CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`210874Orig1s000
`
`CLINICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`
`CLINICAL REVIEW
`Application Type New Drug Application (NDA) / Supplemental NDA (sNDA)
`Application Number(s) NDA 210874 / NDA 209091/S-002
`Priority or Standard Standard
`Submit Date(s)
`July 2, 2018
`Received Date(s)
`July 2, 2018
`PDUFA Goal Date May 2, 2019
`Division/Office Division of Metabolism and Endocrinology Products (DMEP)
`Reviewer Name(s) Frank Pucino, PharmD, MPH
`Review Completion Date March 25, 2019
`Established/Proper Name Dapagliflozin + Saxagliptin + Metformin HCl Extended-Release /
`Dapagliflozin + Saxaglitpin HCl
`
`(Proposed) Trade Name QTERNMET XR / QTERN
`Applicant AstraZeneca
`Dosage Form(s) QTERNMET XR: The Applicant is seeking approval of film-coated
`tablets containing the following dapagliflozin/saxagliptin/metformin
`extended-release dosage strengths: 2.5 mg/2.5 mg/1000 mg; 5
`mg/2.5 mg/1000 mg; 5 mg/5 mg/1000 mg; 10 mg/5 mg/1000 mg
`
`
`
`QTERN: Film-coated tablets containing 10 mg of dapagliflozin and 5
`mg of saxagliptin are currently approved. The Applicant is seeking
`approval of a dapagliflozin 5 mg/saxagliptin 5 mg dosage strength.
`QTERNMET XR: Once daily oral administration.
`QTERN: Once daily oral administration.
`QTERNMET XR: As an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus (T2D)
`
`
`
`
`
`
`
`
`QTERN: As an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus
`
`
`
`Approval pending labeling negotiations.
`
`
`
`The recommended labeling change for Section 1 of QTERNMET XR and
`QTERN to include:
`As an adjunct to diet and exercise to improve glycemic control in
`adults with type 2 diabetes mellitus.
`The recommended labeling change for Section 2.2 to include:
`No dose adjustment is needed in patients with an eGFR ≥45
`mL/min/1.73 m2 and to contraindicate use with an eGFR below 45
`mL/min/1.73 m2.
`
`
`
`1
`
`Applicant Proposed Dosing
`Regimen(s)
`Applicant Proposed
`Indication(s)/Population(s)
`
`Recommendation on
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`
`
`
`Reference ID: 4427479
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`
`Table of Contents
`
`Glossary ........................................................................................................................................... 8
`
`1. Executive Summary ............................................................................................................... 13
` Product Introduction ...................................................................................................... 13
` Conclusions on the Substantial Evidence of Effectiveness ............................................ 14
` Benefit-Risk Assessment ................................................................................................ 16
` Patient Experience Data ................................................................................................. 21
`
`2. Therapeutic Context .............................................................................................................. 22
` Analysis of Condition ...................................................................................................... 22
` Analysis of Current Treatment Options ......................................................................... 23
`
`3. Regulatory Background ......................................................................................................... 28
` U.S. Regulatory Actions and Marketing History ............................................................. 28
`Summary of Presubmission/Submission Regulatory Activity ........................................ 31
`
`Foreign Regulatory Actions and Marketing History ....................................................... 39
`
`
`4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety................................................................................................................. 39
` Office of Scientific Investigations (OSI) .......................................................................... 39
` Product Quality .............................................................................................................. 42
` Clinical Microbiology ...................................................................................................... 44
` Nonclinical Pharmacology/Toxicology ........................................................................... 44
` Clinical Pharmacology .................................................................................................... 45
` Mechanism of Action .............................................................................................. 46
` Pharmacodynamics ................................................................................................. 46
` Pharmacokinetics .................................................................................................... 46
` Devices and Companion Diagnostic Issues .................................................................... 48
` Consumer Study Reviews ............................................................................................... 48
`
`5. Sources of Clinical Data and Review Strategy ....................................................................... 49
` Table of Clinical Studies .................................................................................................. 49
` Review Strategy .............................................................................................................. 54
`
`
`
`
`Reference ID: 4427479
`
`
`
`2
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`6. Review of Relevant Individual Trials Used to Support Efficacy ............................................. 54
` Phase 3 Trials .................................................................................................................. 54
` Overview and Objectives ........................................................................................ 54
` Study Designs .......................................................................................................... 56
` Inclusion and Exclusion Criteria .............................................................................. 57
` Study Treatments .................................................................................................... 59
` Administrative Structure of the QTERNMET XR and QTERN Development Program .. 61
` Protocol Procedures and Schedule ......................................................................... 63
` Study Endpoints ...................................................................................................... 66
` Statistical Analysis Plan ........................................................................................... 68
` Protocol Amendments ............................................................................................ 69
`Study Results ................................................................................................... 69
`
`
`7.
