Public Assessment Report Scientific discussion

FSME-Immun 0,5 ml Tick-borne encephalitis (TBE) virus, inactivated

AT/H/0126/002

This module reflects the scientific discussion for the approval of FSME-Immun 0,5 ml. The procedure was finalised on 30.12.2003. For information on changes after this date please refer to the module ‘Update’. Bundesamt für Sicherheit im Gesundheitswesen Traisengasse 5 l A-1200 Wien l www.basg.at l www.ages.at DVR: 2112611 l Konto Nr.: 50670 871 619 l BLZ: 12000 l IBAN: AT97 1200 0506 7087 1619 l BIC/SWIFT: BKAUATWW

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I.

INTRODUCTION

FSME-Immun is indicated for the active immunization against infection caused by TBE Virus in adolescents from 16 years of age and adults. This vaccine which is produced in chick embryo-fibroblast cells, contains a Tick-Borne-Encephalitis Virus (whole Virus, inactivated with formaldehyde), strain Neudörfl, and is absorbed on aluminium hydroxide. The recommended dose is 0.5ml for each injection; the primary vaccination series consists of three doses followed by a booster dose no more than 3 years after the third dose. Sequential booster doses should be given following official recommendations, but not less than three years after the last booster dose. A national marketing authorisation was granted for FSME-Immun 0.5ml on 1996-07-19. So far three Mutual Recognition Procedures (MRPs) were conducted. On December 30, 2003, the first wave MRP (AT/H/0126/002/001) for FSME-Immun 0.5 ml with Austria as Reference Member State (RMS) was successfully completed in the following Concerned Member States (CMS): Belgium, Denmark, Finland, France, Iceland, Ireland, Italy, Luxembourg, the Netherlands, Norway, Portugal, Sweden and the UK. On November 30, 2005, a repeat use MRP (AT/H/0126/002/E01) was performed to include the following CMSs: Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Slovak Republic and Slovenia. On February 17, 2012, a third wave MRP (AT/H/0126/002/E02) was successfully completed in the following CMSs: Bulgaria, Greece and Romania. In total, 25 countries are currently licensed through the MRP procedure. The vaccine is also licensed using purely national routes in Croatia, Canada, Germany, Russia, Switzerland. A renewal of FSME-Immun 0.5 ml license was granted in the MRP countries on 18 January 2007. It has been agreed to use 19 July 2006 as the common renewal date (harmonized with FSME-Immun 0.25 ml Junior).

II.

QUALITY ASPECTS

II.1

Introduction

FSME-Immun 0,5 ml is a Suspension for injection in a pre-filled syringe which is presented in a type I glass syringe with a plunger stopper (chlorobutyl isoprene rubber), with attached needle.

II.2

Drug Substance

The active substance in FSME-Immun 0,5 ml is tick-borne encephalitis (TBE) virus, inactivated. The specification of the active substance meets the current scientific requirements. The adequate quality of the active substance has been shown by submitting the appropriate control data. The stability of the active substance has been tested under ICH conditions. The results of the stability studies support the established retest-period.

II.3

Medicinal Product

FSME-Immun 0,5 ml contains the following excipients: Human albumin Bundesamt für Sicherheit im Gesundheitswesen Traisengasse 5 l A-1200 Wien l www.basg.at l www.ages.at DVR: 2112611 l Konto Nr.: 50670 871 619 l BLZ: 12000 l IBAN: AT97 1200 0506 7087 1619 l BIC/SWIFT: BKAUATWW

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Sodium chloride Disodium phosphate-dihydrate Potassium dihydrogenphosphate Water for injections Sucrose Aluminium hydroxide, hydrated. The manufacturer responsible for batch release is Baxter AG, Industriestrasse 67, A-1221 Vienna, Austria. The development of the product has been sufficiently made and deemed appropriate. The usage of all the excipients has been described. The release specification includes the check of all parameters relevant to this pharmaceutical form. Appropriate data concerning the control of the finished product support the compliance with the release specifications. The packaging of the medicinal product complies with the current legal requirements. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SmPC, with a shelf life of 30 months when stored in a refrigerator (2°C - 8°C) without freezing and stored in the original package to protect from light.

The pharmaceutical quality of FSME-Immun 0,5 ml has been adequately shown.

II.4

Discussion on chemical, pharmaceutical and biological aspects

Information on development, manufacture and control of active substance and medicinal product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics.

III.

NON-CLINICAL ASPECTS

At the time of introducing the vaccine to the market no toxicity data were required before marketing. Nevertheless a single dose toxicity study was performed in three different animal species and two local tolerance studies with subcutaneous, as well as intradermal application didn`t reveal any safety concern regarding FSME-Immun.

