Invokana - CHMP AR - final PDF
Preview Invokana - CHMP AR - final
19 September 2013 EMA/374133/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Canagliflozin International non-proprietary name: Canagliflozin Procedure No. EMEA/H/C/002649/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union Product information Name of the medicinal product: Invokana Applicant: Janssen-Cilag International N.V. Turnhoutseweg 30 B-2340 Beerse BELGIUM Active substance: canagliflozin International Nonproprietary Name/Common canagliflozin Name: Drugs used in diabetes, other blood glucose Pharmaco-therapeutic group lowering drugs, excluding insulins (A10BX11) (ATC Code): Invokana is indicated in adults aged 18 years and older with type 2 diabetes mellitus to Therapeutic indication(s): improve glycaemic control as: Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications. Add-on therapy Add-on therapy with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4, 4.5, and 5.1 for available data on different add-on therapies). Pharmaceutical form: Film-coated tablet Strengths: 100 mg and 300 mg Assessment report EMA/718531/2013 Page 2/115 Route of administration: Oral use Packaging: blister (PVC/Alu) Package sizes: 10 tablets, 30 tablets, 90 tablets and 100 tablets Assessment report EMA/718531/2013 Page 3/115 Table of contents 1. Background information on the procedure ........................................... 12 1.1. Submission of the dossier ................................................................................... 12 1.2. Manufacturers ................................................................................................... 13 1.3. Steps taken for the assessment of the product ...................................................... 13 2. Scientific discussion ............................................................................. 14 2.1. Introduction ...................................................................................................... 14 2.2. Quality aspects ................................................................................................. 14 2.2.1. Introduction ................................................................................................... 14 2.2.2. Active Substance ............................................................................................ 15 2.2.3. Finished Medicinal Product ............................................................................... 15 2.2.4. Discussion on chemical, pharmaceutical and biological aspects ............................. 16 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ..................... 18 2.2.6. Recommendation(s) for future quality development ............................................ 18 2.3. Non-clinical aspects ........................................................................................... 18 2.3.1. Introduction ................................................................................................... 18 2.3.2. Pharmacology ................................................................................................ 18 2.3.3. Pharmacokinetics ............................................................................................ 19 2.3.4. Toxicology ..................................................................................................... 21 2.3.5. Ecotoxicity/environmental risk assessment ........................................................ 25 2.3.6. Discussion on non-clinical aspects...................................................................... 26 2.3.7. Conclusion on the non-clinical aspects ................................................................ 29 2.4. Clinical aspects .................................................................................................. 29 2.4.1. Introduction .................................................................................................... 29 2.4.2. Pharmacokinetics ............................................................................................ 31 2.4.3. Pharmacodynamics ......................................................................................... 36 2.4.4. Discussion on clinical pharmacology .................................................................. 38 2.4.5. Conclusions on clinical pharmacology ................................................................ 40 2.5. Clinical efficacy ................................................................................................. 