Conditions: Bleeding
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 108
Healthy volunteers: yes

Brief summary:
"This is a single-center, randomized, double-blind, and placebo-controlled trial designed to: 1) demonstrate the degree to which administered andexanet doses can reverse Factor Ten A (FXa)-inhibitor induced anticoagulation; and 2) evaluate the safety and PK/PD of andexanet in healthy Japanese subjects taking direct FXa inhibitors at therapeutic doses."

Detailed description:

Arms:
arm 1: Apixaban + low dose andexanet arm 2: Rivaroxaban + high dose andexanet arm 3: Edoxaban + high dose andexanet arm 4: Edoxaban + high dose andexanet arm 5: Apixaban + low dose andexanet arm 6: Apixaban + high dose andexanet arm 7: Edoxaban + low dose andexanet arm 8: Apixaban + low dose andexanet arm 9: Rivaroxaban + low dose andexanet arm 10: Edoxaban + low dose andexanet

Interventions: intervention 1: Andexanet alfa intervention 2: Apixaban intervention 3: Rivaroxaban intervention 4: Edoxaban intervention 5: Placebo
Intervention descriptions: intervention 1: fXa inhibitor antidote intervention 2: factor Xa inhibitor intervention 3: factor Xa inhibitor intervention 4: factor Xa inhibitor intervention 5: Placebo

Protocol document:
SAP_002.pdf: 
NCT03310021  
 
Statistical Analysis Plan: Part 2 
 
A Phase 2 Randomized, Double‐Blinded, Placebo‐Controlled Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of 
Andexanet Alfa Administered to Healthy Japanese and Caucasian Subjects 
 
Document Date: 06‐June‐2019 





























































Prot_001.pdf: 
NCT03310021  
 
Protocol Amendment 5 
 
A Phase 2 Randomized, Double‐Blinded, Placebo‐Controlled Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of 
Andexanet Alfa Administered to Healthy Japanese and Caucasian Subjects 
 
Document Date: 19‐February‐2019 


 
 
Clinical Study 16-508 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 1 
  
A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS/PHARMACODYNAMICS OF ANDEXANET ALFA 
ADMINISTERED TO HEALTHY JAPANESE AND CAUCASIAN SUBJECTS 
 
Drug Name: 
andexanet alfa (PRT064445) 
Protocol Number: 
16-508 
Phase: 
2 
IND 
015089 
 
 
Sponsor:   
Portola Pharmaceuticals, Inc. 
 
270 East Grand Avenue, Suite 22 
 
South San Francisco, CA  94080  USA 
 
Phone:  (650) 246-7000 
 
FAX:  (650) 246-7766 
 
 
Medical Monitor: 
Patrick Yue, MD 
 
Portola Pharmaceuticals, Inc. 
 
Phone:  (650) 246-7039 
 
Fax:  (650) 246-7766 
 
 
Amendment 5 
Amendment 4 
19-February-2019 
01-February-2019 
Amendment 3 
Amendment 2 
Amendment 1 
Original Protocol: 
16-November-2018 
04-December-2017 
08-September-2017  
30-June-2017 
 
 
 
This protocol, the property of Portola Pharmaceuticals, Inc., is a confidential communication.  Acceptance implies 
an agreement not to disclose information contained herein that is not otherwise publicly available, with the 
exception that it may be disclosed to an institutional review board (IRB)/Ethics Committee (EC) for the purpose 
of obtaining approval to conducting the study.  The IRB/EC is requested and expected to maintain confidentiality.  
This document may not be used or published without the consent of Portola Pharmaceuticals, Inc. 
 






Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
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Page 4 
TABLE OF CONTENTS 
Page 
INVESTIGATOR’S AGREEMENT.................................................................................................... 2 
SPONSOR’S AGREEMENT ................................................................................................................. 3 
PROTOCOL SYNOPSIS ...................................................................................................................... 11 
1.0 
INTRODUCTION ..................................................................................................................... 21 
1.1. 
BACKGROUND .................................................................................................................... 21 
1.2. 
DESCRIPTION OF ANDEXANET .................................................................................... 21 
1.3. 
SUMMARY OF RELEVANT NONCLINICAL EXPERIENCE WITH 
ANDEXANET ........................................................................................................................ 22 
1.3.1. 
Nonclinical Pharmacology ........................................................................................... 22 
1.3.2. 
Nonclinical Toxicology and Safety ............................................................................ 23 
1.4. 
SUMMARY OF CLINICAL EXPERIENCE WITH ANDEXANET IN 
HEALTHY SUBJECTS ........................................................................................................ 24 
1.4.1. 
Phase 1 Study of Andexanet Alone in Healthy Subjects ......................................... 24 
1.4.2. 
Phase 1 Study of Andexanet in Healthy Younger versus Older Subjects .............. 24 
1.4.3. 
Phase 2 Study of Andexanet with Factor Xa Inhibitors in Healthy Subjects ........ 24 
1.4.4. 
Phase 3 Studies in Healthy Older Volunteers ............................................................ 27 
1.4.5. 
Summary of Safety from Clinical Studies of Healthy Subjects .............................. 29 
1.4.6. 
Phase 3b Study in Patients with Acute Major Bleeding........................................... 29 
1.5. 
RATIONALE FOR PRESENT STUDY ............................................................................. 30 
2.0 
STUDY OBJECTIVES ............................................................................................................ 31 
3.0 
INVESTIGATIONAL PLAN ................................................................................................. 32 
3.1. 
STUDY DESIGN ................................................................................................................... 32 
3.2. 
BLINDING AND RANDOMIZATION ............................................................................. 34 
3.2.1. 
Randomization ............................................................................................................... 34 
3.2.2. 
Blinding .......................................................................................................................... 34 
3.2.3. 
Unblinding ...................................................................................................................... 34 
3.3. 
DURATION OF STUDY ...................................................................................................... 35 
3.4. 
FACTOR XA INHIBITOR AND ANDEXANET DOSING 
CONSIDERATIONS ............................................................................................................. 35 
3.5. 
SAFETY PLAN AND MONITORING .............................................................................. 35 
4.0 
SELECTION OF SUBJECTS ................................................................................................ 37 
4.1. 
INCLUSION CRITERIA ...................................................................................................... 37 
4.2. 
EXCLUSION CRITERIA ..................................................................................................... 39 
4.3. 
SUBJECT REPLACEMENT ............................................................................................... 40 
5.0 
STUDY MATERIALS AND DOSING ................................................................................. 41 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
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5.1. 
CLINICAL SUPPLIES, FORMULATION, AND STORAGE ....................................... 41 
5.1.1. 
Andexanet ....................................................................................................................... 41 
5.1.2. 
Placebo (Vehicle Control) ............................................................................................ 41 
5.1.3. 
Apixaban......................................................................................................................... 41 
5.1.4. 
Edoxaban ........................................................................................................................ 41 
5.1.5. 
Rivaroxaban ................................................................................................................... 41 
5.2. 
DISPENSING OF STUDY MEDICATION (FACTOR XA INHIBITORS AND 
ANDEXANET) ...................................................................................................................... 41 
5.3. 
FACTOR XA INHIBITOR DOSING ................................................................................. 42 
5.3.1. 
Factor Xa Inhibitor Dosing—Fed/Fasting Conditions ............................................. 42 
5.4. 
ANDEXANET DOSING ...................................................................................................... 42 
5.5. 
DIETARY RESTRICTIONS ................................................................................................ 43 
5.6. 
CONCOMITANT MEDICATIONS ................................................................................... 43 
6.0 
ENROLLMENT AND STUDY PROCEDURES ............................................................... 44 
6.1. 
SCREENING VISIT PROCEDURES (DAYS -45 TO -2) .............................................. 44 
6.2. 
RESCREENING PROCEDURES ....................................................................................... 45 
6.3. 
DAY -1 (ADMISSION DAY) PROCEDURES ................................................................ 46 
6.4. 
FACTOR XA INHIBITOR DOSING PERIOD (DAYS 1–5) ......................................... 46 
6.4.1. 
Day 1 ............................................................................................................................... 46 
6.4.2. 
Days 2 to 4...................................................................................................................... 47 
6.4.3. 
Day 5 ............................................................................................................................... 47 
6.5. 
ANDEXANET/PLACEBO DOSING DAY (DAY 6) ...................................................... 48 
6.6. 
INPATIENT POST-TREATMENT FOLLOW UP (DAYS 7–10) ................................. 50 
6.6.1. 
Day 7 ............................................................................................................................... 50 
6.6.2. 
Days 8 to 9...................................................................................................................... 50 
6.6.3. 
Day 10 ............................................................................................................................. 51 
6.7. 
OUTPATIENT POST-TREATMENT FOLLOW UP (DAYS 11–36) .......................... 51 
6.7.1. 
Day 20 (+3) Outpatient Visits ..................................................................................... 51 
6.7.2. 
Day 36 (+3) Outpatient Termination Visit ................................................................. 51 
6.8. 
UNSCHEDULED VISIT ...................................................................................................... 52 
6.9. 
EARLY TERMINATION VISIT ......................................................................................... 52 
6.10. NON-CONTACT DAILY EXERCISE ............................................................................... 53 
6.11. EARLY DISCONTINUATION FROM STUDY .............................................................. 53 
7.0 
CLINICAL ASSESSMENTS .................................................................................................. 54 
7.1. 
BLOOD COLLECTION ....................................................................................................... 54 
7.2. 
SCREENING/ELIGIBILITY ASSESSMENTS ................................................................ 54 
7.2.1. 
Urine Drugs of Abuse Screen ...................................................................................... 54 


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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
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7.2.2. 
Breathalyzer Ethanol Screen ........................................................................................ 54 
7.2.3. 
Blood Laboratory Testing ............................................................................................ 54 
7.3. 
EFFICACY ASSESSMENTS .............................................................................................. 55 
7.3.1. 
Coagulation Assays ....................................................................................................... 55 
7.4. 
PHARMACOKINETIC ASSESSMENTS ......................................................................... 55 
7.5. 
SAFETY ASSESSMENTS ................................................................................................... 55 
7.5.1. 
Vital Signs ...................................................................................................................... 56 
7.5.2. 
Physical Examination ................................................................................................... 56 
7.5.3. 
Clinical Venous Thromboembolism Assessment ..................................................... 56 
7.5.4. 
Oxygen Saturation ......................................................................................................... 56 
7.5.5. 
Electrocardiogram ......................................................................................................... 56 
7.5.6. 
Fecal Occult Blood Testing ......................................................................................... 56 
7.5.7. 
Clinical Laboratory Blood Testing ............................................................................. 57 
7.5.8. 
Urine Studies .................................................................................................................. 57 
7.5.9. 
Immunogenicity ............................................................................................................. 57 
8.0 
ADVERSE EVENTS/SAFETY MONITORING ............................................................... 58 
8.1. 
GENERAL SAFETY CONSIDERATIONS ...................................................................... 58 
8.2. 
ADVERSE EVENT DEFINITION ..................................................................................... 59 
8.3. 
SERIOUS ADVERSE EVENT DEFINITION .................................................................. 59 
8.4. 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) ...... 60 
8.5. 
ADVERSE EVENTS OF SPECIAL INTEREST .............................................................. 60 
8.6. 
PROCEDURES FOR RECORDING AND REPORTING AES AND SAES ............... 60 
8.7. 
PROCEDURES FOR REPORTING SUSARS .................................................................. 62 
8.8. 
MONITORING OF ADVERSE EVENTS AND PERIOD OF OBSERVATION ....... 62 
8.9. 
PROCEDURES FOR REPORTING PREGNANCY EXPOSURE AND BIRTH 
EVENTS .................................................................................................................................. 62 
9.0 
PHARMACOKINETIC ANALYSES ................................................................................... 64 
10.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ................................... 66 
10.1. STUDY OBJECTIVES AND STUDY DESIGN .............................................................. 66 
10.2. GENERAL CONSIDERATIONS ....................................................................................... 66 
10.3. RANDOMIZATION .............................................................................................................. 66 
10.4. ANALYSIS POPULATIONS .............................................................................................. 66 
10.4.1. Efficacy Analysis Population ...................................................................................... 66 
10.4.2. Safety Analysis Population .......................................................................................... 66 
10.4.3. PK Analysis Population ................................................................................................ 67 
10.5. ENDPOINTS .......................................................................................................................... 67 
10.5.1. Efficacy Endpoints ........................................................................................................ 67 


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Portola Pharmaceuticals, Inc. 
 
 
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10.5.1.1. Primary Efficacy Endpoint ................................................................................. 67 
10.5.1.2. Secondary Efficacy Endpoint ............................................................................. 67 
10.5.1.3. Exploratory Efficacy Endpoints ......................................................................... 68 
10.5.2. Safety Endpoints ............................................................................................................ 68 
10.5.2.1. Non-Laboratory-Based Endpoints ..................................................................... 68 
10.5.2.2. Laboratory-Based Endpoints .............................................................................. 68 
10.5.3. PK Endpoints ................................................................................................................. 69 
10.6. STATISTICAL ANALYSES ............................................................................................... 69 
10.6.1. Baseline and Demographics ......................................................................................... 69 
10.6.2. Efficacy Analysis .......................................................................................................... 69 
10.6.2.1. Primary Efficacy Analysis .................................................................................. 69 
10.6.2.2. Secondary Efficacy Analyses ............................................................................. 69 
10.6.2.3. Exploratory Efficacy Analyses ........................................................................... 69 
10.6.2.4. Handling of Missing Data ................................................................................... 69 
10.6.3. Subgroup Analysis ........................................................................................................ 70 
10.6.4. Safety Analysis .............................................................................................................. 70 
10.6.4.1. Extent of Exposure ............................................................................................... 70 
10.6.4.2. Analysis of Adverse Events ................................................................................ 70 
10.6.4.3. Concomitant Medications ................................................................................... 70 
10.6.4.4. Analysis of Laboratory Parameters .................................................................... 70 
10.6.4.5. Analysis of Other Safety Parameters ................................................................. 71 
10.6.5. PK Analysis .................................................................................................................... 71 
10.6.6. Interim Analysis ............................................................................................................ 71 
10.7. SAMPLE SIZE CONSIDERATIONS ................................................................................ 71 
10.7.1. Part 1 ............................................................................................................................... 71 
10.7.1.1. Apixaban (Cohorts 1 and 5) ................................................................................ 71 
10.7.1.2. Rivaroxaban (Cohort 2) ....................................................................................... 72 
10.7.1.3. Edoxaban (Cohort 3; andexanet dosing at 3 hours post-edoxaban) .............. 72 
10.7.1.4. Edoxaban (Cohort 4; andexanet dosing at 90 minutes post-edoxaban) ........ 72 
10.7.2. Part 2 ............................................................................................................................... 72 
10.7.2.1. Apixaban 10 mg BID (Cohort 6:  andexanet dosing at 3 hours post 
apixaban) ............................................................................................................... 72 
10.7.2.2. Edoxaban 30 mg QD (Cohort 7:  andexanet dosing at 90 min post 
edoxaban) .............................................................................................................. 73 
10.7.2.3. Apixaban 10 mg BID (Cohort 8:  andexanet dosing at 8 hours post 
apixaban) ............................................................................................................... 73 


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10.7.2.4. Rivaroxaban 15 mg BID (Cohort 9:  andexanet dosing at 8 hours post 
rivaroxaban) .......................................................................................................... 73 
10.7.2.5. Edoxaban 60 mg QD (Cohort 10:  andexanet dosing at 8 hours post 
edoxaban) .............................................................................................................. 73 
10.8. INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE ............................. 74 
10.9. INFORMED CONSENT ....................................................................................................... 74 
10.10. DATA REPORTING AND CASE REPORT FORMS ..................................................... 74 
10.11. RETENTION OF DATA ...................................................................................................... 74 
10.12. DEVIATION FROM THE PROTOCOL ............................................................................ 75 
10.13. STUDY MONITORING ....................................................................................................... 75 
10.14. DRUG ACCOUNTABILITY ............................................................................................... 75 
11.0 
DISCLOSURE OF DATA ....................................................................................................... 76 
12.0 
REFERENCES ........................................................................................................................... 77 
13.0 
APPENDICES ............................................................................................................................ 78 
APPENDIX A. 
STUDY EVENTS FLOW CHART (PART 1) ............................................. 79 
APPENDIX B. 
STUDY EVENTS FLOW CHART (PART 2) ............................................. 85 
APPENDIX C. 
WELLS SCORES .............................................................................................. 90 
APPENDIX D. 
US PACKAGE INSERT FOR APIXABAN (ELIQUIS) .......................... 91 
APPENDIX E. 
US PACKAGE INSERT FOR EDOXABAN (SAVAYSA) .................... 103 
APPENDIX F. 
US PACKAGE INSERT FOR RIVAROXABAN (XARELTO) ........... 115 
APPENDIX G. 
PROTOCOL SUMMARY OF CHANGES 
(AMENDMENT 4 VS. AMENDMENT 5) ......................................................................... 131 
 
List of Tables 
Table 1: 
Cohort Details ......................................................................................................................... 33 
Table 2: 
Dosing Specifications by Test Product and Cohort ................................................................ 43 
 
List of Figures 
Figure 1: 
Structures of Human Factor X and Andexanet ....................................................................... 22 
Figure 2: 
Rapid Onset and Reduction of Anti-fXa Activity (Study 12-502) ......................................... 26 
Figure 3: 
Rapid Onset and Significant Reduction of Apixaban and Rivaroxaban Anti-fXa 
Activity in Older Healthy Subjects by Andexanet (Study 14-504) ........................... 28 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
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Page 9 
LIST OF ABBREVIATIONS 
Term 
Definition 
ACT 
Activated clotting time 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BID 
Twice daily 
BP 
Blood pressure 
b-TG 
Beta thromboglobulin 
CFR 
Code of Federal Regulations 
CL 
Clearance 
CLr 
Renal clearance 
Cmax/min 
Maximum/minimum observed concentration 
CRF 
Case report form 
CRO 
Contract research organization 
DVT 
Deep venous thrombosis 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
e-CRF 
Electronic case report form 
F1+2 
Prothrombin fragment 1+2 
FDA 
(US) Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FX 
Factor X 
FXa 
Factor Xa 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
ICF 
Informed Consent Form 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
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Term 
Definition 
ISC 
Independent Safety Committee 
IV 
Intravenous 
LCMS 
Liquid chromatography mass spectrometry 
λz 
Terminal or elimination rate constant 
MI 
Myocardial infarction 
min 
Minute 
mL 
Milliliter 
ng 
Nanogram 
PAP 
Plasmin-antiplasmin complex 
PD 
Pharmacodynamic 
PE 
Pulmonary embolism 
PF4 
Platelet Factor 4 
PK 
Pharmacokinetic 
PO 
Orally 
PT 
Prothrombin time 
Q 
Every 
QD 
Once daily 
RAST 
Radioallergosorbent 
RR 
Respiratory rate 
RVVT 
Russell’s Viper Venom Time 
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
sTM 
Soluble thrombomodulin 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Half-life 
TAFI 
Thrombin activatable fibrinolysis inhibitor 
TAT 
Thrombin-antithrombin complex 
TEAE 
treatment-emergent adverse event 
TFPI 
Tissue factor pathway inhibitor 
Tmax 
Time to maximum observed concentration 
tPA 
Tissue plasminogen activator 
ULN 
Upper limit of normal 
Vss 
Volume at steady state 
VTE 
Venous thromboembolism 
 


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PROTOCOL SYNOPSIS 
Title 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, 
Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Andexanet Alfa 
Administered to Healthy Japanese and Caucasian Subjects 
Study Number 
16-508 
Study Phase 
2 
Target Patient 
Population  
Healthy Japanese subjects dosed to steady state with apixaban, rivaroxaban, and edoxaban; 
healthy Caucasian subjects dosed to steady state with apixaban 
Objectives 
The objectives of this study are to assess the following in healthy subjects dosed to steady state 
with direct oral FXa inhibitors (apixaban, rivaroxaban, and edoxaban): 
Primary Efficacy Objective 
 
To compare andexanet and placebo with respect to reversal of each FXa inhibitor as 
measured by anti-fXa activity.                                                            
Secondary Efficacy Objectives 
 
To assess andexanet and placebo with respect to reversal of each FXa inhibitor as measured 
by free fraction of the inhibitor. 
 
To assess andexanet and placebo with respect to reversal of each FXa inhibitor as measured 
by restoration of thrombin generation. 
 
