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Pentosan Polysulfate Sodium 23 March 2016 EMA/287422/2017 Committee for Medicinal Products for Human Use (CHMP) Assessment report elmiron International non-proprietary name: pentosan polysulfate sodium Procedure No. EMEA/H/C/004246/0000 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, 2017. Reproduction is authorised provided the source is acknowledged. 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. Problem statement ............................................................................................... 9 2.1.1. Disease or condition ........................................................................................... 9 2.1.2. Epidemiology .................................................................................................... 9 2.1.3. Aetiology and pathogenesis ................................................................................ 9 2.1.4. Clinical presentation, diagnosis .......................................................................... 10 2.1.5. Management ................................................................................................... 10 2.2. Quality aspects .................................................................................................. 19 2.2.1. Introduction .................................................................................................... 19 2.2.2. Active Substance ............................................................................................. 19 2.2.3. Finished Medicinal Product ................................................................................ 21 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 23 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 23 2.2.6. Recommendations for future quality development................................................ 23 2.3. Non-clinical aspects ............................................................................................ 23 2.3.1. Introduction .................................................................................................... 23 2.3.2. Pharmacology ................................................................................................. 24 2.3.3. Pharmacokinetics............................................................................................. 27 2.3.4. Toxicology ...................................................................................................... 28 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 34 2.3.1. Discussion on non-clinical aspects...................................................................... 35 2.3.2. Conclusion on the non-clinical aspects ................................................................ 36 2.4. Clinical aspects .................................................................................................. 37 2.4.1. Introduction .................................................................................................... 37 2.4.2. Pharmacokinetics............................................................................................. 46 2.4.3. Pharmacodynamics .......................................................................................... 51 2.4.4. Discussion on clinical pharmacology ................................................................... 54 2.4.5. Conclusions on clinical pharmacology ................................................................. 55 2.5. Clinical efficacy .................................................................................................. 56 2.5.1. Dose response study(ies) ................................................................................. 56 2.5.2. Main studies ................................................................................................... 56 2.5.3. Discussion on clinical efficacy ............................................................................ 89 2.5.4. Conclusions on the clinical efficacy ..................................................................... 96 2.6. Clinical safety .................................................................................................... 97 2.6.1. Discussion on clinical safety ............................................................................ 102 2.6.2. Conclusions on the clinical safety ..................................................................... 103 2.7. Risk Management Plan ...................................................................................... 104 2.8. Pharmacovigilance ............................................................................................ 106 2.9. Product information .......................................................................................... 106 Assessment report EMA/287422/2017 Page 2/115 2.9.1. User consultation ........................................................................................... 106 3. Benefit-Risk Balance............................................................................ 106 3.1. Therapeutic Context ......................................................................................... 106 3.1.1. Disease or condition ....................................................................................... 106 3.1.2. Available therapies and unmet medical need ..................................................... 107 3.1.3. Main clinical studies ....................................................................................... 107 3.2. Favourable effects ............................................................................................ 108 3.3. Uncertainties and limitations about favourable effects ........................................... 109 3.4. Unfavourable effects ......................................................................................... 109 3.5. Uncertainties and limitations about unfavourable effects ....................................... 110 3.6. Effects Table .................................................................................................... 110 3.7. Benefit-risk assessment and discussion ............................................................... 113 3.7.1. Importance of favourable and unfavourable effects ............................................ 113 3.7.2. Balance of benefits and risks ........................................................................... 113 3.8. Conclusions ..................................................................................................... 114 4. Recommendations ............................................................................... 114 Assessment report EMA/287422/2017 Page 3/115 List of abbreviations AE Adverse event API active pharmaceutical ingredient aPTT activated partial thromboplastin time ASMF Active Substance Master File ATUn Autorisation Temporaire d’Utilisation nominative AUA American urology association BC maximal bladder capacity BCS Biopharmaceutics Classification System BPS bladder pain syndrome CEP Certificate of Suitability of the EP CFU Colony forming units CI 95 % confidence interval DDD defined daily doses DDI Drug drug interaction DMSO Dimethyl sulfoxide EAU European Association of Urology EC European Commission ESSIC International Society for the Study of Bladder Pain Syndrome EU European Union FDA Food and Drug Administration FT-IR Fourrier Transform Infrared Spectroscopy GAG Glycosaminoglycan GPC Gel permeation chromatography GRA global response assessment GTI gastrointestinal HDPE High Density Polyethylene HPLC high performance liquid chromatography HSCIC Health and Social Care Information Centre IC Interstitial Cystitis ICH International Conference on Harmonisation of Technical Requirements for Registration of ICPI O'Leary-Sant Interstitial Cystitis Problem Index Assessment report EMA/287422/2017 Page 4/115 ICSI O’Leary-Sant Interstitial Cystitis Symptom Index lgG Immunoglobulin G INR International Normalized Ratio IRA investigator RA IR Infrared ITT Intention to Treat IV, i.v. Intravenous LIVIVO German National Library of Medicine LOCF last-observation-carried forward LoD loss of drying MAA Marketing Authorisation Application/Marketing Authorisation Applicant MCC Microcrystalline Cellulose MO Major Objection MOA Mechanism of action MTD Maximum Tolerated Dose N/A not applicable/ available NIDDK National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (USA) NLT not less than NMR Nuclear Magnetic Resonance NMT not more than NS not significant OC Other Concern PBS Painful Bladder Syndrome Pbo Placebo PD pharmacodynamics Ph. Eur. European Pharmacopoeia PI Prescribing Information PK Pharmacokinetic P.O Per Os PORIS Patient’s overall rating of Symptoms Index PP Polypropylene PRA Patient responder
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