40 2.5.1. Dose response studies ..................................................................................... 40 2.5.2. Main studies .................................................................................................. 41 2.5.3. Discussion on clinical efficacy ........................................................................... 76 2.5.4. Conclusions on the clinical efficacy .................................................................... 81 2.6. Clinical safety ................................................................................................... 82 2.6.1. Discussion on clinical safety ........................................................................... 101 2.6.2. Conclusions on the clinical safety .................................................................... 104 2.7. Pharmacovigilance ........................................................................................... 105 2.8. Risk Management Plan ..................................................................................... 105 2.9. User consultation ............................................................................................ 110 Assessment report EMA/718531/2013 Page 4/115 3. Benefit-Risk Balance .......................................................................... 110 4. Recommendations .............................................................................. 114 Assessment report EMA/718531/2013 Page 5/115 List of abbreviations %CV percent coefficient of variation 3-OMG 3-O-methyl glucose ACE angiotensin converting enzyme ADR adverse drug reaction Ae Cumulative amount excreted into the urine Ae,%dose Total amount excreted into the urine, expressed as a percentage of the administered dose Aet1-t2 Amount excreted into urine during a collection interval from t1 to t2 AHA antihyperglycaemic agent ALP alkaline phosphatase ALT alanine aminotransferase AMG a-methylglucoside ANOVA Analysis of variance APD60 action potential duration at 60% repolarization API Active Pharmaceutical Ingredient Apo B apolipoprotein B AR Assessment Report ARB angiotensin II receptor blocker ASM Active Substance Manufacturer AST aspartate aminotransferase AUC area under the concentration-time curve AUC24 area under the plasma concentration-time curve from time 0 to 24 hours AUC∞ area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration AUCinf area under the plasma concentration-time curve from time 0 to infinite time AUClast area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration AUMC Area under the first moment of the concentration versus time curve from the time of dosing up to a specific time, t, to infinite time, or to the time of the last measurable concentration BA bioavailability BG blood glucose BID twice daily BLQ below the limit of quantitation BMD bone mineral density BrdU bromo-deoxyuridine BSA body surface area Ca calcium CANA Canagliflocin CANVAS Study DIA3008 CFU Colony Forming Units CHD coronary heart disease CHMP Committee for Medicinal Products for Human Use Assessment report EMA/718531/2013 Page 6/115 CHOK1 Chinese hamster ovary cell line K1 CI confidence interval Cl chloride CL total systemic clearance CLCR creatinine clearance Cmax maximum plasma concentration CoA Certificate of Analysis CV cardiovascular CYP cytochrome P450 DBP diastolic blood pressure DDI drug-drug interactions DIO diet induced obese DNJ 1-deoxynorjirimycin DPP-4 dipeptidyl-peptidase-4 DSC differential scanning calorimetry DXA dual-energy x-ray absorptiometry EAC endpoint adjudication committee ECG electrocardiogram eCRF electronic case report form eGFR estimated glomerular filtration rate EMA European Medicines Agency EOP2 end of Phase 2 ESRD End-Stage Renal Disease ESRD end-stage renal disease FBG fluid-bed granulation FDA Food and Drug Administration Fe Total amount excreted into the feces Fe,% Total radioactivity excreted into the feces, expressed as a percentage of the administered dose dose, FPG fasting plasma glucose FPG fasting plasma glucose FS-MMTT frequently-sampled mixed-meal tolerance test FT-IR Fourier transform infrared spectroscopy FT- Fourier transform Raman spectroscopy Raman GC Gas Chromatography GCP Good clinical practise GFR glomerular filtration rate GGT gamma-glutamyltransferase GLP Good Laboratory Practice GLP-1 glucagon-like peptide-1 GLUT1 glucose transporter 1 GLUT2 glucose transporter 2 GLUT4 glucose transporter 4 GMP Good