To assess the pharmacodynamics of andexanet in Japanese subjects and Caucasian 
subjects, as measured by anti-fXa activity, free fraction of the FXa inhibitor (apixaban), 
and restoration of thrombin generation. 
Safety Objective 
 
To evaluate the safety of andexanet in Japanese subjects. 
Pharmacokinetics Objectives 
 
To evaluate the pharmacokinetics of andexanet in Japanese subjects. 
 
To compare the pharmacokinetics of andexanet in Japanese subjects to the 
pharmacokinetics of andexanet in Caucasian subjects. 
 Study Design 
This is a single-center, randomized, double-blind, and placebo-controlled trial designed to:  
1) demonstrate the degree to which administered andexanet doses can reverse FXa-inhibitor-
induced anticoagulation; and 2) evaluate the safety and PK of andexanet in healthy Japanese 
subjects taking direct FXa inhibitors at therapeutic doses.  Reversal of anticoagulation will be 
evaluated by measuring anti-fXa activity, unbound FXa inhibitor plasma levels, and thrombin 
generation.  The study is divided into two parts, Part 1 is to evaluate andexanet reversal effect 
in the Japanese subjects, safety, and PK/PD, and also evaluate similarity with Caucasian data 
when andexanet is administered 4 hours after FXa inhibitor dosing.  Part 2 will be conducted to 
evaluate andexanet reversal effect of FXa inhibitor dosing regimens and the administration of 
andexanet at 8 hours after FXa inhibitor dosing.  The design of Part 2 may be adjusted based on 
Part 1 outcomes. 
Following screening, study subjects will be randomized and domiciled at the study site for 
~10 days, during which time they will be administered apixaban, rivaroxaban, or edoxaban 
(depending on cohort; see table) on Days 1–6.  Andexanet (or matching placebo) bolus and 
continuous infusion doses will be administered on Day 6, at various times after the last 
administration of FXa inhibitor.  Study subjects will be discharged from the clinical site on 
Day 10 and followed for safety through Day 36 (+3). 
The primary endpoint is the difference in the percent change from baseline anti-fXa activity 
between andexanet- and placebo-treated subjects in each cohort.  That is, the percent change 
from baseline (where baseline is the time point immediately prior to the administration of 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
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Study Design 
(Cont’d) 
andexanet) in anti-fXa activity to its nadir as measured during the evaluation period.  Nadir is 
defined as the smallest value for anti-fXa activity between the 110-minute time point 
(10 minutes prior to the end of the continuous andexanet infusion) and the 5-minute time point 
after the end of the continuous infusion (inclusive). 
The study will be conducted in up to 10 cohorts grouped into two parts.  Part 1 (with 5 cohorts) 
will enroll first.  Based on the results of Part 1, Part 2 will be carried out (with up to 
5 additional cohorts).  To compare the PK of andexanet between Japanese and Caucasian 
subjects, Cohort 5 will include Caucasian subjects administered 5 mg BID apixaban followed 
by the stipulated andexanet dose (400 mg bolus followed by 4 mg/min infusion for 2 hours).  
For all cohorts, placebo groups are included for assessment of the efficacy and safety of 
andexanet in healthy volunteers. 
For all cohorts, subjects will be randomized in a 2:1 ratio of treatment with andexanet or 
placebo, respectively.  If enrolled subjects discontinue early from the study or have missing 
data for any reason, the Sponsor may elect to add up to 3 additional subjects (with newly 
blinded treatment assignments) within the discontinued subject’s assigned cohort. 
Part 1 will include the following cohorts: 
 
Cohort 
FXa Inhibitor 
Andexanet 
N (Active/Placebo) 
1 
Apixaban 
5 mg BID 
400 mg bolus + 4 mg/min 
120 minute infusion/placebo 
(andexanet dosing at 3 hours 
post-apixaban) 
Japanese 9 (6/3) 
2 
Rivaroxaban 
15 mg BID 
800 mg bolus + 8 mg/min 
120 minute infusion/placebo 
(andexanet dosing at 4 hours 
post-rivaroxaban) 
Japanese 9 (6/3) 
3 
Edoxaban 
60 mg QD 
800 mg bolus + 8 mg/min 
120 minute infusion/placebo 
(andexanet dosing at 3 hours 
post-edoxaban) 
Japanese 12 (8/4) 
4 
Edoxaban 
60 mg QD 
800 mg bolus + 8 mg/min 
120 minute infusion/placebo 
(andexanet dosing at 90 minutes 
post-edoxaban) 
Japanese 12 (8/4) 
5 
Apixaban 
5 mg BID 
400 mg bolus + 4 mg/min 
120 minute infusion/placebo 
(andexanet dosing at 3 hours 
post-apixaban) 
Caucasian 9 (6/3) 
 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
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Study Design 
(Cont’d) 
Part 2 will include the following cohorts: 
 
Cohort 
FXa Inhibitor 
Andexanet 
N (Active/Placebo) 
6 
Apixaban 
10 mg BID 
800 mg bolus + 8 mg/min 120 minute 
infusion/Placebo 
 (andexanet dosing at 3 hours post 
apixaban) 
Japanese 9 (6/3) 
7 
Edoxaban 
30 mg QD 
400 mg bolus + 4 mg/min 120 minute 
infusion/placebo 
 (andexanet dosing at 90 min post 
edoxaban) 
Japanese 12 (8/4) 
8 
Apixaban 
10 mg BID 
400 mg bolus + 4 mg/min 120 minute 
infusion/placebo 
 (andexanet dosing at 8 hours post 
apixaban) 
Japanese 9 (6/3) 
9 
Rivaroxaban 
15 mg BID 
400 mg bolus + 4 mg/min 120 minute 
infusion/placebo 
 (andexanet dosing at 8 hours post 
rivaroxaban) 
Japanese 15(10/5) 
10 
Edoxaban 
60 mg QD 
400 mg bolus + 4 mg/min 120 minute 
infusion/placebo 
 (andexanet dosing at 8 hours post 
edoxaban) 
Japanese 12 (8/4) 
Study Schematic 
 
Study Periods 
 
Screening:  Days -45 days to -1 day 
 
Anticoagulant Dosing:  Days 1 to 6 (only morning dose on Day 6 for apixaban, 
rivaroxaban, and edoxaban) 
 
Andexanet Dosing:  Day 6 
 
Safety Follow-up:  Days 7 to 36 (+3) 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 14 
Inclusion 
Criteria 
To be eligible for study enrollment, study subjects must meet the following inclusion criteria: 
1) Must be in reasonably good health as determined by the Investigator based on medical 
history, full physical examination (including blood pressure and pulse rate measurement), 
12-lead ECG, and clinical laboratory tests.  Subjects with well-controlled, chronic, stable 
conditions (e.g., controlled hypertension, non-insulin dependent diabetes, osteoarthritis, 
hypothyroidism) may be enrolled based on the clinical judgment of the Investigator. 
2) For all cohorts except Cohort 5, subjects must be of Japanese ethnicity, defined as having 
four ethnic Japanese grandparents.  Subjects may not have lived outside of Japan for more 
than 10 years.  For Cohort 5, subjects must be of Caucasian race. 
3) Must be between the ages of 18 and 75 years, inclusive, at the time of signing of the ICF. 
4) Agrees to have any dietary or nutritional supplements reviewed by the Investigator and 
potentially held during the study if advised by the Investigator.  Standard multivitamin and 
mineral supplementation will be permitted. 
5) Agrees to comply with the contraception and reproduction restrictions of the study: 
 Men whose sexual partner is of childbearing potential and/or who are not monogamous 
must be using two acceptable methods of contraception, at least one of which must be a 
barrier method (e.g., spermicidal gel plus condom), for the entire duration of the study 
and for at least 1 month following study-drug administration; and men must refrain from 
attempting to father a child or donating sperm in the 1 month following the study-drug 
administration.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
 Men who report surgical sterilization (e.g., bilateral vasectomy) must have had the 
procedure at least 6 months before study drug administration. 
 Surgical sterilization procedures should be supported with clinical documentation and 
noted in the Relevant Medical History/Current Medical Conditions section of the CRFs. 
 Women of childbearing potential must be using two medically acceptable methods of 
contraception, at least one of which must be a barrier method (e.g., non-hormone 
containing intra-uterine device plus condom, spermicidal gel plus condom, diaphragm 
plus condom), from the time of Screening and for the duration of the study, through at 
least 1 month following study drug administration.  NOTE:  Oral and topical hormonal 
contraceptive use, as well as the use of hormone-containing intra-uterine devices, is not 
permitted due to their increased risk of thromboembolism.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal are not 
acceptable methods of contraception; 
OR 
 Postmenopausal women must have had no regular menstrual bleeding for at least 1 year 
before initial dosing and either be over the age of 60 years or have an elevated plasma 
follicle-stimulating hormone (FSH) level (i.e., > 40 mIU/mL) at Screening 
OR 
 Women who report surgical sterilization (i.e., hysterectomy, tubal ligation, and/or 
bilateral oophorectomy) must have had the procedure at least 6 months before study drug 
administration.  Surgical sterilization procedures should be supported with clinical 
documentation and noted in the Relevant Medical History/Current Medical Conditions 
section of the CRF; 
AND 
 All female subjects must have a documented negative pregnancy test result at Screening 
and on Study Day -1. 


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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
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Inclusion 
Criteria (Cont’d) 
6) Systolic blood pressure < 160 mmHg and diastolic blood pressure < 90 mmHg at 
Screening and Day -1. 
7) The following laboratory values must be within the normal laboratory reference range 
within 45 days of Day -1:  PT, aPTT, and ACT; hemoglobin, hematocrit, and platelet 
count. 
8) The following laboratory values must be equal to or below 2 times the upper limit of 
normal (ULN) range within 45 days of Day -1:  Aspartate aminotransferase (AST)/alanine 
aminotransferase (ALT) and total bilirubin. 
9) The Screening serum creatinine must be below 1.5 mg/dL within 45 days of Day -1. 
10) Body mass index of less than 30 kg/m2, inclusive, and body weight between 50 kg and 
80 kg, inclusive, at Screening.  In addition, subjects must be greater than 60 kg for Cohorts 
3, 4, and 10. 
11) Agrees to abstain from alcohol consumption for the duration of the domicile period, and 
from the use of drugs of abuse for the duration of the study. 
12) Able to read and give written informed consent and has signed a consent form approved 
by the Investigator’s Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC). 
Exclusion 
Criteria 
To be eligible for study enrollment, potential study subjects must not meet the following 
exclusion criteria: 
1) 
Previous use of andexanet or previous participation in the current study (even if the 
subject received placebo). 
2) 
History of abnormal bleeding, signs or symptoms of active bleeding, or risk factors for 
bleeding. 
3) 
Has a stool specimen that was positive for occult blood within 6 months of study 
Screening or during the Screening Period. 
4) 
Past or current medical history of thrombosis, any sign or symptom that suggests an 
increased risk of a systemic thrombotic condition or thrombotic event, or recent events 
that may increase risk of thrombosis. 
a. For example, subjects with a known or suspected hypercoagulable state, history of 
VTE, DVT, stroke, myocardial infarction (MI), cancer (other than non-melanoma skin 
cancer), atrial fibrillation, heart failure, cardiomyopathy, phlebitis, lower extremity 
edema, major surgery, or trauma within 2 months of Study Day -1, airplane travel with a 
planned flight time for any single flight segment ≥ 6 hours during the 4 weeks prior to Study 
Day -1, or general immobility are excluded. 
5) 
Absolute or relative contraindication to anticoagulation or treatment with apixaban, 
rivaroxaban, and/or edoxaban. 
6) 
Prior consumption of (by any route) one or more doses of aspirin (including baby 
aspirin), salicylate or subsalicylate, other antiplatelet drugs (e.g., ticlopidine, clopidogrel), 
non-steroidal anti-inflammatory drugs, fibrinolytic, or any anticoagulant within 7 days 
prior to Day -1 or is anticipated to require such drugs during the study. 
7) 
Receipt of (by any route) hormonal contraception, post- menopausal hormone 
replacement therapy (HRT) (including over-the-counter products), or testosterone during 
the 4 weeks prior to Study Day -1 or is anticipated to require such drugs during the study. 
8) 
Family history of or risk factors for a hypercoagulable or thrombotic condition, including 
one of the following: 
a. 
Factor V Leiden carrier or homozygote. 
b. Protein C, S, or ATIII activity below the normal range. 
9) 
History of adult asthma or chronic obstructive pulmonary disease or current regular or as-
needed use of inhaled medications. 
10) Active HBV, HCV, or HIV-1/2 infection. 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
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19 February 2019 
Page 16 
11) Use of any drugs that are strong dual inhibitors or inducers of CYP3A4 (apixaban and 
rivaroxaban cohorts only) and P-gp (all cohorts) within 7 days prior to Study Day -1 or 
anticipated need for such drugs during the study. 
12) Participation in an investigational drug study within 45 days of Day -1 or Day -1 is within 
5 half-lives of the investigational compound. 
13) Positive screen for drugs of abuse at Day -1 that is not explained by a prescription 
medication that the subject is known to be taking. 
14) A medical or surgical condition that may impair drug (anticoagulant or andexanet) 
metabolism. 
15) Allergy to any of the vehicle ingredients:  Tris, arginine, sucrose, hydrochloric acid, 
mannitol, and polysorbate 80. 
16) Allergy to soy or soy products. 
17) Current breastfeeding or a positive pregnancy test at Screening or Day -1. 
18) Any condition that could interfere with, or for which the treatment might interfere with, 
the conduct of the study or interpretation of the study results, or that would in the opinion 
of the Investigator increase the risk of the subject’s participation in the study.  This would 
include but is not limited to alcoholism, drug dependency or abuse, psychiatric disease, 
epilepsy, or any unexplained blackouts. 
19) The subject is not judged by the study staff to have adequate bilateral venous access. 
20) Unwillingness to adhere to the activity requirements of the study. 
Test Product, 
Dose, and Mode 
of 
Administration 
The andexanet dose regimens to be examined in this study are as follows (see table below): 
 
Cohorts 1, 5, 7, 8, 9, and 10:  400 mg IV bolus at a target rate of approximately 
30 mg/min, followed by a continuous infusion of 480 mg at 4 mg/min for 120 minutes. 
 
Cohorts 2, 3, 4, and 6:  800 mg IV bolus at a target rate of approximately 30 mg/min, 
followed by a continuous infusion of 960 mg at 8 mg/min for 120 minutes. 
Cohort 
Test Product 
Dose /Mode of Administration 
1, 5, 7, 8, 9, 10 
andexanet 200 mg Vial 
400 mg bolus + 4 mg/min 
120 minutes infusion IV 
2, 3, 4, 6 
andexanet 200 mg Vial 
800 mg bolus + 8 mg/min 
120 minutes infusion IV 
 
Reference 
Therapy and 
Mode of 
Administration 
Placebo 400 mg or 800 mg (depending on cohort) dosed via IV bolus at a target rate of 
approximately 30 mg/min, followed by a continuous infusion at 4 mg/min or 8 mg/min 
(depending on cohort) for 120 minutes. 


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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
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Efficacy 
Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the difference in percent change in the anti-fXa activity from 
baseline to the nadir, where nadir is defined as the smallest value for anti-fXa activity between the 
110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5- minute time 
point after the end of the continuous infusion (inclusive).  The primary analysis will be performed 
on all individual cohorts separately. 
 
Secondary Efficacy Endpoints 
 
The percent change from baseline in anti-fXa activity at its nadir, where nadir is defined 
as the smallest value for anti-fXa activity at the +2 minute or +5 minute time point after 
the completion of the andexanet bolus. 
 
The change from baseline in free FXa inhibitors concentration (ng/mL) at its nadir, 
where nadir is defined as the smallest value for free FXa inhibitors at the +2 minute or 
+5 minute time point after the completion of the andexanet bolus. 
 
The change from baseline in free FXa inhibitors concentration (ng/mL) at its nadir, 
where nadir is defined as the smallest value for free FXa inhibitors between the 
110-minute time point (10 minutes prior to the end of the continuous infusion) and the 
5-minute time point after the end of the continuous infusion (inclusive). 
 
The change in thrombin generation from baseline to its peak, where peak is defined as 
the largest value for thrombin generation between the +2 minute time point and the 
+5 time point after the end of the andexanet bolus (inclusive). 
 
The occurrence of thrombin generation above the lower limit of the normal range at its 
peak, between the +2 minute time point and the +5 time point after the end of the 
andexanet bolus (inclusive). 
 
The change in thrombin generation from baseline to its peak, where peak is defined as 
the largest value for thrombin generation between the 110-minute time point 
(10 minutes prior to the end of the continuous infusion) and the 5-minute time point 
after the end of the continuous infusion (inclusive). 
 
The occurrence of thrombin generation above the lower limit of the normal range at its 
peak, where peak is defined as the largest value for thrombin generation between the 
110-minute time point (10 minutes prior to the end of the continuous infusion) and the 
5-minute time point after the end of the continuous infusion (inclusive) and assess the 
thrombin generation during 24 hours after administration of FXa inhibitors. 
 
Exploratory Efficacy Endpoints 
 
For Parts 1 and 2 of the study, tissue factor pathway inhibitor (TFPI) activity, a marker 
of endogenous anticoagulation, will be evaluated for the purpose of monitoring the 
potential procoagulant activity of andexanet (due to andexanet-TFPI interaction). 
 
For Part 1 of the study the following markers will also be examined: PT, aPTT, ACT, 
FX, fibrinogen, tPA, PAP, TAFI, TFPI (total and free antigen), b-TG, PF4, and sTM. 
Safety Endpoints The following safety parameters will be analyzed: 
 
Adverse events, physical exam, vital signs, oxygen saturation, ECG, clinical laboratory 
values Serial clinical assessments for venous thromboembolic events. 
 
Antibodies to andexanet, FX, FXa, and HCPs; neutralizing antibodies to andexanet, FX, 
and FXa. 
 
Coagulation markers:  D-dimer, F1+2, and TAT. RVVT will be collected in Part 1 only. 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
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19 February 2019 
Page 18 
Pharmacokinetic 
Endpoints 
Andexanet:  Blood samples for andexanet will be collected at multiple time points on Day 6 
through Day 8. 
 
The following non-compartmental PK parameters will be computed for plasma 
andexanet:  Cmax, Tmax, AUC(0-last), AUC(0-∞), t1/2, CL, Vss, and λz. 
 
The following non-compartmental parameter estimates will be evaluated to compare the 
pharmacokinetics of andexanet in Japanese versus Caucasian subjects; Cmax, AUC(0-∞), 
t1/2, CL, Vss, and λz. 
 
Factor Xa inhibitors:  Plasma concentrations of both unbound and total FXa inhibitors will be 
measured in this study.  Blood samples for FXa inhibitors (total and unbound) will be collected 
on Day 1 (pre-dose only), multiple time points on Day 5 through Day 8 and once on Day 9 and 
Day 10. 
 
The following non-compartmental PK parameters will be computed for total plasma 
apixaban, rivaroxaban, edoxaban, and the edoxaban metabolite D21-2393:  Cmax, Cbolus 
(end of bolus + 2 minutes), Tmax, CL/F, AUC(0-last), AUC(0-τ), t1/2, and λz. 
Statistical 
Methods 
Analysis 
Analysis populations: 
The safety analysis population will include all enrolled subjects who received any amount of 
study drug (andexanet or placebo) treatment. 
The efficacy analysis population will include all randomized subjects who took any amount of 
study medication (andexanet or placebo) during the double-blind treatment period.  For the 
efficacy analysis, subjects will be presented in the treatment group to which they were 
randomized.  Subjects will be included in the efficacy analysis set on change or percent change 
from baseline if they have a baseline value and at least one measurement post-baseline for the 
time point under consideration.  The PK analysis populations will consist of all subjects who 
receive study drug and have sufficient data to calculate each PK parameter. 
Efficacy endpoint analyses: 
The primary analysis will be performed to compare the difference in the primary endpoint 
between andexanet- and placebo-treated subjects by cohort.  The analysis will be performed in 
all cohorts.  The comparison will be conducted using a two sample exact Wilcoxon rank sum 
test.  All hypothesis tests will be 2-sided and performed at the 0.05 significance level.  
No adjustment for multiplicity is necessary since each cohort is considered as an independent 
population. 
No formal statistical hypothesis testing will be performed for the secondary endpoints but point 
estimates and two-sided 95% confidence intervals will be produced to assess the treatment 
effects with respect to the secondary endpoints. 
Sample Size 
Determination 
Part 1:  
Apixaban 5 mg BID (Cohort 1 and Cohort 5) 
The mean (SD) of the primary endpoint in Study 14-503 Part 2 which assessed the reversal of 
apixaban 5 mg BID anticoagulation with andexanet administered as an IV bolus followed by a 
2-hour infusion were -92.3% (SD = 2.8%) and -32.7% (SD = 5.6%) for andexanet and placebo 
arms, respectively.  Based on these results, the percent changes from baseline in anti-fXa 
activity in this study are assumed to be -90% (SD = 5%) and -35% (SD = 10%) for andexanet 
and placebo arms, respectively.  The standard deviations in both arms are assumed larger than 
the observed values in the previous study to provide adequate power for the comparison.  Under 
these assumptions, a total number of 9 subjects (6 active and 3 placebo) will provide at least 
90% power to detect the difference at a significance level of 0.05 (two-sided) using the two 
sample exact Wilcoxon rank sum test. 


