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Assessment Report 26 February 2015 EMA/154879/2015 Committee for Medicinal Products for Human Use (CHMP) Assessment report Jinarc International non-proprietary name: tolvaptan Procedure No. EMEA/H/C/002788/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 5 1.1. Submission of the dossier ..................................................................................... 5 1.2. Manufacturers ..................................................................................................... 6 1.3. Steps taken for the assessment of the product ........................................................ 6 2. Scientific discussion ................................................................................ 7 2.1. Introduction ........................................................................................................ 7 2.2. Quality aspects .................................................................................................. 10 2.2.1. Introduction ................................................................................................... 10 2.2.2. Active Substance ............................................................................................. 10 2.2.3. Finished Medicinal Product ................................................................................ 11 2.2.4. Discussion on chemical, pharmaceutical and biological aspects ............................. 14 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 14 2.2.6. Recommendation(s) for future quality development ............................................. 14 2.3. Non-clinical aspects ............................................................................................ 14 2.3.1. Introduction ................................................................................................... 14 2.3.2. Pharmacology ................................................................................................. 15 2.3.3. Pharmacokinetics ............................................................................................ 23 2.3.4. Toxicology ...................................................................................................... 24 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 27 2.3.6. Discussion on non-clinical aspects ..................................................................... 28 2.3.7. Conclusion on the non-clinical aspects ............................................................... 29 2.4. Clinical aspects .................................................................................................. 29 2.4.1. Introduction ................................................................................................... 29 2.4.2. Pharmacokinetics ............................................................................................ 37 2.4.3. Pharmacodynamics .......................................................................................... 49 2.4.4. Discussion on clinical pharmacology .................................................................. 56 2.4.5. Conclusions on clinical pharmacology ................................................................. 61 2.5. Clinical efficacy .................................................................................................. 61 2.5.1. Dose response studies ..................................................................................... 61 2.5.2. Main study ..................................................................................................... 62 2.5.3. Discussion on clinical efficacy............................................................................ 81 2.5.4. Conclusions on the clinical efficacy .................................................................... 87 2.6. Clinical safety .................................................................................................... 88 2.6.1. Discussion on clinical safety .............................................................................. 96 2.6.2. Conclusions on the clinical safety ...................................................................... 99 2.7. Pharmacovigilance ........................................................................................... 100 2.8. Risk Management Plan ...................................................................................... 100 2.9. Product information .......................................................................................... 117 2.9.1. User consultation .......................................................................................... 117 3. Benefit-Risk Balance ........................................................................... 117 4. Recommendations ............................................................................... 122 Assessment Report EMA/154879/2015 Page 2/124 List of abbreviations ADPKD Autosomal dominant polycystic kidney disease ARPKD Autosomal recessive polycystic kidney disease ADR Adverse drug reaction AE Adverse event ALT Alanine transaminase AST Aspartate transaminase AUC Area under the curve AVP Arginine vasopressin b.d Twice daily BMI Body mass index BP Blood pressure cAMP Cyclic adenosine monophosphate CI Confidence interval CKD Chronic kidney disease CL/F Oral clearance Cmax Maximum plasma concentration COMP Committee for orphan medicinal products CrCL Creatinine clearance CRISP Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease CT Computed tomography CV Coefficient of variability CYP3A/3A4 Cytochrome P450 3A enzyme ECG Electrocardiogram EOT End of treatment eCrCLCG Creatinine clearance estimated by Cockcroft-Gault equation eGFR Estimated glomerular filtration rate eGFR-EPI Estimated glomerular filtration rate, using the Kidney Disease Epidemiology Collaboration formula eGFR-MDRD Estimated glomerular filtration rate, using the Modification Of Diet In Renal Disease formula ESRD End stage renal failure ET Early termination F Bioavailability FDA Food And Drug Administration (USA) GFR Glomerular filtration rate GI Gastrointestinal GMP Good manufacturing practice HR Hazard ratio HTN Hypertension htTKV Height-corrected total kidney volume ICH International Committee For Harmonisation IMP Investigational medicinal product IOP Intraocular pressure ITT Intention to treat KDIGO Kidney Disease Improving Global Outcomes group Ki Inhibition constant LOCF Last observation carried forward MAA Marketing authorisation application MCP-1 Monocyte chemotactic protein-1 mGFR Measured glomerular filtration rate MHRD Maximum human recommended dose MMRM Mixed-effect model repeated measure Assessment Report EMA/154879/2015 Page 3/124 mOsm/kg Milliosmole per kilogram MRI Magnetic resonance imaging n Number ND Not determined PASS Post authorisation safety study PD Pharmacodynamic P-gp P-glycoprotein PK Pharmacokinetic PKD Polycystic kidney disease PKD1, PKD2 Polycystin 1, 2 q.d Once daily QT QT interval QTc Corrected QT interval Rac Accumulation ratio RHD Recommended human dose RMP Risk management plan RPF Renal plasma flow SAP Statistical analysis plan SD Standard deviation SMQ Standardised medical query SmPC Summary of product characteristics ss Steady state t1/2 Half-life TEAE Treatment emergent adverse event TKV Total kidney volume Tmax Time of maximum concentration ULN Upper limit of normal UTI Urinary tract infection V1a, V1b, V2 Vasopressin receptor subtypes Assessment Report EMA/154879/2015 Page 4/124 1. Background information on the procedure 1.1. Submission of the dossier The applicant Otsuka Pharmaceutical Europe Ltd submitted on 29 November 2013 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Jinarc, through the centralised procedure falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004 . The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 19 December 2013. Jinarc was designated as an orphan medicinal product EU/3/13/1175 on 5 August 2013. Jinarc was designated as an orphan medicinal product in the following indication: Treatment of autosomal dominant polycystic kidney disease. Following the CHMP positive opinion and at the time of the review of the orphan designation by the Committee on Orphan Medicinal Products (COMP), this product was withdrawn from the Community Register of designated orphan medicinal products on 26.03.2015 on request of the sponsor. The applicant applied for the following indication: Jinarc is indicated to slow the progression of kidney disease in patients with autosomal dominant polycystic kidney disease (ADPKD). Jinarc is indicated in adults. The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC - complete and independent application. The applicant indicated that tolvaptan was considered to be a known active substance. The application submitted is composed of administrative information, complete quality data, non-clinical and clinical data based on applicants’
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