CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`
`214120Orig1s000
`
`
`MULTI-DISCIPLINE REVIEW
`Summary Review
`Office Director
`Cross Discipline Team Leader Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
`
`

`

`NDA Multidisciplinary Review and Evaluation
`
`Application Number
`Application Type
`Priority or Standard
`Submit Date
`Received Date
`PDUFA Goal Date
`Office/Division
`Review Completion Date
`Applicant
`Established Name
`(Proposed) Trade Name
`Pharmacologic Class
`Formulations
`Applicant Proposed
`Indication/Population
`
`NDA 214120
`Type 3
`Priority
`3/3/2020
`3/3/2020
`9/3/2020
`OOD/DHM1
`9/1/2020
`Celgene Corporation
`Azacitidine
`Onureg
`Nucleoside metabolic inhibitor
`Tablet (200 mg, 300 mg)
`
`Recommendation on Regulatory
`Action
`Recommended Indication/
`Population
`
`SNOMED CT for the Recommended
`Indication/Population
`Recommended Dosing Regimen
`
`
`
`
`
`Regular approval
`
`For continued treatment of adult patients with acute
`myeloid leukemia who achieved first complete
`remission (CR) or complete remission with
`incomplete blood count recovery (CRi) following
`intensive induction chemotherapy and are not able to
`complete intensive curative therapy.
`
`91861009
`
`300 mg orally daily on Days 1 through 14 of each
`28-day cycle
`
`
`
`
`
`Reference ID: 4664570
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`(b) (4)
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`

`

`NDA Multidisciplinary Review and Evaluation
`NDA 214120
`Onureg (azacitidine tablets)
`
`
`TABLE OF CONTENTS
`TABLE OF CONTENTS ................................................................................................................................... 2
`TABLE OF TABLES ........................................................................................................................................ 5
`TABLE OF FIGURES ...................................................................................................................................... 8
`REVIEWERS OF THE MULTIDISCIPLINARY REVIEW AND EVALUATION ...................................................... 9
`GLOSSARY .................................................................................................................................................. 10
`1 EXECUTIVE SUMMARY ................................................................................................................. 12
`1.1 Product Introduction ....................................................................................................... 12
`1.2 Conclusions on the Substantial Evidence of Effectiveness ............................................. 12
`1.3 Benefit-Risk Assessment ................................................................................................. 14
`1.4 Patient Experience Data .................................................................................................. 16
`2 THERAPEUTIC CONTEXT ............................................................................................................ 16
`2.1 Analysis of Condition ........................................................................................................ 16
`2.2 Analysis of Current Treatment Options ........................................................................... 18
`3 REGULATORY BACKGROUND ................................................................................................... 18
`3.1 U.S. Regulatory Actions and Marketing History ............................................................... 18
`3.2 Summary of Presubmission/Submission Regulatory Activity ........................................... 18
`4 SIGNIFICANT ISSUES FROM OTHER REVIEW DISCIPLINES PERTINENT TO CLINICAL
`CONCLUSIONS ON EFFICACY AND SAFETY ............................................................................. 19
`4.1 Office of Scientific Investigations ..................................................................................... 19
`4.2. Product Quality ............................................................................................................... 19
`4.3 Devices and Companion Diagnostic Issues ...................................................................... 19
`5 NONCLINICAL PHARMACOLOGY/TOXICOLOGY .................................................................. 20
`5. 1 Executive Summary ......................................................................................................... 20
`5.2 Referenced NDAs, BLAs, DMFs ........................................................................................ 21
`5.3 Pharmacology ................................................................................................................... 22