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Andexanet Alfa 
 
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Sample Size 
Determination 
(Cont’d) 
Rivaroxaban 15 mg BID (Cohort 2) 
The mean (SD) of the primary endpoint in Study 14-504 Part 2 which assessed the reversal of 
rivaroxaban 20 mg QD anticoagulation with andexanet administered as an IV bolus followed by 
a 2-hour infusion were -96.7% (SD = 1.8%) and -44.8% (SD = 11.7%) for andexanet and 
placebo arms, respectively.  Based on these results, the percent changes from baseline in anti-
fXa activity are assumed to be -90% (SD = 5%) and -45% (SD = 15%) for andexanet and 
placebo arms, respectively.  Under these assumptions, a total number of 9 subjects (6 active and 
3 placebo) will provide at least 90% power to detect the difference at a significance level of 
0.05 (two-sided) using the two sample exact Wilcoxon rank sum test. 
Edoxaban 60 mg QD (Cohort 3:  andexanet dosing at 3 hours post-edoxaban) 
In Cohort 2 of Study 12-502 Module 4 which assessed the reversal of edoxaban anticoagulation 
with andexanet, the mean (SD) of the percent change from baseline anti-fXa activity at the end 
of infusion was -70.28% (SD = 5.64%) for the andexanet arm.  In Cohort 1 and Cohort 2 of the 
same study, the mean (SD) of the percent change from baseline at 2 hours after the end of bolus 
was -40.31% (SD = 12.25%) for placebo.  Based on these results, the percent changes from 
baseline in anti-fXa activity for andexanet and placebo are assumed as -70% (SD = 6%) 
and -40% (SD = 15%), respectively.  Under these assumptions, a total number of 12 subjects 
(8 active and 4 placebo) will provide at least 90% power to detect the difference at a 
significance level of 0.05 (two-sided) using the two sample exact Wilcoxon rank sum test. 
Edoxaban 60 mg QD (Cohort 4:  andexanet dosing at 90 minutes post-edoxaban) 
There are no actual data of andexanet administration at 90 minutes after edoxaban dosing.  
Based on the result predicted by the PK-PD model developed using the data of Study 12-502, 
the percent changes from baseline in anti-fXa activity for andexanet and placebo are assumed as 
-70% (SD = 15%) and -30% (SD = 15%), respectively.  Under these assumptions, a total 
number of 12 subjects (8 active and 4 placebo) will provide at least 90% power to detect the 
difference at a significance level of 0.05 (two-sided) using the two sample exact Wilcoxon rank 
sum test. 
Part 2:  
Apixaban 10 mg BID (Cohort 6:  andexanet dosing at 3 hours post apixaban) 
A total number of 9 subjects (6 active and 3 placebo) will provide at least 90% power to detect 
the difference at a significance level of 0.05 (two-sided) using the two sample exact Wilcoxon 
rank sum test.  The underlying assumptions are supported by data from Cohort 8 of the 16-512 
study, which the mean (SD) of %change from baseline in anti-fXa activity (%CHB in anti-fXa 
activity) at nadir around EOI were -97% (SD = 0.8%) and –36% (SD = 3.3%) for andexanet 
and placebo arms, respectively.  In the power calculation, -95% (SD = 10%) and -40% 
(SD = 10%) are assumed. 
Edoxaban 30 mg QD (Cohort 7:  andexanet dosing at 90 min post edoxaban) 
A total number of 12 subjects (8 active and 4 placebo) will provide approximately 90% power 
to detect the difference at a significance level of 0.05 (two-sided) using the two sample exact 
Wilcoxon rank sum test.  Given the dose proportionality, the underlying assumptions are 
supported by data from Cohort 4 of the 16-508 study, which the mean (SD) of %CHB in 
anti-fXa activity at nadir around EOI were -71% (SD = 13.6%) and –34% (SD = 12.8%) for 
andexanet and placebo arms, respectively.  In the power calculation, -70% (SD = 15%) 
and -35% (SD = 15%) are assumed. 
Apixaban 10 mg BID (Cohort 8:  andexanet dosing at 8 hours post apixaban) 
A total number of 9 subjects (6 active and 3 placebo) will provide at least 90% power to detect 
the difference at a significance level of 0.05 (two-sided) using the two sample exact Wilcoxon 
rank sum test.  For placebo arm, the underlying assumptions are supported by data from Cohort 
8 of the 16-512 study, which the mean (SD) of %CHB in anti-fXa activity at 3.5 hours after 
EOI was -51% (SD = 9.5%).  For andexanet arm, the mean of %CHB in anti-fXa activity 
predicted by the PK-PD model that is 91.6% was used as reference because there are no actual 
data.  In the power calculation, -90% (SD = 10%) and -50% (SD = 10%) are assumed. 


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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
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Page 20 
Sample Size 
Determination 
(Cont’d) 
Rivaroxaban 15 mg BID (Cohort 9:  andexanet dosing at 8 hours post rivaroxaban) 
A total number of 15 subjects (10 active and 5 placebo) will provide approximately 87% power 
to detect the difference at a significance level of 0.05 (two-sided) using the two sample exact 
Wilcoxon rank sum test.  For placebo arm, the underlying assumptions are supported by data 
from Cohort 2 of the 16-508 study, which the mean (SD) of %CHB in anti-fXa activity at 
1.5 hours after EOI was -56% (SD = 12.1%).  For andexanet arm, the mean of %CHB in anti-
fXa activity predicted by the PK-PD model that is 86.5% was used as reference because there 
are no actual data.  In the power calculation, -85% (SD = 15%) and -55% (SD = 15%) are 
assumed. 
Edoxaban 60 mg QD (Cohort 10:  andexanet dosing at 8 hours post edoxaban) 
A total number of 12 subjects (8 active and 4 placebo) will provide at least 90% power to detect 
the difference at a significance level of 0.05 (two-sided) using the two sample exact Wilcoxon 
rank sum test.  The underlying assumptions are supported by data from Cohort 11 of the 16-512 
study, which the mean (SD) of %CHB in anti-fXa activity at nadir around EOI were -64% 
(SD = 9.0%) and –39% (SD = 6.0%) for andexanet and placebo arms, respectively.  In the 
power calculation, -65% (SD = 10%) and -40% (SD = 10%) are assumed. 
Study Centers 
One study site in the US. 
 


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1.0 
INTRODUCTION 
1.1. 
Background 
Anticoagulant medications are frequently utilized for a variety of indications, including stroke 
prophylaxis in atrial fibrillation, the prevention of venous thromboembolism in hip or knee 
replacement surgery, and the prevention and treatment of deep venous thrombosis (DVT) and 
pulmonary embolism (PE).  In recent years a new class of oral anticoagulants, direct factor Xa 
(FXa) inhibitors, has been approved for use in the above indications (Appendix D to 
Appendix F).  These drugs (including apixaban, edoxaban, and rivaroxaban) have become 
widely adopted after demonstrating a favorable safety and efficacy profile, as well as increased 
ease of use, versus vitamin K antagonists such as warfarin.  Despite the popularity of these 
drugs, a significant limitation has been the lack of a reversal agent to be used in cases of severe 
and/or life-threatening bleeding events.  There is thus currently an unmet medical need for an 
approved effective antidote for these drugs.  With the increasing use of direct FXa inhibitors in 
contemporary clinical practice, this need is only expected to increase in the coming years. 
1.2. 
Description of Andexanet 
Andexanet alfa is a recombinant version of human FXa that has been rationally modified to 
render it functionally inactive (Figure 1).  To achieve this aim, two key structural modifications 
were made to native human FXa.  First, the substitution of a serine residue with an alanine at the 
active site eliminated the protein’s catalytic activity.  Second, the removal of the Gla domain 
eliminates its ability to assemble into the prothrombinase complex thus removing any 
anticoagulant effect.  Reversal of anticoagulation is achieved because andexanet retains the 
ability to bind FXa inhibitor drugs with high affinity, thereby preventing them from binding to 
and inhibiting native FXa. 


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Figure 1: 
Structures of Human Factor X and Andexanet 
 
 
Additional information about the mechanism and structure of andexanet can be found in the 
andexanet Investigator’s Brochure. 
1.3. 
Summary of Relevant Nonclinical Experience with Andexanet 
1.3.1. 
Nonclinical Pharmacology 
In vivo animal models have been used to demonstrate the correlation between reversal of the 
anticoagulant effects of direct FXa inhibitors (e.g., apixaban, edoxaban, rivaroxaban) and 
indirect FXa inhibitors (e.g., enoxaparin, fondaparinux) as measured by pharmacokinetic (PK) 
and pharmacodynamic (PD) parameters (such as plasma unbound fraction of the anticoagulant, 
whole blood international normalized ratio [INR], anti-fXa activity, and reduction of blood loss 
in anticoagulated rodents [1, 2] and rabbits [3, 4]). 
In a more clinically relevant in vivo model of visceral bleeding caused by liver laceration refs[3-
5], andexanet was administered to rivaroxaban-anticoagulated rabbits either prophylactically or 
following tissue injury.  Intravenous bolus andexanet administration reversed rivaroxaban-
induced anticoagulation as measured by plasma anti-fXa activity (97% decrease), prothrombin 
time (PT; 77% decrease), and unbound fraction of the anticoagulant (93% decrease); these PD 
markers correlated with reduction of blood loss (76% decrease) as compared to vehicle controls. 


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Taken together, the results from these two different pre-clinical bleeding models demonstrate a 
strong correlation between reversal of anti-fXa activity, decrease in free fraction of 
anticoagulant, and decrease in blood loss.  These data support the hypothesis that andexanet 
rapidly binds and sequesters the FXa inhibitor, thus reversing the anticoagulant effect of FXa 
inhibition and allowing for the return of thrombin generation, which mediates restoration 
of normal hemostatic mechanisms. 
Additional information about these experiments can be found in the andexanet Investigator’s 
Brochure. 
1.3.2. 
Nonclinical Toxicology and Safety 
Good Laboratory Practice (GLP) toxicology studies have been conducted in both the rat and 
cynomolgus monkey.  Andexanet was evaluated in two 14-day repeat dose toxicology studies, 
one each in the rat and monkey.  Both toxicology studies performed administered andexanet 
twice daily (BID) as a maximal feasible dose (60 mg/kg/day), either daily for 14 days (rats) or 
every third day (cynomolgus monkeys), followed by a 28-day recovery period.  There were no 
test article-related adverse effects in either study.  In the more relevant species, cynomolgus 
monkeys, the animals were administered andexanet in the presence and absence of an FXa 
inhibitor (rivaroxaban, apixaban, betrixaban, or enoxaparin).  The only significant finding in the 
14-day repeat bolus IV study was a male monkey, dosed 60 mg/kg/day with andexanet that on 
Day 13 of the study (last dose) experienced anaphylaxis immediately after dosing.  This animal 
recovered with administration of antihistamines and epinephrine.  Based on the lack of adverse 
findings in both species at the highest doses tested, the No Observed Adverse Effect Level 
(NOAEL) dose in rat and cynomolgus monkeys is 60 mg/kg/day. 
As might be expected after repeated dosing with a foreign protein in an animal species, all 
groups of monkeys and rats receiving andexanet developed antibodies to andexanet that persisted 
to the end of the 4-week recovery period.  Despite the presence of these antibodies, andexanet 
was still able to reverse the anticoagulant effect of FXa inhibitors from Day 1 to Day 14 in 
cynomolgus monkey studies in vitro or in vivo.  Antibody development in both rat and 
cynomolgus monkey studies did not change the toxicokinetics of andexanet from Day 1 to 
Day 14.  Russell’s Viper Venom Time (RVVT) was used to measure antibody production against 
endogenous FX or FXa and no changes suggestive of antibodies against FX or FXa were seen in 
RVVT measurements in monkeys administered andexanet. 
There were no adverse findings in the male rat central nervous system and respiratory safety 
pharmacology studies up to, and including, the maximum feasible dose of 30 mg/kg when 
administered by IV bolus.  Additionally, andexanet was evaluated for cardiovascular safety as a 
component study of the 14-day repeat IV bolus study in cynomolgus monkeys and was found not 
to affect electrocardiographic or blood pressure parameters.   
Additional details from these studies can be found in the andexanet Investigator’s Brochure. 


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1.4. 
Summary of Clinical Experience with Andexanet in Healthy Subjects 
Andexanet has been studied in 211 healthy subjects in 5 completed studies.  The trials include a 
completed single ascending dose Phase 1 study (Study 11-501) in healthy subjects, as well as a 
number of studies in combination with FXa inhibitors, including a Phase 1 study comparing the 
PK and PD of andexanet in younger vs. older subjects receiving apixaban (Study 14-506), the 
Phase 2 dose-range finding Study 12-502 (apixaban, rivaroxaban, edoxaban, and enoxaparin) and 
the confirmatory Phase 3 studies in healthy older subjects (50–75 years) with apixaban 
(Study 14-503) and rivaroxaban (Study 14-504), respectively.  Summaries of these clinical 
studies are presented in the Investigator’s Brochure. 
1.4.1. 
Phase 1 Study of Andexanet Alone in Healthy Subjects 
Study 11-501 was a Phase 1 randomized, double-blind, placebo-controlled study of the safety, 
PK, and PD of andexanet in 32 healthy subjects, each of whom received one of four doses of 
andexanet (30 mg, 90 mg, 300 mg, or 600 mg) (n=24) or placebo (n=8).  The safety data from 
this study are summarized in Section 1.4.5. 
1.4.2. 
Phase 1 Study of Andexanet in Healthy Younger versus Older Subjects 
Study 14-506 was a Phase 1 non-randomized, open-label study of andexanet in healthy younger 
(18–45 years of age) subjects and healthy older (≥ 65 years of age) subjects.  Ten younger and 
10 older subjects were enrolled, with all subjects dosed to steady-state with apixaban then 
receiving a 400 mg bolus of andexanet.  In this study, the PK of andexanet and the PD effects on 
anti-fXa activity and thrombin generation in older and younger subjects were similar. 
1.4.3. 
Phase 2 Study of Andexanet with Factor Xa Inhibitors in Healthy Subjects 
Study 12-502 was a Phase 2, randomized, double-blind, placebo-controlled study of the safety, 
PK, and PD of andexanet in healthy subjects receiving one of four direct or indirect FXa 
inhibitors:  apixaban, rivaroxaban, edoxaban, or enoxaparin.  Each FXa inhibitor was examined 
in a separate study module, within which multiple dosing regimens of andexanet are given in 
cohorts of 9 healthy subjects (6 active, 3 placebo).  The anticoagulant was dosed to steady state 
over 5 to 6 days, before administration of andexanet or placebo on Study Day 6.  Healthy 
subjects were then followed through Study Day 13 in a domiciled Phase 1 study unit and, 
subsequently, through Day 48 as outpatients. 
Apixaban (Module 1) was administered at a dose of 5 mg orally (PO) twice each day for 
5.5 days, rivaroxaban (Module 2) was administered at a dose of 20 mg PO once daily (QD) for 
6 days, enoxaparin (Module 3) was administered at a dose of 40 mg subcutaneously (SQ) QD for 
6 days, and edoxaban (Module 4) was administered at dose of 60 mg PO once daily.  Andexanet 
was administered on Day 6, (typically 3 hours after the anticoagulant dose [Cmax]). 


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The total dose of andexanet across dosing cohorts ranged from 90 mg to 1,760 mg.  These 
cohorts included the evaluation of several dosing regimens:  single bolus, double bolus, and 
bolus followed by a continuous infusion. 
Andexanet exhibited dose-proportional PK for both Cmax and area under the curve (AUC) with a 
mean terminal t½ of approximately 5 hours and an effective (pharmacodynamic) t½ of 
approximately 50 to 60 minutes. 
For apixaban, rivaroxaban, edoxaban, and enoxaparin, administration of andexanet resulted in a 
dose-dependent reduction in anti-fXa activity (Figure 2).  “Baseline” was defined as the time 
immediately prior to andexanet administration, which occurred 3 hours following the last 
anticoagulant dose (the anticoagulant steady-state Cmax). 
Administration of andexanet was associated with a rapid and immediate decrease in unbound 
apixaban, rivaroxaban, and edoxaban that was dose-dependent, with the greatest effect observed 
at the highest doses tested (420 mg dose for apixaban, and 800 mg dose for rivaroxaban and 
edoxaban).  When andexanet was administered as a bolus followed by a continuous infusion, the 
decrease in unbound (free fraction) of apixaban, rivaroxaban, and edoxaban was sustained. 
Additionally, apixaban, rivaroxaban, edoxaban, and enoxaparin inhibited thrombin generation 
relative to the pre-anticoagulant baseline (Study Day 1).  These anticoagulant effects of 
apixaban, rivaroxaban, and edoxaban were reversed in a dose-dependent fashion by 
administration of andexanet.  These effects are consistent with restoration of hemostatic 
mechanisms after andexanet administration.  The safety data from this study are summarized in 
Section 1.4.5. 


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Figure 2: 
Rapid Onset and Reduction of Anti-fXa Activity (Study 12-502) 
 
A. Apixaban was administered at 5 mg orally (PO) twice a day (BID) for 5.5 days; andexanet was administered on 
Day 6 as a 420 mg IV bolus or 420 mg IV bolus + 480 mg infusion (120 minutes at 4 mg/min). 
B. Rivaroxaban was administered at 20 mg once daily (QD) for 6 days; andexanet was administered on Day 6 as 
either a 600 mg IV bolus or an 800 mg IV bolus + 960 mg infusion (120 minutes at 8 mg/min). 
C. Edoxaban was administered at 60 mg once daily (QD) for 6 days; andexanet was administered on Day 6 as either 
a 600 mg IV bolus or an 800 mg IV bolus + 480 mg infusion (60 minutes at 8 mg/min). 
D. Enoxaparin was administered at 40 mg subcutaneously (SQ) QD for 6 days; andexanet was administered on 
Day 6 as a 210 mg or 420 mg IV bolus.  Andexanet administration was timed with the approximate steady-state 
Cmax of each anticoagulant (3 hours after the last dose).  Data are shown as mean ± standard error of the mean 
(SEM). 
 
A. apixaban
B. rivaroxaban
C. edoxaban
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0
0.2
0.4
0.6
0
100
200
300
400
1
2
3
4
5
6
7
8
9
10
End of Bolus
End of Infusion
Placebo (Cohorts 1-3, n=9)
800 mg bolus + 960 mg infusion x 2 hrs (n=6)
600 mg bolus only (n=6)
Time after bolus (hr)
Anti-fXa (IU/mL)
0.0
0.2
0.4
0.6
0.0
0.1
0.2
0.3
0.4
0.5
1
2
3
4
5
6
7
8
9
10
End of bolus
Placebo (Cohorts 1-2, n=6)
210 mg bolus only (n=6)
420 mg bolus only (n=6)
Lower limit of
quantitation
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0
0.2
0.4
0.6
0
50
100
150
200
250
1
2
3
4
5
6
7
8
9
10
End of Bolus
End of Infusion
420 mg bolus only (n=6)
Placebo (Cohorts 1-3, n=9)
420 mg bolus + 480 mg infusion x 2 hr (n=6)
D. enoxaparin
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0
0.2
0.4
0.6
0
50
100
150
200
250
300
1
2
3
4
5
6
7
8
9
10
End of Bolus
End of Infusion
600 mg bolus only (n=5-6)
800 mg bolus + 480 mg infusion x 1 hr (n=6)
Placebo (Cohorts 1-2, n=5-6)


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1.4.4. 
Phase 3 Studies in Healthy Older Volunteers 
Two randomized, double-blind, placebo-controlled studies were designed to evaluate reversal of 
anticoagulation in older subjects (ages 50–75 years) anticoagulated with apixaban 
(Study 14-503) or rivaroxaban (Study 14-504).  In these studies, the anticoagulant was dosed to 
steady state over 4 days (rivaroxaban) or 3.5 days (apixaban) before administration of andexanet 
or placebo on Study Day 4.  The subjects were then followed through Study Day 8 in a 
domiciled Phase 1 study unit and, subsequently, through Day 43 as outpatients.  Andexanet was 
administered either as an IV bolus (Part 1, data available) or an IV bolus plus a continuous 
infusion for 120 minutes (Part 2).  Reversal of anticoagulation was measured using anti-fXa 
activity, anticoagulant free fraction, thrombin generation, and other coagulation markers.  A 
single IV bolus of andexanet rapidly and significantly reversed the anti-fXa activity of apixaban 
and rivaroxaban (Figure 3), reduced unbound apixaban and rivaroxaban concentrations, and 
restored normal thrombin generation.  These effects were sustained by the follow-on infusion. 


