Invokana - CHMP AR - final

115 Pages·2013·1.77 MB·English

by  Jehlarova Mira

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.

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Telephone [phone] Facsimile [phone]
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

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Route of administration: Oral use

Packaging: blister (PVC/Alu)

Package sizes: 10 tablets, 30 tablets, 90 tablets and 100
tablets

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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

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3. Benefit-Risk Balance .......................................................................... 110
4. Recommendations .............................................................................. 114

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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

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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

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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

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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

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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

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