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Assessment Report 23 July 2015 EMA/596950/2015 Committee for Medicinal Products for Human Use (CHMP) Assessment report Cresemba International non-proprietary name: isavuconazole Procedure No. EMEA/H/C/002734/0000 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 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ..................................................................................... 7 2. Scientific discussion ................................................................................ 9 2.1. Introduction ........................................................................................................ 9 2.1.1. Problem statement ............................................................................................ 9 2.1.2. About the product ........................................................................................... 10 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction.................................................................................................... 13 2.2.2. Active Substance ............................................................................................. 13 2.2.3. Finished Medicinal Product ................................................................................ 17 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 24 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 24 2.2.6. Recommendation(s) for future quality development ............................................. 24 2.3. Non-clinical aspects ............................................................................................ 24 2.3.1. Introduction.................................................................................................... 24 2.3.2. Pharmacology ................................................................................................. 24 2.3.3. Pharmacokinetics ............................................................................................ 27 2.3.4. Toxicology ...................................................................................................... 31 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 36 2.3.6. Discussion on non-clinical aspects ..................................................................... 38 2.3.7. Conclusion on the non-clinical aspects ............................................................... 38 2.4. Clinical aspects .................................................................................................. 39 2.4.1. Introduction.................................................................................................... 39 2.4.2. Pharmacokinetics ............................................................................................ 57 2.4.3. Pharmacodynamics .......................................................................................... 64 2.4.4. Discussion on clinical pharmacology ................................................................... 73 2.4.5. Conclusions on clinical pharmacology ................................................................. 77 2.5. Clinical efficacy .................................................................................................. 77 2.5.1. Dose response studies ..................................................................................... 78 2.5.2. Main studies ................................................................................................... 78 2.5.3. Discussion on clinical efficacy .......................................................................... 120 2.5.4. Conclusions on the clinical efficacy .................................................................. 123 2.6. Clinical safety .................................................................................................. 123 2.6.1. Discussion on clinical safety ............................................................................ 145 2.6.1. Conclusions on the clinical safety .................................................................... 146 2.7. Risk Management Plan ...................................................................................... 146 2.8. Pharmacovigilance ........................................................................................... 155 2.9. Product information .......................................................................................... 155 Assessment report EMA/596950/2015 Page 2/162 2.9.1. User consultation .......................................................................................... 155 2.9.2. Additional monitoring ..................................................................................... 155 3. Benefit-Risk Balance ........................................................................... 155 4. Recommendations ............................................................................... 160 Assessment report EMA/596950/2015 Page 3/162 List of abbreviations AE adverse event AUC area under the concentration-time curve AUCinf area under the concentration-time curve till infinity AUCt area under the concentration-time curve till the last sampling time ΔΔQTcF time-matched baseline-and placebo-adjusted QT interval corrected for heart rate using Fridericia's formula AFT antifungal therapy ALP alkaline phosphatase ALT alanine transaminase AST Aspartate transaminase AmB amphotericin B AML acute myeloid leukemia ANC absolute neutrophil count AST aspartate transaminase AUC area under the concentration time curve BAL4815 isavuconazole BAL8557 isavuconazonium sulfate (prodrug) BAL8728 Inactive cleavage product of isavuconazonium sulfate β-HCG urine or serum pregnancy test b.i.d. twice daily BLQ below the limit of quantification BMI body mass index BMT bone marrow transplant bpm beats per minute BRCP Breast cancer resistance protein BUN blood urea nitrogen BW body weight CI confidence interval CL clearance Clcr creatinine clearance Clint intrinsic clearance Clr renal clearance CLSI clinical and Laboratory Standards Institute Cmax maximal plasma concentration Cmin minimum plasma concentration CMH Cochran-Mantel-Haenszel CNS central nervous system CPK creatinine phosphokinase CrCl creatinine clearance CRF case record form CSF cerebrospinal fluid CT computed tomography Cτ concentration at the end of the dosing interval Ctrough trough plasma concentration Assessment report EMA/596950/2015 Page 4/162 DRC Data Review Committee ECG electrocardiogram ESCMID/ECMM European Society of Clinical Microbiology and Infectious Diseases/European Confederation of Medical Mycology ECV epidemiological cut off value eGFR estimated glomerular filtration rate eGFR-MDRD estimated glomerular filtration rate calculated using the Modification of Diet in Renal Disease formula EOT end-of-treatment visit EORTC/MSG European Organisation for the Research and Treatment of Cancer/Mycoses Study Group ESCMID European Society of Clinical Microbiology and Infectious Diseases EUCAST European Committee on Antimicrobial Susceptibility Testing FDA US Food and Drug Administration FLU fluconazole FU follow-up period GCP Good Clinical Practice GGT gamma glutamyl transpeptidase GM galactomannan GMR geometric mean ratio GTI Genotoxic Impurity h hour HIV human immunodeficiency virus HSCT hematopoietic stem cell transplant IA Invasive aspergillosis IDSA Infectious Diseases Society of America IFD Invasive Fungal Disease ISA Isavuconazole ITT intent-to-treat population IV intravenous l-AmB lipid-based formulations of amphotericin B l liter LDH lactate dehydrogenase LFU late follow-up visit LLN Lower limit of normal LLOQ Lower limit of quantification LRTD Lower respiratory tract disease MAA Marketing Authorisation Application MedDRA Medical Dictionary for Regulatory Activities MIC minimum inhibitory concentration MIC50 MIC at which 50% of the isolates are inhibited at the specified endpoint MIC90 MIC at which 90% of the isolates are inhibited at the specified endpoint mITT modified ITT ml mililiter MRI Magnetic Resonance Imaging myITT mycological ITT NA not available N/A not applicable Assessment report EMA/596950/2015 Page 5/162 ND not detected NIM Non-inferiority margin NOS not otherwise specified NRI non renally impaired patients OCT1 or OCT2 Organic cation transporters 1 or 2 P-gp P-glycoprotein PIP Paediatric Investigation Plan PKAS pharmacokinetic analysis set popPK population pharmacokinetic analysis PPS-ITT Per-protocol set (subset of ITT analysis set) PPS-mITT Per-protocol set (subset of mITT analysis set) PTA Probability of target attainment q.d. (QD) once daily QIDP Qualified Infectious Disease Product QTc QT interval corrected for heart rate QTcB QT interval corrected for heart rate using Bazett’s formula QTcF QT interval corrected for heart rate by Fridericia formula RI renally impaired patients RMP Risk Management Plan SAE serious adverse event SBECD sulfobutyl ether beta-cyclodextrin sodium SCAR severe cutaneous adverse reactions s.d. (SD) standard deviation SFU short-term follow-up
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