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Figure 3: 
Rapid Onset and Significant Reduction of Apixaban and Rivaroxaban 
Anti-fXa Activity in Older Healthy Subjects by Andexanet (Study 14-504) 
 
Legend:  Anti-fXa activity was measured prior to and after andexanet or placebo administration on study Day 4.  
Dashed lines indicate the end of bolus or infusion. 
A. Apixaban—with andexanet 400 mg IV bolus. 
B. Rivaroxaban—with andexanet 800 mg IV bolus. 
C. Apixaban—with andexanet 400 mg IV bolus plus 4 mg/minute infusion for 120 minutes. 
D. Rivaroxaban—with andexanet 800 mg IV bolus plus 8 mg/minute infusion for 120 minutes. 
Note:  A break in the X axis was added to better visualize the immediate, short-term dynamics of anti-fXa activity 
following andexanet treatment.  The points on the graph represent the mean anti-fXa activity level and error bars 
illustrate standard error.  There was a statistically significant difference (p < 0.05) in the percent change of anti-fXa 
activity normalized to pre-bolus between andexanet and placebo until 2 hours after administration of bolus (Part 1) 
or infusion (Part 2).  The horizontal dashed-line represents the anti-fXa activity at 30 ng/mL, the estimated non-
effective level for FXa inhibition [6]. 
 
The results from the Phase 3 studies of apixaban and rivaroxaban were very similar to results 
obtained in the Phase 2 study, demonstrating the reproducibility of andexanet’s ability to reverse 
inhibition of FXa activity.  This reproducibility of the data allowed Portola to use PK-PD 
modeling to select doses of andexanet for reversal edoxaban and enoxaparin. 
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
50
100
150
200
250
1 2 3 4 5 6 7 8 9 101112
End of Bolus
400 mg bolus (n=24)
Placebo (n=9)
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
50
100
150
200
250
1 2 3 4 5 6 7 8 9 101112
End of Bolus
Placebo (n=8)
400 mg bolus + 480 mg x 2hr infusion (n=23)
End of Infusion
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
100
200
300
400
1 2 3 4 5 6 7 8 9 101112
End of Bolus
Placebo (n=13)
800 mg bolus + 960 mg x 2hr infusion (n=26)
End of Infusion
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
100
200
300
400
1 2 3 4 5 6 7 8 9 101112
End of Bolus
Placebo (n=14)
800 mg bolus (n=27)
Apixaban
Rivaroxaban
Bolus
Bolus
Plus
Infusion
A
B
C
D


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1.4.5. 
Summary of Safety from Clinical Studies of Healthy Subjects 
Andexanet has been generally well tolerated in healthy volunteers in the Phase 1, 2, and 3 studies 
at the doses studied (i.e., total doses of 30 mg, 90 mg, 210 mg, 300 mg, 420 mg, 600 mg, 
900 mg, 960 mg, and 1,760 mg) with no apparent pattern of safety signals with the exception of 
mild-moderate infusion reactions.  A single Adverse Event (AE) (bilateral pneumonia) met 
Serious Adverse Event (SAE) criteria in the Phase 1 study.  This SAE, which was deemed by the 
Investigator as unlikely to be related to andexanet, occurred 18 days after andexanet dosing in a 
subject treated at a dose of 30 mg.  No severe or life-threatening AEs have been reported.  No 
Thrombotic Events (TEs) have been reported in either the healthy volunteer studies.  Infusion 
reactions have been mild to moderate in severity, do not appear to be dose dependent and have 
rarely required treatment (2 healthy subjects received one dose each of diphenhydramine).  With 
the exception of two healthy subjects in the Phase 1 study who received a 90 mg dose of 
andexanet, infusion reactions have not led to premature discontinuation of andexanet at doses of 
up to 1,760 mg total dose.  Therefore, to date, infusion reactions have not been dose-limiting. 
Andexanet was associated with dose-dependent increases in F1+2, TAT, and D-dimer and with 
concomitant decrease in Tissue Factor Pathway Inhibitor (TFPI) activity, all of which reversed 
quickly after discontinuation of andexanet.  These changes returned to baseline on average by 
4 days after discontinuation of andexanet.  These findings were not associated with a clinical TE 
in any subject.  Compared with administration of andexanet alone (Study 11-501), the effects on 
F1+2, TAT, D-dimer, and TFPI were attenuated (all to a similar extent) in the presence of 
apixaban, rivaroxaban, enoxaparin, and edoxaban. 
Among healthy subjects treated with andexanet, 12.1% developed low-titer non-neutralizing 
antibody to andexanet.  However, there have been no neutralizing antibodies, nor antibodies to 
native FX or FXa. 
1.4.6. 
Phase 3b Study in Patients with Acute Major Bleeding 
Study 14-505 (ANNEXA-4) is an ongoing, multi-national, prospective, open-label, single-arm 
clinical study of andexanet in patients with acute major bleeding while taking a factor Xa 
inhibitor (specifically apixaban, edoxaban, enoxaparin, and rivaroxaban).  As of 09 June 2016, 
57 patients with complete safety data had been enrolled in the study.  Baseline characteristics 
included a median age of 80 years, 51% female, 81% Caucasian, and median BMI 27.2 kg/m2.  
Twenty-six patients (46%) had gastrointestinal or urinary bleeding, 23 patients (40%) had an 
intracranial hemorrhage, and 8 patients (14%) had other types of bleeding. 
Of the 57 patients with complete safety data, 30 (53%) experienced a total of 72 treatment 
emergent AEs.  The most frequently reported AEs (occurring in ≥ 2% of subjects) by preferred 
term were deep vein thrombosis in 4 patients (7.0%); pneumonia, headache, and respiratory 
failure in 3 patients each (5.3%); and cardiogenic shock, sepsis, and pulmonary embolism in 
2 patients each (3.5%).  Two AEs (2.8%) were considered by the investigator to be possibly or 


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probably related to andexanet.  Eighteen patients (25%) experienced a total of 36 treatment 
emergent SAEs.  The most common SAEs (occurring in ≥ 2% of subjects) were cardiogenic 
shock (fatal) in 2 patients (3.5%), pulmonary embolism (severe) in 2 patients (3.5%), and 
respiratory failure (severe) in 2 patients (3.5%).  One SAE (ischemic stroke) was assessed as 
probably related to andexanet. 
There were 8 deaths (14%) in the study.  The cause of most deaths (75%; 6/8) were non-
cardiovascular and included respiratory failure in 2 patients, accident/trauma in 1 patient, 
bleeding in 1 patient, and other/non-vascular cause in 1 patient.  In addition, 7 patients (12%) 
experienced an adjudicated clinical thromboembolic event (3 deep vein thromboses, 1 acute 
myocardial infarction, 1 cerebral infarction, 1 embolic stroke, 1 ischemic stroke).  Importantly, 
of the 7 patients with a thromboembolic event, only 2 had been reanticoagulated prior to the 
event.  There were no reported re-bleeding events in the study. 
No clinically meaningful changes in laboratory values (including hematocrit and hemoglobin) 
were detected in the study.  Similarly, no changes in vital signs and/or physical exam findings 
have been observed.  Finally, 5 patients (8.8%) developed non-neutralizing antibodies to 
andexanet after 30 days of follow up.  However, as in the healthy subjects treated with 
andexanet, no neutralizing antibodies have been detected to andexanet. 
1.5. 
Rationale for Present Study 
Though andexanet has been studied extensively in clinical trials, most subjects enrolled in these 
studies have been Caucasian.  While there is no a priori reason to expect racial and/or ethnic 
differences in the efficacy, safety, and PK profiles for protein therapeutics, potential differences 
with andexanet have not been tested clinically.  The present study therefore aims to evaluate for 
such potential differences.  In this study, the efficacy of andexanet to reverse FXa inhibitor-
induced anticoagulation, and the safety of andexanet in this context, will be evaluated in 
individuals of Japanese descent.  In addition, the PK and PD of andexanet in Japanese subjects 
dosed to steady-state with apixaban will be evaluated and compared to a parallel cohort of 
Caucasian subjects dosed to steady-state with apixaban. 


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2.0 
STUDY OBJECTIVES 
The objectives of this study are to assess the following in healthy subjects dosed to steady state 
with direct oral FXa inhibitors (apixaban, rivaroxaban, and edoxaban): 
Primary Efficacy Objective 
• To compare andexanet and placebo with respect to reversal of each FXa inhibitor as 
measured by anti-fXa activity. 
Secondary Efficacy Objectives 
• To assess andexanet and placebo with respect to reversal of each FXa inhibitor as measured 
by free fraction of the inhibitor. 
• To assess andexanet and placebo with respect to reversal of each FXa inhibitor as measured 
by restoration of thrombin generation. 
• To assess the pharmacodynamics of andexanet in Japanese subjects and Caucasian 
subjects, as measured by anti-fXa activity, free fraction of the FXa inhibitor (apixaban), 
and restoration of thrombin generation. 
Safety Objective 
• To evaluate the safety of andexanet in Japanese subjects. 
Pharmacokinetics Objectives 
• To evaluate the pharmacokinetics of andexanet in Japanese subjects. 
• To compare the pharmacokinetics of andexanet in Japanese subjects to the 
pharmacokinetics of andexanet in Caucasian subjects. 
 


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3.0 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
This is a single-center, randomized, double blind, and placebo-controlled trial designed to 
evaluate the efficacy, safety, and PK-PD of andexanet in healthy Japanese subjects taking direct 
FXa inhibitors at therapeutic doses.  Reversal of anticoagulation will be evaluated by measuring 
anti-fXa activity, unbound FXa inhibitor plasma levels, and thrombin generation. 
A total of 10 cohorts of approximately 9 to 12 evaluable subjects (6–8 active, 3–4 placebo) in 
Part 1, and 9 to 15 evaluable subjects (6-10 active, 3-5 placebo) in Part 2 will be studied in two 
parts (Table 1): 
• Part 1 will evaluate the efficacy (as assessed by FXa inhibitor reversal), safety, and PK of 
andexanet in Japanese subjects, and evaluate for similarities between analogous data from 
Caucasian subjects.  
• Part 2 will evaluate andexanet reversal effect of FXa inhibitor with additional dosing 
regimens.  The dosing regimens in Part 2 were informed by the preliminary results of 
Part 1.   
 


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Table 1: 
Cohort Details  
Part 1 Cohorts 
Cohort 
FXa Inhibitor 
Andexanet 
N (Active/Placebo) 
1 
Apixaban 
5 mg BID 
400 mg bolus + 4 mg/min 120 min infusion/placebo 
(andexanet dosing at 3 hours post-apixaban) 
Japanese 9 (6/3) 
2 
Rivaroxaban 
15 mg BID 
800 mg bolus + 8 mg/min 120 min infusion/placebo 
(andexanet dosing at 4 hours post-rivaroxaban) 
Japanese 9 (6/3) 
3 
Edoxaban 
60 mg QD 
800 mg bolus + 8 mg/min 120 min infusion/placebo 
(andexanet dosing at 3 hours post-edoxaban) 
Japanese 12 (8/4) 
4 
Edoxaban 
60 mg QD 
800 mg bolus + 8 mg/min 120 min infusion/placebo 
(andexanet dosing at 90 minutes post-edoxaban) 
Japanese 12 (8/4) 
5 
Apixaban 
5 mg BID 
400 mg bolus + 4 mg/min 120 min infusion/placebo 
(andexanet dosing at 3 hours post-apixaban) 
Caucasian 9 (6/3) 
Part 2 Cohorts 
6 
Apixaban 
10 mg BID 
800 mg bolus + 8 mg/min 120 min infusion/placebo 
 (andexanet dosing at 3 hours post apixaban) 
Japanese 9 (6/3) 
7 
Edoxaban 
30 mg QD 
400 mg bolus + 4 mg/min 120 min infusion/placebo 
 (andexanet dosing at 90 min post edoxaban) 
Japanese 12 (8/4) 
8 
Apixaban 
10 mg BID 
400 mg bolus + 4 mg/min 120 min infusion/placebo 
 (andexanet dosing at 8 hours post apixaban) 
Japanese 9 (6/3) 
9 
Rivaroxaban 
15 mg BID 
400 mg bolus + 4 mg/min 120 min infusion/placebo 
 (andexanet dosing at 8 hours post rivaroxaban) 
Japanese 15 (10/5) 
10 
Edoxaban 
60 mg QD 
400 mg bolus + 4 mg/min 120 min infusion/placebo 
 (andexanet dosing at 8 hours post edoxaban) 
Japanese 12 (8/4) 
BID = Twice a day; FXa = Factor Xa; QD = Once daily 
 
Following screening, study subjects will be randomized and domiciled at the study site for 
~10 days, during which time they will be administered apixaban 5 or 10 mg PO BID, 
rivaroxaban 15 mg PO BID, or edoxaban 30 or 60 mg PO QD (depending on cohort; see above) 
on Days 1 to 6.  Andexanet or matching placebo bolus and continuous infusion doses will be 
administered on Day 6, at various times after the last administration of FXa inhibitor.  Study 
subjects will be discharged from the clinical site on Day 10 and followed for safety through 
Day 36 (+3). 
The primary endpoint is the difference in the percent change from baseline anti-fXa activity 
between andexanet- and placebo-treated subjects in each cohort.  That is, i.e., the percent change 
from baseline (where baseline is the time point immediately prior to the administration of 
andexanet) in anti-fXa activity to its nadir.  The nadir is defined as the smallest value for 
anti-fXa activity between the 110-minute time point (10 minutes prior to the end of the 
continuous andexanet infusion) and the 5-minute time point after the end of the continuous 
infusion (inclusive). 


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For all cohorts, subjects will be randomized at a 2:1 ratio to treatment with andexanet or placebo, 
respectively.  If enrolled subjects discontinue early from the study or have missing data for any 
reason, the Sponsor may elect to add up to 3 additional subjects (with newly blinded treatment 
assignments) within the discontinued subject’s assigned cohort. 
To compare the PK-PD of andexanet between Japanese and Caucasian subjects, the results of 
Cohorts 1 (Japanese only) and 5 (Caucasian only) will be evaluated in context with each other. 
The number of subjects expected to enroll in this study is approximately 108 evaluable subjects 
across all 10 cohorts.  The Sponsor may also elect to end enrollment early if, for example, an 
acceptable number of evaluable subjects is achieved.  Each subject will participate in only one 
andexanet dosing regimen and will be domiciled for 10 days, during which time they will be 
dosed to steady state (up to 6 days) on the anticoagulant and then followed for 3 days after 
receiving andexanet.  Blood and urine samples will be obtained according to a pre-determined 
schedule.  Regular clinical examinations will be conducted throughout the study. 
3.2. 
Blinding and Randomization 
3.2.1. 
Randomization 
In all cohorts, subjects will be randomized in a 2:1 ratio to receive andexanet or placebo, 
respectively, using permuted blocks.  The randomization code will be generated and maintained 
by a Contract Research Organization (CRO).  Subjects will be randomized on Day 1, at which 
time the unblinded research pharmacist or designee will obtain the subject’s treatment 
assignment.  If subjects are added to a given cohort in the event of an early study discontinuation 
or missing data, they will be newly randomized by the procedure described above (as opposed to 
being given the same treatment assignment as the discontinued subject). 
3.2.2. 
Blinding 
Within each cohort, each FXa inhibitor will be administered to all subjects and therefore no 
blinding is required for the FXa inhibitor.  Andexanet or its placebo will be administered to 
subjects in a double-blind fashion using a randomization schedule provided by the CRO.  The 
unblinded dispensing pharmacist or designated qualified individual may unblind a subject in an 
emergency or at the request of the PI or Medical Monitor to determine if the subject received 
active drug.  In that event, the Sponsor’s Medical Monitor must be immediately notified.  A 
subsequent written report, including all pertinent details, must be submitted to the Sponsor’s 
Medical Monitor. 
3.2.3. 
Unblinding 
The blind is to be strictly maintained.  However, in the event of a medical emergency for which 
the treatment assignment needs to be known in order to manage the subject, the blind may be 
broken by the Investigator or qualified designee.  The Investigator must make every effort to 
contact the Sponsor’s Medical Monitor prior to unblinding a subject, unless the emergent nature 


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of the situation precludes this communication.  The Investigator must notify the Medical Monitor 
as soon as possible if the blind is broken for any reason.  A subsequent written report, including 
all pertinent details, must be submitted to the Medical Monitor. 
3.3. 
Duration of Study 
For each individual subject, the study duration will be approximately 6–12 weeks, depending on 
the length of Screening.  The study periods are as follows: 
• Screening:  Days -45 to -1 
• Anticoagulant Dosing:  Days 1 to 6 
• Andexanet Dosing:  Day 6 
• Safety Follow-Up:  Days 7 to 36 (+3) 
 
Study subjects will be domiciled from Day -1 to Day 10, and then discharged from the inpatient 
facility on Day 10 to continue outpatient follow-up through Day 36 (+3). 
3.4. 
Factor Xa Inhibitor and Andexanet Dosing Considerations 
The doses of FXa inhibitors used in the study are currently approved doses used in most patients.  
As such, these doses are not expected to pose any significant safety risk to a healthy subject 
population.  Additionally, andexanet doses of up to an 800 mg bolus and 960 mg infusion over 
120 minutes have been studied previously in healthy subjects and were well tolerated.  
Importantly, FXa inhibitors and andexanet have been used concurrently at the doses used in the 
study in prior studies of healthy volunteers (12-502, 14-503, 14-504); no safety concerns have 
arisen during the conduct of these studies. 
3.5. 
Safety Plan and Monitoring 
While this type of study is typically designed as a 2-period crossover trial, a parallel group 
design is used in this case in order to minimize the risk of antigenicity in healthy subjects.  
Furthermore, to monitor for immunogenicity, blood specimens will be serially evaluated at each 
outpatient follow-up visit (Days 20 and 36) for antibodies against andexanet and against FX and 
FXa.  Samples that are positive for antibodies to andexanet will be further assayed for the ability 
to neutralize the activity of andexanet.  Samples at specific time points will be tested for 
potential neutralizing antibody activity against FX or FXa using a modified Bethesda assay. 
Subjects will be monitored while domiciled in the clinical site for the entire period that they are 
anticoagulated with FXa inhibitors and for 3 days after administration of andexanet.  Although 
there have been no thromboembolic events in any healthy subjects dosed with andexanet thus 
far, some pro-thrombotic markers (D-dimer, F1+2, and TAT) increase following andexanet 
infusion, generally resolving within 4 days after treatment.  This increase is typically diminished 
when andexanet is co-administered with an FXa inhibitor, as will be the case in the present 
study.  D-dimer, F1+2, and TAT will be obtained and reviewed in the present study.  


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Furthermore, a clinical assessment of venous thromboembolism risk (via Wells scoring) will be 
performed at multiple time points during the study. 
Prior and ongoing clinical studies have identified infusion reactions of mild or moderate intensity 
as the most common adverse event related to administration of andexanet.  Although no severe 
or serious infusion reactions have occurred to date in healthy subjects receiving andexanet, 
subjects in this study will receive andexanet in an inpatient, monitored setting under medical 
supervision and immediate access to resuscitative measures.  Notably, infusion reactions 
observed in prior and ongoing studies have had their onset during the infusion itself.  Therefore, 
in addition to vital signs, oxygen saturation will be monitored during the infusion. 
To monitor for occult bleeding, stool occult blood testing will be performed on any stool samples 
produced throughout the period subjects are domiciled.  The relatively short t½ of all FXa 
inhibitors predicts a loss of anticoagulant effects within one day of the end of treatment.  
Following discharge from the clinical site, subjects will return for follow-up on Days 20 and 
36 for safety follow-up. 
Finally, safety data will be reviewed by the Sponsor on an ongoing basis. 


