CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`215859Orig1s000
`
`CLINICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`CLINICAL REVIEW
`Application Type 505b2 NDA for a new formulation and two indications
`Application Number(s) NDA 215859
`Priority or Standard Priority review containing a response to a Written Request
`Submit Date(s) 06/22/21
`Received Date(s) 06/22/21
`PDUFA Goal Date 12/22/2021
`Division/Office DNH/OCHEN
`Reviewer Name(s) Carrie Diamond, MD
`Ann T. Farrell, MD (this also serves as the DD and CDTL review)
`Review Completion Date 12/20/2021
`Established/Proper Name XARELTO
`(Proposed) Trade Name rivaroxaban
`Applicant
`Janssen
`Dosage Form(s) Currently marketed – tablets; proposed formulation – oral
`solution
`Age and weight-based algorithm ranging from 1 to 3 times a
`day
`1) Treatment of Venous Thromboembolism and Reduction in
`Risk of Recurrent Venous Thromboembolism in Pediatric
`Patients
`XARELTO is indicated for the treatment of venous
`thromboembolism (VTE) and the reduction in the risk of
`recurrent VTE in pediatric patients from birth to less than 18
`years after at least 5 days of initial parenteral anticoagulant
`treatment.
`2) Thromboprophylaxis in Pediatric Patients with Congenital
`Heart Disease after the Fontan Procedure
`XARELTO is indicated for thromboprophylaxis in pediatric
`patients aged 2 years and older with congenital heart disease
`who have undergone the Fontan procedure.
`
`Applicant Proposed Dosing
`Regimen(s)
`Applicant Proposed
`Indication(s)/Population(s)
`
`Recommendation on
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`Approval
`
`1) Treatment of Venous Thromboembolism and Reduction in
`Risk of Recurrent Venous Thromboembolism in Pediatric
`Patients
`XARELTO is indicated for the treatment of venous
`thromboembolism (VTE) and the reduction in the risk of
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`1
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`recurrent VTE in pediatric patients from birth to less than 18
`years after at least 5 days of initial parenteral anticoagulant
`treatment.
`2) Thromboprophylaxis in Pediatric Patients with Congenital
`Heart Disease after the Fontan Procedure
`XARELTO is indicated for thromboprophylaxis in pediatric
`patients aged 2 years and older with congenital heart disease
`who have undergone the Fontan procedure.
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`2
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`Table of Contents
`
`Glossary ........................................................................................................................................11
`
`1.
`
`Executive Summary...............................................................................................................14
`1.1.
`Product Introduction......................................................................................................14
`1.2.
`Conclusions on the Substantial Evidence of Effectiveness.............................................15
`1.3.
`Benefit-Risk Assessment ................................................................................................17
`1.4.
`Patient Experience Data.................................................................................................26
`
`2.
`
`Therapeutic Context..............................................................................................................26
`2.1. Analysis of Condition......................................................................................................26
`2.2. Analysis of Current Treatment Options .........................................................................29
`
`3. Regulatory Background .........................................................................................................32
`3.1. U.S. Regulatory Actions and Marketing History.............................................................32
`3.2.
`Summary of Presubmission/Submission Regulatory Activity ........................................33
`3.3.
`Foreign Regulatory Actions and Marketing History .......................................................33
`
`4.
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ................................................................................................................33
`4.1. Office of Scientific Investigations (OSI) ..........................................................................33
`4.2.
`Product Quality .............................................................................................................33
`4.3.
`Clinical Microbiology......................................................................................................34
`4.4. Nonclinical Pharmacology/Toxicology ...........................................................................34
`4.5.
`Clinical Pharmacology ....................................................................................................34
`4.6. Devices and Companion Diagnostic Issues ....................................................................34
`4.7.
`Consumer Study Reviews...............................................................................................34
`
`5.
`
`Sources of Clinical Data and Review Strategy .......................................................................34
`5.1.
`Table of Clinical Studies .................................................................................................34
`5.2.
`Review Strategy .............................................................................................................47
`
`6. Review of Relevant Individual Trials Used to Support Efficacy .............................................48
`6.1.
`EINSTEIN JR ....................................................................................................................48
`6.1.1. Study Design ...........................................................................................................48
`CDER Clinical Review Template
`3
`Version date: September 6, 2017 for all NDAs and BLAs
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`6.3.
`
`6.4.
