Ticagrelor AbZ 90 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete - Ticagrelor AbZ 90 mg Filmtabletten

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Ticagrelor AbZ 60 mg Filmtabletten Ticagrelor AbZ 90 mg Filmtabletten + GRELATA 60 mg Filmtabletten GRELATA 90 mg Filmtabletten
Name of the drug substance (INN name):	Ticagrelor
Pharmaco-therapeutic group (ATC Code):	B01AC24
Pharmaceutical form(s) and strength(s):	Film-Coated Tablet, 60mg ; 90mg
Reference Number(s) for the Decentralised Procedure	DE/H/7374/001–002/DC DE/H/7375/001–002/DC
Reference Member State:	DE
Concerned Member States:	DE/H/7374/001–002/DC: AT; BE, CZ, DK, EE, FI, FR, IE, IT, LT, LV, NL, NO; PT; SE; SK DE/H/7375/001–002/DC: BG; PL
Legal basis of application:	Generic Art 10.1 Dir 2001/83/EC
Applicant (name and address)	Teva B.V. Swensweg 5 2031GA Haarlem
Names and addresses of all manufacturer(s) responsible for batch release in the EEA	DE/H/7374/001–002/DC PLIVA Hrvatska d.o.o. (PLIVA Croatia Ltd.), Prilaz baruna Filipovića 25, Zagreb, 10000, Croatia DE/H/7375/001–002/DC: BG; PL PLIVA Hrvatska d.o.o. (PLIVA Croatia Ltd.), Prilaz baruna Filipovića 25, Zagreb, 10000, Croatia and Teva Operations Poland Sp. z.o.o., ul. Mogilska 80, Kraków, 31–546, Poland

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Ticagrelor AbZ 60 mg, 90 mg Filmtabletten (procedure DE/H/7374/001–002/DC) and GRELATA 60 mg, 90 mg Filmtabletten (procedure DE/H/7375/001–002/DC), in the treatment of

“Ticagrelor, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with

- acute coronary syndromes (ACS)
- a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic

event (see sections 4.2 and 5.1).”

is approved.

II EXECUTIVE SUMMARY

II.1 Problem statement

Since this is a generic application, this section is not applicable.

II.2 About the product

Ticagrelor is an oral, direct acting, selective and reversibly binding P2Y12 receptor antagonist that prevents ADP-mediated P2Y12 dependent platelet activation and aggregation.

Claimed indication

“Ticagrelor, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with

- acute coronary syndromes (ACS)
- a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic

event (see sections 4.2 and 5.1).”

II.3 General comments on the submitted dossier

The current applications for a marketing authorisation are submitted under Article 10(1) (so called “generic application”) of Directive 2001/83/EC as amended.

With Germany as the Reference Member State in this Decentralized Procedure, Teva B.V. applied for the Marketing Authorisations for Ticagrelor in AT, BE, CZ, DK, EE, ES, FI, FR, IE, IT, LT, LV, NL, NO, PT, SE, SK (procedure DE/H/7374/001–002/DC) and BG, PL (procedure DE/H/7375/001–002/DC) as CMS.

The originator product is Brilique® (ticagrelor 60 mg / 90 mg film-coated tablets) by AstraZeneca AB, registered via centralised procedures (EU/1/10/655/007–011 and EU/1/10/655/001–006) since December 03, 2010.

In module 1.5.2, the applicant states that the product(s) applied for are a generic version of the reference (originator) medicinal product Brilique® (ticagrelor 60 mg / 90 mg film-coated tablets) by AstraZeneca AB, showing the same qualitative and quantitative composition in terms of active substance(s) and the same pharmaceutical form (film coated tablet). Essential similarity between the products is claimed. The indications applied for are the same as the indications approved for the reference (originator) product.

The application for marketing authorisation of the generic ticagrelor formulations is based on the submitted bioequivalence studies demonstrating bioequivalence of the test product with the approved reference (originator) product and thus to prove the surrogate of equivalent efficacy and safety of the products.