`
`Integrated Review of Effectiveness ....................................................................................... 82
` Assessment of Efficacy Across Trials .............................................................................. 82
` Primary Endpoints ................................................................................................... 82
` Secondary and Other Endpoints ............................................................................. 83
` Subpopulations ....................................................................................................... 83
` Dose and Dose-Response........................................................................................ 83
` Onset, Duration, and Durability of Efficacy Effects ................................................ 83
` Additional Efficacy Considerations ................................................................................. 83
` Considerations on Benefit in the Postmarket Setting ............................................ 83
` Other Relevant Benefits .......................................................................................... 84
`Integrated Assessment of Effectiveness ........................................................................ 84
`
`
`
`8. Review of Safety .................................................................................................................... 86
`Safety Review Approach ................................................................................................ 86
`
` Review of the Safety Database ...................................................................................... 87
` Overall Exposure ..................................................................................................... 87
` Relevant Characteristics of the Safety Population ................................................. 90
` Adequacy of the safety database: .......................................................................... 92
` Adequacy of Applicant’s Clinical Safety Assessments .................................................... 92
`
`
`
`
`Reference ID: 4427479
`
`
`
`3
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`
`
`
` Issues Regarding Data Integrity and Submission Quality ....................................... 92
` Categorization of Adverse Events ........................................................................... 92
` Routine Clinical Tests .............................................................................................. 94
`Safety Results ................................................................................................................. 94
` Deaths ..................................................................................................................... 97
` Serious Adverse Events ........................................................................................... 99
` Dropouts and/or Discontinuations Due to Adverse Effects ................................. 106
` Significant Adverse Events .................................................................................... 110
` Treatment Emergent Adverse Events and Adverse Reactions ............................. 110
` Laboratory Findings .............................................................................................. 112
` Vital Signs .............................................................................................................. 115
` Electrocardiograms (ECGs) .................................................................................... 115
` QT .......................................................................................................................... 115
`Immunogenicity ............................................................................................. 116
`
` Analysis of Submission-Specific Safety Issues .............................................................. 116
` Genital Infections .................................................................................................. 116
` Urinary Tract Infections ........................................................................................ 117
` Hypoglycemia ........................................................................................................ 117
` Renal Failure/Impairment ..................................................................................... 118
` Malignancies ......................................................................................................... 119
` Fractures ............................................................................................................... 120
