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Glibenclamide 22 February 2018 EMA/153558/2018 Committee for Medicinal Products for Human Use (CHMP) CHMP assessment report Amglidia International non-proprietary name: glibenclamide Procedure No. EMEA/H/C/004379/0000 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, 2018. Reproduction is authorised provided the source is acknowledged. Administrative information Name of the medicinal product: Amglidia Applicant: Ammtek 15, rue Beranger 75003 Paris FRANCE Active substance: GLIBENCLAMIDE International Nonproprietary Name: glibenclamide Pharmaco-therapeutic group BLOOD GLUCOSE LOWERING DRUGS, EXCL. (ATC Code): INSULINS, Sulfonylureas (A10BB01) Amglidia is indicated for the treatment of neonatal diabetes mellitus, for use in Therapeutic indication: newborns, infants and children. Sulphonylureas like Amglidia have been shown to be effective in patients with mutations in the genes coding for the β-cell ATP-sensitive potassium channel and chromosome 6q24-related transient neonatal diabetes mellitus. Pharmaceutical form Oral suspension Strengths: 0.6 mg/ml and 6 mg/ml Route of administration: Oral use Packaging: bottle (glass) Package size(s): 1 bottle + 1 bottle adapter + one oral syringe (1ml or 5ml) CHMP assessment report EMA/153558/2018 Page 2/60 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 ........................................................ 9 2. Scientific discussion .............................................................................. 11 2.1. Introduction ...................................................................................................... 11 2.2. Quality aspects .................................................................................................. 12 2.2.1. Introduction.................................................................................................... 12 2.2.2. Finished medicinal product ............................................................................... 14 Adventitious agents ............................................................................................... 17 2.2.3. Discussion on chemical, and pharmaceutical aspects ........................................... 18 2.2.4. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 18 2.2.5. Recommendations for future quality development ............................................... 18 2.3. Non-clinical aspects ............................................................................................ 18 2.3.1. Introduction.................................................................................................... 18 2.3.2. Pharmacology ................................................................................................. 19 2.3.3. Pharmacokinetics ............................................................................................ 21 2.3.4. Toxicology ...................................................................................................... 22 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 22 2.3.6. Discussion on non-clinical aspects ..................................................................... 23 2.3.7. Conclusion on the non-clinical aspects ............................................................... 23 2.4. Clinical aspects .................................................................................................. 23 2.4.1. Introduction.................................................................................................... 23 2.4.2. Pharmacokinetics ............................................................................................ 24 2.4.3. Pharmacodynamics .......................................................................................... 29 2.4.4. Clinical efficacy ............................................................................................... 31 Dose-response studies and main clinical studies ................................................... 32 2.4.5. Clinical safety ................................................................................................. 37 2.4.6. Post marketing experience ............................................................................... 43 2.4.7. Discussion on clinical safety .............................................................................. 43 2.4.8. Conclusions on clinical safety ............................................................................ 44 2.5. Risk Management Plan ........................................................................................ 44 Risk is described in the section Warnings and precautions ....................... 45 2.6. Pharmacovigilance ............................................................................................. 48 2.7. Product information ............................................................................................ 48 2.7.1. User consultation ............................................................................................ 48 3. Benefit-risk assessment ........................................................................ 49 3.1. Therapeutic Context ....................................................................................... 49 CHMP assessment report EMA/153558/2018 Page 3/60 3.1.1. Disease or condition ........................................................................................ 49 3.1.2. Available therapies and unmet medical need ....................................................... 49 3.1.3. Main clinical studies ......................................................................................... 50 3.2. Favourable effects .......................................................................................... 51 3.3. Uncertainties and limitations about favourable effects ................................... 52 3.4. Unfavourable effects ....................................................................................... 52 3.5. Uncertainties and limitations about unfavourable effects ............................... 52 3.6. Effects Table ................................................................................................... 53 3.7. Benefit-risk assessment and discussion ................................................................. 56 3.7.1. Importance of favourable and unfavourable effects .............................................. 56 3.8. Balance of benefits and risks ............................................................................... 57 3.9. Additional considerations on the benefit-risk balance .............................................. 57 4. Recommendation .................................................................................. 58 CHMP assessment report EMA/153558/2018 Page 4/60 List of abbreviations 6q24 a gene locus associated with neonatal diabetes mellitus ABCC8 gene encoding SUR1 CEP Certificate of Suitability of the EP DAD Diode-Array Detection DCD Developmental coordination disorder DEND Developmental delay, Epilepsy and Neonatal Diabetes EDQM European Directorate for the Quality of Medicines GC Gas Chromatography HDPE High Density Polyethylene HPLC High performance liquid chromatography ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use iDEND intermediate DEND IDDM insulin dependent diabetes mellitus IR Infrared IUGR Intrauterine growth restriction KATP channel ATP-sensitive potassium channel KCNJ11 gene encoding Kir6.2 Kir6.2 Potassium inward rectifier 6.2 MRI Magnetic resonance imaging NEJM The New England Journal of Medicine ND Neonatal Diabetes NDM Neonatal Diabetes mellitus NSH neonatal syndromic hyperglycaemia PDCO Paediatric Committee Ph. Eur. European Pharmacopoeia PIP paediatric investigation plan PND Permanent ND PNDM Permanent NDM CHMP assessment report EMA/153558/2018 Page 5/60 PNSH Permanent neonatal syndromic hyperglycaemia PNIDDM permanent IDDM of neonatal onset PP Polypropylene PSD Particle size distribution SU Sulfonylurea SUR1 Sulfonylurea receptor 1 TLC Thin layer chromatography TND Transient ND TNDM Transient NDM TNSH Transient neonatal syndromic hyperglycaemia UV Ultraviolet XRD X-Ray Diffraction XRPD X-Ray Power Diffraction CHMP assessment report EMA/153558/2018 Page 6/60 1. Background information on the procedure 1.1. Submission of the dossier The applicant Pharma Services submitted on 6 October 2016 an application for marketing authorisation to the European Medicines Agency (EMA) for Amglidia, through the centralised procedure under Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004. The application was transferred from Pharma Services to Ammtek during the submission of responses to the CHMP consolidated List of Questions on 20 April 2017. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 28 January 2016. The application concerns a hybrid medicinal product as defined in Article 10(3) of Directive
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