`5.3.1 Primary Pharmacology .......................................................................................... 22
`5.3.2 Secondary Pharmacology ...................................................................................... 35
`5.3.3 Safety Pharmacology ............................................................................................. 37
`5.4 ADME/PK .......................................................................................................................... 39
`5.5 Toxicology ........................................................................................................................ 41
`5.5.1 General Toxicology ................................................................................................ 41
`5.5.2 Genetic Toxicology ................................................................................................ 47
`5.5.3 Carcinogenicity ...................................................................................................... 47
`5.5.4 Reproductive and Developmental Toxicology ...................................................... 47
`5.5.5 Other Toxicology Studies ....................................................................................... 49
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`NDA Multidisciplinary Review and Evaluation
`NDA 214120
`Onureg (azacitidine tablets)
`
`6 CLINICAL PHARMACOLOGY ........................................................................................................ 56
`6.1 Executive Summary ........................................................................................................... 56
`6.2 Summary of Clinical Pharmacology Assessment .............................................................. 58
`6.2.1 Pharmacology and Clinical Pharmacokinetics ...................................................... 58
`6.2.2 General Dosing and Therapeutic Individualization............................................... 59
`6.3 Comprehensive Clinical Pharmacology Review ................................................................ 61
`6.3.1 General Pharmacology and Pharmacokinetic Characteristics ................................ 61
`6.3.2 Clinical Pharmacology Questions .......................................................................... 64
`7 SOURCES OF CLINICAL DATA AND REVIEW STRATEGY .................................................... 75
`7.1 Table of Clinical Studies ..................................................................................................... 75
`7.2 Review Strategy ............................................................................................................... 76
`8 STATISTICAL AND CLINICAL EVALUATION .......................................................................... 77
`8.1 Review of Relevant Individual Trials Used to Support Efficacy .......................................... 77
`8.1.1. Study CC-486-AML-001 (QUAZAR) ....................................................................... 77
`8.1.1. Additional Studies of Activity of Oral Azacitidine in AML .................................. 105
`8.2 Integrated Review of Effectiveness ................................................................................ 107
`8.2.1 Assessment of Efficacy Across Trials .................................................................. 107
`8.2.2 Integrated Assessment of Effectiveness ............................................................. 112
`8.3 Review of Safety ............................................................................................................. 113
`8.3.1. Safety Review Approach .................................................................................... 113
`8.3.2. Review of the Safety Database .......................................................................... 114
`8.3.3. Adequacy of Applicant’s Clinical Safety Assessments ......................................... 116
`8.3.4. Safety Results ..................................................................................................... 116
`8.3.5 Analysis of Submission-Specific Safety Issues ..................................................... 127
`8.3.6 Safety Analyses by Demographic Subgroups ...................................................... 127
`8.3.7 Clinical Outcomes Assessments Informing Tolerability/Safety .......................... 128
`8.3.8 Specific Safety Studies/Clinical Trials (including dose-related safety) ................ 128
`8.3.9 Additional Safety Explorations ............................................................................ 130
`8.3.10 Safety in the Postmarket Setting ...................................................................... 130
`8.3.11 Integrated Assessment of Safety ....................................................................... 132