Manufacturing Practice GMR Geometric mean ratio Assessment report EMA/718531/2013 Page 7/115 HbA1c haemoglobin A1c (glycated haemoglobin) HCl Hydrochloric acid HCT haematocrit HDL-C high-density lipoprotein-cholesterol HEK human embryonic kidney HGB haemoglobin High DIA3005 substudy in subjects with more severe hyperglycemia (HbA >10.0% to £12.0%) 1c Glycaemic Substudy HOMA2- homeostatic model assessment of beta-cell function using HOMA2 calculations %B HPbCD hydroxypropyl-b-cyclodextrin HPLC high-performance liquid chromatography HR hazard ratio HSG high-shear granulation HSG high-shear granulation hSGLT1 human SGLT1 hSGLT2 human SGLT2 hSGLT4 human sodium glucose co-transporter-4 hSGLT6 human sodium glucose co-transporter-6 hSMIT1 human sodium/myo-inositol co-transporter-1 IAS Integrated Analysis of Safety IC50 inhibiting concentration at 50% ICH International Conference on Harmonisation IPC In-process control IR Infrared ISE Integrated Summary of Efficacy ISS Integrated Summary of Safety J&JPRD Johnson & Johnson Pharmaceutical Research & Development, LLC JNJ- Canagliflozin 28431754 JRD Janssen Research & Development, LLC (the company) K potassium Kd equilibrium dissociation constant KF Karl Fischer KIM-1 kidney injury molecule-1 (also known as TIM-1) LCT Leydig cell tumor LDL-C low-density lipoprotein-cholesterol LH luteinizing hormone LOA Letter of Access LOCF last observation carried forward LOD (1) Loss on Drying, (2) Limit of Detection LoQ List of Questions LOQ Limit of Quantification LS least-squares MAA Marketing Authorisation Application MACE major adverse cardiovascular events Assessment report EMA/718531/2013 Page 8/115 MACE MACE and hospitalized unstable angina (UA). plus MDCKII Madin-Darby canine kidney II MDR1 multi-drug resistance 1 MDRD Modification of Diet in Renal Disease MMTT mixed-meal tolerance test MPG Mean plasma glucose MPG mean plasma glucose concentrations from 0 to 24 hours 24 MRP2 multidrug resistance-associated protein 2 MRT the time corresponding to the average time the number of molecules absorbed reside in the body MS Mass Spectrometry MTPC Mitsubishi Tanabe Pharma Corporation (the development partner) N/A not applicable Na sodium NADP nicotinamide adenine dinucleotid phosphate NAG N-acetyl β-D-glucosaminidase ND Not detected NDA New Drug Application NLT Not less than NMR Nuclear Magnetic Resonance NMT Not more than NOAEL no-observed-adverse-effect level NPE non-particle-engineered NT Not tested OECD Organisation for Economic Co-Operation and Development OGTT oral glucose tolerance test OOS Out of Specifications OSOM outer stripe of the outer medulla P phosphorus PD Pharmacodynamic PDE Permitted Daily Exposure PDLC predefined limit of change PE particle-engineered PE Polyethylene P-gp P-glycoprotein Ph.Eur. European Pharmacopoeia PIP Paediatric Investigation Plan PK pharmacokinetic PP per protocol PPARγ peroxisome proliferator-activated receptor-gamma PPG post-prandial glucose Ppm parts per million PTH parathyroid hormone PTT prothrombin time PWG Pathology Working Group Assessment report EMA/718531/2013 Page 9/115 QD once daily RBC red blood cell count RH Relative Humidity RLG radioluminography ROW rest of world RRT Relative retention time RSD Relative standard deviation RTG/RT renal threshold for glucose G RTT(s) renal tubular tumor(s) S9 exogenous mammalian metabolic activation system SAP statistical analysis plan SBP systolic blood pressure SCE Summary of Clinical Efficacy SD standard deviation SE standard error Sec section SEM standard error of the mean SGLT1 sodium-glucose co-transporter-1 SGLT2 sodium-glucose co-transporter -2 SMIT1 sodium/myo-inositol co-transporter-1 SOC system organ class SU sulphonylurea t½ elimination half-life T2DM type 2 diabetes mellitus TAMC Total Aerobic Microbial Count TG Triglyceride TGA thermal gravimetric analysis TLC Thin Layer Chromatography t time to reach maximum concentration max TMDS 1,1,3,3-tetramethyldisiloxane TR total radioactivity TS tosylate salt TSE Transmissible Spongiform Encephalopathies TTC Threshold of Toxicological Concern TYMC Total Yeasts and Moulds Count UDPGA uridine 5'-diphospho-glucuronic acid UGE urinary glucose excretion UGE 24-hour urinary glucose excretion 24 UGT uridine diphosphate glucuronyl transferase ULN upper limit of normal UreaN urea nitrogen US United States USP United States Pharmacopoeia UV ultraviolet UV-A ultraviolet A Assessment report EMA/718531/2013 Page 10/115
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