`
`6.1.2. Study Results ..........................................................................................................52
`6.2. UNIVERSE .......................................................................................................................66
`6.2.1. Study Design ...........................................................................................................66
`6.2.2. Study Results ..........................................................................................................70
`Study 14373 ...................................................................................................................82
`6.3.1. Study Design ...........................................................................................................82
`6.3.2. Study Results ..........................................................................................................84
`Study 14374 ...................................................................................................................88
`6.4.1. Study Design ...........................................................................................................88
`6.4.2. Study Results ..........................................................................................................91
`Study 17618 ...................................................................................................................96
`6.5.1. Study Design ...........................................................................................................96
`6.5.2. Study Results ..........................................................................................................99
`Study 17992 .................................................................................................................103
`6.6.1. Study Design .........................................................................................................103
`6.6.2. Study Results ........................................................................................................105
`Study 12892 .................................................................................................................109
`6.7.1. Study Design .........................................................................................................109
`6.7.2. Study Results ........................................................................................................111
`
`6.5.
`
`6.6.
`
`6.7.
`
`7.
`
`Integrated Review of Effectiveness.....................................................................................114
`7.1.
`Integrated Assessment of Effectiveness ......................................................................115
`
`8. Review of Safety..................................................................................................................116
`8.1.
`Safety Review Approach ..............................................................................................117
`8.2.
`Review of the Safety Database ....................................................................................118
`8.2.1. Overall Exposure...................................................................................................118
`8.2.2. Relevant characteristics of the safety population: ...............................................120
`8.2.3. Adequacy of the safety database: ........................................................................120
`8.3. Adequacy of Applicant’s Clinical Safety Assessments..................................................121
`8.3.1. Issues Regarding Data Integrity and Submission Quality......................................121
`8.3.2. Categorization of Adverse Events.........................................................................121
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`4
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`8.4.
`
`8.3.3. Routine Clinical Tests............................................................................................122
`Safety Results...............................................................................................................123
`8.4.1. Deaths...................................................................................................................123
`8.4.2. Serious Adverse Events.........................................................................................124
`8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects..................................133
`8.4.4. Significant Adverse Events....................................................................................136
`8.4.5. Treatment Emergent Adverse Events and Adverse Reactions .............................140
`8.4.6. Laboratory Findings ..............................................................................................149
`8.4.7. Vital Signs..............................................................................................................153
`8.4.8. Electrocardiograms (ECGs) ...................................................................................153
`8.4.9. QT .........................................................................................................................153
`8.4.10.
`Immunogenicity.............................................................................................153
`8.5. Analysis of Submission-Specific Safety Issues ..............................................................154
`8.5.1. Bleeding ................................................................................................................154
`8.5.2. Drug Induced Liver Injury......................................................................................158
`8.5.3. Pleural Effusion.....................................................................................................160
`8.5.4. Thrombocytopenia ...............................................................................................161
`8.5.5. Vomiting ...............................................................................................................164
`Safety Analyses by Demographic Subgroups ...............................................................166
`8.6.
`Specific Safety Studies/Clinical Trials ...........................................................................166
`8.7.
`8.8. Additional Safety Explorations.....................................................................................170
`8.8.1. Human Carcinogenicity or Tumor Development ..................................................170
`8.8.2. Human Reproduction and Pregnancy...................................................................170
`8.8.3. Pediatrics and Assessment of Effects on Growth .................................................170
`8.8.4. Overdose, Drug Abuse Potential, Withdrawal, and Rebound ..............................170
`Safety in the Postmarket Setting .................................................................................170
`8.9.1. Safety Concerns Identified Through Postmarket Experience ...............................170
`8.9.2. Expectations on Safety in the Postmarket Setting................................................171
`8.9.3. Additional Safety Issues From Other Disciplines ..................................................172
`8.10.
`Integrated Assessment of Safety..............................................................................172
`
`8.9.
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`5
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`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`9. Advisory Committee Meeting and Other External Consultations .......................................174
`
`10. Labeling Recommendations ................................................................................................174
`10.1.
`Prescription Drug Labeling .......................................................................................174
`10.2.
`Nonprescription Drug Labeling.................................................................................174
`
`11. Risk Evaluation and Mitigation Strategies (REMS) ..............................................................175
`
`12. Postmarketing Requirements and Commitments...............................................................175
`
`13. Appendices..........................................................................................................................175
`13.1.
`References................................................................................................................175
`13.2.