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4.0 
SELECTION OF SUBJECTS 
Men and women with an unremarkable medical history, physical examination, and routine 
clinical laboratory results will be selected for screening for this study. 
To be eligible for study enrollment, subjects must satisfy the following inclusion and exclusion 
criteria: 
4.1. 
Inclusion Criteria 
1. 
Must be in reasonably good health as determined by the Investigator based on medical 
history, full physical examination (including blood pressure and pulse rate 
measurement), 12-lead ECG, and clinical laboratory tests.  Subjects with 
well-controlled, chronic, stable conditions (e.g., controlled hypertension, non-insulin 
dependent diabetes, osteoarthritis, hypothyroidism) may be enrolled based on the 
clinical judgment of the Investigator. 
2. 
For all cohorts except Cohort 5, subjects must be Japanese, defined as having four ethnic 
Japanese grandparents.  Subjects may not have lived outside of Japan for more than 
10 years.  Subjects in Cohort 5 must be of Caucasian race. 
3. 
Must be between the ages of 18 and 75 years, inclusive, at the time of signing of 
the Informed Consent Form (ICF). 
4. 
Agrees to have any dietary or nutritional supplements reviewed by the Investigator and 
potentially held during the study if advised by the Investigator.  Standard multivitamin 
and mineral supplementation will be permitted. 
5. 
Agrees to comply with the contraception and reproduction restrictions of the study: 
○ Men whose sexual partner is of childbearing potential and/or who are not 
monogamous must be using two acceptable methods of contraception, at least one of 
which must be a barrier method (e.g., spermicidal gel plus condom), for the entire 
duration of the study and for at least 1 month following study-drug administration; 
and men must refrain from attempting to father a child or donating sperm in the 
1 month following the study-drug administration.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
○ Men who report surgical sterilization (e.g., bilateral vasectomy) must have had the 
procedure at least 6 months before study drug administration. 
○ Surgical sterilization procedures should be supported with clinical documentation and 
noted in the Relevant Medical History/Current Medical Conditions section of the Case 
Report Forms (CRFs). 
 Women of childbearing potential must be using two medically acceptable methods of 
contraception, at least one of which must be a barrier method (e.g., non-hormone containing 
intra-uterine device plus condom, spermicidal gel plus condom, diaphragm plus condom), 


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from the time of Screening and for the duration of the study, through at least 1 month 
following study drug administration.  NOTE:  Oral and topical hormonal contraceptive use, 
as well as the use of hormone-containing intra-uterine devices, is not permitted due to their 
increased risk of thromboembolism.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception; 
 
OR 
 Postmenopausal women must have had no regular menstrual bleeding for at least 1 year 
before initial dosing and either be over the age of 60 years or have an elevated plasma 
follicle-stimulating hormone (FSH) level (i.e., > 40 mIU/mL) at Screening; 
 
OR 
 Women who report surgical sterilization (i.e., hysterectomy, tubal ligation, and/or bilateral 
oophorectomy) must have had the procedure at least 6 months before study drug 
administration.  Surgical sterilization procedures should be supported with clinical 
documentation and noted in the Relevant Medical History/Current Medical Conditions 
section of the CRF; 
 
AND 
 All female subjects must have a documented negative pregnancy test result at Screening 
and on Study Day -1. 
 
6. 
Systolic blood pressure < 160 mmHg and diastolic blood pressure < 90 mmHg at 
Screening and Day -1. 
7. 
The following laboratory values must be within the normal laboratory reference range 
within 45 days of Day -1:  PT, aPTT, and ACT; Hemoglobin, hematocrit, and platelet 
count. 
8. 
The following laboratory values must be equal to or below 2 times the upper limit of 
normal (ULN) range within 45 days of Day -1:  Aspartate aminotransferase 
(AST)/alanine aminotransferase (ALT) and total bilirubin. 
9. 
The Screening serum creatinine must be below 1.5 mg/dL within 45 days of Day -1. 
10. Body mass index of less than 30 kg/m2, inclusive, and body weight between 50 to 80 kg, 
inclusive, at Screening.  Subjects in Cohorts 3, 4, and 10 must be at least 60 kg in weight. 
11. Agrees to abstain from alcohol consumption for the duration of the domicile period, and 
from the use of drugs of abuse for the duration of the study. 
12. Able to read and give written informed consent and has signed a consent form approved 
by the Investigator’s Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC). 
 


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4.2. 
Exclusion Criteria 
1. Previous use of andexanet or previous participation in the current study (even if the subject 
received placebo). 
2. 
History of abnormal bleeding, signs or symptoms of active bleeding, or risk factors for 
bleeding. 
3. 
Has a stool specimen that was positive for occult blood within 6 months of study 
Screening or during the Screening Period. 
4. 
 Past or current medical history of thrombosis, any sign or symptom that suggests an 
increased risk of a systemic thrombotic condition or thrombotic event, or recent events 
that may increase risk of thrombosis. 
a. For example, subjects with a known or suspected hypercoagulable state, history of 
VTE, DVT, stroke, myocardial infarction [MI], cancer [other than non-melanoma 
skin cancer], atrial fibrillation, heart failure, cardiomyopathy, phlebitis, lower 
extremity edema, major surgery or trauma within 2 months of Study Day -1, airplane 
travel with a planned flight time for any single flight segment ≥ 6 hours during the 
4 weeks prior to Study Day -1, or general immobility are excluded. 
5. 
Absolute or relative contraindication to anticoagulation or treatment with apixaban, 
rivaroxaban, and/or edoxaban. 
6. 
Prior consumption (by any route) of one or more doses of aspirin (including baby 
aspirin), salicylate or subsalicylate, other antiplatelet drugs (e.g., ticlopidine, 
clopidogrel), non-steroidal anti-inflammatory drugs, fibrinolytic, or any anticoagulant 
within 7 days prior to Day -1 or is anticipated to require such drugs during the study. 
7. 
Receipt of (by any route) hormonal contraception, post-menopausal hormone replacement 
therapy (HRT) (including over-the-counter products), or testosterone during the 4 weeks 
prior to Study Day -1 or is anticipated to require such drugs during the study. 
8. 
Family history of or risk factors for a hypercoagulable or thrombotic condition, including 
one of the following: 
a. Factor V Leiden carrier or homozygote; 
b. Protein C, S, or ATIII activity below the normal range. 
9. 
History of adult asthma or chronic obstructive pulmonary disease or current regular or 
as-needed use of inhaled medications. 
10. Active HBV, HCV, or HIV-1/2 infection. 
11. Use of any drugs that are strong dual inhibitors or inducers of CYP3A4 (apixaban and 
rivaroxaban cohorts only) and P-gp (all cohorts) within 7 days prior to Study Day -1 or 
anticipated need for such drugs during the study. 
12. Participation in an investigational drug study within 45 days of Day -1 or Day -1 is 
within 5 half-lives of the investigational compound. 


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13. Positive screen for drugs of abuse at Day -1 that is not explained by a prescription 
medication that the subject is known to be taking. 
14. A medical or surgical condition that may impair drug (anticoagulant or andexanet) 
metabolism. 
15. Allergy to any of the vehicle ingredients:  tris, arginine, sucrose, hydrochloric acid, 
mannitol, and polysorbate 80. 
16. Allergy to soy or soy products. 
17. Current breastfeeding or a positive pregnancy test at Screening or Day -1. 
18. Any condition that could interfere with, or for which the treatment might interfere with, 
the conduct of the study or interpretation of the study results, or that would in the 
opinion of the Investigator increase the risk of the subject’s participation in the study.  
This would include but is not limited to alcoholism, drug dependency or abuse, 
psychiatric disease, epilepsy, or any unexplained blackouts. 
19. The subject is not judged by the study staff to have adequate bilateral venous access. 
20. Unwillingness to adhere to the activity requirements of the study. 
 
4.3. 
Subject Replacement 
No subject will be replaced (i.e., no subjects’ data will be excluded from analysis).  If a subject 
discontinues the study early or otherwise has missing data, up to 3 additional subjects per cohort 
may be added at the discretion of the Sponsor to ensure evaluability of the study endpoints. 


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5.0 
STUDY MATERIALS AND DOSING 
5.1. 
Clinical Supplies, Formulation, and Storage 
5.1.1. 
Andexanet 
Andexanet for Injection (200 mg/vial) is supplied by Portola Pharmaceuticals, Inc. as a 
lyophilized product for reconstitution for IV injection.  The labeled storage condition is 
refrigerated (i.e., 2–8°C).  The lyophilized product needs to be reconstituted using Sterile Water 
for Injection before use.  For details on reconstituting/preparing andexanet, please refer to the 
Pharmacy Manual. 
5.1.2. 
Placebo (Vehicle Control) 
Lyophilized placebo product (100 mg/vial) with the same appearance and container closure and 
containing all ingredients in the active product except andexanet will serve as the placebo 
control. 
5.1.3. 
Apixaban 
Apixaban is an approved product in Europe, Japan, and the United States.  Apixaban (5 mg 
tablets) will be obtained by the Contract Research Organization (CRO) from commercial supply.  
Apixaban should be stored according to the instructions in the apixaban (Eliquis®) US package 
insert (Appendix D).  For additional information on the 5 mg tablets, see the apixaban US 
package insert. 
5.1.4. 
Edoxaban 
Edoxaban is an approved product in Europe, Japan, and the United States.  Edoxaban (30 and 
60 mg tablets) will be obtained by the CRO from commercial supply.  Edoxaban should be 
stored according to the instructions in the edoxaban (Savaysa®) US package insert (Appendix E).  
For additional information on the 30 and 60 mg tablets, see the edoxaban US package insert. 
5.1.5. 
Rivaroxaban 
Rivaroxaban is an approved product in Europe, Japan, and the United States.  Rivaroxaban 
(15 mg tablets) will be obtained by the CRO from commercial supply.  Rivaroxaban should be 
stored according to the instructions in the rivaroxaban (Xarelto®) package insert (Appendix F).  
For additional information on the 15 mg tablets, see the rivaroxaban US package insert. 
5.2. 
Dispensing of Study Medication (Factor Xa Inhibitors and Andexanet) 
The dispensing pharmacist or designated qualified individual will write the date dispensed, dose 
dispensed, and the subject’s identification number or initials on the Drug Accountability Source 
Documents.  All used medication supplies and/or partially used drug supplies will be destroyed 
at the site in accordance with approved written site procedures, or returned to the Sponsor only 
after written authorization is obtained from the Sponsor.  The Investigator will maintain a record 


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of the amount and dates when unused supplies were either destroyed or returned to the Sponsor.  
All records will be retained as noted in Section 10.11. 
5.3. 
Factor Xa Inhibitor Dosing 
All FXa inhibitors will be administered open label.  FXa inhibitors will be administered for 
6 days, and according to the following dosing schedule: 
• Cohorts 1, 5, 6, and 8 (apixaban):  5 mg or 10 mg orally, every 12 hours, fasted; last dose 
morning of Day 6 
• Cohorts 2 and 9 (rivaroxaban):  15 mg orally, every 12 hours, with food; last dose 
morning of Day 6 
• Cohorts 3, 4, 7, and 10 (edoxaban):  30 mg or 60 mg orally, once daily, in the morning, 
fasted; last dose morning of Day 6 
 
5.3.1. 
Factor Xa Inhibitor Dosing—Fed/Fasting Conditions 
For Cohorts 1, 5, 6, and 8 (apixaban) subjects will fast (i.e., nothing by mouth except water) for 
at least 8 hours before and 2 hours after the AM dose of apixaban.  A standard breakfast will be 
served ~2 hours after the morning apixaban dose.  A standard lunch will be served ~4 hours after 
the AM dose.  A standard dinner will be served ~8 hours after the morning dose and a standard 
light snack may be served ~1 hour after the PM dose of apixaban.  Subjects are required to fast 
for at least 3 hours prior to the PM dose of apixaban.  On the day of andexanet dosing, the timing 
of lunch may be moved to after the infusion for cohorts with an extended continuous infusion. 
For Cohorts 2 and 9 (rivaroxaban), subjects will be administered rivaroxaban in the fed state, 
using a meal calendar that is the same for all subjects within the cohort. 
For Cohorts 3, 4, 7, and 10 (edoxaban), subjects will fast (i.e., nothing by mouth except water) 
for at least 8 hours before and 2 hours after the dose of edoxaban.  A standard breakfast will be 
served ~2 hours after the edoxaban dose.  A standard lunch will be served ~4 hours after the 
dose.  A standard dinner will be served ~8 hours after the dose of edoxaban.  On the day of 
andexanet dosing, the timing of lunch may be moved to after the infusion for cohorts with an 
extended continuous infusion. 
All FXa inhibitors will be administered with 240 mL of water. 
5.4. 
Andexanet Dosing 
Table 2 outlines the dosing specifications for each cohort. 


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In Cohorts 1, 5, 7, 8, 9, and 10, andexanet 400 mg or its placebo equivalent will be administered 
as a slow IV bolus at a target rate of approximately 30 mg/min starting 3 hours or 8 hours after 
the last dose of FXa inhibitor, followed by a continuous infusion at a rate of approximately 
4 mg/min for 120 minutes (480 mg). 
In Cohorts 2, 3, 4, and 6, andexanet 800 mg or its placebo will be administered as a slow IV 
bolus at a target rate of approximately 30 mg/min starting 1.5, 3, or 4 hours after the last dose of 
FXa inhibitor, followed by a continuous infusion at a rate of approximately 8 mg/min for 
120 minutes (960 mg). 
Table 2: 
Dosing Specifications by Test Product and Cohort 
Cohort 
Test Product 
Dose/Mode of Administration 
1, 5, 7, 8, 9, 10 
Andexanet 200 mg vial 
400 mg bolus + 4 mg/min 
120 minute infusion IV 
2, 3, 4, 6 
Andexanet 200 mg vial 
800 mg bolus + 8 mg/min 
120 minute infusion IV 
 
Reference Therapy 
 
All 
Reference therapy 
Placebo 100 mg vial 
Placebo 400 or 800 mg bolus, 
+ 4 or 8 mg/min 
120 minute infusion IV 
IV = Intravenous 
 
5.5. 
Dietary Restrictions 
No alcohol may be consumed 48 hours prior to dosing and during the in-house period.  Meals 
will be identical for all subjects and will be provided at the same time relative to dosing each day 
during the treatment period and per clinic protocol.  Identical meals will be served on respective 
days of each treatment period.  Smoking must be restricted to < 4 cigarettes/day (or equivalent). 
5.6. 
Concomitant Medications 
The use of any prescription, over-the-counter, or herbal medication (including oral 
contraceptives) during study conduct, especially during the domiciled portion of the study, is 
prohibited.  Acetaminophen may be used at a maximum dose of 2 g/day at the discretion of the 
Investigator, however.  If it is medically necessary to initiate any concomitant medications 
during the course of the study, they will be recorded on the appropriate CRF and the Sponsor’s 
Medical Monitor must be notified within 24 hours of initiation.  The eligibility of any subject 
who receives a concomitant medication other than acetaminophen to continue in the study will 
be determined.  All medications taken within 30 days of the study entry will be recorded on the 
appropriate CRF. 


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6.0 
ENROLLMENT AND STUDY PROCEDURES 
Subjects will be considered enrolled into the study once they have signed the ICF and satisfied 
all inclusion and exclusion criteria.  At this time, subjects will be assigned a subject 
identification number.  The study duration for any individual subject will be up to 65 days, 
including a screening period of up to 45 days, an in-house stay at the clinical site of 10 days and 
a follow-up period of up to 27 days after discharge.  A detailed description of the subject visits 
and clinical evaluations can be found in Appendix B:  Schedule of Activities (Part 1) and 
Appendix B:  Schedule of Activities (Part 2). 
At time points when phlebotomy coincides with vital sign determinations and other activities, 
priority should be given to obtaining the PK sample as precisely at the due time as possible.  All 
vital signs will be collected in the sitting position (after 5 minutes).  In addition to fecal occult 
blood testing at Day -1, stool will be tested daily (if produced) during the domiciled portion for 
fecal occult blood. 
With respect to intravenous access there are several important considerations: 
1. 
A peripheral IV line may be used for PK sampling, however, this line should be in the 
opposite arm. 
2. 
If obtaining PK specimens through a peripheral IV line, it should be through a dedicated 
IV line.  That is, PK samples should not be drawn from IVs used to administer study 
drug. 
 
In accordance with good clinical practice, any AEs or clinically significant abnormal laboratory 
results will be followed until resolved or stabilized. 
6.1. 
Screening Visit Procedures (Days -45 to -2) 
This visit to the study facility will take place within 45 days of the first dosing day, and may be 
performed on more than one day. 
• Obtain written informed consent. 
• Review inclusion/exclusion criteria. 
• Obtain, review, and record medical history. 
• Record medication history over last 30 days (including prescription drugs, over-the-
counter medications, supplements, and herbal products). 
• Obtain height, weight, and vital signs:  blood pressure (BP), respiratory rate (RR), heart 
rate (HR), and temperature (sitting) (see Section 7.5.1). 
• Obtain a 12-lead ECG (record electronically) and record the Investigator’s reading 
(See Section 7.5.5). 


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• Collect local laboratory samples and urinalysis (see Appendix B, Appendix B and 
Section 7.2.2, Section 7.5.7, and Section 7.5.8); Local laboratory samples must be drawn 
within 45 days of Day -1. 
• Confirm negative serum pregnancy test for women and verify FSH is in the 
postmenopausal range, if applicable (see Section 7.2.3). 
• Test stool samples submitted by subject for occult blood (see Section 7.5.6). 
• Instruct subjects regarding the alcohol restrictions and contraception requirements. 
• Instruct subjects on dietary restrictions related to fecal occult blood testing, and provide 
them with 3 stool testing cards to return at any time during the Screening period or 
Day -1.  Only 1 stool specimen submitted for fecal occult blood testing is required prior to 
Day 1; the 3 testing cards are provided for convenience purposes. 
• Assess clinical thromboembolic risk. 
• If screened over multiple visits, record AEs since most recent visit, starting with the 
second visit. 
 
6.2. 
Rescreening Procedures 
A subject may be rescreened on a case-by-case basis, provided that they fulfill all eligibility 
criteria at the time of rescreening, with the prior written approval of the Investigator and the 
Medical Monitor.  If a subject is rescreened, the following procedures should be 
performed/repeated during the Rescreening Visit: 
• Review inclusion/exclusion criteria. 
• Review medical history and record changes since prior Screening Visit. 
• Record medication history and record changes since prior Screening Visit. 
• Perform physical examination. 
• Obtain height, weight, and vital signs:  Blood Pressure (BP), Respiratory Rate (RR), Heart 
Rate (HR), and temperature (sitting) (see Section 7.5.1). 
• Obtain a 12-lead ECG (record electronically) and record the Investigator’s reading (see 
Section 7.5.5). 
• Collect local laboratory samples and urinalysis (see Appendix B, Appendix B and 
Section 7.2.3, Section 7.5.7, and Section 7.5.8); local laboratory samples must be drawn 
within 28 days of Day -1.  Hepatitis B and C, HIV 1 and 2, Factor V Leiden, Protein C 
and S, and antithrombin III testing does not need to be repeated. 
• Test stool samples submitted by the subject for occult blood (see Section 7.5.6). 
• Instruct subjects regarding the alcohol restrictions and contraception requirements. 


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• Instruct subjects on dietary restrictions related to fecal occult blood testing, and provide 
then with 3 stool testing cards to return at any time during the Screening period or Day -1.  
Only 1 stool specimen submitted for fecal occult blood testing is required prior to Day 1; 
the 3 testing cards are provided for convenience purposes. 
• Assess clinical thromboembolic risk. 
• If screened over multiple visits, record AEs since most recent screening visit, starting with 
the second visit. 
 
6.3. 
Day -1 (Admission Day) Procedures 
• Admit the subject to the inpatient facility. 
• Review eligibility requirements, including any changes. 
• Perform a physical examination (see Section 7.5.2) and clinical VTE screening 
(see Section 7.5.3). 
• Obtain vital signs (BP, HR, RR, and temperature) (sitting). 
• Collect local and central laboratory samples and urinalysis (see Appendix B, 
Appendix B). 
• Confirm negative drugs of abuse/breathalyzer screen (see Section 7.2.1 Section 7.2.2). 
• Confirm negative serum pregnancy test for women. 
• Record concomitant medications. 
• Test stool samples submitted by subject for occult blood (if not already completed at 
Screening). 
• Assess clinical thromboembolic risk. 
• Serve standardized meals at fixed times (see Section 5.5). 
• Record AEs that occurred since most recent screening visit. 
 