IV.

CLINICAL ASPECTS

IV.1

Pharmacokinetics

Pharmacokinetic studies are generally not required for injectable vaccines, since the kinetic properties of vaccines do not provide information useful for establishing adequate dosing recommendations.

IV.2

Pharmacodynamics

Bundesamt für Sicherheit im Gesundheitswesen Traisengasse 5 l A-1200 Wien l www.basg.at l www.ages.at DVR: 2112611 l Konto Nr.: 50670 871 619 l BLZ: 12000 l IBAN: AT97 1200 0506 7087 1619 l BIC/SWIFT: BKAUATWW

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The pharmacodynamic effect of the FSME-Immun 0.5 ml vaccine consists of the induction of a sufficiently high TBE antibody response to provide protection against the TBE virus.

IV.3

Clinical efficacy

Immunogenicity was determined by serological analysis (determination of TBE antibodies) in nine clinical studies (studies 062, 201, 202, 208, 213, 223, 225, 690501 and 690601). The results of these studies show that FSME-Immun is highly immunogenic when administered according to the recommended dosing schedule.

IV.4

Clinical safety

The safety of the FSME-Immun 0.5 ml vaccine was investigated in nine clinical studies (studies 062, 201, 202, 208, 213, 223, 225, 690501 and 690601). These studies established an excellent safety profile for FSME-Immun 0.5 ml. Safety endpoints were the occurrence of fever, systemic (excluding fever) and local reactions for each vaccination.

IV.5

Discussion on the clinical aspects

Clinical and pharmacovigilance data show that the thiomersal-free, inactivated TBE virus vaccine FSME-Immun 0.5 ml with target 2.4 μg antigen containing HSA is well tolerated and induces a strong immune response when administered in adults aged 16 years and older.

V.

OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

The pharmaceutical quality of FSME-Immun 0,5 ml has been adequately shown. Based on data from numerous clinical studies and the long experience in the field it is obvious that FSME-Immun 0.5 ml is both well tolerated and highly immunogenic. Moreover, a field effectiveness study (Heinz et al., 2007) shows that the overall effectiveness in regular vaccinated persons is about 99%. Overall, from a nonclinical and clinical point of view the benefit-risk-ratio for FMSE-Immun is unambiguously positive. User consultation The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was English. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. Bundesamt für Sicherheit im Gesundheitswesen Traisengasse 5 l A-1200 Wien l www.basg.at l www.ages.at DVR: 2112611 l Konto Nr.: 50670 871 619 l BLZ: 12000 l IBAN: AT97 1200 0506 7087 1619 l BIC/SWIFT: BKAUATWW

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This module reflects the procedural steps and scientific information after the finalisation of the initial procedure.

Scope

Procedure number

Product information affected Y/N

Date of start of procedure

Date of end of procedure

Approval/ non approval

Change in manufacturing process of drug substance harmonisation of SPC Change in manufacturing process of the finished product introduction of a qualification scheme for suppliers of auxiliary materials update of the MRP approved dossier prior to CTD conversion and subsequent initiation of Repeat Use of MRP Change in manufacturer Harmonisation of SPC, PL and lab. Change in manufacturing process of the finished product update SmPC Minor change in the manufacturing process of the active substance Changes in the quality control program of DS and DP

AT/H/0126/002/II/006

N

20.12.2004

20.03.2005

Approved

Assessment report attached Y/N (version) N

AT/H/0126/002/II/007 AT/H/0126/002/II/008

Y N

17.03.2005 17.03.2005

15.06.2005 15.06.2005

Approved Approved

N N

AT/H/0126/002/II/009

N

17.03.2005

15.06.2005

Approved

N

AT/H/0126/002/II/010

N

17.03.2005

15.06.2005

Approved

N

AT/H/0126/002/II/011 AT/H/0126/002/II/014

N Y

20.07.2005 12.05.2006

11.08.2005 10.08.2006

Approved Approved

N N

AT/H/0126/002/II/015

N

13.07.2007

11.09.2007

Approved

N

AT/H/0126/002/II/016 AT/H/0126/002/II/018

Y N

29.08.2008 28.11.2008

06.05.2009 27.01.2009

Approved Approved

N N

AT/H/0126/002/II/021

N

23.10.2009

22.12.2009

Approved

N

Bundesamt für Sicherheit im Gesundheitswesen Traisengasse 5 l A-1200 Wien l www.basg.at l www.ages.at DVR: 2112611 l Konto Nr.: 50670 871 619 l BLZ: 12000 l IBAN: AT97 1200 0506 7087 1619 l BIC/SWIFT: BKAUATWW

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