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Esmya 5 Mg Tablets, INN-Ulipristal

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Esmya 5 Mg Tablets, INN-Ulipristal 15 December 2011 EMA/486902/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report Esmya ulipristal Procedure No.: EMEA/H/C/002041//0000 Note 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 Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged. Product information Name of the medicinal product: Esmya PregLem France SAS. Applicant: 32, route de l’Eglise F-74140 Massongy France Active substance: ulipristal acetate International Non-proprietary Name: ulipristal Pharmaco-therapeutic group Uterine myoma (ATC Code): Ulipristal acetate is indicated for pre-operative Therapeutic indication(s): treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. The duration of treatment is limited to 3 months (see section 4.4) Pharmaceutical form: Tablet Strength: 5 mg Route of administration: Oral use PVC/PE/PVDC/Alu blisters Packaging: Package size: 28 tablets Esmya CHMP assessment report Page 2/106 Rev06.11 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 Information on Paediatric requirements ......................................................................... 7 Information relating to orphan market exclusivity ........................................................... 7 Applicant’s request for consideration ............................................................................. 7 Scientific Advice.......................................................................................................... 7 Licensing status .......................................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion .............................................................................. 10 2.1. Introduction....................................................................................................... 10 2.2. Quality aspects .................................................................................................. 10 2.3. Non-clinical aspects ............................................................................................ 14 2.4. Clinical aspects .................................................................................................. 27 2.5. Clinical efficacy .................................................................................................. 37 2.6. Clinical safety .................................................................................................... 72 2.7. Pharmacovigilance .............................................................................................. 96 2.8. Significance of paediatric studies ........................................................................ 100 2.9. User consultation ............................................................................................. 101 3. Benefit-Risk Balance ......................................................................... 101 Benefits ................................................................................................................. 101 Risks ..................................................................................................................... 101 Benefit-risk balance ................................................................................................ 103 4. Recommendations ............................................................................. 103 Outcome ................................................................................................................ 103 Conditions or restrictions regarding supply and use ..................................................... 103 Conditions and requirements of the Marketing Authorisation ........................................ 104 Esmya CHMP assessment report Page 3/106 Rev06.11 List of abbreviations AAS Atomic Absorption Spectrometry ACTH Adrenocorticotropic hormone ADME Absorption, Distribution, Metabolism and Elimination ADR Adverse drug reaction AE Adverse event AESI Adverse Event of Special Interest ALAT Alanine aminotransferase ALP Alkaline phosphatase AP Applicant's Part (or Open Part) of a DMF API Active Pharmaceutical Ingredient AR Assessment Report ASM Active Substance Manufacturer ASMF Active Substance Master File = Drug Master File ASR Annual Safety Report AST Asparate Transaminase ASV Aqueous suspending vehicle AUC Area under the curve BMI Body mass index BP British Pharmacopoeia CEP Certificate of Suitability of the European Pharmacopoeia CFU Colony Forming Units CHMP Committee for Medicinal Product for Human Use Cmax Maximum concentration CMS Concerned Member State CoA Certificate of Analysis CPK Creatine phosphokinase CRS Chemical Reference Substance (official standard) CT Computed Tomography DCM Dichloromethane DB Double Blind D&C Dilation and Curettage DDI Drug-Drug Interaction DILI Drug Induced Liver Injury DMF Drug Master File = Active Substance Master File DP Decentralised (Application) Procedure DSC Differential Scanning Calorimetry E2 Estradiol ECG Electrocardiogram EDQM European Directorate for the Quality of Medicines EEA European Economic Area EMA European Medicines Agency EU-RMP European Risk Management Plan FDA Food and Drug Administration FSH Follicle-stimulating hormone GCP Good Clinical Practice GLP Good laboratory practice GMP Good manufacturing practice GnRH Gonadotropin releasing hormone GPRD General Practice Research Database Hb Hemoglobin Hct Hematocrit HDPE High Density Polyethylene IPC In-process control HERG Human ether-a-go-go gene ICH International Conference on Harmonisation IND Investigational new drug INN International Non proprietary Name IR Infrared ITT Intent-to-treat IU International Units Esmya CHMP assessment report Page 4/106 Rev06.11 IUD Intrauterine Device JP Japanese Pharmacopoeia LCL Lower confidence limit LC-MS /MS Liquid chromatography tandem mass spectrometry LDH Lactate dehydrogenase LDPE Low Density Polyethylene LH Luteinising Hormone LLT Lower Level Term LOA Letter of Access LOD Limit of Detection LOQ (1) Limit of Quantification, (2) List of Questions MA Marketing Authorisation MAH Marketing Authorisation holder MD Multiple Dose MEB Medicines Evaluation Board MedDRA Medical Dictionary for Regulatory Activities MRI Magnetic resonance imaging MS Mass Spectrometry ND Not detected NICE National Institute of Health and Clinical Excellence NICHD National Institute of Child Health and Human Development NIH National Institutes of Health NLT Not less than NMR Nuclear Magnetic Resonance NMT Not more than NOEL No observed effect level OOS Out of Specifications P4 Progesterone PAEC Progesterone Receptor Modulator Associated Endometrial Changes PB Population Based PBAC Pictorial Bleeding Assessment Chart PD Pharmacodynamic PDE Permitted Daily Exposure PE Polyethylene Ph.Eur. European Pharmacopoeia PIL Patient Information Leaflet PIP Paediatric investigational plan PK Pharmacokinetic PL Patient Leaflet p.o. per os (oral) PP Per-protocol PR Progesterone receptor PR-A Progesterone receptor isoform A PR-B Progesterone receptor isoform B PRM Progesterone Receptor Modulator PSUR Periodic Safety Update Report PT Prothrombin Time PVC Poly vinyl chloride QD Quality Development QoL Quality of Life QOS Quality Overall Summary RBA Relative binding affinity RIA Radioimmunoassay RH Relative Humidity RMP Risk Management Plan RMS Reference Member State RP Restricted Part (or Closed Part) of a DMF RRT Relative retention time RSD Relative standard deviation RTI Research Triangle Institute RVG # Marketing Authorisation number in NL SAE Serious adverse event Esmya CHMP assessment report Page 5/106 Rev06.11 s.c. subcutaneous SD Standard deviation SF-MPQ Short Form McGill Pain Questionnaire SOC System organ class SmPC Summary of Product Characteristics SMQ Standardised MedDRA Query SOC System organ class SPRM Selective Progesterone Receptor Modulator t½ half-life TEAE Treatment emergent adverse event TGA Thermo-Gravimetric Analysis Tmax Time of maximum concentration TSH Thyroid-stimulating hormone UAE Uterine Artery Embolisation UFS-QoL Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire ULN Upper Limit of Normal Range UV Ultraviolet USP/NF United States Pharmacopoeia/National Formulary VAS Visual analog scale VEGF Vascular endothelial growth factor WHO World Health Organization XRD X-Ray Diffraction Esmya CHMP assessment report Page 6/106 Rev06.11 1. Background information on the procedure 1.1. Submission of the dossier The applicant PregLem France S.A.S. submitted on 19 November 2010 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Esmya, through the centralised procedure under Article 3(2) (a) of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 29 September 2009. The applicant initially applied for the following indication: treatment of symptoms (heavy uterine bleeding and/or pain) in patients with uterine fibroids who are eligible for
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