`SUMMARY AND CONCLUSIONS ............................................................................................. 134
`8.4 Statistical Issues .............................................................................................................. 134
`8.5 Conclusions and Recommendations ............................................................................... 135
`9 ADVISORY COMMITTEE MEETING ........................................................................................ 135
`10 PEDIATRICS ................................................................................................................................. 135
`11 LABELING RECOMMENDATIONS ........................................................................................... 136
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`NDA Multidisciplinary Review and Evaluation
`NDA 214120
`Onureg (azacitidine tablets)
`
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`11.1 Prescribing Information ................................................................................................ 136
`11.2 Patient Labeling ............................................................................................................ 139
`12 RISK EVALUATION AND MITIGATION STRATEGIES (REMS) ........................................ 139
`13 POSTMARKETING REQUIREMENTS AND COMMITMENTS ........................................... 139
`14 DIVISION DIRECTOR (DHM1) ................................................................................................. 140
`15 APPENDICES ................................................................................................................................ 141
`15.1 References.................................................................................................................... 141
`15.2 Financial Disclosure ...................................................................................................... 143
`15.3 Nonclinical Pharmacology/Toxicology ......................................................................... 143
`15.4 OCP Appendices ........................................................................................................... 144
`15.4.1 Pharmacometrics Review .................................................................................. 144
`15.4.2 Bioanalytical ...................................................................................................... 152
`15.5 Additional Statistical Analyses ..................................................................................... 154
`15.5.1 Subgroup Analysis of OS .................................................................................... 154
`15.5.2 Subgroup Analysis of RFS per Applicant Definition ........................................... 156
`15.6 FDA Grouped Terms ..................................................................................................... 158
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`Reference ID: 4664570
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`NDA Multidisciplinary Review and Evaluation
`NDA 214120
`Onureg (azacitidine tablets)
`
`
`TABLE OF TABLES
`
`............................................. 53
` ....................................................................... 54
`
`....................................................................................................................................................... 72
`
`Table 1: Gene Biogroups regulated by AZA and DAC in KG-1a Cells ...................................... 31
`Table 2: Toxicokinetic Parameters (2-Week Oral Toxicology Study in Dogs) ....................... 46
`Table 3: Exposure Multiples: Embryofetal and Developmental Toxicities ............................ 48
`Table 4: Exposure Multiples: Carcinogenicity and Male Fertility ........................................... 48
`Table 5: Summary of Impurities/Degradants in Drug Product ............................................... 49
`Table 6: Acceptance Criterion versus Qualified Limits of Degradants in Drug Product ....... 50
`Table 7: Histopathological findings in female mice
`Table 8: Toxicokinetic parameters
`Table 9. TEAE Summary During Oral Azacitidine 7- day QD Schedule by Oral Dose Level –
`Oral Azacitidine Population (AZA PH US 2007 CL 005) ........................................................... 65
`Table 10. Changes in Global DNA Methylation Score (GDMS) with Subcutaneous Azacitidine
`or Oral Azacitidine in 7-Day or Extended (14-Day and 21-Day) Dosing Schedules .............. 65
`Table 11. Azacitidine Exposure in Patients with or without Renal Dysfunction (AZA PH US
`2007 PK 006) ............................................................................................................................... 71
