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TAVLESSE, INN-Fostamatinib 14 November 2019 EMA/CHMP/654949/2019 Committee for Medicinal Products for Human Use (CHMP) Assessment report Tavlesse International non-proprietary name: fostamatinib Procedure No. EMEA/H/C/005012/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Administrative information Name of the medicinal product: Tavlesse Applicant: Rigel Pharmaceuticals B.V. Avenue Ceramique 223 6621 KX Maastricht NETHERLANDS Active substance: Fostamatinib disodium hexahydrate International Non-proprietary Name/Common fostamatinib Name: Pharmaco-therapeutic group Blood and blood forming organs, (ATC Code): antihemorrhagics, vitamin K and other hemostatics, other systemic hemostatics, (B02BX09) Tavlesse is indicated for the treatment of chronic immune thrombocytopenia (ITP) in Therapeutic indication(s): adult patients who are refractory to other treatments (see section 5.1). Pharmaceutical form(s): Film-coated tablet Strength(s): 100 mg and 150 mg Route(s) of administration: Oral use Packaging: bottle (HDPE) Package size(s): 60 tablets Assessment report EMA/CHMP/654949/2019 Page 2/166 Table of contents 1. Background information on the procedure .............................................. 9 1.1. Submission of the dossier ..................................................................................... 9 1.2. Steps taken for the assessment of the product ...................................................... 10 2. Scientific discussion .............................................................................. 11 2.1. Problem statement ............................................................................................. 11 2.1.1. Disease or condition ........................................................................................ 11 2.1.2. Epidemiology .................................................................................................. 11 2.1.3. Aetiology and pathogenesis .............................................................................. 11 2.1.4. Clinical presentation, diagnosis ......................................................................... 12 2.1.5. Management ................................................................................................... 12 2.2. Quality aspects .................................................................................................. 15 2.2.1. Introduction.................................................................................................... 15 2.2.2. Active Substance ............................................................................................. 15 2.2.3. Finished Medicinal Product ................................................................................ 18 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 24 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 24 2.2.6. Recommendations for future quality development ............................................... 24 2.3. Non-clinical aspects ............................................................................................ 24 2.3.1. Pharmacology ................................................................................................. 24 2.3.2. Pharmacokinetics ............................................................................................ 30 2.3.3. Toxicology ...................................................................................................... 32 2.3.4. Ecotoxicity/environmental risk assessment ......................................................... 46 2.3.5. Discussion on non-clinical aspects ..................................................................... 46 2.3.6. Conclusion on the non-clinical aspects ............................................................... 48 2.4. Clinical aspects .................................................................................................. 48 2.4.1. Introduction.................................................................................................... 48 2.4.2. Pharmacokinetics ............................................................................................ 50 2.4.3. Pharmacodynamics .......................................................................................... 69 2.4.4. Discussion on clinical pharmacology ................................................................... 76 2.4.5. Conclusions on clinical pharmacology ................................................................. 78 2.5. Clinical efficacy .................................................................................................. 78 2.5.1. Dose response study........................................................................................ 78 2.5.2. Main study(ies) ............................................................................................... 81 2.5.3. Discussion on clinical efficacy .......................................................................... 118 2.5.4. Conclusions on the clinical efficacy .................................................................. 121 2.6. Clinical safety .................................................................................................. 121 2.6.1. Discussion on clinical safety ............................................................................ 152 2.6.2. Conclusions on the clinical safety .................................................................... 153 2.7. Risk Management Plan ...................................................................................... 154 2.8. Pharmacovigilance ........................................................................................... 157 Assessment report EMA/CHMP/654949/2019 Page 3/166 2.9. New Active Substance ...................................................................................... 157 2.10. Product information ........................................................................................ 158 2.10.1. User consultation ......................................................................................... 158 2.10.2. Additional monitoring ................................................................................... 158 3. Benefit-Risk Balance ........................................................................... 158 3.1. Therapeutic Context ......................................................................................... 158 3.1.1. Disease or condition ...................................................................................... 158 3.1.2. Available therapies and unmet medical need ..................................................... 159 3.1.3. Main clinical studies ....................................................................................... 159 3.2. Favourable effects ............................................................................................ 160 3.3. Uncertainties and limitations about favourable effects ........................................... 161 3.4. Unfavourable effects ......................................................................................... 161 3.5. Uncertainties and limitations about unfavourable effects ....................................... 161 3.6. Effects Table .................................................................................................... 162 3.7. Benefit-risk assessment and discussion ............................................................... 163 3.7.1. Importance of favourable and unfavourable effects ............................................ 163 3.7.2. Balance of benefits and risks .......................................................................... 164 3.7.3. Additional considerations on the benefit-risk balance ......................................... 164 3.8. Conclusions ..................................................................................................... 164 4. Recommendations ............................................................................... 165 Assessment report EMA/CHMP/654949/2019 Page 4/166 List of abbreviations 5-FU 5-fluorouracil AAS Atomic Absorption Spectrometry ADME Absorption, distribution, metabolism, and excretion AE Adverse event AH ambient humidity AIHA Autoimmune hemolytic anemia ALT Alanine aminotransferase ANC Absolute neutrophil count AP Applicant's Part (or Open Part) of an ASMF API Active Pharmaceutical Ingredient AR Assessment Report AS active substance ASM Active Substance Manufacturer ASMF Active Substance Master File = Drug Master File AST Aspartate aminotransferase AUC Area under the plasma concentration-time curve BCR B-cell receptor BCRP Breast cancer resistance protein BCS Biopharmaceutics Classification System BFC Blue film-coated bid Twice daily BP Blood pressure CBC Complete blood count CEP Certificate of Suitability of the Ph.Eur. CFU Colony Forming Units CHMP Committee for Medicinal Products for Human Use CI Confidence interval CLL Chronic lymphocytic leukemia Cmax Maximum serum concentration CMCS chloromethylchlorosulfate CMS Concerned Member State CoA Certificate
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