` Confirmed Adjudicated Cardiovascular Events .................................................... 121
` Confirmed Adjudicated Hepatic Events ................................................................ 122
` Decreased Lymphocyte and Platelet Counts ........................................................ 122
`Pancreatitis .................................................................................................... 122
`
`Severe Cutaneous Adverse Reactions ........................................................... 122
`
`Severe Hypersensitivity Reactions................................................................. 123
`
`Volume Depletion .......................................................................................... 124
`
` Metabolic Acidosis ......................................................................................... 124
` Myopathy/Rhabdomyolysis ........................................................................... 124
`
`
`
`
`Reference ID: 4427479
`
`
`
`4
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`
`Other Adverse Events Associated with SGLT2 Inhibitors, DPP-4 Inhibitors, and
`
`Metformin ....................................................................................................................... 124
`Safety Analyses by Demographic Subgroups ............................................................... 127
`
`Specific Safety Studies/Clinical Trials ........................................................................... 127
`
` Additional Safety Explorations ..................................................................................... 127
` Human Carcinogenicity or Tumor Development .................................................. 127
` Human Reproduction and Pregnancy ................................................................... 127
` Pediatrics and Assessment of Effects on Growth ................................................. 128
` Overdose, Drug Abuse Potential, Withdrawal, and Rebound .............................. 129
`Safety in the Postmarket Setting.................................................................................. 131
` Safety Concerns Identified Through Postmarket Experience ............................... 131
` Expectations on Safety in the Postmarket Setting ............................................... 131
` Additional Safety Issues from Other Disciplines ................................................... 132
`Integrated Assessment of Safety .............................................................................. 132
`
`
`
`
`
`9. Advisory Committee Meeting and Other External Consultations ....................................... 133
`
`10. Labeling Recommendations ................................................................................................ 133
`Prescription Drug Labeling ....................................................................................... 133
`
`Nonprescription Drug Labeling ................................................................................. 135
`
`
`11. Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 135
`
`12. Postmarketing Requirements and Commitments ............................................................... 135
`
`13. Appendices .......................................................................................................................... 136
`References ................................................................................................................ 136
`
`Financial Disclosure .................................................................................................. 150
`
`Antihyperglycemic Products Approved in the United States ................................... 152
`
`Study Designs for the Relevant Phase 3 Trials ......................................................... 213
`
`Adverse Events of Special Interest (System/Custom MedDRA Queries) ................. 218
`
`Adverse Event Summary (3-study pool) ................................................................... 244
`
`Serious Adverse Events by System Organ Class (7-study pool) ................................ 245
`
`Adverse Events of Special Interest (7-study pool, Broad CMQs) ............................. 246
`
`
`
`
`
`Reference ID: 4427479
`
`
`
`5
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`
`Table of Tables
`
`
`Table 1: Approved Therapeutic Options for the Management of Type 2 Diabetes Mellitus ....... 24
`Table 2: Summary of Presubmission/Submission Regulatory History for NDA 210874 and NDA
`209091/S-002 ................................................................................................................................ 32
