Sialanar H-3883 EPAR - European Medicines Agency

1 21 July 2016. EMA/555265/2016. Committee for Medicinal Products for Human Use (CHMP). Assessment report Sialanar International non-proprietary name: glycopyrronium bromide Procedure No. EMEA/H/C/003883/0000. 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 An Agency of the European Union Table of contents 1. Background information on the procedure .. 8. Submission of the dossier .. 8. Steps taken for the assessment of the product .. 8. Steps taken for the re-examination procedure.

2 10. 2. Scientific discussion .. 10. Introduction .. 10. Quality aspects .. 16. 16. Active Substance .. 16. Finished Medicinal Product .. 17. Discussion on chemical, pharmaceutical and biological 19. Conclusions on the chemical, pharmaceutical and biological aspects .. 19. Recommendations for future quality development .. 19. Non-clinical aspects .. 20. 20. Pharmacology .. 20. Pharmacokinetics .. 21. Toxicology .. 22. Ecotoxicity/environmental risk assessment .. 25. Discussion on non-clinical aspects .. 26. Conclusion on the non-clinical aspects .. 28. Clinical aspects .. 28. 28. Pharmacokinetics .. 29. Pharmacodynamics .. 33. Discussion on clinical 35. Conclusions on clinical pharmacology.

3 37. Clinical efficacy .. 37. Dose response study(ies) .. 37. Main studies .. 38. Discussion on clinical efficacy .. 58. Conclusions on the clinical efficacy .. 62. Clinical safety .. 62. Discussion on clinical safety .. 78. Conclusions on the clinical safety .. 81. Pharmacovigilance .. 82. Risk Management Plan .. 82. Product information .. 88. User consultation .. 88. Assessment report EMA/CHMP/436684/2016 Page 2/143. 3. Benefit-Risk Balance .. 88. 4. 94. 5. Re-examination of the CHMP opinion of 28 April 2016 .. 96. Risk Management Plan .. 122. Pharmacovigilance .. 132. Product information .. 132. User consultation .. 132. 6. Benefit-risk balance .. 133. 7. Recommendations following re-examination.

4 139. Assessment report EMA/CHMP/436684/2016 Page 3/143. List of abbreviations Ach acetylcholine ADI acceptable daily intake ADRs adverse drug reactions AE adverse event ALP alkaline phosphatase ALT alanine aminotransferase AP Applicant's Part (or Open Part) of a ASMF. API Active Pharmaceutical Ingredient APPM Association of Paediatric Palliative Medicine Master Formulary AR Assessment Report ASM Active Substance Manufacturer ASMF Active Substance Master File (Drug Master File). ATC Anatomical Therapeutic Chemical Classification System AUC area under the time-concentration curve AUC (0-t) area under the plasma concentration vs. time curve, from time zero to t, where t was the last quantifiable concentration AUC (0- ) area under the plasma concentration vs.

5 Time curve, with extrapolation to infinity BA bioavailability BE bioequivalence BMI Body Mass Index BNFc British National Formulary for Children BP British Pharmacopoeia or blood pressure bpm beats per minute CE Conformit Europ ene CEP Certificate of Suitability of the CHMP Committee for Medicinal Products for Human Use CHO chinese hamster ovary Cmax maximum concentration in plasma (or serum). CI confidence interval Cl (total plasma) clearance CMS Concerned Member State CNS central nervous system CoA Certificate of Analysis CP cerebral palsy CRS Chemical Reference Substance (official standard). CSF cerebrospinal fluid CSR clinical study report %CV intra-subject coefficient of variation DAP Drug Approval Package (FDA).

6 DMF Drug Master File (active substance master file). DP Decentralised (Application) Procedure EC European Commission EC 50 Effective concentration 50%. ECG electrocardiogram Assessment report EMA/CHMP/436684/2016 Page 4/143. EDQM European Directorate for the Quality of Medicines EMA European Medicines Agency ESI Electro Spray Ionisation EU European Union F bioavailability FDA Food and Drug Administration (United States). GB glycopyrronium bromide GBOS glycopyrronium bromide oral solution GC gas chromatography GCP Good Clinical Practice GGT gamma-glutamyl transpeptidase GI gastrointestinal GLP Good Laboratory Practice GMP Good Manufacturing Practice GP glycopyrronium H hour(s).

7 HDPE high density polyethylene HPLC high performance liquid chromatography HR heart rate ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use intramuscular(ly). IU International Units IPC in-process control IR Infrared intravenous(ly). kg kilogram(s). z terminal elimination rate constant L litre(s). LD 50 lethal dose 50%. LDPE low density polyethylene LLOQ Lower Limit of Quantification LoA Letter of Access LOD loss on drying LoD limit of detection LoQ limit of quantitation M muscarinic (receptor). MA Marketing Authorisation MAA Marketing Authorisation Application MAH Marketing Authorisation Holder mBMRS Modified Behavioural and Medical Rating Scale mg milligram(s).

8 MHRA Medicines and Healthcare Products Regulatory Agency mL millilitre(s). min minute(s). mITT Modified Intended to Treat Assessment report EMA/CHMP/436684/2016 Page 5/143. mM millimolar MoA mechanism of action MS Mass Spectrometry g microgram mTDS Modified Teacher's Drooling Scale NICE National Institute for Health and Care Excellence TEAE treatment-emergent adverse event ND not detected NDA New Drug Application NHS National Health Service NLT not less than NMR Nuclear Magnetic Resonance NMT not more than NOEL no effect level NS not significant NSAID Non-Steroidal Anti-Inflammatory Drug OOS Out of Specification OTC over-the-counter PAH Pulmonary Arterial Hypertension P/C parent(s)/caregiver PCA prescription cost analysis data PD pharmacodynamics PD Parkinson disease PD 50 preventive dose 50%.

9 PDCO Paediatric Committee PDE permitted daily exposure pg picogram Ph. Eur. European Pharmacopoeia PhV PharmacoVigilance PI Prescribing Information (United States). PL/PIL Package Leaflet PIP Paediatric Investigational Plan PK pharmacokinetics PUMA Paediatric Use Marketing Authorisation QC quality control QoL quality of life QOS quality overall summary RH relative humidity RMS Reference Member State RP Restricted Part (or Closed Part) of a ASMF. RRT relative retention time RSD relative standard deviation SA sino-atrial Subcutaneous(ly). SD standard deviation SmPC Summary of Product Characteristics Assessment report EMA/CHMP/436684/2016 Page 6/143. SOP Standard Operating Procedure t time t half-life t z apparent terminal elimination half-life TEAE treatment-emergent adverse event three times daily Tmax time to maximum observed plasma concentration TSE transmissible spongiform encephalopathies UK United Kingdom ULN upper limit of the normal range USP/NF United States Pharmacopoeia/National Formulary US United States UV Ultraviolet VAS visual analogue scale V volume of distribution in the elimination phase Vss volume of distribution at steady state WEU Well Established Use XRD X-Ray Diffraction Ci microcurie M micromolar *Not all abbreviations may be used.

10 Assessment report EMA/CHMP/436684/2016 Page 7/143. 1. Background information on the procedure Submission of the dossier The applicant Proveca Limited submitted on 28 November 2014 an application for a Paediatric Use Marketing Authorisation in accordance with Article 30 of Regulation (EC) No 1901/2006, to the European Medicines Agency (EMA) for Sialanar , through the centralised procedure under Article 31 of Regulation (EC) No 1901/2006. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 24 October 2013. The applicant applied for the following indication: Treatment of sialorrhoea (chronic pathological drooling) in children aged 2 to <18 years with neurological disorders.