Two bioequivalence studies with the ticagrelor 90 mg strength (as intact tablet and as suspended crushed tablet) has been performed under fasting conditions. The reference product used in the bioequivalence studies is the originator product Brilique® 90 mg (ticagrelor) film-coated tablets, from the UK and Romanian market, respectively.

For the 60 mg strength formulation, a biowaiver for additional strengths is requested based on linearity of PK of Ticagrelor in line with “Guideline on the Investigation on Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ), 2010, Committee for Medicinal Products for Human Use CHMP), European Medicines Agency, London, UK.

The active substance (ticagrelor) is not considered a new active substance.

For a generic application, a PIP is not required. Sections 1.6.1–3 of the paediatric regualation EC No 1901/2006 are not applicable for a generic medicinal product.

There is no medicinal product designated as an orphan medicinal product for a condition relating to the indication proposed in this application.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.

GMP

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.

GMP active substance

Regarding the statement on GMP for the active substances statements/declarations are provided from the manufacturers responsible for manufacture of the finished product and batch release situated in the EU.

Clinical GCP/GLP:

According to the applicant, all bioequivalence studies were 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 drug substance Ticagrelor used for the manufacture of the drug product Ticagrelor 60 mg/ 90 mg film-coated tablets is monographed in the Ph. Eur.

Finished product manufacturer provided an acceptable common specification for API. It is confirmed that Ph.Eur. reference standards will be used for control of API in future. Acceptable.

Valid QP declarations are presented.

Drug Product

Objective of this development was to obtain a formulation bioequivalent to the relevant originator product Brilique®, AstraZeneca. Brilique® approved in the Europe contains Ticagrelor, an antiplatelet drug co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (ACS) or a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event.

The manufacturing process of Ticagrelor film-coated tablets consists of wet granulation, compressing to tablets and film-coating.

The ingredients and the manufacturing process of the drug are considered suitable to produce a pharmaceutical product of the proposed quality.

All relevant quality characteristics of the drug substance and the drug product (release and shelf-life) are specified.. The description of the analytical methods used to analyse the drug product are adequate, the validation results are plausible.

Functionality related characteristics of excipients have been evaluated and relevant characteristics are included in the specifications in P.4. This is acceptable.

The claimed shelf life of 36 months is acceptable.

III.2 Non clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of ticagrelor are well known. As ticagrelor 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 Ticagrelor AbZ 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

Two bioequivalence studies with the ticagrelor 90 mg strength (as intact tablet and as suspended crushed tablet) have been performed under fasting conditions.

Study 1

The submitted bioequivalence study is an open-label, randomized, single-dose, two treatments, two sequence, two period, two-way cross-over bioequivalence study of a generic formulation of ticragelor 90 mg film-coated tablets versus the reference product Brilique® (ticagrelor) 90 mg film-coated tablets in healthy male subjects under fasting conditions.

The aim of the study was to evaluate and compare the bioavailability and therefore to assess the bioequivalence between a generic test formulation of ticagrelor 90 mg film-coated tablets, following a 90 mg oral dose versus an equal dose of one tablet formulation used as reference medication Brilique®90 mg film-coated tablet, , each administered twice to 30 fasting healthy volunteers.

The study conduct, bioanalytical methods and statistical analyses are considered appropriate.

The results are summarized below:

Table Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max median, range) for ticagrelor in study 1

Treatment	AUC 0-t ng/ml/h	AUC 0-∞ ng/ml/h	C max ng/ml	t max h
Test	7497.21 + 2402.12	7772.46 + 2618.98	891.55 + 210.22	2.33 (1.00–4.00)
Reference	7260.64 + 2403.90	7512.57 + 2549.10	851.62 + 203.01	2.67 (1.33–4.00)
*Ratio*	103.57		104.51
AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0–72h canbe reported instead of AUC0-t, 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. AUC0-∞ does not need to be reported when AUC0–72h is reported instead of AUC0-t C max Maximum plasma concentration t max Time until Cmax is reached

ln-transformed values

The 90% confidence intervals calculated for AUC0-t and Cmax for ticagrelor consistently fall within the 80–125% acceptance range after single dose administration under fasting conditions. According to the EU-Guideline “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/Corr, London, 20 January 2010, section 4.1.6) test formulation and reference formulation can be considered bioequivalent.