`Table 12. Select TEAEs Reported for ≥ 10% in the CC-486 Treatment Group with Any
`Baseline Renal Function Status by SOC and PT – Safety Population (Excluding AML Relapse)
`Table 13. Select Grade 3 or 4 TEAEs Reported for ≥ 10% in the CC-486 Treatment Group
`with Any Baseline Renal Function Status by SOC and PT – Safety Population (Excluding
`AML Relapse) ............................................................................................................................... 72
`Table 14. Effect of Food on The Absorption of Azacitidine with Tablet Formulation (300 mg
`strength, F9) ................................................................................................................................ 73
`Table 15. Effect of omeprazole (40 mg QD) on exposure of azacitidine (300 mg PO) .......... 74
`Table 16. Clinical Trials in NDA 214120 ................................................................................... 75
`Table 17. sBLA Submission and Amendments .......................................................................... 76
`Table 18. Primary Censoring Rules for RFS .............................................................................. 83
`Table 19. Significant Amendments to Study CC-486-AML-001 (QUAZAR) ............................ 85
`Table 20. CC-486-AML-001: Demographics (ITT) .................................................................... 87
`Table 21. CC-486-AML-001: Disease Characteristics (ITT) ..................................................... 88
`Table 22. CC-486-AML-001: Baseline Laboratory Test Results (ITT) .................................... 90
`Table 23. CC-486-AML-001: Prior Induction (ITT) ................................................................. 90
`Table 24. CC-486-AML-001: Prior Consolidation (ITT) .......................................................... 91
`Table 25. CC-486-AML-001: Study Drug Treatment Compliance (ITT) ................................. 91
`Table 26. CC-486-AML-001: Summary of Dose Intensity by Cycle (Cycles 1-12) .................. 92
`Table 27. CC-486-AML-001: Prophylactica Antiemetic Use by Cycle (Cycles 1-5) ................ 92
`Table 28. CC-486-AML-001: Subsequent AML Therapies (ITT) .............................................. 93
`Table 29. CC-486-AML-001: First Subsequent Regimens for AML (ITT) ............................... 93
`Table 30. CC-486-AML-001: Summary of OS (ITT) .................................................................. 94
`Table 31. CC-486-AML-001: Summary of RFS by Applicant and FDA Definitions ................. 96
`Table 32. CC-486-AML-001: Summary of Time to Relapse (ITT) ........................................... 97
`Table 33. CC-486-AML-001: Summary of Time to Treatment Discontinuation Due to
`Disease Relapse (ITT) ................................................................................................................. 98
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`Reference ID: 4664570
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`(b) (4)
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`(b) (4)
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`

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`NDA Multidisciplinary Review and Evaluation
`NDA 214120
`Onureg (azacitidine tablets)
`
`
`..................................................................................................................................................... 100
`
`Table 34. CC-486-AML-001: Subgroup Analysis of OS by Response Status per Applicant
`Definition Achieved after Induction .......................................................................................... 99
`Table 35. CC-486-AML-001: Subgroup Analysis OS by FDA-Adjudicated Response Status at
`Study Baseline ............................................................................................................................. 99
`Table 36. CC-486-AML-001: Subgroup Analysis of OS by Number of Consolidation Cycles
`Table 37. CC-486-AML-001: Subgroup Analysis of OS by Geographic Region ..................... 100
`Table 38: CC-486-AML-001: Applicant Results for OS from Fully Stratified Subgroup
`Analysis and Shrinkage Model ................................................................................................. 102
`Table 39. CC-486-AML-001: Multivariate Cox Regression Model for OS (US and EU Patients
`Only) ........................................................................................................................................... 103
`Table 40. CC-486-AML-001: OS Subgroup Analysis by MRD Status at Screening ............... 105
`Table 41. CC-486-AML-001: Summary Subgroup Analysis of OS by Disease Status ........... 110
