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Winfuran, INN-Nalfurafine 19 December 2013 EMA/CHMP/138212/2014 Committee for Medicinal Products for Human Use (CHMP) Assessment report Winfuran International non-proprietary name: nalfurafine Procedure No. EMEA/H/C/002683/0000 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 7418 8416 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged. Product information Name of the medicinal product: Winfuran Applicant: Toray International U.K. Limited Verulam Gardens 70 Gray's Inn Road London WC1X 8NH UNITED KINGDOM Active substance: NALFURAFINE HYDROCHLORIDE International Nonproprietary Name/Common NALFURAFINE Name: Pharmaco-therapeutic group nalfurafine (ATC Code): (V03AX02) Treatment of severe uraemic pruritus (UP) in Therapeutic indication(s): patients of 18 years of age or older, with end stage renal disease (ESRD) undergoing regular dialysis. Pharmaceutical form(s): Concentrate for solution for infusion Strength(s): 10 micrograms/ml Route(s) of administration: Intravenous use Packaging: ampoule (glass) Package size(s): 5 ampoules, 6 ampoules, 10 ampoules and 12 ampoules Winfuran Assessment report EMA/CHMP/138212/2014 Page 2/114 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion ................................................................................ 9 2.1. Introduction......................................................................................................... 9 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction .................................................................................................... 11 2.2.2. Active substance ............................................................................................ 12 2.2.3. Finished medicinal product ................................................................................ 13 2.2.4. Discussion on chemical, and pharmaceutical aspects ............................................ 15 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 15 2.2.6. Recommendation(s) for future quality development ............................................. 15 2.3. Non-clinical aspects ............................................................................................ 15 2.3.1. Introduction .................................................................................................... 15 2.3.2. Pharmacology ................................................................................................. 16 2.3.3. Pharmacokinetics............................................................................................. 31 2.3.4. Toxicology ...................................................................................................... 34 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 49 2.3.6. Discussion on non-clinical aspects...................................................................... 50 2.3.7. Conclusion on the non-clinical aspects ................................................................ 52 2.4. Clinical aspects .................................................................................................. 52 2.4.1. Introduction .................................................................................................... 52 2.4.2. Pharmacokinetics............................................................................................. 54 2.4.3. Pharmacodynamics .......................................................................................... 58 2.4.4. Discussion on clinical pharmacology ................................................................... 59 2.4.5. Conclusions on clinical pharmacology ................................................................. 61 2.5. Clinical efficacy .................................................................................................. 61 2.5.1. Dose response study ........................................................................................ 62 2.5.2. Main studies ................................................................................................... 63 2.5.3. Discussion on clinical efficacy ............................................................................ 90 2.5.4. Conclusions on the clinical efficacy ..................................................................... 92 2.6. Clinical safety .................................................................................................... 92 2.6.1. Discussion on clinical safety ............................................................................ 103 2.6.2. Conclusions on the clinical safety ..................................................................... 105 2.7. Pharmacovigilance ............................................................................................ 105 2.8. Risk Management Plan ...................................................................................... 105 2.9. User consultation ............................................................................................. 109 3. Benefit-Risk Balance............................................................................ 110 4. Recommendations ............................................................................... 113 Winfuran Assessment report EMA/CHMP/138212/2014 Page 3/114 List of abbreviations ADR Adverse drug reaction AE Adverse event ANCOVA Analysis of covariance AUC Area under the plasma concentration-time curve AUC0-t Area under the curve from time 0 until time t AUC0-∞ Area under the curve from time 0 to infinity AUCD AUC difference BMI Body mass index CAPD Continuous ambulatory peritoneal dialysis CHF Congestive heart failure CI Confidence interval Cmax Maximum drug concentration CMH Cochran-Mantel-Haenszel Cmin Minimum drug concentration CL Body clearance CNS Central nervous system CRI Chronic renal insufficiency CYP Cytochrome P de-CPM 17-decyclopropylmethylated nalfurafine DEVD Dialysis effect of VAS difference ECG Electrocardiography EMA European medicines Agency ESRD End stage renal disease FAS Full Analysis Set GI Gastrointestinal HD Haemodialysis ICH International Conference on Harmonisation IgA Immunoglobulin A i.d. Intradermal i.m. Intramuscular i.v. Intravenous Kelim Elimination rate constant Ki Inhibition constant LC/MS/MS Liquid chromatography/mass spectrometry/mass spectrometry LOCF Last observation carried forward MedDRA Medical Dictionary for Regulatory Activities Winfuran Assessment report EMA/CHMP/138212/2014 Page 4/114 MPA Medical Products Agency MRT Mean residence time NDEVD Non-dialysis effect of VAS difference NF Nalfurafine Toray NFU Nalfurafine Toray NFA-G 3-glucuronide of nalfurafine NNT Number needed to treat NYHA New York Heart Association PD Pharmacodynamics PI Pain intensity PIR Pruritus intensity relief PK Pharmacokinetics PL Placebo p.o. Oral PP Per protocol PPID Peak pruritus intensity difference scores PPIR Percentage change in PIR PPR Peak pruritus relief PT Preferred term PU Pain bothering QoL Quality of life QTc Corrected QT SAE Serious adverse event SD Standard Deviation s.c. Subcutaneous SOC System Organ Class SPID Summed pruritus intensity difference score t1/2 Elimination half-life TEAE Treatment emergent adverse event Tmax Time to maximum drug concentration TPR Total pruritus relief TRK-820 Nalfurafine Toray UK United Kingdom UP Uraemic pruritus USA (US) United States of America VAS Visual Analogue Scale Vd Volume of distribution Vss Volume of distribution at steady state Dose All doses expressed in this document are per body e.g. 5 µg is a Winfuran Assessment report EMA/CHMP/138212/2014 Page 5/114 fixed dose of 5 µg per body. Winfuran Assessment report EMA/CHMP/138212/2014 Page 6/114 1. Background information on the procedure 1.1. Submission of the dossier The applicant Toray International U.K. Limited submitted on 28 June 2012 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Winfuran, 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 20 April 2007. Winfuran, was designated as an orphan medicinal product EU/3/02/115 on 11 September 2002. Winfuran was designated as an orphan medicinal product in the following indication: treatment of uraemic pruritus. The applicant applied for the following indication: Treatment of severe uraemic pruritus (UP) in patients of 18 years of age or older, with end stage renal disease (ESRD) undergoing regular dialysis. The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application. The applicant indicated that nalfurafine was considered to be a new active substance. The application submitted is composed of administrative information,
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