`Financial Disclosure ..................................................................................................177
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`6
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`Table of Tables
`
`Table 1: Summary of Treatment Armamentarium Relevant to Proposed Indications .................29
`Table 2 Listing of Clinical Trials Relevant to this NDA/BLA ...........................................................35
`Table 3 Patient Disposition, Trial 14372.......................................................................................54
`Table 4 Disposition with Respect to Entry into Extension Treatment, Trial 14372 ......................55
`Table 5 Baseline Demographic and Clinical Characteristics, Safety Population, Trial 14372 .......56
`Table 6. Medical History (>10% of Patients), Safety Population, Trial 14372...............................58
`Table 7. VTE risk factors, Trial 14372............................................................................................59
`Table 8 Body Weight-Adjusted Rivaroxaban Dosing Schedule for Children for Trial 14372 ........60
`Table 9 Patients Having Imaging Classified as Uncertain by CIAC, Trial 14372 ............................62
`Table 10. Composite of Recurrent VTE and Asymptomatic Deterioration During the Main
`Treatment Period, Trial 14372......................................................................................................63
`Table 11. Thrombotic Burden Assessment at the End of the Main Treatment Period, Trial 14372
`......................................................................................................................................................64
`Table 12 Duration of Exposure, Safety Population, Trial 14372...................................................65
`Table 13 Patient Disposition for Trial 3001 ..................................................................................72
`Table 14: Demographic characteristics of the patients enrolled in 3001.....................................74
`Table 15 Duration between Fontan Procedure and First Dose of Study Agent, in days for Trial
`3001..............................................................................................................................................75
`Table 16 Underlying Congenital Cardiac, Familial and Genetic Disorders for Trial 3001 .............76
`Table 17. Surgical and Medical Procedures for Trial 3001 ...........................................................77
`Table 18 Dosing for rivaroxaban administration in 3001 (oral suspension).................................78
`Table 19 CIAC Adjudicated Primary Efficacy Outcome to End of Treatment (Month 12 or End of
`Study Medication) using Full Analysis Set for Trial 3001..............................................................80
`Table 20 - Duration of Exposure, Safety Population, Trial CHD3001............................................81
`Table 21: Demographic Characteristics of the Pediatric Patients Enrolled and Treated in Trial
`14373............................................................................................................................................86
`Table 22: Demographic Characteristics of the Pediatric Patients Enrolled and Treated on Trial
`14374............................................................................................................................................94
`Table 23: Demographic Characteristics of the Pediatric Patients Enrolled and Treated in Trial
`17618..........................................................................................................................................100
`Table 24: Demographic Characteristics of Pediatric Patients Enrolled in Trial 17992................106
`Table 25: Demographic Characteristics of Pediatric Patients Enrolled in Trial 12892 ...............112
`Table 26. Duration of Exposure (Main Treatment Period and Extended), Safety Population, Trial
`14372..........................................................................................................................................118
`Table 27. Duration of Exposure in Main Treatment Period for Pediatric patients with CVST, non-
`CVC-VTE or CVC-VTE > 2 years, Safety Population, Trial 14372..................................................118
`Table 28. Duration of Exposure in Main Treatment Period for Pediatric patients with CVC-VTE <
`2 years, Safety Population, Trial 14372 ......................................................................................119
`Table 29. Duration of Exposure, Safety Population, Trial CHD3001...........................................119
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`7
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`Table 30. Patient Age in Main Treatment Period, Safety Population, Trial 14372 .....................120
`Table 31 Serious Adverse Events by System Organ Class and Preferred Term, Safety Population,
`Trial 14372..................................................................................................................................124
`Table 32 Serious Adverse Events by System Organ Class and FDA Medical Query (Narrow),
`Safety Population, Trial 14372....................................................................................................128
`Table 33 Serious Adverse Events by System Organ Class and Preferred Term, Safety Population,
`Trial CHD3001.............................................................................................................................130
`Table 34 Serious Adverse Events by System Organ Class and FDA Medical Query (Narrow),
`Safety Population, Trial CHD3001...............................................................................................132