`Table 42. CC-486-AML-001: Summary Subgroup Analysis of OS by Number of Consolidation
`Cycles .......................................................................................................................................... 110
`Table 43. Trials of Oral Azacitidine for Treatment of AML .................................................... 111
`Table 44. Safety Database – Studies of Oral Azacitidine Monotherapy by Dose and Disease
`Table 45. Safety Population – Exposure .................................................................................. 114
`Table 46. Safety Population – Key Characteristics ................................................................. 115
`Table 47. Safety Population – Deaths ...................................................................................... 117
`Table 48. Safety Population – On-treatment Serious Adverse Events by SOC ..................... 119
`Table 49. Safety Population – TEAEs Leading Dose Discontinuation or Reduction ............ 120
`Table 50. Safety Population – Common (≥ 10%) On-treatment TEAEs in Patients Treated
`with Oral Azacitidine with ≥ 2% Difference Compared to Placebo – Any Cycle .................. 121
`Table 51. Safety Population – Common (≥ 10%) On-treatment TEAEs in Patients Treated
`with Oral Azacitidine with ≥ 2% Difference Compared to Placebo – Cycles 1-5 ................. 122
`Table 52. CC-486-AML-001 – Antiemetic Use for Treatment of Adverse Reaction (Cycles 1-
`5) ................................................................................................................................................. 123
`Table 53. CC-486-AML-001 – Antidiarrheal Use for Treatment of Adverse Reaction (Cycles
`1-5) ............................................................................................................................................. 123
`Table 54. CC-486-AML-001 – Selected Hematologic Laboratory Shifts in Subjects with
`Baseline Grade ≤ 2 ..................................................................................................................... 124
`Table 55. CC-486-AML-001 – Selected Hematologic Laboratory Abnormalities Excluding
`Relapse ....................................................................................................................................... 124
`Table 56. CC-486-AML-001 – Nonhematologic Laboratory Shifts in Subjects with Baseline
`Grade ≤ 2 – Any Cycle ................................................................................................................ 125
`Table 57. CC-486-AML-001 – Nonhematologic Laboratory Shifts in Subjects with Baseline
`Grade ≤ 2 – Cycles 1-5 ............................................................................................................... 126
`Table 58. CC-486-AML-001 – Common (≥ 10%) All Grade TEAEs by Age Group – Cycles 1-5
`Table 59: Parameter Estimates of the Final Population Pharmacokinetics Model of
`Azacitidine ................................................................................................................................. 144
`Table 60: OFV and Parameter Estimates Comparison across Different Covariate Models . 146
`
`..................................................................................................................................................... 114
`
`..................................................................................................................................................... 127
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`NDA Multidisciplinary Review and Evaluation
`NDA 214120
`Onureg (azacitidine tablets)
`
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`Table 61: Parameter Estimates of Reviewer’s Final Model with Covariance Included ....... 147
`Table 62: Treatment Emergent ≥ Grade 3 Neutropenia Rate by Body Weight Median for
`Study CC-486-AML-001 ............................................................................................................ 150
`Table 63: Distribution of Baseline Factors Across AUC Tertiles vs Placebo ........................ 151
`Table 64. Summary of bioanalytical methods used in CC-486 clinical program ................. 152
`Table 65: Summary of Bioanalytical Method Performance for Analysis of Clinical Study
`Samples ...................................................................................................................................... 153
`Table 66. Subgroup Analysis of RFS by Region ....................................................................... 157
`Table 67. Subgroup Analysis of RFS by Number of Consolidation Cycles ............................ 158
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`Reference ID: 4664570
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`NDA Multidisciplinary Review and Evaluation