Study 2

The submitted bioequivalence study is an open-label, randomized, single-dose, two treatment, two period, two sequence cross-over bioequivalence study of a generic formulation of suspended crushed ticragelor 90 mg film-coated tablets versus the reference product suspended crushed Brilique® (ticagrelor) 90 mg film-coated tablets in healthy male subjects under fasting conditions.

The aim of the study was to evaluate and compare the bioavailability and therefore to assess the bioequivalence between a generic test formulation of suspended crushed ticagrelor 90 mg film-coated tablets, following a 90 mg oral dose versus an equal dose of a suspended crushed tablet formulation used as reference medication Brilique®90 mg film-coated tablet.

The study conduct, bioanalytical methods and statistical analyses are considered appropriate.

The results are summarized below:

Table Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max median, range) for ticagrelor in study 2

Treatment	AUC 0-t ng/ml/h	AUC 0-∞ ng/ml/h	C max ng/ml	t max h
Test	6718.36 + 1873.556	6980.73 + 1992.227	903.71 + 182.464	2.33 (1.35–4.52)
Reference	6714.79 + 1979.723	6972.92 + 2124.895	864.56 + 208.287	1.67 (1.02–4.50)
*Ratio	99.78		104.80
AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0–72h canbe reported instead of AUC0-t, 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. AUC0-∞ does not need to be reported when AUC0–72h is reported instead of AUC0-t C max Maximum plasma concentration t max Time until Cmax is reached

*ln-transformed values

EU-Guideline “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/Corr, London, 20 January 2010, section 4.1.6) test formulation and reference formulation (as suspended crushed tablets) can be considered bioequivalent.

Pharmacokinetic conclusion

Based on the submitted bioequivalence studies ticagrelor 90 mg tablets (as intact tablet and as suspended crushed tablet) are considered bioequivalent with the originator product Brilique® (ticagrelor) 90 mg tablets under fasting conditions.

According to the guideline “Ticagrelor film-coated tablets 60 mg and 90 mg product-specific bioequivalence guidance” (EMA/CHMP/177281/2016/Corr., 1 April 16) a single dose bioequivalence study using the ticagrelor 90 mg strength under fasting conditions is sufficient.

Strength waiver

No separate bioequivalence study was performed with the ticagrelor 60 mg strength applied for.

A bio-waiver is requested by the applicant for the ticagrelor 60 mg strength based on the results of the bioequivalence study with the ticagrelor 90 mg strength because the criteria were fulfilled in accordance with the current “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr):

– the ticagrelor 60 mg and 90 mg tablets are manufactured by the same manufacturer and manufacturing process
– the qualitative composition of the 60 mg and 90 mg strengths is the same
– the composition of the strengths are quantitatively (dose) proportional, i.e. the ratio between the amount of each excipient to the amount of the active substance is the same for all strengths
– ticagrelor has been shown to be linear over the therapeutic dose range
– the dissolution data demonstrated in vitro similarity between the different strengths.

The justification of the bio-waiver of the additional ticagrelor 60 mg strength applied for can be accepted.

The results of the bioequivalence studies with the 90 mg ticagrelor formulation can be extrapolated to the other strength of 60 mg ticagrelor, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr, section 4.1.6.

The requirements of the EU-Guideline CPMP/EWP/QWP/1401/98 Rev. 1/Corr (section 4.1.6) have been fulfilled.

Pharmacodynamics

Pharmacodynamic characteristics of ticagrelor are well known. No own data were submitted.

Clinical efficacy

The efficacy of ticagrelor in the proposed indications is established in clinical use. No own data were submitted.

Clinical safety

The overall safety profile of ticagrelor is established and generally known. Ticagrelor has an acceptable adverse event profile when contraindications and precautions are considered properly.

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 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.