6.4. 
Factor Xa Inhibitor Dosing Period (Days 1–5) 
6.4.1. 
Day 1 
Prior to the morning dose of FXa inhibitor: 
• Obtain vital signs within 90 minutes before FXa inhibitor administration. 
• Collect central laboratory samples within 90 minutes before FXa inhibitor administration 
(see Appendix B, Appendix B). 
• Test stool samples submitted by subject for occult blood (if produced). 
• Once the above procedures are completed, administer the morning dose of FXa inhibitor. 


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• For apixaban and rivaroxaban cohorts, administer the evening dose of apixaban and 
rivaroxaban approximately 12 hours after the morning dose. 
• Standardized meals are to be served at fixed times in relation to FXa inhibitor dosing; 
please note that these times may occur before or after dosing, depending on the identity of 
the inhibitor. 
• Concomitant medications and AEs should be recorded periodically throughout the day. 
 
6.4.2. 
Days 2 to 4 
• Obtain vital signs within 90 minutes before FXa inhibitor administration. 
• Collect F1+2, TAT, D-dimer, and TFPI activity samples within 5 minutes before FXa 
inhibitor administration (see Appendix B, Appendix B).  TFPI (total and free antigen) 
collected in Part 1 only. 
• Test stool samples submitted by subject for occult blood (if produced). 
• Administer the morning dose of FXa inhibitor. 
• For apixaban and rivaroxaban cohorts, administer the evening dose of apixaban and 
rivaroxaban approximately 12 hours after the morning dose. 
• Standardized meals are to be served at fixed times in relation to FXa inhibitor dosing; 
please note that these times may occur before or after dosing, depending on the identity of 
the inhibitor. 
• Record concomitant medications and AEs. 
 
6.4.3. 
Day 5 
Procedures that Occur Throughout the Day 
• Test stool samples submitted by subject for occult blood 
• Record concomitant medications and AEs. 
 
Prior to the Morning Dose of FXa Inhibitor 
• Vital signs should be recorded within 90 minutes before FXa inhibitor administration. 
• Obtain a 12-lead ECG and record the Investigator’s reading.   
• Collect local and central laboratory blood and urine samples at various times after dosing 
as delineated in Appendix B, Appendix B. 
• Establish IV access into a peripheral vein at least 90 minutes prior to the FXa inhibitor 
dose (see Pharmacy Manual for further instructions) 
 


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Following the above, the FXa inhibitor should be administered.  After the dose, the following 
should be performed (see Appendix B, Appendix B): 
• Collect local and central laboratory and PK blood samples at various times after dosing as 
delineated in Appendix B, Appendix B. 
• Administer second dose of FXa inhibitor as appropriate (See Appendix B, Appendix B). 
 
Standardized meals are to be served at fixed times in relation to FXa inhibitor dosing; please note 
that these times may occur before or after dosing, depending on the identity of the inhibitor 
(see Section 5.5). 
6.5. 
Andexanet/Placebo Dosing Day (Day 6) 
Procedures that Occur Throughout the Day 
• Test stool samples submitted by subject for occult blood (if produced). 
• Record concomitant medications and AEs. 
 
Prior to the Dose of FXa Inhibitor 
• Perform physical examination. 
• Vital signs should be recorded within 90 minutes before FXa inhibitor administration. 
• Perform pulse oximetry (see Section 7.5.4). 
○ Obtain 12-lead ECG (record electronically) and record Investigator’s reading. 
○ Collect local and central laboratory samples and urinalysis (see Appendix B, 
Appendix B). 
○ Establish IV access into a peripheral vein at least 90 minutes prior to the andexanet 
dose (see Pharmacy Manual for further instructions). 
○ Serve standardized meals at fixed times as appropriate. 
 
Administer the (Final) Dose of FXa Inhibitor 
Depending on the cohort, andexanet dosing (and all downstream assessments) will start at 
various times after the final dose of FXa inhibitor.  For Cohorts 1, 3, 5, and 6, andexanet will be 
administered beginning 3 hours after the final anticoagulant dose.  For Cohort 2, andexanet will 
be administered beginning 4 hours after the final dose of rivaroxaban.  For Cohorts 4 and 7, 
andexanet will be administered starting 90 minutes after the last dose of edoxaban.  For Cohorts 
8, 9, and 10, andexanet will be given 8 hours after the last dose of FXa inhibitor. 


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After the (Final) Dose of FXa Inhibitor, Prior to the Start of Andexanet 
• Obtain vital signs and pulse oximetry immediately prior to the start of andexanet. 
• Collect local and central laboratory samples as delineated in Appendix B, Appendix B 
after administering the FXa inhibitor. 
 
Administer Andexanet/Placebo Bolus 
• Bolus is to start 3 hours after administering FXa inhibitor for Cohorts 1, 3, 5, and 6. 
• Bolus is to start 4 hours after administering rivaroxaban for Cohort 2. 
• Bolus is to start 1.5 hours after administering edoxaban in Cohorts 4 and 7. 
• Bolus is to start 8 hours after administering FXa inhibitor for Cohorts 8 to 10. 
 
During Andexanet/Placebo Bolus 
• Obtain vital signs and pulse oximetry at 3 minutes and 10 minutes after the start of 
andexanet/placebo bolus. 
 
After Andexanet/Placebo Bolus 
• Start andexanet/placebo infusion immediately after andexanet bolus is completed. 
• Obtain vital signs and pulse oximetry 2 and 5 minutes after the bolus is completed. 
• Collect local and central laboratory samples 2 and 5 minutes after the bolus is completed. 
• Obtain 12-lead ECG (record electronically) and record investigator’s assessment 
5 minutes after the bolus is completed. 
 
Forty-Five Minutes into the Continuous Infusion 
• Obtain vital signs and pulse oximetry. 
• Collect local and central laboratory samples (see Appendix B, Appendix B). 
 
Ninety Minutes into the Continuous Infusion 
• Collect central laboratory samples (see Appendix B, Appendix B). 
 
One Hundred Ten Minutes into the Continuous Infusion 
• Collect central laboratory samples (see Appendix B, Appendix B). 
 


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Two Minutes Prior to the End of the Continuous Infusion 
• Collect central laboratory samples (see Appendix B, Appendix B). 
 
After the Continuous Infusion 
• Obtain vital signs and pulse oximetry at 5 minutes after the end of the continuous 
infusion. 
• Obtain 12-lead ECG (record electronically) 5 minutes after the end of the continuous 
infusion and record Investigator’s assessment. 
• Collect local and central laboratory samples at the following times after the end of the 
continuous infusion:  5, 30, 60, 90, 120, 150, 180, 210, 270, 330, 390, 450, 510, and 
870 minutes (see Appendix B, Appendix B).  For Cohorts 8-10, no laboratory samples 
should be drawn at the 870 minute time point. 
• Perform clinical VTE screening 180 minutes (± 30 minutes) after the end of the 
continuous infusion. 
 
6.6. 
Inpatient Post-Treatment Follow Up (Days 7–10) 
6.6.1. 
Day 7 
The following procedures should be performed approximately 24 hours after the last dose of the 
FXa inhibitor on Day 6: 
• Perform physical exam and clinical VTE screening. 
• Obtain vital signs. 
• Obtain 12-lead ECG (record electronically) and record Investigator’s assessment. 
• Test stool samples submitted by subject for occult blood (if produced). 
• Collect local and central laboratory samples and urinalysis (see Appendix B, 
Appendix B). 
• Record concomitant medications and AEs. 
 
6.6.2. 
Days 8 to 9 
• Obtain vital signs. 
• Test stool samples submitted by subject for occult blood (if produced). 
• Collect local and central laboratory samples (see Appendix B, Appendix B). 
• Record concomitant medications and AEs. 
 


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6.6.3. 
Day 10 
• Perform physical examination and clinical VTE screen. 
• Obtain vital signs. 
• Obtain 12-lead ECG (record electronically) and record Investigator’s assessment. 
• Collect local and central laboratory samples and urinalysis (see Appendix B, 
Appendix B). 
• Obtain serum pregnancy test in women. 
• Test stool samples submitted by subject for occult blood (if produced). 
• Record concomitant medications and AEs. 
• Instruct subjects regarding the contraception requirements. 
• Instruct subjects to contact the study site to report any AEs and new concomitant 
medications. 
• Instruct subjects to return for the Day 20 outpatient visit. 
• Discharge subjects from the study facility. 
 
6.7. 
Outpatient Post-Treatment Follow Up (Days 11–36) 
6.7.1. 
Day 20 (+3) Outpatient Visits 
The following procedures should be performed at the Day 20 Outpatient Visit: 
• Perform VTE screen. 
• Record vital signs. 
• Record AEs since last study visit. 
• Record concomitant medication use since last study visit. 
• Collect central laboratory samples (see Appendix B, Appendix B). 
• Instruct subjects to contact the study site to report any AEs and new concomitant 
medications. 
• Instruct subjects to return for the Day 36 outpatient visit. 
 
6.7.2. 
Day 36 (+3) Outpatient Termination Visit 
• Perform physical examination and VTE screen. 
• Record vital signs. 
• Obtain 12-lead ECG (record electronically) and record Investigator’s assessment. 
• Record AEs since last study visit. 


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• Record concomitant medication use since last study visit. 
• Collect local and central laboratory samples and urinalysis (see Appendix B, 
Appendix B). 
• Obtain a serum pregnancy test in women. 
• Confirm negative drugs of abuse/breathalyzer screen. 
• Discharge the patient from the study. 
 
6.8. 
Unscheduled Visit 
Additional clinical visits may be scheduled at the Investigators’ discretion in order to follow or 
evaluate AEs.  The reason for a given unscheduled visit will be recorded. 
The following must be performed at an unscheduled visit: 
• Record the reason for the unscheduled visit. 
• Perform physical examination and VTE screen. 
• Record vital signs. 
• Record AEs since last study visit. 
• Record concomitant medication use since last study visit. 
 
The following may be performed at an unscheduled visit as deemed necessary by the 
Investigator: 
• Collect local and/or central laboratory samples. 
• Obtain 12-lead ECG and record Investigator’s assessment. 
 
6.9. 
Early Termination Visit 
Should Early Termination be required, every effort should be made to have the subject return to 
the clinical site for an Early Termination Visit.  The following procedures should be performed 
at the Early Termination Visit: 
• Record the reason for early termination. 
• Perform physical examination and VTE screening. 
• Record vital signs. 
• Obtain 12-lead ECG (record electronically) and record Investigator’s assessment. 
• Record AEs since last study visit. 
• Record concomitant medication use since last study visit. 


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• Collect local laboratory samples for hematology and serum chemistry.   Coagulation tests 
(PT, aPTT, and ACT) collected in Part 1 only. 
• Collect central laboratory samples for anti-fXa activity, FXa inhibitor PK, thrombin 
generation, D-dimer, F1+2, anti-fX, -fXa, and –andexanet antibodies, and additional 
plasma sample if the Early Termination Visit occurs after andexanet has been 
administered. 
• Perform any additional needed evaluation for AEs as determined by the Investigator. 
• Collect serum pregnancy test. 
 
6.10. 
Non-Contact Daily Exercise 
While domiciled, subjects are encouraged to engage in regular, low level, non-contact exercise 
(e.g., walking laps within the research unit) to minimize the risk of thrombosis from inactivity.  
Because subjects will be anticoagulated some of this time, however, it is imperative no vigorous, 
contact sports are initiated as they may increase the risk of bleeding. 
6.11. 
Early Discontinuation from Study 
Subject discontinuation of study drug and/or the study will occur: 
• If, in the opinion of the Investigator or Medical Monitor the subject cannot safely perform 
the procedures required by the protocol. 
• If the subject has an AE that is unacceptable to the subject, Investigator or Medical 
Monitor. 
• If there is a need for concomitant medication which makes the subject ineligible for 
further participation in the study. 
• If the Investigator or Medical Monitor decides it is in the subject’s best interest. 
• If the subject decides to withdraw for whatever reason. 
• If the subject is involved in a significant protocol deviation. 
 
Subjects are free to withdraw from the study at any time for any reason, however, to the extent 
possible, all subjects should continue to participate in the study once they have enrolled, even if 
they discontinue study drug(s) early.  Reasons for all withdrawals/discontinuation of study 
medications will be recorded and the Medical Monitor should be informed of all such cases as 
they occur.  If a subject discontinues the study drug due to an AE, that AE must be evaluated for 
its reportability as an SAE.  All SAEs must be reported to the Sponsor within 24 hours by the 
Investigator.  The procedures described under the Study Termination/Day 40 Visit will be 
performed, if possible. 
Normal study termination is defined as the completion of all procedures listed under 
Study Methods. 


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7.0 
CLINICAL ASSESSMENTS 
7.1. 
Blood Collection 
Up to approximately 815 mL in Part 1 and 709 mL in Part 2 of blood will be drawn from each 
subject over the 6 to 10 week course of the study.  Approximately 650 mL in Part 1 and 555 mL 
in Part 2 of blood (comparable to the amount of blood drawn over ~10 minutes during a single 
Red Cross blood donation—480 mL) will be drawn over the 10 day domiciled period of the 
study, and the remaining amount of blood will be drawn during Screening (~31 mL) or the 
~5 week post-discharge follow up period (~134 mL in Part 1 and ~123 mL in Part 2). 
7.2. 
Screening/Eligibility Assessments 
7.2.1. 
Urine Drugs of Abuse Screen 
The following panel will be obtained on Day -1 and the Termination Visit (Day 36 +3) to ensure 
study subjects are not using drugs of abuse:  amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, ethanol, and opiates. 
7.2.2. 
Breathalyzer Ethanol Screen 
To evaluate for the recent ingestion of ethanol, a breathalyzer test will be performed on 
Day -1 and the Termination Visit (Day 36 +3). 
7.2.3. 
Blood Laboratory Testing 
Blood will be obtained to measure several parameters for the purposes of screening and 
assessment of eligibility.  All test samples will be analyzed by a laboratory at the discretion of 
the study center.  Specifically, these will include the following: 
• Screening for asymptomatic pro-thrombotic, hypercoagulable conditions by testing for 
Factor V Leiden, Protein S, Protein C, and Anti-Thrombin III at the Screening Visit. 
• Hepatitis B surface antigen at the Screening Visit. 
• Hepatitis C antibody at the Screening Visit. 
• HIV-1 and HIV-2 antibodies at the Screening Visit. 
• Blood will be obtained at Screening, Day -1, Day 10, and Termination Visit (Day 36 +3) 
from all female subjects to determine their pregnancy status (serum pregnancy test and/or 
FSH as appropriate). 
 


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7.3. 
Efficacy Assessments 
7.3.1. 
Coagulation Assays 
Blood will be obtained to determine the effects of andexanet on various components of the 
human coagulation system, as a marker of both safety and PD activity, at various time points 
throughout the study.  Specifically, these will include the following: 
Part 1 
• Anti-fXa activity and thrombin generation will be measured using plasma samples 
collected at the site to assess the ability of observed andexanet blood levels to reverse the 
anticoagulant effect of apixaban, edoxaban, and rivaroxaban.   
• PT, aPTT, and ACT, all of which will be measured/analyzed locally at the study site. 
• FX, F1+2, TAT, D-dimer (fibrin degradation fragment), fibrinogen, TFPI [total and free 
antigen], TFPI activity), Russell’s Viper Venom Time (RVVT), TAFI, tPA, b-TG, PF4, 
sTM, and PAP will be assessed in plasma samples collected at the site and shipped to an 
outside laboratory for analysis.   
Part 2 
• Anti-fXa activity and thrombin generation will be measured using plasma samples 
collected at the site to assess the ability of observed andexanet blood levels to reverse the 
anticoagulant effect of apixaban, edoxaban, and rivaroxaban.   
• PT, aPTT, and ACT will be measured/analyzed locally at the study site at screening only. 
• F1+2, TAT, D-dimer (fibrin degradation fragment), and TFPI activity will be assessed in 
plasma samples collected at the site and shipped to an outside laboratory for analysis.   
7.4. 
Pharmacokinetic Assessments 
Plasma samples will be obtained at selected time points and analyzed for the concentration of 
andexanet and the FXa inhibitors.  Sample assays for drug concentrations will be performed 
using validated electrochemiluminescent (andexanet) or LCMS (apixaban, edoxaban, and 
rivaroxaban) methods.  Unbound plasma concentrations for apixaban, edoxaban, and rivaroxaban 
will be determined by an equilibrium dialysis method followed by LCMS for quantitation.  
Details on the collection, processing, storage, and shipment of samples are contained in the 
Study Manual.  Specific PK parameters to be evaluated are listed in Section 9.0. 
7.5. 
Safety Assessments 
Safety and tolerability will be determined by symptoms, signs, and laboratory test abnormalities.  
The Investigator will monitor the laboratory test findings.  If any laboratory test is abnormal 
during the course of the study, it will be followed at the discretion of the Investigator.  
Abnormalities of laboratory tests may, in the opinion of the Investigator be considered clinically 
significant and, thus, constitute or be associated with an AE.  In such cases, they must be 
reported on the Adverse Event Form. 


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In the event of an AE such as an allergic reaction, additional laboratory tests including the 
following should be considered for inclusion in the workup:  hematology with differential, 
chemistry panel, cortisol level, Radioallergosorbent Test (RAST), tryptase, immunoglobulin 
levels (e.g., Immunoglobulin E).  If possible, and necessary for interpreting such an AE, these 
labs may also be retroactively added to the baseline assessment to determine if the laboratory test 
changed in the context of the AE. 
7.5.1. 
Vital Signs 
Vital signs include temperature, respiratory rate, heart rate, and blood pressure.  Additionally, 
height and weight will be measured at Screening.  Whenever possible, vital signs will be 
obtained after at least 5 minutes in the sitting position or, when necessary, in a semi-recumbent 
position.  If vital signs must be obtained in the supine position due to ongoing drug infusion, an 
attempt should be made to obtain peri-infusion vital signs (e.g., the vital sign time points 
preceding and following the infusion) in the sitting position as well. 
7.5.2. 
Physical Examination 
Scheduled physical exams must include at a minimum an examination of the head, ears, nose and 
throat, heart, lungs, abdomen, skin, extremities, and peripheral pulses, and a brief neurologic 
exam. 
7.5.3. 
Clinical Venous Thromboembolism Assessment 
In addition to regular assessment of all AEs, specific scoring systems designed to detect risk of 
thromboembolic disease will be systematically administered throughout the conduct of the study.  
These tools—the Wells score for DVT and PE, respectively - offer an additional mechanism and 
improved surveillance for evidence of thrombotic events.  The scoring systems may be found in 
Appendix C. 
7.5.4. 
Oxygen Saturation 
Oxygen saturation will be monitored by pulse oximetry during andexanet administration.  It is 
recommended, though not required, that oxygen saturations not be measured on an extremity 
undergoing an active intravenous infusion. 
7.5.5. 
Electrocardiogram 
At specified time points, a standard 12-lead resting ECG will be recorded electronically after at 
least 10 minutes in the supine position. 
7.5.6. 
Fecal Occult Blood Testing 
Stool fecal occult blood testing will be performed daily from Day -1 to Day 10, inclusive.  
Occult blood testing may be deferred if no stool is available on a given day.  A potential subject 
is excluded during Screening if a stool sample is positive for occult blood during Screening or 


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Day -1.  During the treatment period (i.e., Days 1–8), occult blood testing may be deferred if no 
stool is available on a given day. 
7.5.7. 
Clinical Laboratory Blood Testing 
Blood specimens for routine chemistry and hematology will be obtained at selected time points.  
The assays will be performed at a local laboratory: 
• Hematology (hemoglobin, hematocrit, White Blood Cell [WBC], platelet count, Complete 
Blood Count [CBC] differential). 
• Serum Chemistry (sodium, potassium, chloride, carbon dioxide [bicarbonate], glucose, 
Blood Urea Nitrogen [BUN], creatinine, Aspartate aminotransferase [AST], Alanine 
aminotransferase [ALT], Creatine Kinase [CK], lactate dehydrogenase, total protein, 
albumin, alkaline phosphatase, calcium, phosphorous, total and fractionated [indirect or 
direct] bilirubin, uric acid). 
 