`Table 35. Adverse Events Leading to Discontinuation by System Organ Class and Preferred
`Term, Safety Population, Trial 14372 .........................................................................................133
`Table 36 Adverse Events Leading to Discontinuation by System Organ Class and FDA Medical
`Query (Narrow), Safety Population, Trial 14372 ........................................................................134
`Table 37. Adverse Events Leading to Discontinuation by System Organ Class and Preferred
`Term, Safety Population, Trial CHD3001 ....................................................................................135
`Table 38. Adverse Event Frequency Leading to Dose Modification, Safety Population, Trial
`14372..........................................................................................................................................136
`Table 39. Adverse Events Leading to Dose Interruption, Safety Population, Trial 14372 ..........137
`Table 40. Adverse Events Frequency Leading to Dose Modification, Safety Population, Trial
`CHD3001 ..................................................................................................................................137
`Table 41. Adverse Events Leading to Dose Interruption, Safety Population, Trial CHD3001
`....................................................................................................................................................138
`Table 42. Severity of Adverse Events, Safety Population, Trial 14372 .............................139
`Table 43. Severity of Adverse Events, Safety Population, Trial CHD3001 ..................................139
`Table 44 Adverse Events by System Organ Class, Safety Population, Trial 14372......................140
`Table 45 Common Adverse Events, Safety Population in >1% of Rivaroxaban Treatment Group,
`Trial 14372..................................................................................................................................141
`Table 46. Adverse Events by System Organ Class and FDA Medical Query (Narrow), Safety
`Population, Trial 14372 ..............................................................................................................143
`Table 48 Common Adverse Events Occurring in >2% of Patients in the Rivaroxaban Group,
`Safety Population, Trial CHD3001...............................................................................................146
`Table 49 Adverse Events by System Organ Class and FDA Medical Query (Narrow), Safety
`Population, Trial CHD3001 .........................................................................................................147
`Table 51 Patients with One or More Liver Biochemistry Analyte Values Outside Specified Levels,
`Safety Population, Trial 14372....................................................................................................150
`Table 52 Patients with One or More Liver Biochemistry Analyte Values Outside Specified Levels,
`Safety Population, Trial CHD3001...............................................................................................151
`Table 53 Potential DILI, Safety Population, Trial CHD3001 ........................................................153
`Table 54. Trial 14372- Bleeding Events: Major, Clinically Relevant non-Major Bleeding and Trivial
`Bleeding in the Main Treatment Period .....................................................................................154
`Table 55. Trial 14372 - Severity of Bleeding by Site by Treatment.............................................154
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`8
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`Table 56. Trial 14372 Bleeding Events by Age Group .................................................................155
`Table 57. Trial 14372- Bleeding Events: Major, Clinically Relevant non-Major Bleeding and Trivial
`Bleeding Any Time After Randomization....................................................................................156
`Table 58. Trial 3001 - Bleeding Events: Major, Clinically Relevant non-Major Bleeding and Trivial
`Bleeding......................................................................................................................................157
`Table 59 Trial 3001 - Severity of Bleeding by Site by Treatment................................................158
`Table 60. Adverse Events of Special Interest, Safety Population, Trial 14372............................159
`Table 61. Subjects with Treatment-Emergent Pleural Effusion, CHD3001.................................160
`Table 62. List of Platelet Count Values ≥Level 2 Criteria (<125,000cells/uL), Safety
`Population, Trial 14372 ...........................................................................................................163
`Table 63. Adverse Events by Gastrointestinal Disorders System Organ Class and FDA Medical
`Query (Narrow), Safety Population, Trial 14372 ........................................................................165
`Table 64. Adverse Events by System Organ Class and FDA Medical Query (Narrow), Safety
`Population, Trial CHD3001 .........................................................................................................166
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`9
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`Table of Figures
`
`Figure 1 Drug-Induced Liver Injury Case Screening Plot, Safety Population, Trial CHD3001......151
`Figure 2. Summary of Bleeding Events from Postmarketing Sources.........................................170
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`10
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`Glossary
`
`AC
`AE
`ALT
`aPTT
`AR
`ASA
`PBPK
`BID or b.i.d.