`NDA 214120
`Onureg (azacitidine tablets)
`
`
`TABLE OF FIGURES
`
`Figure 1: Metabolic Pathways of Azacitidine after Cellular Uptake ........................................ 24
`Figure 2: Inhibition of DNA Methyltransferases by Azacitidine (Hypomethylation) ............ 28
`Figure 3: AZA and DAC Cause Depletion of DNMT1 Protein and DNA Damage in KG-1a and
`THP-1 Cells ................................................................................................................................... 29
`Figure 4: Azacitidine and Decitabine (DAZ) on Cell Viability .................................................. 30
`Figure 5: Lineage-Associated Drug-Responsive (Active) or Resistance (Inactive) chromatin
`structural Changes in Leukemia Cells ........................................................................................ 33
`Figure 6: Summary of Azacitidine Metabolism Pathways and Metabolites ........................... 41
`Figure 7. Kaplan-Meier Curves for OS and RFS by AUCss Quantile .......................................... 66
`Figure 8. Logistic Model of Probability of Grade ≥ 3 Neutropenia .......................................... 68
`Figure 9. Logistic Model of Probability of Dose Modifications Due to Relapse or AEs .......... 68
`Figure 10. Azacitdine CL/F by Hepatic Impairment Categories .............................................. 70
`Figure 11. Forest Plot of CLcr on CL/F in Final pop PK Model ................................................ 71
`Figure 12. Study Design .............................................................................................................. 79
`Figure 13. CC-486-AML-001 – Schedule of Safety Assessments ............................................. 79
`Figure 14. Study CC-486-AML-001: Patient Disposition .......................................................... 86
`Figure 15. CC-486-AML-001: Kaplan-Meier Plot of OS for CC-486 versus Placebo (ITT) ..... 95
`Figure 16. CC-486-AML-001: Kaplan-Meier Plot of RFS for CC-486 versus Placebo ............. 96
`Figure 17. CC-486-AML-001: Cumulative Incidence Distribution of Time to Relapse (ITT) 97
`Figure 18. CC-486-AML-001: Time to Treatment Discontinuation Due to Disease Relapse
`(ITT) ............................................................................................................................................. 98
`Figure 19. CC-486-AML-001: Shrinkage Estimations for OS (US vs Europe) ....................... 102
`Figure 20. CC-486-AML-001: Time to Definitive HRQoL Deterioration (HRQoL-evaluable
`Population) ................................................................................................................................ 104
`Figure 21. Reports of Hypersensitivity with Vidaza/Azacitidine in the Postmarketing
`Setting ......................................................................................................................................... 131
`Figure 22: Goodness of Fit of the Population Pharmacokinetics Model of Azacitidine ....... 145
`Figure 23: Correlation between Body Weight and Creatinine Clearance ............................. 147
`Figure 24: Kaplan-Meier Curve for Overall survival and Relapse-Free Survival by
`Azacitidine Exposure ................................................................................................................ 148
`Figure 25: Logistic Model of Probability of Neutropenia of Grade ≥ 3 ................................. 148
`Figure 26: Kaplan-Meier Plots of Overall Survival (Left Panel) and Relapse Free Survival
`(Right Panel) by Treatment and Body Weight Subgroups ..................................................... 150
`Figure 27: Time to Adverse Event Related Dose Modification by Treatment and Body
`Weight Subgroups ..................................................................................................................... 150
`Figure 28. Forest Plot of OS by Demographics (ITT) ............................................................. 154
`Figure 29. Forest Plot of OS by Disease Characteristics (ITT) ............................................... 155
`Figure 30. Forest Plot of RFS by Demographics (ITT) ........................................................... 156
`Figure 31. Forest Plot of RFS by Disease Characteristics (ITT) ............................................. 157
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`Reference ID: 4664570
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`NDA Multidisciplinary Review and Evaluation
`NDA 214120
`Onureg (azacitidine tablets)
`
`REVIEWERS OF THE MULTIDISCIPLINARY REVIEW AND EVALUATION
`
`Nonclinical Reviewer
`Nonclinical Team Leader
`Office of Clinical Pharmacology Reviewer(s)
`Office of Clinical Pharmacology Team Leader(s)
