Decentralised Procedure

Public Assessment Report

Ebastin Micro Labs 10 mg Filmtabletten Ebastin Micro Labs 20 mg Filmtabletten

Ebastine

DE/H/5393/001-002/DC

Applicant: Micro Labs GmbH

Date: 06.02.2020

This module reflects the scientific discussion for the approval of Ebastin Micro Labs 10 / 20 mg Filmtabletten. The procedure was finalised on 2nd October 2019.

TABLE OF CONTENTS

I. INTRODUCTION ...... 4 II. EXECUTIVE SUMMARY ...... 4 II.1 Problem statement ...... 4 II.2 About the product ...... 4 II.3 General comments on the submitted dossier ...... 5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles .. 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION ...... 5 III.1 Quality aspects ...... 5 III.2 Non-clinical aspects ...... 6 III.3 Clinical aspects ...... 6 IV. BENEFIT RISK ASSESSMENT ...... 8

Ebastin Micro Labs 10/20 mg Filmtabletten, DE/H/5393/001-002/DC Public AR 2/8

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal Ebastin Micro Labs 10 mg Filmtabletten product in the RMS Ebastin Micro Labs 20 mg Filmtabletten Name of the drug substance (INN Ebastine name):

Pharmaco-therapeutic group R06AX22 (ATC Code): Pharmaceutical form(s) and Film-coated tablet, 10mg; 20mg strength(s): Reference Number(s) for the DE/H/5393/001-002/DC Decentralised Procedure Reference Member State: DE Concerned Member States: SE, DK NO was withdrawn during clock stop Legal basis of application: Article 10(1) Generic application Applicant (name and address) Micro Labs GmbH Lyoner Str. 14 D-60528 Frankfurt/Main Germany

Names and addresses of all proposed Centre Specialites Pharmaceutiques manufacturer(s) responsible for ZAC des Suzots - 35 rue de la Chapelle batch release in the EEA F-63450 SAINT-AMANT-TALLENDE

Micro Labs GmbH Lyoner Str. 14 D-60528 Frankfurt/Main

Ebastin Micro Labs 10/20 mg Filmtabletten, DE/H/5393/001-002/DC Public AR 3/8

I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Ebastine Micro Labs 10 mg Filmtabletten with the following indications: For the symptomatic treatment of - seasonal and perennial allergic rhinitis with or without allergic conjunctivitis. - urticaria. and Ebastine Micro Labs 20 mg Filmtabletten with the following indications For the symptomatic treatment of - severe seasonal and perennial allergic rhinitis with or without allergic conjunctivitis, is approved.

II. EXECUTIVE SUMMARY II.1 Problem statement For generic applications this section is not applicable.

II.2 About the product Pharmacotherapeutic group: Other Antihistamines for systemic use ATC Code: RO6AX22

Ebastine is a second-generation long-acting H1-receptor antagonist, which binds preferentially to peripheral H1-receptors in vivo. Ebastine is an antihistamine characterized by negligible anticholinergic and antiserotoninergic properties and the lack of sedative effects, which first-generation drugs such as diphenhydramine, promethazine, chlorpheniramine and hydroxyzine exhibit.

Ebastine is a prodrug that become active in the body through conversion to carboxyl group-containing (carebastine) compound.

Indications as proposed by the applicant: Ebastine Micro Labs 10 mg Filmtabletten: For the symptomatic treatment of - seasonal and perennial allergic rhinitis with or without allergic conjunctivitis - urticaria

Ebastine Micro Labs 20 mg Filmtabletten: - symptomatic treatment of severe seasonal and perennial allergic rhinitis with or without allergic conjunctivitis

Proposed Posology: Allergic rhinitis: The following dosage recommendations apply to children above 12 years and adults:

1 film-coated tablet (10 mg Ebastine) once daily. The dose can be increased on 2 film-coated tablets (20 mg Ebastine) once daily for severe symptoms and for perennial allergic rhinitis.

Urticaria For adults over 18 years the following dosage recommendations apply: 1 film-coated tablet (10 mg Ebastine) once daily (see also Section 5.1).

Special groups of persons In patients under 18 years of age, no clinical experience has yet been demonstrated for the effectiveness of urticaria.

No dose adjustment is required in patients with mild, moderate or severe renal or hepatic impairment.