`BPCA
`BRF
`CAD
`CBER
`CDER
`CDRH
`CDS
`CDTL
`CFR
`CIAC
`CMC
`COSTART
`CRF
`CRO
`CRNM
`CRT
`CSR
`CSS
`CVAD
`CVC
`CVST
`DMC
`DVT
`ECG
`eCTD
`ESMD
`ETASU
`FDA
`
`advisory committee
`adverse event
`alanine transaminase
`activated partial thromboplastin time
`adverse reaction
`aspirin
`physiological based pharmacokinetic
`twice a day
`Best Pharmaceuticals for Children Act
`Benefit Risk Framework
`coronary artery disease
`Center for Biologics Evaluation and Research
`Center for Drug Evaluation and Research
`Center for Devices and Radiological Health
`Clinical Data Scientist
`Cross-Discipline Team Leader
`Code of Federal Regulations
`central and independent adjudication committee
`chemistry, manufacturing, and controls
`Coding Symbols for Thesaurus of Adverse Reaction Terms
`case report form
`contract research organization
`clinically relevant non-major (in reference to bleeding)
`clinical review template
`clinical study report
`Controlled Substance Staff
`central venous access device
`Central venous catheter
`Cerebral vein and venous sinus
`data monitoring committee
`deep venous thrombosis
`electrocardiogram
`electronic common technical document
`early study medication discontinuation
`elements to assure safe use
`Food and Drug Administration
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`11
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`FDAAA
`FDASIA
`FMQ
`GCP
`GRMP
`Hb
`HIT
`HITT
`ICH
`IND
`ISE
`ISS
`ITT
`LMWH
`MedDRA
`mITT
`NCI-CTCAE
`NDA
`NME
`o.i.d
`OCS
`OPQ
`OSE
`OSI
`PAD
`PBRER
`PD
`PE
`PI
`PK
`PMC
`PMR
`PP
`PPI
`PREA
`PRO
`PSUR
`PT
`REMS
`SAE
`SAP
`
`Food and Drug Administration Amendments Act of 2007
`Food and Drug Administration Safety and Innovation Act
`FDA Medical Queries
`good clinical practice
`good review management practice
`hemoglobin
`heparin induced thrombocytopenia
`heparin induced thrombocytopenia and thrombosis
`International Council for Harmonization
`Investigational New Drug Application
`integrated summary of effectiveness
`integrated summary of safety
`intent to treat
`low molecular weight heparin
`Medical Dictionary for Regulatory Activities
`modified intent to treat
`National Cancer Institute-Common Terminology Criteria for Adverse Event
`new drug application
`new molecular entity
`once daily
`Office of Computational Science
`Office of Pharmaceutical Quality
`Office of Surveillance and Epidemiology
`Office of Scientific Investigation
`peripheral artery disease
`Periodic Benefit-Risk Evaluation Report
`pharmacodynamics
`pulmonary embolism
`prescribing information or package insert
`pharmacokinetics
`postmarketing commitment
`postmarketing requirement
`per protocol
`patient package insert
`Pediatric Research Equity Act
`patient reported outcome
`Periodic Safety Update report
`prothrombin time
`risk evaluation and mitigation strategy
`serious adverse event
`statistical analysis plan
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`12
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`SCS
`SD
`SGE
`SOC
`TE
`TEAE
`TID or t.i.d.
`UFH
`ULN
`UPSI
`VKA
`VTE
`
`summary of clinical safety
`standard deviation
`special government employee
`standard of care
`thromboembolism
`treatment emergent adverse event
`three times a day
`unfractionated heparin
`upper limit of normal
`United States Prescribing Information
`vitamin K antagonist
`venous thromboembolism
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`13
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`1. Executive Summary
`
`1.1.
`
`Product Introduction
`
`Proprietary Name Xarelto®
`Established Name- rivaroxaban
`Dosage Forms - Tablets: 2.5 mg, 10 mg, 15 mg, and 20 mg
`Granules for oral solution: 1 mg/ml after reconstitution-pending
`Chemical Class- Small molecule
`Pharmacologic Class- Factor Xa inhibitor
`Mechanism of Action - Factor Xa inhibitor and inhibitor of prothrombinase activity
`
`Rivaroxaban is an oral anticoagulant approved since 2011 for the following indications for use
`in adult patients:
`Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
`Treatment of Deep Vein Thrombosis
`Treatment of Pulmonary Embolism
`Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism
`Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
`Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for
`Thromboembolic Complications Not at High Risk of Bleeding
`To Reduce the Risk of Major Cardiovascular Events in Patients with Coronary Artery Disease
`(CAD)
`To Reduce the Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery
`Disease (PAD), Including Patients after Recent Lower Extremity Revascularization Due to
`Symptomatic PAD
`
`Rivaroxaban is not approved for any pediatric indication. This submission contains data to fulfill
`a Written Request and support two indications for use of rivaroxaban in the pediatric
`population. The Applicant’s proposed indications are proposed below:
`
`#1- Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous
`Thromboembolism in Pediatric Patients
`
`XARELTO is indicated for the treatment of venous thromboembolism (VTE) and the reduction in
`the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5
`days of initial parenteral anticoagulant treatment.
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`14
`
`Reference ID: 4907803
`
`

`

`Clinical/CDTL/DD Review
`Ann T. Farrell, MD
`NDA 215859
`XARELTO/rivaroxaban
`
`#2-