The results of tests run local to the study site will be stored in the study database. 
7.5.8. 
Urine Studies 
Urine will be obtained at selected time points for the following laboratory tests:   
• Complete urinalysis (specific gravity, pH, glucose, protein, hemoglobin, and microscopic 
urinalysis). 
 
The results of tests run at the study site will be stored in the study database. 
7.5.9. 
Immunogenicity 
Monitoring for antibodies to andexanet, human FX, and human FXa will be done at specific time 
points using validated electrochemiluminescent methods at a central laboratory.  For any sample 
which is confirmed positive for antibodies to andexanet, the potential for neutralizing antibody 
activity will be assessed by measuring the functional activity of andexanet in plasma.  This test 
will be performed at a central laboratory.  Plasma samples at specific time points will be tested 
for potential neutralizing antibody activity against endogenous FX/FXa using a modified 
Bethesda assay.  This test will be performed at a central laboratory. 


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8.0 
ADVERSE EVENTS/SAFETY MONITORING 
8.1. 
General Safety Considerations 
While this type of study is typically designed as a 2-period crossover trial, a parallel group 
design is used in this case in order to minimize the risk of immunogenicity in healthy subjects.  
Furthermore, to monitor for immunogenicity, blood specimens will be serially evaluated at each 
outpatient follow-up visit (Days 20 and 36) for antibodies against andexanet, FX, and FXa.  
Samples that are positive for antibodies to andexanet will be further assayed for the ability to 
neutralize the activity of andexanet.  Plasma samples at specific time points will be tested for 
potential neutralizing antibody activity against endogenous FX/FXa using a modified Bethesda 
assay. 
Subjects will be monitored while domiciled in the clinical site for the entire period that they are 
anticoagulated with FXa inhibitors and for 4 days after administration of andexanet.  Although 
there have been no thromboembolic events in any healthy subjects dosed with andexanet thus 
far, some prothrombotic markers (D-dimer, F1+2, and TAT) transiently increase following 
andexanet infusion, generally resolving within 4 days after andexanet treatment.  This increase is 
diminished when andexanet is coadministered with an FXa inhibitor, as will be the case in the 
present study.  D-dimer, F1+2, and TAT will be obtained and reviewed in the present study.  
Furthermore, a clinical assessment of venous thromboembolism risk (via Wells Scoring) will be 
performed at multiple time points during the study. 
Prior and ongoing clinical studies have identified infusion reactions of mild or moderate intensity 
as the most common adverse event related to administration of andexanet.  Although no severe 
or serious infusion reactions have occurred to date in healthy subjects receiving andexanet, 
subjects in this study will receive andexanet in an inpatient, monitored setting under medical 
supervision and immediate access to resuscitative measures.  Notably, infusion reactions 
observed in prior and ongoing studies have had their onset during the infusion itself.  Therefore, 
in addition to vital signs, oxygen saturation will be monitored during the infusion. 
To monitor for occult bleeding, stool occult blood testing will be performed daily on stool 
samples produced throughout the period subjects are domiciled.  The relatively short t½ of each 
FXa inhibitor predicts a loss of anticoagulant effects within 24 hours of the end of treatment.  
Following discharge from the clinical site, subjects will return for follow-up on Days 20 and 
36 for safety follow-up. 
Finally, safety data will be reviewed by the Sponsor on an ongoing basis. 


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8.2. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product, 
which may or may not have a causal relationship with the treatment.  An AE can be any 
unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the study drug, whether or not it is considered to be 
study drug-related.  This includes any newly occurring event or previous condition that has 
increased in severity or frequency since the administration of study drug. 
8.3. 
Serious Adverse Event Definition 
An SAE is any AE, occurring at any dose and regardless of causality that: 
• Results in death. 
• Is life-threatening.  Life-threatening means that in the opinion of the Investigator or Study 
Sponsor, the patient/subject was at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction which hypothetically might have caused death 
had it occurred in a more severe form. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered AEs if the illness or disease 
existed before the subject was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  An important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in 
the definitions for SAEs.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
Clarification should be made between the terms “serious” and “severe” since they are not 
synonymous.  The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe pain); the event itself, however, may be of relatively minor 
medical significance.  This is not the same as “serious,” which is based on the strict regulatory 
definitions listed above.  A severe adverse event does not necessarily need to be considered 
serious.  For example, persistent nausea of several hours duration may be considered severe 
nausea but not an SAE if the event does not meet the serious criteria.  On the other hand, a stroke 


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resulting in only a minor degree of disability may be considered mild, but would be defined as an 
SAE based on the above noted serious criteria.  Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
8.4. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
SUSARs are serious AEs that are both unexpected (i.e., the nature or severity is not expected 
from the information provided in the Investigator’s Brochure) and assessed by the Investigator or 
the Sponsor’s Medical Monitor to have a reasonable possibility of a causal relationship to the 
investigational medical product.  The study Sponsor is required to submit to the FDA any 
SUSAR as an IND Safety Report within an expedited timeline; thus it is important for the 
Investigator to submit all SAEs promptly to the Sponsor for determination of expedited reporting 
to FDA. 
8.5. 
Adverse Events of Special Interest 
The following are Adverse Events of Special Interest (AESIs) and should be reported as adverse 
events (or as SAEs, if appropriate) within 24 hours after which the Investigator is made aware of 
them, as described in Section 8.6: 
• VTE of any severity 
• Severe infusion reaction 
• Antibodies to factor X or factor Xa 
 
8.6. 
Procedures for Recording and Reporting AEs and SAEs 
All AEs spontaneously reported by the patient/subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination or other diagnostic 
procedures will be recorded on the appropriate forms in the electronic Case Report Form 
(e-CRF).  Any clinically relevant deterioration in laboratory assessments or other clinical 
findings is considered an AE and must be recorded on the appropriate forms in the e-CRF.  
When possible, signs and symptoms indicating a common underlying pathology should be noted 
as one comprehensive event.  For example, the combination of general malaise, mild fever, 
headache and rhinitis should be described as “common cold” symptoms rather than for each 
symptom to be listed separately. 
All SAEs and AESIs that occur during the course of the study, as defined by the protocol, must 
be reported by the Investigator to Portola Product Safety by faxing the SAE Form within 
24 hours from the point in time when the Investigator becomes aware of the SAE or AESI.  In 
addition, all SAEs including all deaths, which occur until the termination visit must be reported 
to Portola Product Safety within 24 hours.  All SAEs, AESIs, and deaths must be reported, 
whether or not considered causally related to the study drug.  The SAE form will be provided to 
each clinical study site.  The information collected will include at minimum the following:  


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subject number, the criteria met for the AE being serious, the event term, a narrative description 
of the event and an assessment by the Investigator as to the severity/intensity of the event and 
relatedness to study drug.  Follow-up information on the SAE or AESI should be sent promptly 
by the Investigator to Portola when any additional relevant information about the SAE becomes 
known to the Investigator, or as requested by Portola. 
SAE Reporting Contact Information 
Portola Pharmacovigilance Vendor: 
C3i Solutions (formerly TELERx) 
Email:  PortolaSafety-SAE-
AE@Telerx.com 
If the question needs further evaluation, 
please contact: 
Portola Pharmacovigilance at: 
PV@portola.com 
 
If a serious AE meets the definition of a SUSAR, Portola will notify the appropriate regulatory 
agency (or agencies) and all participating Investigators on an expedited basis.  Additionally, 
Portola will promptly notify the Investigator if any additional safety or toxicology information 
becomes available during the study.  It is the responsibility of the Investigator to promptly notify 
the IRB/IEC of all unexpected serious adverse drug reactions involving risk to human subjects.  
An unexpected event is one that is not listed by nature or severity in the Investigator’s Brochure. 
Planned hospital admissions or surgical procedures for an illness or disease which existed before 
the subject was enrolled in the trial or before study drug was given are not to be considered AEs 
unless they occur at a time other than the planned date for a reason such as a worsening of the 
underlying disease/illness/symptoms. 
For both serious and non-serious AEs, the Investigator must determine both the severity of the 
event and the relationship of the event to study drug. 
The severity should be defined according to the following criteria: 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with normal daily activities 
Severe 
Inability to perform normal daily activities 
Life Threatening 
Immediate risk of death from the reaction as it occurred 
Fatal 
Event resulted in death 
 


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The causal association of AEs to study drug administration (the factor Xa inhibitor, andexanet, or 
matching placebo) should be determined as follows: 
Unrelated/Unlikely  
The current state of knowledge indicates that a relationship is not 
reasonable or is unlikely.  Other plausible explanations exist for the AE. 
Possible/Probable 
There is a reasonable possibility that the AE may have been caused by 
the drug, either because of temporal relationship to study drug 
administration, plausibility based on study drug pharmacology and PKs, 
and/or lack of evidence suggesting other possible causes of the event 
(e.g., intercurrent illness, concomitant medication). 
 
8.7. 
Procedures for Reporting SUSARs 
All SAEs, regardless of relationship to study drug, should be promptly reported by the 
Investigator to the Sponsor using the SAE reporting email. 
A SUSAR which is fatal or life threatening must be reported to the FDA and ethics committee 
immediately (within 7 days) after the Sponsor became aware of the event.  A follow up report 
with as much additional information as is available will be filed within 8 additional calendar 
days. 
A SUSAR which is not fatal or life-threatening, but meets other criteria of seriousness, must be 
reported by the Sponsor to the FDA and Ethics Committee as soon as possible (no later than 
15 calendar days) after the Sponsor becomes aware of the event. 
8.8. 
Monitoring of Adverse Events and Period of Observation 
Adverse events, both serious and non-serious, occurring between signing informed consent and 
up to and including the Termination Visit will be recorded on the e-CRFs.  All AEs and SAEs 
should be monitored until they are resolved, reach a level of stability and are not expected to 
improve further, or are clearly determined to be due to a subject’s stable or chronic condition or 
intercurrent illness. 
Any AE or SAE that occurs with an onset date after completion of the study, and that the 
Investigator considers to be related to study medication, must be reported to Portola.   
8.9. 
Procedures for Reporting Pregnancy Exposure and Birth Events 
If a woman who is a study subject becomes pregnant or a woman partner of a male study subject 
becomes pregnant from a male study subject (between study drug administration and up to 
16 weeks after the termination visit), the Investigator should be informed immediately.  The 
Sponsor must in turn also be notified by the Investigator immediately by completing a Pregnancy 
Form and faxing it to Portola Product Safety (see Section 8.5).  In the event a female partner of a 
male subject is pregnant or suspects she is pregnant by the male subject, the male subject will be 
advised by the study Investigator to have his female pregnant partner inform her treating 


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physician immediately.  The pregnancy must be followed up through delivery or other fetal 
outcome.  For any abnormal fetal outcome, including congenital anomaly or birth defect, 
spontaneous or therapeutic abortion, still birth, pre-mature birth, or other outcome other than live 
normal birth, the Investigator should promptly report to the Sponsor the abnormal fetal outcome 
on an SAE form. 


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9.0 
PHARMACOKINETIC ANALYSES 
The following noncompartmental PK parameters for plasma andexanet will be calculated for all 
subjects: 
• Plasma t½, determined by linear regression of the log concentration on the distribution and 
terminal portion of the plasma concentration–time curve.  Distribution half-life is 
calculated as ln(2)/(- α), where α is the slope of the distribution portion of the log 
concentration–time curve.  Terminal half-life is calculated as ln(2)/(- β), where β is the 
slope of the terminal portion of the log concentration–time curve; 
• Time to maximum observed plasma concentration (Tmax) 
• Cmax 
• Area under the plasma concentration–time curve from 0 to last measurable concentration 
(AUC(0–last)) computed using the linear trapezoidal rule 
• Total area under the plasma concentration–time curve from time 0 to infinity (AUC(0-∞)), 
computed as: 
AUC(0-∞) = AUC(0–last) + Cplast /(- β) 
where AUC(0–last) is the AUC from time 0 to the time point of the last measurable 
concentration above the quantitation limit; Cplast is the last measurable concentration 
above the quantitation limit; and β is defined as above 
• Clearance (CL) 
• Volume of distribution at steady state (Vss) 
• The terminal or elimination rate constant (λz) 
 
The following non-compartmental parameter estimates from Cohorts 1 and 5 will be calculated 
to evaluate the PK of andexanet in Japanese versus Caucasian subjects: 
• Cmax 
• AUC(0-∞) 
• AUC (0–last) 
• t½ 
• CL 
• Vss 
• λz 
 


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PK parameters for apixaban, rivaroxaban, edoxaban, and the edoxaban metabolite D21-2393 will 
be assessed at Day 1 (pre-dose only), multiple time points on Day 5 through Day 8 and once on 
Day 9 and Day 10.  The following PK parameters will be calculated for apixaban, edoxaban, and 
rivaroxaban based on total plasma concentrations: 
• t½ 
• Tmax 
• Cmax 
• Cbolus (end of the bolus plus 2 minutes) 
• AUC (0–last) 
• Area under the plasma concentration–time curve between dosing interval (AUC(0-)) 
• Clearance (CL/F) 
• λz 
 


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10.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
10.1. 
Study Objectives and Study Design 
The study objectives and study design are described in Section 2.0 and Section 3.1, respectively. 
10.2. 
General Considerations 
All statistical summaries will be performed using SAS Version 9.2 (SAS Institute, Inc., Cary, 
NC, USA) or higher.  Additional software may be used for the production of graphics. 
A Statistical Analysis Plan (SAP) will be created for this study, with appropriate details and 
definitions of all analyses.  For selected interim analyses, the SAP will be archived prior to any 
interim database lock associated with that respective analysis. 
All hypothesis tests will be two-sided and performed at the 0.05 significance level. 
10.3. 
Randomization 
Depending on cohort assignment, subjects will be randomized in a 2:1 ratio to receive andexanet 
or placebo, respectively.  The detailed randomization process is described in Section 3.2.1.  
Subjects will be randomized on Day 1, once it is ascertained that they meet all of the 
inclusion/exclusion criteria.  At this time the unblinded research pharmacist or designee will 
obtain the subject’s treatment assignment.  The randomization code and starting seed will be 
generated by a CRO and maintained by a CRO.  The code will not be provided to the Sponsor, 
the site (aside from the unblinded research pharmacist or designee), or subjects until the database 
has been locked, except as required for non-study personnel in the regulatory reporting of SAEs. 
10.4. 
Analysis Populations 
10.4.1. 
Efficacy Analysis Population 
The efficacy analysis population will include all randomized subjects who took any amount of 
study medication (andexanet or placebo) during the double-blind treatment period.  For the 
efficacy analysis, subjects will be presented in the treatment group to which they were 
randomized.  Subjects will be included in the efficacy analysis on change or percent change from 
baseline if they have a baseline and at least one measurement post-baseline for the time point 
under consideration. 
10.4.2. 
 Safety Analysis Population 
The safety analysis population will consist of all subjects randomized and treated with study 
medication (andexanet or placebo).  All safety analyses will be performed by actual treatment 
received.  Subjects who received one or more doses of FXa inhibitor but discontinued prior to 
receiving study drug will be listed separately. 


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10.4.3. 
PK Analysis Population 
The PK analysis populations will consist of all subjects who have received the requisite 
treatments and have sufficient data to calculate each PK parameter.  Any windows for timing of 
measurements, etc. will be specified in the SAP. 
10.5. 
Endpoints 
10.5.1. 
Efficacy Endpoints 
10.5.1.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the difference in percent change in the anti-fXa activity from 
baseline to the nadir level at the end of the infusion between andexanet- and placebo-treated 
subjects.  Nadir is defined as the smallest value for anti-fXa activity between the 110-minute 
time point (10 minutes prior to the end of the continuous andexanet infusion) and the 5-minute 
time point after the end of the continuous infusion (inclusive).  The primary analysis will be 
performed on all individual cohorts separately. 
10.5.1.2. Secondary Efficacy Endpoint 
The secondary efficacy endpoints include the following: 
• The percent change from baseline in anti-fXa activity at its nadir, where nadir is defined 
as the smallest value for anti-fXa activity at the +2 minute or +5 minute time point after 
the completion of the andexanet bolus. 
• The change from baseline in free FXa inhibitor concentration (ng/mL) at its nadir, where 
nadir is defined as the smallest value for free FXa inhibitors at the +2 minute or +5 minute 
time point after the completion of the andexanet bolus. 
• The change from baseline in free FXa inhibitor concentration (ng/mL) at its nadir, where 
nadir is defined as the smallest value for free FXa inhibitors between the 110-minute time 
point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point 
after the end of the continuous infusion (inclusive). 
• The change in thrombin generation from baseline to its peak, where peak is defined as the 
largest value for thrombin generation between the +2 minute time point and the +5 minute 
time point after the end of the andexanet bolus (inclusive). 
• The occurrence of thrombin generation above the lower limit of the normal range at its 
peak, between the +2 minute time point and the +5 minute time point after the end of the 
andexanet bolus (inclusive). 
• The change in thrombin generation from baseline to its peak, where peak is defined as the 
largest value for thrombin generation between the 110-minute time point (10 minutes prior 
to the end of the continuous infusion) and the 5-minute time point after the end of the 
continuous infusion (inclusive). 


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• The occurrence of thrombin generation above the lower limit of the normal range at its 
peak, where peak is defined as the largest value for thrombin generation between the 
110-minute time point (10 minutes prior to the end of the continuous infusion) and the 
5-minute time point after the end of the continuous infusion (inclusive) and assess the 
thrombin generation during 24 hours after administration of FXa inhibitors. 
 
10.5.1.3. Exploratory Efficacy Endpoints 
For Parts 1 and 2 of the study, TFPI activity, a marker of endogenous anticoagulation, will be 
evaluated for the purpose of monitoring the potential procoagulant activity of andexanet (due to 
andexanet-TFPI interaction).  
For Part 1 of the study the following additional markers will also be examined: 
 PT 
 aPTT 
 ACT 
 FX 
 fibrinogen 
 tPA 
 PAP 
 TAFI 
 b-TG 
 PF4 
 sTM 
 TFPI (total and free antigen) 
10.5.2. 
Safety Endpoints 
10.5.2.1. Non-Laboratory-Based Endpoints 
Safety will be evaluated by assessment of adverse events, venous thromboembolic events, 
physical exam findings, vital signs, oxygen saturation, fecal occult blood testing, and 12-lead 
ECGs. 
10.5.2.2. Laboratory-Based Endpoints 
Routine clinical laboratory parameters to be evaluated include hematology, chemistry, 
urinalyses, and coagulation markers (D-dimer, F1+2, and TAT). 
Immunogenicity will be evaluated by measurement of antibodies to andexanet, FX, and FXa.  In 
addition, neutralizing antibodies for any confirmed antibody response will be measured for 
andexanet.  Furthermore, potential neutralizing antibody activity against FX/FXa will be 
assessed by a clotting based modified Bethesda assay. 