`Table 3: Protocol/Site Identification ............................................................................................. 40
`Table 4: Listing of Clinical Trials Relevant to NDA 210874 and NDA 209091/S-002 .................... 50
`Table 5: Summary of Key Inclusion and Exclusion Criteria by Phase 3 Trial ................................. 57
`Table 6: Insulin Dose Titration Scheme (up to Week 8) ............................................................... 61
`Table 7: Administrative Structure of the Phase 3 Efficacy Trials .................................................. 62
`Table 8: Criteria for Initiation of Antihyperglycemic Rescue Therapy .......................................... 64
`Table 9: Criteria for Initiation of Antihyperglycemic Rescue Therapy .......................................... 65
`Table 10: Sequential Testing Order for Key Secondary Endpoints by Trial .................................. 67
`Table 11: Subject Disposition for Phase 3 Efficacy Trials (Randomized Population) .................... 71
`Table 12: Baseline Demographics for Phase 3 Efficacy Trials (Randomized Population)* ........... 73
`Table 13: Clinical Characteristics for Phase 3 Efficacy Trials (Randomized Population)* ............ 74
`Table 14: HbA1c Change from Baseline Analyses (Phase 3 Trials) ............................................... 76
`Table 15: Secondary Endpoint Analyses (Phase 3 Trials) .............................................................. 79
`Table 16: Agency Analysis of Mean Change in HbA1c from Baseline to Week 24 or 52 for Phase
`3 Trials to Support Efficacy (Data after Rescue/Discontinuation Included) ................................. 82
`Table 17: Integrated Safety Population, Size and Duration of Exposure (3-study pool) .............. 88
`Table 18: Integrated Safety Population, Size and Duration of Exposure (5-study pool) .............. 88
`Table 19: Integrated Safety Population, Size and Duration of Exposure (7-study pool) .............. 89
`Table 20: Demographics and Clinical Characteristics (7-study pool)*.......................................... 90
`Table 21: Summary of Adverse Events (Integrated 5- and 7-study pools Safety) ........................ 96
`Table 22: Summary of Serious Adverse Events (Integrated 5- and 7-study pools Safety) ......... 100
`Table 23: Summary of Discontinuations Due to Adverse Events (Integrated 5- and 7-study pools
`Safety) ......................................................................................................................................... 107
`Table 24: Summary of Common Treatment-Emergent Adverse Events (Integrated 5- and 7-study
`pools Safety) ............................................................................................................................... 111
`Table 25: Summary of Marked Laboratory Abnormalities (Integrated 7-study pools Safety) .. 113
`Table 26: Summary of Renal Impairment/Failure AESI (7-study pool) ....................................... 119
`Table 27: Summary of Fractures (7-study pool) ......................................................................... 120
`Table 28: Summary of Heart Failure Events (7-study pool) ........................................................ 121
`Table 29: Summary Table of Approved Antihyperglycemic Products ........................................ 152
`Table 30: Summary of Adverse Events (Integrated 3-study pool) .............................................. 244
`Table 31: Summary of Serious Adverse Events by SOC (7-study pool) ...................................... 245
`Table 32: Summary of AESI by Custom MedDRA Query (7-study pool) ..................................... 246
`
`
`
`
`
`
`
`Reference ID: 4427479
`
`
`
`6
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`
`
`
`Table of Figures
`
`
`Figure 1: Formulation Design of QTERNMET XR FCDP Tablet .......................................................... 43
`Figure 2: Formulation Design of QTERN FCDP Tablet ..................................................................... 44
`Figure 3: Change from Baseline to Week 52 in HbA1c Trial CV181365........................................ 81
`Figure 4: Study Design of Trial D1683C00005 ............................................................................ 213
`Figure 5: Study Design of Trial CV181169 ................................................................................... 214
`Figure 6: Study Design of Trial CV181168 ................................................................................... 215
`Figure 7: Study Design of Trial CV181365 ................................................................................... 216