Ebastin Micro Labs 10/20 mg Filmtabletten, DE/H/5393/001-002/DC Public AR 4/8

There is no experience for patients with severe hepatic impairment for doses above 10 mg; therefore, a dose of 10 mg should not be exceeded in patients with severe hepatic impairment.

Method of administration To take The film-coated tablets should be taken unchewed with a little liquid. Ebastine can be taken with or without food.

Duration of administration The doctor decides about the duration of the usage.

II.3 General comments on the submitted dossier The active substance is not considered a new active substance and is subject to medical prescription.

With Germany as the Reference Member State in these Decentralised Procedures, Micro Labs GmbH is applying for the Marketing Authorisations for Ebastine Micro Labs 10/20 mg Filmtabletten in DE, DK and SE. The applicant has stated that NO withdraw from the applications of these Procedures. Hence, the same has removed from the Risk Management Plan.

It concerns two generic applications of ebastine according to article 10(1) generic application of Directive 2001/83/EC.

The originator product is Ebastel® 10 mg Filmtabletten, registered since 1997-12-29 and Ebastel® 20 mg Filmtabletten by Almirall S.A., registered since 2004-11-05.

Scientific Advice given by the RMS on 2015-08-26. Topic discussed related to the requirement for ebastine 10 mg and 20 mg film-coated tablets that bioequivalence investigation is expected for both dosage strengths. The applicant followed that with BE study 0740-17.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles GMP A copy of the valid GMP certificate issued by MHRA for the finished drug product manufacturer has been provided which covers the manufacture of the current dosage form.

Copies of manufacturer authorizations and/or GMP certificates are provided for the secondary packaging sites in the EU, batch control sites in the EU and batch release sites in the EU.

QP declarations from the batch release sites in the EEA (Micro Labs GmbH, Germany and Centre Specialités Pharmaceutiques, France) concerning GMP compliant manufacture of the active substance by the proposed ASM are provided. The QP declarations are based on an audit not older than 3 years; accepted.

GLP No new non-clinical studies were performed for these generic applications. The bioanalytical phases of the bioequivalence studies BE 0319-16 and BE 0740-17 have been conducted in accordance with GLP.

GCP The bioequivalence studies BE 0319-16 and BE 0740-17 have been conducted in accordance with GCP. The clinical and bio-analytical study site, respectively the pharmacokinetic/statistical analysis site have been inspected by various EU authorities from 2009 to 2015.

III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance

Ebastin Micro Labs 10/20 mg Filmtabletten, DE/H/5393/001-002/DC Public AR 5/8

The drug substance ebastine is covered by a Ph. Eur. monograph. A valid EDQM´s certificate of suitability is presented for ebastine from the proposed ASM. The ASM´s specification and the drug product manufacturer´s specification are in line with Ph. Eur. and the CEP. The additional tests on particle size limits and microbial purity are accepted. Compliant batch results are provided. The retest period of 12 months without storage conditions is justified by compliant long-term and accelerated stability data.

Drug Product The qualitative composition of the 10 mg and the 20 mg film-coated tablets are identical, and the quantitative composition is dose-proportional. Pharmaceutical development is described. The manufacturing process has been validated on the smallest production-scale. The excipients are compendial. The drug product specifications cover appropriate parameters for this dosage form, and the acceptance criteria are justified. The analytical procedures are described and validated. Compliant batch results are presented. Compliant long-term and accelerated results of both drug products at 25°C/60% RH and 40°C/75% RH are presented and support the proposed shelf-life of 36 months of the 10 mg drug product and the 20 mg drug product without storage recommendations.

III.2 Non-clinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of ebastine are well known. For a generic application of a widely used, well-known active substance no further preclinical studies are required. Instead, A non-clinical overview was written by a qualified expert and relies on published data only. The overview covers all relevant non-clinical aspects and is acceptable.

Environmental Risk Assessment (ERA) Since Ebastin Micro Labs 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.

III.3 Clinical aspects Pharmacokinetics Ebastine belongs to the piperidine group of antihistamines and is a second-generation long-acting H1- receptor antagonist, which binds preferentially to peripheral H1-receptors in vivo. It is an antihistamine characterized by negligible anticholinergic and antiserotoninergic properties and the lack of sedative effects, which first-generation drugs such as diphenhydramine, promethazine, chlorpheniramine and hydroxyzine exhibit.