`Clinical Reviewer
`Clinical Team Leader
`Statistical Reviewer
`Statistical Team Leader
`Associate Director for Labeling (OCE)
`Cross‐Discipline Team Leader
`Division Director (DHOT)
`Division Director (OCP)
`Division Director (OB)
`Division Director (DHM1)
`
`
`ADDITIONAL REVIEWERS OF APPLICATION
`
`Shwu-Luan Lee, PhD
`Brenda Gehrke, PhD
`Meng Li, PhD; Hongshan Li, PhD
`Ruby Leong, PharmD; Lian Ma, PhD
`Emily Jen, MD, PhD
`Donna Przepiorka, MD, PhD
`Xin Wang, PhD
`Jonathon Vallejo, PhD
`Stacy S. Shord, Pharm.D.
`Donna Przepiorka, MD, PhD
`Haleh Saber, PhD
`Brain Booth, PhD
`Thomas E. Gwise, PhD
`Angelo De Claro, MD
`
`
`
`
`
`Regulatory Project Manager (DHM1) Rachel McMullen, MPH, MHA
`Associate Director for Safety (OOD) Shanthi Marur, MD
`CDRH
`Jacqueline Cleary, MS
`COA
`Julia Ju, PharmD, PhD
`DMPP
`Susan Redwood, BSN, MPH
`OPDP
`Rachael Conklin, RN, MS
`OPQ
`Sherita McLamore, PhD; Karina Zuck, PhD, Haripada
`Sarker, PhD; Nina Ni, PhD; Anamitro Banerjee, PhD;
`Huiquan Wu, PhD; Bogdan Kurtyka, PhD ; Min Kang,
`PhD; Om Anand, PhD; Raanan Bloom, PhD
`Nicole Iverson, PharmD; Hina Mehta, PharmD
`Connie Cheng, PharmD; Afrouz Nayenama, PharmD
`Anthony Orencia, MD; Min Lu, MD, MPH
`Belinda Kallimanis, PhD
`
`OSE/DMEPA
`OSE/DPV2
`OSI
`PFDD (OCE)
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`Reference ID: 4664570
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`NDA Multidisciplinary Review and Evaluation
`NDA 214120
`Onureg (azacitidine tablets)
`
`
`GLOSSARY
`
`advisory committee
`AC
` absorption, distribution, metabolism, excretion
`ADME
`adverse event
`AE
`adverse reaction
`AR
`biologics license application
`BLA
`Best Pharmaceuticals for Children Act
`BPCA
`Benefit Risk Framework
`BRF
`Center for Biologics Evaluation and Research
`CBER
`Center for Drug Evaluation and Research
`CDER
`Center for Devices and Radiological Health
`CDRH
`Cross-Discipline Team Leader
`CDTL
`Code of Federal Regulations
`CFR
`chemistry, manufacturing, and controls
`CMC
`COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms
`CRF
`case report form
`CRO
`contract research organization
`CRT
`clinical review template
`CSR
`clinical study report
`CSS
`Controlled Substance Staff
`DHOT
`Division of Hematology Oncology Toxicology
`DMC
`data monitoring committee
`ECG
`electrocardiogram
`eCTD
`electronic common technical document
`ETASU
`elements to assure safe use
`FDA
`Food and Drug Administration
`FDAAA
`Food and Drug Administration Amendments Act of 2007
`FDASIA
`Food and Drug Administration Safety and Innovation Act
`GCP
`good clinical practice
`GRMP
`good review management practice
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`NDA Multidisciplinary Review and Evaluation
`NDA 214120
`Onureg (azacitidine tablets)
`
`International Conference on Harmonisation
`ICH
`Investigational New Drug
`IND
`integrated summary of effectiveness
`ISE
`integrated summary of safety
`ISS
`intent to treat
`ITT
`MedDRA Medical Dictionary for Regulatory Activities
`mITT
`modified intent to treat
`NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Event
`NDA
`new drug application
`NME
`new molecular entity
`OCS
`Office of Computational Science
`OPQ
`Office of Pharmaceutical Quality
`OSE
`Office of Surveillance and Epidemiology
`OSI
`Office of Scientific Investigation
`PBRER
`Periodic Benefit-Risk Evaluation Report PDpharmacodynamics
`PI
`prescribing information
`PK
`pharmacokinetics
`PMC
`postmarketing commitment
`PMR
`postmarketing requirement
`PP
`per protocol
`PPI
`patient package insert
`PREA
`Pediatric Research Equity Act
`PRO
`patient reported outcome
`PSUR
`Periodic Safety Update report
`REMS
`risk evaluation and mitigation strategy SAE serious adverse event
`SAP
`statistical analysis plan
`SGE
`special government employee
`SOC
`standard of care
`TEAE
`treatment emergent adverse event
`
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`NOA Multidisciplinary Review and Evaluation
`NOA 214120
`Onureg (azacitidine tablets)
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`1 EXECUTIVE SUMMARY
`
`1.1 PRODUCT INTRODUCTION
`
`Proposed Trade Name:
`
`Onureg®
`
`Established Name:
`
`Azacitidine
`
`Also Known As:
`
`CC-486, 5-azacitidine
`
`Chemical Name:
`
`4-amino-1-~-D-ribofuranosyl-s-triazin-2(1H)-one
`
`Molecular Form ula:
`
`Molecular Weight:
`
`244 g/mol
`
`Chemical
`
`Structure:
`
`Dosage Forms:
`
`Tablet (200 mg, 300 mg)
`
`Therapeutic Class:
`
`Anti neoplastic
`
`Chemical Class:
`
`Small molecule
`
`Pharmacologic Class:
`
`Nucleoside metabolic inhibitor
`
`Mechanism of Action:
`
`Azacitidine is a pyrimidine nucl eoside analog of cytidine that
`inhibits DNA and RNA methyltransferase.
`
`41
`NOA 214120 for Onureg was submitted under the 505(b)(l) pathway for the indication 'lb)<
`
`1.2 CONCLUSIONS ON THE SUBSTANTIAL EVIDENCE OF E