Decentralised Procedure

Public Assessment Report

Ebastin Micro Labs 10 mg Schmelztabletten

Ebastine

DE/H/5578/001/DC

Applicant: Micro Labs GmbH

Date: 06.02.2020

This module reflects the scientific discussion for the approval of “Ebastin Micro Labs 10 mg Schmelztabletten”. The procedure was finalised on 11th November 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 ...... 4 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 mg Schmelztabletten, DE/H/5578/001/DC Public AR 2/8

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal Ebastin Micro Labs 10 mg Schmelztabletten product in the RMS Name of the drug substance (INN Ebastine name): Pharmaco-therapeutic group R06AX22 (ATC Code): Pharmaceutical form(s) and Orodispersible tablet; 10 mg strength(s): Reference Number(s) for the DE/H/5578/001/DC Decentralised Procedure Reference Member State: DE Concerned Member States: SE, DK, withdrawn: NO Legal basis of application: Article 10(1) Generic application Applicant (name and address) Micro Labs GmbH Lyoner Str. 14 D-60528 Frankfurt/Main Germany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

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I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Ebastin Micro Labs 10 mg Schmelztabletten with the following indications:

For the symptomatic treatment of: . seasonal and perennial allergic rhinitis . urticaria is approved.

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

II.2 About the product Pharmacotherapeutic group: Other Antihistamines for systemic use ATC Code: R06AX22

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.

Proposed indications: - Symptomatic treatment of: . seasonal and perennial allergic rhinitis . urticaria

Proposed Posology: Adults and adolescents (aged 12 years and older) . Seasonal and perennial allergic rhinitis: 10 to 20 mg per day in 1 daily dose during or after meals, . Urticaria: 10 mg per day taken once daily during or after meals.

Special population There is no need to adjust the dose in patients with mild, moderate or severe renal impairment or mild to moderate hepatic impairment. There is no experience with doses greater than 10 mg in patients with severe hepatic impairment. Therefore, the 10 mg dose should not be exceeded in patients with severe hepatic impairment. Treatment should be continued until symptoms disappear.

Method of administration The orodispersible tablets of ebastine should be placed on the tongue, where it disperses instantly. It can be administered without taking any water or some other liquid to swallow it. The orodispersible tablets should be used immediately after opening the blister. The blister should be carefully opened with dry hands to remove the orodispersible tablets from the blister without crushing it.

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 this Decentralised Procedure, Micro Labs GmbH is applying for the Marketing Authorisation for Ebastin Micro Labs 10 mg Schmelztabletten in DE, DK, NO and SE. However, the applicant decided to withdraw the application in NO.

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

The originator product is not authorised anymore in Germany. The European Reference Product used for BE study 0320-16 is KESTINYLO® 10 mg orodispersible tablets (=lyophilisat oral, Almirall SAS), which is registered in France since 2004-12-22.

No clinical Scientific Advice was given.

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 at all proposed sites.

Copies of manufacturer authorizations and/or GMP certificates (based on audits not older than 3 years) are provided for the batch control sites, secondary packaging sites and batch release sites in the EEA and are accepted.

QP declarations from the batch release sites in the EEA 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 this generic application. The bioanalytical phase of the bioequivalence study BE 0320-16 has been conducted in accordance with GLP.

GCP The bioequivalence study BE 0320-16 has 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 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. Compliant batch results are provided. The retest period of 5 years without storage conditions is accepted.

Drug Product The development of the drug product has been described, the choice of excipients is justified and their functions explained. The manufacturing process (complete dissolution of ebastine, wet granulation with fluid bed equipment, prelubrication and lubrication of granulate, followed by compression) is described. The manufacturing process has been validated. The excipients are compendial, except for the flavouring mixture. The in-house specification of the flavouring mixture is accepted. The release and shelf-life specification are presented and cover relevant parameters. The acceptance criteria have been justified. Impurity limits above the qualification threshold have been qualified. Analytical procedures are described and validated. Batch results were compliant. Compliant long-term and accelerated results at 25°C/60% RH (36 months) and 40°C/75% RH (6 months) are presented. The shelf-life of 36 months without storage temperature restriction, but with the storage instruction “Store in the blister package in order to protect from moisture and light.” is accepted.

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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 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, is found to be linear within the recommended therapeutic dosage window of 10 to 20 mg.

Bioequivalence In support of the application, the applicant has submitted as report one bioequivalence study, BE study 0320-16 with ebastine 10 mg orodispersible tablets as test product. The study was conducted as two single-dose, crossover bioequivalence study under fasting conditions in healthy, adult, male volunteers.

The European Reference Product used for BE study 0320-16 is KESTINLYO® 10 mg orodispersible tablets (=lyophilisat oral, Almirall SAS), which is registered in France since 2004-12-22.

The clinical part of the study, bioanalysis and statistical analysis were performed for BE study 0320-16.

In each of the two periods of BE study 0320-16, the subjects received one orodispersible tablet oral of ebastine 10 mg of either the test or reference product. The study periods were separated by a washout period of 11 days.

BE study 0320-16 included 52 healthy, male, adult subjects of which 49 subjects completed both periods of the study and were used for pharmacokinetic and statistical analysis.

For BE study 0320-16, bioequivalence was demonstrated for the metabolite carebastine as was predefined in the protocol. Pharmacokinetic characterization is adequately performed. In the Questions & Answers: Position on specific questions addressed 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 0320-16 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 in BE study 0320-16.

The bioequivalence of test and reference product has been shown in BE study 0320-16.

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Clinical efficacy This is a generic application and as such, no further clinical studies are submitted and none required. This application contain an adequate review of published data, and bioequivalence has been demonstrated for the 10 mg dosage strength of Ebastine Micro Labs orodispersible tablets with the bioequivalence study BE 0320-16.

Legal Status Medicinal product is subject to medical prescription.

User Testing Fourteen scored questions cover all critical aspects of the Patient Information Leaflet in a total of 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 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/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.

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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 application for marketing authorization is approvable from the quality and non-clinical point of view. From the clinical point of view, the application contain an adequate review of published data, and bioequivalence has demonstrated for the 10 mg dosage strength of Ebastine Micro Labs orodispersible tablets with BE study 0320-16. The texts of the SmPC and PL are adequate. The application is approved. For intermediate amendments see current product information.

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