`Figure 8: Study Design of Trial CV181369 ................................................................................... 217
`
`
`
`
`Reference ID: 4427479
`
`
`
`7
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`
`Glossary
`
`4MSU
`AACE
`
`ABNL
`
`AC
`
`ACCORD
`ACE
`
`ACEI
`
`ACP
`
`ADA
`
`AE
`
`AESI
`
`AHA
`
`AKI
`
`ALT
`
`ANCOVA
`ARB
`
`AST
`
`AUC
`
`AZ
`
`β-cell
`
`BE
`
`BG
`
`BILI
`
`BMD
`
`BMI
`
`BMS
`
`BP
`
`BUN
`
`BW
`
`CDC
`
`CDER
`
`CDS
`
`CEC
`
`CFR
`
`CGM
`
`CHMP
`CI
`
`
`
`
`
`Reference ID: 4427479
`
`4-Month Safety Update
`American Association of Clinical Endocrinologists
`Abnormal
`
`Advisory Committee
`Action to Control Cardiovascular Risk in Diabetes Trial
`American College of Endocrinology
`Angiotensin Converting Enzyme Inhibitor
`American College of Physicians
`American Diabetes Association
`Adverse Event
`Adverse Event of Special Interest
`Antihyperglycemic Agent
`Acute Kidney Injury
`Alanine Aminotransferase
`Analysis of Covariance
`Angiotensin Receptor Blocker
`Aspartate Aminotransferase
`Area-Under-the-Curve
`AstraZeneca
`Beta-Cell
`Bioequivalence
`Blood Glucose
`Bilirubin
`Bone Mineral Density
`Body Mass Index
`Bristol-Myers Squibb
`Blood Pressure
`Blood Urea Nitrogen
`Body Weight
`Center for Disease Control and Prevention
`Center for Drug Evaluation and Research
`Core Data Sheet
`Clinical Event Committee
`Code of Federal Regulations
`Continuous Glucose Monitoring
`Committee for Medicinal Products for Human Use
`Confidence Interval
`
`
`
`8
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`CKD 3A
`ClinRO
`Cmax
`
`CMC
`
`CMQ
`
`COA
`
`COPD
`C-Peptide
`CR
`
`CRCL
`
`CRF
`
`CRL
`
`CRO
`
`CRT
`
`CSP
`
`CSR
`
`CV
`
`CVD
`
`CVOT
`
`CT
`
`Dapa
`
`DB
`
`DBP
`
`D/C
`
`DCCT
`
`DKA
`
`DPP-4
`EASD
`
`EC
`
`ECG
`
`eCRF
`
`EF
`
`eGFR
`
`EMA
`
`EOS
`
`EOT
`
`ESRD
`
`ETMF
`
`EU
`
`FAERS
`FAS
`
`
`Chronic Kidney Disease Stage 3A
`Clinician Reported Outcome
`Maximum Plasma Concentration
`Chemistry, Manufacturing, and Controls
`Custom MedDRA Query
`Clinical Outcome Assessment
`Chronic Obstructive Lung Disease
`Connecting Peptide
`Complete Response
`Creatinine Clearance
`Case Report Form
`Complete Response Letter
`Contract Research Organization
`Clinical Review Template
`Clinical Study Protocol
`Clinical Study Report
`Cardiovascular
`Cardiovascular Disease
`Cardiovascular Outcomes Trial
`Computed Tomography
`Dapagliflozin
`Double-Blind
`Diastolic Blood Pressure
`Discontinuation
`Diabetes Control and Complication Trial
`Diabetic Ketoacidosis
`Dipeptidyl Peptidase-4
`European Association for the Study of Diabetes
`Ethics Committee
`Electrocardiogram
`Electronic Case Report Form
`Ejection Fraction
`Estimated Glomerular Filtration Rate
`European Medicines Agency
`End-Of-Study
`End-Of-Treatment
`End Stage Renal Disease
`Electronic Trial Master File
`European Union
`FDA Adverse Event Reporting System
`Full Analysis Set
`
`
`
`
`Reference ID: 4427479
`
`
`
`9
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`
`FCDP
`
`FDA
`
`FFA
`
`FPG
`
`GCP
`GLP-1
`GM
`
`GRand
`H
`
`HbA1c
`HCl
`
`HDL-C
`HDPE
`
`HF
`
`HIV
`
`HLGT
`
`HLT
`
`HX
`
`ICF
`
`ICH
`
`IND
`
`IP
`
`iPSP
`
`IQR
`
`IRB
`
`ITT
`
`IVRS
`
`IWRS
`
`LDL-C
`
`LLN
`
`LOCF
`
`LT
`
`LTSS
`
`MACE
`MAR
`
`MDRD
`MedDRA
`MEDS
`MET
`
`MTT
`
`MMRM
`
`Fixed Combination Drug Product
`Food and Drug Administration
`Free Fatty Acids
`Fasting Plasma Glucose
`Good Clinical Practice
`Glucagon-Like Peptide 1
`Geometric Mean
`Global Randomization
`Hour
`Hemoglobin A1c (Glycosylated Hemoglobin)
`Hydrochloride
`High-Density Lipoprotein Cholesterol
`High-Density Polyethylene
`Heart Failure
`Human Immunodeficiency Virus
`High Level Group Term
`High Level Term
`History
`Informed Consent Form
`International Conference on Harmonization
`Investigational New Drug
`Investigational Product
`Initial Pediatric Study Plan
`Interquartile Range
`Institutional Review Board
`Intention-to-treat
`Interactive Voice Response System
`Interactive Web Response System
`Low-Density Lipoprotein Cholesterol
`Lower Limit of Normal
`Last Observation Carried Forward
`Long-term
`Long Term Stability Study
`Major Adverse Cardiovascular Event
`Missing at Random
`Modification in Diet and Renal Disease
`Medical Dictionary for Regulatory Activities
`Medications
`Metformin
`Mixed Meal Tolerance Test
`Mixed Effects Model with Repeated Measures
`
`
`
`
`Reference ID: 4427479
`
`
`
`10
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`
`NAI
`
`NDA
`
`NGSP
`
`NO
`
`NLR
`NYHA
`OAI
`
`ObsRO
`OSI
`
`PBRER
`PDLC
`
`PDUFA
`PeRC
`
`PerfO
`PIND
`
`PK
`
`PLLR
`
`PMC
`
`PMR
`
`PO
`
`PPG
`
`PREA
`
`PRO
`
`PT
`
`QD
`
`R
`
`REMS
`SAE
`
`SAP
`
`SAXA
`
`SBP
`
`Scr
`
`SGLT2
`SLC
`
`SMQ
`
`sNDA
`
`SOC
`
`SPOOS
