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Vabomere, Through the Centralised Procedure Under Article 3 (2) (A) of Regulation (EC) No 726/2004

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Vabomere, Through the Centralised Procedure Under Article 3 (2) (A) of Regulation (EC) No 726/2004 20 September 2018 EMA/CHMP/700663/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report Vabomere International non-proprietary name: meropenem / vaborbactam Procedure No. EMEA/H/C/004669/0000 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. 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 .............................................................................. 10 2.1. Problem statement ............................................................................................. 10 2.1.1. Disease or condition ......................................................................................... 10 2.1.2. Epidemiology .................................................................................................. 10 2.1.3. Aetiology and pathogenesis .............................................................................. 10 2.1.4. Clinical presentation, diagnosis .......................................................................... 11 2.1.5. Management ................................................................................................... 11 2.2. Quality aspects .................................................................................................. 12 2.2.1. Introduction .................................................................................................... 12 2.2.2. Active Substance ............................................................................................. 12 2.2.3. Finished Medicinal Product ................................................................................ 16 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 19 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 20 2.2.6. Recommendations for future quality development................................................ 20 2.3. Non-clinical aspects ............................................................................................ 21 2.3.1. Introduction .................................................................................................... 21 2.3.2. Pharmacology ................................................................................................. 21 2.3.3. Pharmacokinetics............................................................................................. 22 2.3.4. Toxicology ...................................................................................................... 25 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 30 2.3.6. Discussion on non-clinical aspects...................................................................... 32 2.3.7. Conclusion on the non-clinical aspects ................................................................ 33 2.4. Clinical aspects .................................................................................................. 33 2.4.1. Introduction .................................................................................................... 33 2.4.2. Pharmacokinetics............................................................................................. 40 2.4.3. Pharmacodynamics .......................................................................................... 50 2.4.4. Discussion on clinical pharmacology ................................................................... 60 2.4.5. Conclusions on clinical pharmacology ................................................................. 64 2.5. Clinical efficacy .................................................................................................. 65 2.5.1. Main studies ................................................................................................... 65 2.5.2. Discussion on clinical efficacy ............................................................................ 81 2.5.3. Conclusions on the clinical efficacy ..................................................................... 84 2.6. Clinical safety .................................................................................................... 85 2.6.1. Discussion on clinical safety .............................................................................. 97 2.6.2. Conclusions on the clinical safety ....................................................................... 97 2.7. Risk Management Plan ........................................................................................ 97 2.8. Pharmacovigilance .............................................................................................. 99 2.9. New Active Substance ......................................................................................... 99 Assessment report EMA/CHMP/700663/2018 Page 2/108 2.10. Product information ........................................................................................ 100 2.10.1. User consultation ......................................................................................... 100 2.10.2. Additional monitoring ................................................................................... 100 3. Benefit-Risk Balance............................................................................ 101 3.1. Therapeutic Context ......................................................................................... 101 3.1.1. Disease or condition ....................................................................................... 101 3.1.2. Available therapies and unmet medical need ..................................................... 101 3.1.3. Main clinical studies ....................................................................................... 102 3.2. Favourable effects ............................................................................................ 102 3.3. Uncertainties and limitations about favourable effects ........................................... 103 3.4. Unfavourable effects ......................................................................................... 104 3.5. Uncertainties and limitations about unfavourable effects ....................................... 104 3.6. Effects Table .................................................................................................... 105 3.7. Benefit-risk assessment and discussion ............................................................... 105 3.7.1. Importance of favourable and unfavourable effects ............................................ 105 3.7.2. Balance of benefits and risks ........................................................................... 106 3.7.3. Additional considerations on the benefit-risk balance ......................................... 106 3.8. Conclusions ..................................................................................................... 106 4. Recommendations ............................................................................... 106 Assessment report EMA/CHMP/700663/2018 Page 3/108 List of abbreviations AM Alveolar Macrophages AmpC hyper AmpC hyperproducer ANOVA Analysis of variance AP Acute Pyelonephritis AST Antimicrobial susceptibility testing AUC0-inf Area under the plasma concentration-time curve from time zero to infinity AUC0-8 Area under the plasma concentration-time curve from 0 to 8 hours AUC0-24 Area under the concentration-time curve from 0 to 24 hours AUC0-t Area under the plasma concentration-time curve time zero to the last measurable concentration AUC:MIC Area under the concentration-time curve (AUC) to MIC AVI Avibactam AZT Aztreonam BAL Bronchoalveolar Lavage BAT Best Available Therapy BLI Beta-lactamase inhibitor BSA Body surface area CAMHB Cation-adjusted Mueller-Hinton broth CAZ Ceftazidime CEP Certificate of Suitability of the European Pharmacopoeia CDC Center for Disease Control and Prevention CFU Colony forming units CI Confidence Interval cIAI Complicated intra-abdominal infections CLcr Creatinine clearance CLd Distributional clearance CLnr Non-renal clearance CLR Renal clearance CLSI Clinical and Laboratory Standards Institute CLt Plasma clearance Cmax Maximum drug concentration CRE Carbapenem-Resistant Enterobacteriaceae cUTI Complicated Urinary Tract Infection CV% Percent coefficient of variation CYP450 Cytochrome P450 DSC Differential Scanning Calorimetry ECG Electrocardiogram eGFR Estimated glomerular filtration ELF Epithelial Lining Fluid Emax Sigmoid maximum reduction EOIVT End of intravenous treatment EOT End of treatment ESBLs Extended-spectrum beta-lactamases ESRD End-stage renal disease EUCAST European Committee on Antimicrobial Susceptibility Testing FDA Food and Drug Administration fe0-8 Percentage of dose excreted in the urine over 8 hours FL Full-length FME Frequencies of mutant emergence g Grams GC-FID Gas Chromatography- Flame Ionization Detector Assessment
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