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  • 25 April 2014 EMA/195551/2014 Committee for Medicinal Products for Human Use (CHMP)

    Assessment report

    Gilenya

    International non-proprietary name: FINGOLIMOD

    Procedure No. EMEA/H/C/002202/II/0021

    Note Variation assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.

    7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom

    An agency of the European Union Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E-mail info@ema.europa.eu Website www.ema.europa.eu

    © European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged.

  • Table of contents

    1. Background information on the procedure .............................................. 4 1.1. Requested Type II variation ................................................................................. 4 1.2. Steps taken for the assessment ............................................................................ 4

    2. Scientific discussion ................................................................................ 5 2.1. Introduction ...................................................................................................... 5 2.2. Non-clinical aspects ............................................................................................ 6 2.3. Clinical efficacy .................................................................................................. 6 2.3.1. Methods – analysis of data submitted ................................................................. 6 2.3.2. Results .......................................................................................................... 8 2.3.3. Discussion .................................................................................................... 23 2.3.4. Conclusions .................................................................................................. 25 2.4. Clinical safety .................................................................................................. 25 2.4.1. Methods – analysis of data submitted ............................................................... 25 2.4.2. Results ........................................................................................................ 26 2.4.3. Discussion .................................................................................................... 31 2.4.4. Conclusions .................................................................................................. 33 2.4.5. PSUR cycle ................................................................................................... 33 2.5. Risk management plan ...................................................................................... 33 Advice on conditions of the marketing authorisation .................................................... 34 2.6. Update of the product information ...................................................................... 43

    3. Benefit-risk balance .............................................................................. 46 3.1.1. Beneficial effects ........................................................................................... 46 3.1.2. Uncertainty in the knowledge about the beneficial effects .................................... 47 3.2. Risks .............................................................................................................. 47 3.2.1. Unfavourable effects ...................................................................................... 47 3.2.2. Uncertainty in the knowledge about the unfavourable effects ............................... 47 3.3. Benefit-risk balance .......................................................................................... 47 3.3.1. Importance of favourable and unfavourable effects ............................................ 47 3.3.2. Benefit-risk balance ....................................................................................... 48

    4. Recommendations ................................................................................. 48

    Assessment report EMA/195551/2014 Page 2/48

  • List of abbreviations

    AE Adverse Events ALT Alanine Aminotransferase ARR Annualised Relapse Rate AV Atrioventricular BCC Basal Cell Carcinoma CHMP Committee for Human Medicinal Product CI Confidence Interval DLP Data Lock Point DMT Disease Modifying Therapy EDSS Expanded Disability Status Scale ERA Environmental Risk Assessment EU European Union FAS Full Analysis Dataset GA Glatiramer acetate Gd Gadolinium GGT gammaglutamyl-transferases HR Hazard Ratio IFN Interferon MAA Marketing Authorisation Application MRI Magnetic Resonance Imaging MS Multiple Sclerosis NB Negative Binomial PEC Predicted Environmental Concentration PML Progressive multifocal leukoencephalopathy PRAC Pharmacovigilance Risk Assessment PSUR Periodic Safety Update Report S1P Sphingosine-1-Phosphate SAE Serious Adverse Event SmPC Summary of Product Characteristics SOC System Organ Class WBC White Blood Cells

    Assessment report EMA/195551/2014 Page 3/48

  • 1. Background information on the procedure

    1.1. Requested Type II variation

    Pursuant to Article 16 of Commission Regulation (EC) No 1234/2008, Novartis Europharm Ltd submitted to the European Medicines Agency on 10 July 2013 an application for a variation.

    This application concerns the following medicinal product:

    Medicinal product: International non-proprietary name:

    Presentations:

    Gilenya FINGOLIMOD See Annex A

    The following variation was requested:

    Variation(s) requested Type C.I.6.a C.I.6.a - Change(s) to therapeutic indication(s) - Addition of a new

    therapeutic indication or modification of an approved one II

    The MAH proposed to modify the indication (section 4.1) of Gilenya to extend the patient population from patients with high disease activity despite treatment with a beta-interferon (IFN) to patients with high disease activity despite treatment with a disease modifying therapy (DMT). Section 1 of the Package Leaflet has been amended accordingly.

    The requested variation proposed amendments to the Summary of Product Characteristics and Package Leaflet.

    Rapporteur: Pierre Demolis

    1.2. Steps taken for the assessment

    Submission date: 10 July 2013 Start of procedure: 26 July 2013 Rapporteur’s preliminary assessment report circulated on: 20 September 2013 CoRapporteur’s preliminary assessment report circulated on: 23 September 2013 Request for supplementary information and extension of timetable adopted by the CHMP on:

    24 October 2013

    MAH’s responses submitted to the CHMP on: 20 December 2013 Rapporteur’s preliminary assessment report on the MAH’s responses circulated on:

    3 February 2014

    Rapporteurs’ joint assessment report on the MAH’s responses circulated on:

    10 February 2014

    Rapporteurs’ final joint assessment report on the MAH’s responses circulated on:

    14 February 2014

    Follow on Request for supplementary information and extension of timetable adopted by the CHMP on:

    20 February 2014

    MAH’s responses submitted to the CHMP on: 26 February 2014 Rapporteur’s preliminary assessment report on the MAH’s responses circulated on:

    28 March 2014

    PRAC RMP Advice and assessment overview 10 April 2014 CHMP opinion: 25 April 2014

    Assessment report EMA/195551/2014 Page 4/48

  • Information on Paediatric requirements

    Pursuant to Article 8 of Regulation (EC) No 1901/2006, the application included an EMA Decision(s) P/117/2013 on the agreement of a paediatric investigation plan (PIP).

    At the time of submission of the application, the PIP P/117/2013 was not yet completed as some measures were deferred.

    2. Scientific discussion

    2.1. Introduction

    Fingolimod, a sphingosine 1-phosphate receptor modulator is a selective immunosuppressant. It is metabolised by sphingosine kinase to the active metabolite fingolimod phosphate. Fingolimod phosphate, binds at low nanomolar concentrations to sphingosine 1-phosphate (S1P) receptors 1, 3, and 4 located on lymphocytes, and readily crosses the blood-brain barrier to bind to S1P receptors 1, 3, and 5 located on neural cells in the central nervous system. By acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate blocks the capacity of lymphocytes to egress from lymph nodes, causing a redistribution, rather than depletion, of lymphocytes. This redistribution is believed to reduce the infiltration of pathogenic lymphocyte cells into the central nervous system, where they would be involved in nerve inflammation and nervous tissue damage.

    Fingolimod (Gilenya) was authorised in the European Union (EU) on 17 March 2011 for the treatment of multiple sclerosis (MS).The recommended dose of Gilenya is one 0.5 mg capsule taken orally once daily. As of May 2013, Gilenya has been approved in more than 70 countries worldwide. The approved wording for the indication in the EU is as follows:

    Gilenya is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following adult patient groups:

    - Patients with high disease activity despite treatment with a beta-interferon.

    These patients may be defined as those who have failed to respond to a full and adequate course (normally

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