The pharmacokinetics of ebastine, as well as that of its active metabolite carebastine, found to be linear within the recommended therapeutic dosage window of 10 to 20 mg.

Bioequivalence In support of the applications, the applicant has submitted as report two bioequivalence studies, BE study 0319-16 with ebastine 10 mg film-coated tablets and in BE study 0740-17 with ebastine 20 mg film-coated tablets as test products. The studies conducted as two single-dose, crossover bioequivalence studies under fasting conditions in healthy, adult, male volunteers.

The reference product used for BE study 0319-16 is KESTIN® 10 mg film-coated tablet (=comprimé pelliculé, Almirall SAS), which is registered in France since 1996-02-01. The reference product used for BE study 0740-17 is Ebastel® 20 mg Filmtabletten (film-coated tablet, Almirall SA), which is registered in Germany since 2004-11-05.

The clinical part of the studies, bioanalysis and statistical analysis were performed at Lamda Therapeutic Research Ltd., Ahmedabad, India from 10.07.–26.07.2016 for BE study 0319-16 and from 06.10.– 19.10.2017 for BE study 0740-17. In each of the two study periods the subjects received one film-coated tablet oral of ebastine 10 mg (BE study 0319-16) or ebastine 20 mg (BE study 0740-17) of either the test or reference product. The study

Ebastin Micro Labs 10/20 mg Filmtabletten, DE/H/5393/001-002/DC Public AR 6/8 periods have separated by a wash out period of 11 days in BE study 0319-16 and 8 days in BE study 0740-17.

BE study 0319-16 included 52 healthy, male, adult subjects of which 50 subjects completed both periods of the study and were used for pharmacokinetic and statistical analysis.

BE study 0740-17 included 40 healthy, male, adult subjects of which 39 subjects completed both periods of the study and were used for pharmacokinetic and statistical analysis.

For BE study 0319-16 and BE study 0740-17, bioequivalence was demonstrated for the metabolite carebastine as was predefined in the protocol. Pharmacokinetic characterization performed adequately. In the Questions & Answers: Position on specific questions adressed to the Pharmacokinetics Working Party (EMA/618604/2008 Rev. 13), it was concluded that demonstration of bioequivalence could be based on either ebastine or carebastine or both.

In this context, the metabolite carebastine for bioequivalence evaluation in BE study 0319-16 and in BE study 0740-17 is considered acceptable to detect formulation related differences between test product and reference product, since the parent compound ebastine is an inactive prodrug with a higher variability in pharmacokinetics than carebastine.

The test to reference ratio of geometric least squares means with corresponding 90% CI for ln- transformed pharmacokinetic parameters Cmax and AUC0-t was within the acceptance range of 80.00- 125% for carebastine for both bioequivalence studies.

Clinical efficacy This is a generic application and as such, no further clinical studies submitted and none required. The applications contain an adequate review of published data, and bioequivalence has been demonstrated for the 10 mg/20 mg dosage strengths of Ebastine Micro Labs film-coated tablets with the bioequivalence studies BE 0319-16 and BE 0740-17.

Legal Status Medicinal product is subject to medical prescription.

User Testing Fourteen scored questions cover all critical aspects of the Package Leaflet in 20 volunteers. The 1st and 2nd round of testing showed that 90% of the participants were able to trace the information for the questions 100% of the time. Each of these participants showed they understood the information by answering the questions correctly 100% of the time. Thus, the RMS considers the tested Package Leaflet adequate.

Summary Pharmacovigilance system The applicant has submitted a signed Summary of the applicant's and/or 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 considers the Summary acceptable.

Risk Management Plan The applicant 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 which is acceptable. Pharmacovigilance Plan

Ebastin Micro Labs 10/20 mg Filmtabletten, DE/H/5393/001-002/DC Public AR 7/8

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.

The applicant 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) Use the below statement in case a substance is listed in the published EURD list. 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. • In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.

IV. BENEFIT RISK ASSESSMENT The applications for marketing authorization are approvable from the quality, non-clinical and clinical point of view. The applications contain an adequate review of published data, and bioequivalence has demonstrated for the 10 mg/20 mg dosage strengths of Ebastine Micro Labs film-coated tablets with BE study 0319-16 and BE study 0740-17. SmPC and PL are adequate. The application is approved. For intermediate amendments see current product information.

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