`ST
`
`T1/2
`
`T1D
`
`
`No Action Indicated
`New Drug Application
`National Glycohemoglobin Standardization Program
`Number
`Normal laboratory range
`New York Heart Association
`Official Action Indicated
`Observer Reported Outcome
`Office of Scientific Investigation
`Periodic Benefit-Risk Evaluation Report
`Predefined Limits of Change
`Prescription Drug User Fee Act
`Pediatric Review Committee
`Performance Outcome
`Pre-Investigational New Drug
`Pharmacokinetics
`Pregnancy and Lactation Labeling Rule
`Postmarketing Commitment
`Postmarketing Requirement
`Orally (‘per os’)
`Postprandial Glucose
`Pediatric Research Equity Act
`Patient Reported Outcome
`Preferred Term
`Daily
`Randomization
`Risk Evaluation and Mitigation Strategy
`Serious Adverse Event
`Statistical Analysis Plan
`Saxagliptin
`Systolic Blood Pressure
`Serum Creatinine
`Sodium-Glucose Cotransporter 2
`Safety Labeling Change
`System MedDRA Query
`Supplemental New Drug Application
`System Organ Class
`Significant Payments of Other Sorts
`Short-term
`Elimination Half-Life
`Type 1 Diabetes Mellitus
`
`
`
`
`Reference ID: 4427479
`
`
`
`11
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`
`T2D
`
`TBILI
`
`TC
`
`TG
`
`TEAE
`
`TIA
`
`TID
`Tmax
`
`Total-C
`TSH
`
`TSI
`
`UA
`
`UACR
`
`UGE
`
`UGT1A9
`ULN
`
`US
`
`USA
`
`USPI
`
`UKPDS
`V
`
`VAI
`
`Wk
`
`WOCBP
`XR
`
`YR
`
`
`
`
`Type 2 Diabetes Mellitus
`Total Bilirubin
`Total Cholesterol
`Triglycerides
`Treatment-Emergent Adverse Event
`Transient Ischemic Attack
`Thrice Daily
`Time to maximum plasma concentration
`Total Cholesterol
`Thyroid-Stimulating Hormone
`Tracked Safety Issue
`Uric Acid
`Urine Albumin-To-Creatinine Ratio
`Urinary Glucose Excretion
`UDP-glucuronosyltransferase 1A9
`Upper Limit of Normal
`United States
`United States of America
`United States Package Insert
`United Kingdom Prospective Diabetes Study
`Visit
`Voluntary Action Indicated
`Week
`Women of Childbearing Potential
`Extended-release
`Year
`
`
`
`
`
`
`Reference ID: 4427479
`
`
`
`12
`
`

`

`Clinical Review
`Frank Pucino, PharmD, MPH
`NDA 210874: QTERNMET XR (dapagliflozin + saxagliptin + metformin extended-release FCDP)
`NDA 209091/S-002: QTERN (dapagliflozin and saxagliptin FCDP)
`
`1. Executive Summary
`
`
`
`Product Introduction
`
`QTERNMET XR (dapagliflozin, saxaglip0tin and metformin HCl extended-release) is a new fixed
`combination drug product (FCDP) submitted for marketing approval by the AstraZeneca
`Pharmaceuticals LP (referred to as the Applicant throughout the remainder of this review) as a
`New Drug Application (NDA 210874) in accordance with Section 505(b)(1) of the Federal Food,
`Drug and Cosmetic Act1 and Section 314 of Title 21 CFR 314.50.2
`
`The components of QTERNMET XR are approved antihyperglycemic agents with an indication as an
`adjunct to diet and exercise to improve glycemic control in adults with T2D. Dapagliflozin is a
`sodium-glucose cotransporter 2 (SGLT2) inhibitor that reduces reabsorption of filtered glucose
`and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.3
`Saxagliptin is a competitive dipeptidyl peptidase-4 (DPP-4) inhibitor that slows the inactivation of
`the incretin hormones, thereby increasing their concentrations in the blood and reducing fasting
`and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2
`diabetes mellitus (T2D).4 Metformin, a biguanide, improves glucose tolerance, decreases hepatic
`glucose production and intestinal absorption of glucose, and improves insulin sensitivity by
`increasing peripheral glucose uptake and utilization.5 The combination of an SGLT2 inhibitor with
`a DPP-4 inhibitor, added onto background metformin therapy6-8 and the combination of an SGLT2
`inhibitor5,9-12 or a DPP-4 inhibitor13-18 with metformin all provide complementary mechanisms of
`action to improve glycemic control.
`
`The proposed indication for QTERNMET XR is as an adjunct to diet and exercise to improve glycemic
`control in adults with T2D
`
` QTERNMET XR will be available as a film-coated tablet for once daily oral
`administration, and will contain the following dapagliflozin/saxagliptin/metformin extended-
`release dosage strengths: 2.5 mg/2.5 mg/1000 mg; 5 mg/2.5 mg/1000 mg; 5 mg/5 mg/1000 mg;
`10 mg/5 mg/1000 mg.
`
`QTERN (NDA 209091) is a dapagliflozin/saxagliptin FCDP approved on February 27, 2017.19 This
`product is indicated as an adjunct to diet and exercise to improve glycemic control in adults with
`T2D who have inadequate control with dapagliflozin or who are already treated with dapagliflozin
`and saxagliptin.6 QTERN is currently only available as a film-coated tablet for once daily oral
`administration, containing 10 mg of dapagliflozin and 5 mg of saxagliptin. The Applicant is