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In Part 1 of the study, Russell’s Viper Venom Time (RVVT) was included as an additional 
assessment. 
10.5.3. 
PK Endpoints 
PK endpoints are summarized in Section 9.0. 
10.6. 
Statistical Analyses 
10.6.1. 
Baseline and Demographics 
Baseline and demographic characteristics will be summarized for the safety and efficacy 
populations of each part of the study.  Data will be summarized overall and by treatment using 
descriptive statistics such as frequencies, means, medians, standard deviations, minimums, and 
maximums.  No inferential statistical analyses of these data are planned. 
10.6.2. 
Efficacy Analysis 
All efficacy analyses will be performed by treatment assigned at randomization. 
10.6.2.1. Primary Efficacy Analysis 
The primary analysis will be performed to compare the difference in the primary endpoint 
between andexanet- and placebo-treated subjects by cohort.  The analysis will be performed in 
all cohorts.  The comparison will be conducted using a two sample exact Wilcoxon rank sum 
test.  All hypothesis tests will be 2-sided and performed at the 0.05 significance level.  No 
adjustment for multiplicity is necessary since each cohort is considered as an independent 
population. 
10.6.2.2. Secondary Efficacy Analyses 
No formal statistical hypothesis testing will be performed for the secondary endpoints but point 
estimates and two-sided 95% confidence intervals will be produced to assess the treatment 
effects with respect to the secondary endpoints. 
10.6.2.3. Exploratory Efficacy Analyses 
Plots of the values and change from baseline over time for TFPI activity will be evaluated by 
treatment in placebo-controlled cohorts from all parts of the study.  For Part 1 of the study, the 
additional exploratory endpoints of TFPI (total and free antigen), PT, aPTT, ACT, FX, 
fibrinogen, tPA, PAP, TAFI, b-TG, P44 and sTM were also collected and will be presented. If 
data permit, the comparison between treatment groups may be made at an appropriate time.   
10.6.2.4. Handling of Missing Data 
If there are insufficient post-baseline data to evaluate the endpoint, imputation will be carried 
out.  Detailed imputation methods will be defined in the Statistical Analysis Plan.  If a subject 


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discontinues prematurely from the study or otherwise has missing data, the Sponsor may elect to 
enroll up to 3 additional subjects per cohort. 
10.6.3. 
Subgroup Analysis 
Due to the size of this study, no inferential subgroup analyses are planned. 
10.6.4. 
Safety Analysis 
10.6.4.1. Extent of Exposure 
Dosing information for each drug and each subject will be listed.  Discontinuation of dosing will 
be summarized by treatment received.  The primary reason for study drug discontinuation will 
also be summarized by treatment received. 
10.6.4.2. Analysis of Adverse Events 
Treatment-Emergent Adverse Events (TEAEs) will be summarized by treatment, system organ 
class, and preferred term defined by the Medical Dictionary for Regulatory Activities 
(MedDRA, version 16.1 or later). 
The number of events, the number of subjects, and the percentage of subjects who experienced at 
least one TEAE will be presented.  TEAEs that are considered by the investigator to be related to 
study medication, TEAEs that lead to early withdrawals, and serious TEAEs will be summarized 
in the same manner. 
The treatment groups will be compared in regards to safety endpoints descriptively.  No 
inferential comparison will be conducted. 
10.6.4.3. Concomitant Medications 
Concomitant medications will be coded using the September 2013 version of WHO-Drug. 
10.6.4.4. Analysis of Laboratory Parameters 
Clinical laboratory parameters including hematology, chemistry, urinalyses, and coagulation 
markers (D-dimer, TAT and F1+2, PT, aPTT, and ACT) will be summarized by treatment group 
and by time point for the cohorts that the data was collected. 
Baseline values, the values at each subsequent visit, and changes from baseline will be 
summarized for each of the quantitative laboratory assessments by treatment. 
Shift tables of chemistry, hematology, and urinalysis results will be used to summarize changes 
from baseline to study termination (or early termination). 
The number and percentage of chemistry, hematology, and urinalysis values outside of normal 
ranges and/or with Potential Clinical Importance will be summarized by visit and treatment. 


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The presence of antibodies (anti-andexanet, anti-fX, anti-fXa, and/or neutralizing antibodies) 
will be listed. 
10.6.4.5. Analysis of Other Safety Parameters 
Vital signs, oxygen saturation, results from clinical VTE assessments, and ECG intervals will be 
summarized using actual values and change from baseline at pre-specified time points for each 
treatment group.  Descriptive statistics, including threshold-based outlier analyses will be 
presented.  ECG abnormalities will be listed. 
10.6.5. 
PK Analysis 
PK parameters defined in Section 10.5.3 will be calculated by subject and summarized by cohort.  
Only subjects with sufficient data to calculate each PK parameter will be included in the 
summary of each PK endpoint. 
10.6.6. 
Interim Analysis 
Following the completion of Part 1, an unblinded analysis of data from Part 1 may be performed 
to inform dosing in Part 2.  Data from Part 2 will remain blinded following the analysis of Part 
1 data.  The parameters to be reviewed will be determined at the time of the analysis.  Additional 
unblinded interim analyses may be performed on selected cohorts following their completion 
(and prior to study completion) to enable and support regulatory submissions or the Sponsor’s 
decision making.  The detailed unblinding procedures for the interim analysis will be separately 
documented in an Unblinding Plan. 
10.7. 
Sample Size Considerations 
10.7.1. 
Part 1 
10.7.1.1. Apixaban (Cohorts 1 and 5) 
The mean (SD) of the primary endpoint in Study 14-503 Part 2 which assessed the reversal of 
apixaban 5 mg BID anticoagulation with andexanet administered as an IV bolus followed by a 
2-hour infusion were -92.3% (SD = 2.8%) and -32.7% (SD = 5.6%) for andexanet and placebo 
arms, respectively.  Based on these results, the percent changes from baseline in anti-fXa activity 
in this study are assumed to be -90% (SD = 5%) and -35% (SD = 10%) for andexanet and 
placebo arms, respectively.  The standard deviations in both arms are assumed larger than the 
observed values in the previous study to provide adequate power for the comparison.  Under 
these assumptions, a total number of 9 subjects (6 active and 3 placebo) will provide at least 90% 
power to detect the difference at a significance level of 0.05 (two-sided) using the two sample 
exact Wilcoxon rank sum test. 


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10.7.1.2. Rivaroxaban (Cohort 2) 
The mean (SD) of the primary endpoint in Study 14-504 Part 2 which assessed the reversal of 
rivaroxaban 20 mg QD anticoagulation with andexanet administered as an IV bolus followed by 
a 2-hour infusion were -96.7% (SD = 1.8%) and -44.8% (SD = 11.7%) for andexanet and 
placebo arms, respectively.  Based on these results, the percent changes from baseline in anti-fXa 
activity are assumed to be -90% (SD = 5%) and -45% (SD = 15%) for andexanet and placebo 
arms, respectively.  Under these assumptions, a total number of 9 subjects (6 active and 
3 placebo) will provide at least 90% power to detect the difference at a significance level of 0.05 
(two-sided) using the two sample exact Wilcoxon rank sum test. 
10.7.1.3. Edoxaban (Cohort 3; andexanet dosing at 3 hours post-edoxaban) 
In Cohort 2 of Study 12-502 Module 4, which assessed the reversal of edoxaban anticoagulation 
with andexanet, the mean (SD) of the percent change from baseline anti-fXa activity at the end 
of infusion was -70.28% (SD = 5.64%) for the andexanet arm.  In Cohort 1 and Cohort 2 of the 
same study, the mean (SD) of the percent change from baseline at 2 hours after the end of bolus 
was -40.31% (SD = 12.25%) for placebo.  Based on these results, the percent changes from 
baseline in anti-fXa activity for andexanet and placebo are assumed as -70% (SD = 6%) 
and -40% (SD = 15%), respectively.  Under these assumptions, a total number of 12 subjects 
(8 active and 4 placebo) will provide at least 90% power to detect the difference at a significance 
level of 0.05 (two-sided) using the two sample exact Wilcoxon rank sum test. 
10.7.1.4. Edoxaban (Cohort 4; andexanet dosing at 90 minutes post-edoxaban) 
There are no actual data of andexanet administration at 90 minutes after edoxaban dosing.  Based 
on the result predicted by the PK-PD model developed using the data of Study 12-502, the 
percent changes from baseline in anti-fXa activity for andexanet and placebo are assumed 
as -70% (SD = 15%) and -30% (SD = 15%), respectively.  Under these assumptions, a total 
number of 12 subjects (8 active and 4 placebo) will provide at least 90% power to detect the 
difference at a significance level of 0.05 (two-sided) using the two sample exact Wilcoxon rank 
sum test.   
10.7.2. 
Part 2 
10.7.2.1. Apixaban 10 mg BID (Cohort 6:  andexanet dosing at 3 hours post apixaban) 
A total number of 9 subjects (6 active and 3 placebo) will provide at least 90% power to detect 
the difference at a significance level of 0.05 (two-sided) using the two sample exact Wilcoxon 
rank sum test.  The underlying assumptions are supported by data from Cohort 8 of the 16-512 
study, which the mean (SD) of %change from baseline in anti-fXa activity (%CHB in anti-fXa 
activity) at nadir around EOI were -97% (SD = 0.8%) and –36% (SD = 3.3%) for andexanet and 
placebo arms, respectively.  In the power calculation, -95% (SD = 10%) and -40% (SD = 10%) 
are assumed. 


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10.7.2.2. Edoxaban 30 mg QD (Cohort 7:  andexanet dosing at 90 min post edoxaban) 
A total number of 12 subjects (8 active and 4 placebo) will provide approximately 90% power to 
detect the difference at a significance level of 0.05 (two-sided) using the two sample exact 
Wilcoxon rank sum test.  Given the dose proportionality, the underlying assumptions are 
supported by data from Cohort 4 of the 16-508 study, which the mean (SD) of %CHB in anti-fXa 
activity at nadir around EOI were -71% (SD = 13.6%) and –34% (SD = 12.8%) for andexanet 
and placebo arms, respectively.  In the power calculation, -70% (SD = 15%) and -35% 
(SD = 15%) are assumed. 
10.7.2.3. Apixaban 10 mg BID (Cohort 8:  andexanet dosing at 8 hours post apixaban) 
A total number of 9 subjects (6 active and 3 placebo) will provide at least 90% power to detect 
the difference at a significance level of 0.05 (two-sided) using the two sample exact Wilcoxon 
rank sum test.  For placebo arm, the underlying assumptions are supported by data from Cohort 8 
of the 16-512 study, which the mean (SD) of %CHB in anti-fXa activity at 3.5 hours after EOI 
was -51% (SD = 9.5%).  For andexanet arm, the mean of %CHB in anti-fXa activity predicted by 
the PK-PD model that is 91.6% was used as reference because there are no actual data.  In the 
power calculation,  
-90% (SD = 10%) and -50% (SD = 10%) are assumed. 
10.7.2.4. Rivaroxaban 15 mg BID (Cohort 9:  andexanet dosing at 8 hours post rivaroxaban) 
A total number of 15 subjects (10 active and 5 placebo) will provide approximately 87% power 
to detect the difference at a significance level of 0.05 (two-sided) using the two sample exact 
Wilcoxon rank sum test.  For placebo arm, the underlying assumptions are supported by data 
from Cohort 2 of the 16-508 study, which the mean (SD) of %CHB in anti-fXa activity at 1.5 
hours after EOI was -56% (SD = 12.1%).  For andexanet arm, the mean of %CHB in anti-fXa 
activity predicted by the PK-PD model that is 86.5% was used as reference because there are no 
actual data.  In the power calculation, -85% (SD = 15%) and -55% (SD = 15%) are assumed. 
10.7.2.5. Edoxaban 60 mg QD (Cohort 10:  andexanet dosing at 8 hours post edoxaban) 
A total number of 12 subjects (8 active and 4 placebo) will provide at least 90% power to detect 
the difference at a significance level of 0.05 (two-sided) using the two sample exact Wilcoxon 
rank sum test.  The underlying assumptions are supported by data from Cohort 11 of the 16-512 
study, which the mean (SD) of %CHB in anti-fXa activity at nadir around EOI were -64% 
(SD = 9.0%) and –39% (SD = 6.0%) for andexanet and placebo arms, respectively.  In the power 
calculation, -65% (SD = 10%) and -40% (SD = 10%) are assumed. 


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10.8. 
Institutional Review Board or Ethics Committee 
The protocol and informed consent for this study must be reviewed and approved by an 
appropriate IRB or EC before subjects are enrolled in the study.  It is the responsibility of the 
Investigator to assure that the study is conducted in accordance with current country and Local 
Regulations, International Conference on Harmonisation (ICH) GCP, and the Declaration of 
Helsinki.  A letter documenting the approval which specifically identifies the protocol by number 
and title, as well as the Investigator must be received by the Sponsor prior to initiation of the 
study.  Amendments to the protocol will be subject to the same requirements as the original 
protocol. 
After the completion or termination of the study, the Investigator will submit a report to the IRB 
or Ethics Committee and to the Sponsor. 
10.9. 
Informed Consent 
Each subject must be provided with oral and written information describing the nature and 
duration of the study, and sign a written informed consent before study entry.  No subject is to be 
treated until an informed consent written in a language in which the subject is fluent has been 
obtained.  The signed and dated informed consent will be retained with the study records.  Each 
subject will also be given a copy of their signed informed consent. 
10.10. 
Data Reporting and Case Report Forms 
Data for each subject will be entered into the e-CRF and verified by the Investigator.  It is the 
Investigator’s responsibility to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported on the subject’s e-CRF.  Source documentation supporting the e-CRF data 
should indicate the subject’s participation in the study and should document the dates and details 
of study procedures, AEs, and subject’s clinical status. 
The Investigator or designated representative should complete the e-CRF as soon as possible 
after information is collected, preferably on the same day that a study subject is seen for an 
examination, treatment or any other study procedure.  Any outstanding entries must be 
completed immediately after the final examination.  CRF data will be processed in a US 21 CFR 
Part 11-compliant system. 
10.11. 
Retention of Data 
United States Federal regulations require that a copy of records (e.g., laboratory data slips, 
source documents, test article disbursement records, etc.), which support case records of this 
study must be retained in the files of the responsible Investigator for a minimum of two years 
following notification by the Sponsor that the FDA has approved a marketing application for the 
drug and indication being investigated, or the investigation has been terminated.   


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10.12. 
Deviation from the Protocol 
The Investigator will not deviate from the protocol without first obtaining approval from the 
Sponsor and the IRB or Ethics Committee.  In medical emergencies, the Investigator will use 
medical judgment and will remove the subject from immediate hazard, then notify the Sponsor’s 
Medical Monitor and the IRB or Ethics Committee immediately regarding the type of emergency 
and course of action taken.  Any action in this regard will be recorded on the appropriate CRF.  
Any other changes or deviations in the protocol will be made as an amendment to the protocol 
and must be approved by the Sponsor and the IRB or Ethics Committee and before they are 
implemented.  The Sponsor will not assume any responsibility or liability for any unapproved 
deviation or change. 
10.13. 
Study Monitoring 
The Investigator will allow representatives of the Sponsor to periodically audit, at mutually 
convenient times before, during and after the study has been completed, all CRFs and relevant 
portions of office, clinical and laboratory records for each subject.  The monitoring visits provide 
the Sponsor with the opportunity to evaluate the progress of the study, verify the accuracy and 
completeness of CRFs, assure that all protocol requirements, applicable regulations and 
Investigator’s obligations are being fulfilled, and resolve any inconsistencies in the study 
records. 
10.14. 
Drug Accountability 
The Investigator must maintain accurate records of the amounts and dates study drugs were 
received from the Sponsor and dispensed to the subjects including the lot numbers, volume and 
concentration of stock suspension prepared and remaining stock suspension volume after dose 
preparation.  All drug supplies must be accounted for at the termination of the study and a 
written explanation provided for any discrepancies.  All partially used or unused drug supplies 
will be destroyed at the site in accordance with approved written procedures or returned to the 
Sponsor after written authorization is obtained from the Sponsor.  The Investigator will maintain 
a record of the amount and dates when unused supplies were either destroyed or returned to the 
Sponsor.  All records will be retained as noted in Section 10.11. 


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11.0 
DISCLOSURE OF DATA 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties other than those noted below is prohibited.  Subject 
confidentiality will be further assured by utilizing subject identification code numbers to 
correspond to treatment data in the computer files.  The study personnel, employees of the 
regulatory agencies, including the US FDA and the study sponsor, Portola Pharmaceuticals, Inc., 
and its agents will need to review subject medical records in order to accurately record 
information for this study.  If results of this study are reported in medical journals or at meetings, 
the subject’s identity will remain confidential. 


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12.0 
REFERENCES 
1. 
Lu, G., et al., Reversal of rivaroxaban mediated anticoagulation in animal models by a 
recombinant antidote protein (r-Antidote, PRT064445). European Heart Journal, 2011. 
32: p. 640-641. 
2. 
Hutchaleelaha, A., et al., Recombinant factor Xa inhibitor antidote (PRT064445) 
mediates reversal of anticoagulation through reduction of free drug concentration: A 
common mechanism for direct factor Xa inhibitors. European Heart Journal, 2012. 33: p. 
496. 
3. 
Hollenbach, S., Tan S, DeGuzman F, Malinowski J, Hutchaleelaha A,Inagaki M, 
Curnutte J, Lu G, PRT064445 reverses rivaroxaban induced anticoagulation in a rabbit 
liver laceration "treatment" model. ESC 2013 abstract/moderated poster presentation. 
European Heart Journal, 2013. 34(Abstract Supplement): p. 24. 
4. 
Hollenbach, S.J., et al., PRT064445 but not recombinant FVIIA reverses rivaroxaban 
induced anticoagulation as measured by reduction in blood loss in a rabbit liver 
laceration model. Blood, 2012. 120(21). 
5. 
Godier, A.M., B. Le Bonniec, M. Durand, A. Fischer, J. Emmerich, C. Marchand-Leroux, 
T. Lecompte, C. Samama CM, Evaluation of prothrombin complex concentrate and 
recombinant activated factor VII to reverse rivaroxaban in a rabbit model. 
Anesthesiology, 2012. 116(1): p. 94-102. 
6. 
Pernod, G., et al., Management of major bleeding complications and emergency surgery 
in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa 
inhibitors: Proposals of the Working Group on Perioperative Haemostasis (GIHP) — 
March 2013. Archives of Cardiovascular Disease, 2013. 106: p. 382-393. 
7. 
Wells, P., ANderson DR, Rodger M., Derviation of a Simple Clinical Model to 
Categorize Patients' Probability of Pulmonary Embolism: Increasing the Models Utilitiy 
with the SimpliRED D-dimer. Thromb Haemost, 2000. 83: p. 416-420. 
8. 
Wells, P., Value of Assessment of Pretest Probability of Deep-vein Thrombosis in 
Clinical Management. Lancet, 1997. 350(9094): p. 1795-1798. 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 78 
13.0 
APPENDICES 
 
APPENDIX A. 
STUDY EVENTS FLOW CHART (PART 1) 
APPENDIX B. 
STUDY EVENTS FLOW CHART (PART 2) 
APPENDIX C. 
WELLS SCORES 
APPENDIX D. 
US PACKAGE INSERT FOR APIXABAN (ELIQUIS)  
APPENDIX E. 
US PACKAGE INSERT FOR EDOXABAN (SAVAYSA)  
APPENDIX F. 
US PACKAGE INSERT FOR RIVAROXABAN (XARELTO)  
APPENDIX G. 
PROTOCOL SUMMARY OF CHANGES  
(AMENDMENT 4 VS. AMENDMENT 5) 
 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 79 
APPENDIX A. 
STUDY EVENTS FLOW CHART (PART 1) 
Visit: 
SCREENING 1 ADMISSION 
INPT 
INPT 
INPT 
INPT 
Day: 
≤ -45 
-1 
1 
2 
3 
4 
Hour 
 
 
0 
0 
0 
0 
Informed Consent 
X 
 
 
 
 
 
Review/Complete I/E 
X 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
Physical Examination 
 
X 
 
 
 
 
Vital Signs (sitting) 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
Local Lab:  Serum Chemistry 
X 
 
 
 
 
 
Local Lab:  Hematology 
X 
X 
 
 
 
 
Local Lab:  Urinalysis 
X 
 
 
 
 
 
Local Lab:  Serum Pregnancy 
X 
X 
 
 
 
 
Local Lab:  FSH 
X 
 
 
 
 
 
Local Lab:  Urine (drugs of abuse) 
 
X 
 
 
 
 
Local Lab:  Breathalyzer (Ethanol screen) 
 
X 
 
 
 
 
Local Lab:  Hep B & C, HIV I & II 
X 
 
 
 
 
 
Local Lab:  Factor V Leiden, Protein S&C, 
Anti-thrombin III 
X 
 
 
 
 
 
Stool (occult blood) (if produced) 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
Administer Anticoagulant 2, 3 
 
 
X 
X 
X 
X 
Central Lab:  Anticoagulant PK (blood) 
 
 
X 4 
 
 
 
Local Lab:  PT, aPTT, ACT 
X 
X 
 
 
 
 
Central Lab:  Thrombin generation 
 
 
X 4 
 
 
 
Central Lab:  Anti-fXa activity 
 
 
X 4 
 
 
 
Central Lab:  F1+2, TAT, D-dimer, total 
TFPI, TFPI activity 
 
 
X 4 
X 5 
X 5 
X 5 
Central Lab:  tPA, PAP, TAFI, free TFPI, 
b-TG, PF4, sTM 
 
 
X 4 
 
 
 
Central Lab:  Fibrinogen, AT-III, FX 
 
 
X 4 
 
 
 
Central Lab:  RVVT 
 
 
X 4 
 
 
 
Central Lab:  Anti-fX, Anti-fXa, Anti-
andexanet Antibodies (Neutralizing 
Antibodies as appropriate) 
 
 
X 4 
 
 
 
VTE Screening 
X 
X 
 
 
 
 
Concomitant Medication 
 
X------------------------------------------------------X 
Adverse Events 
 
X -------------------------------------------------------- X 
1 Screening activities may be done on more than one day. 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 80 
2 qAM for edoxaban; q12h for apixaban and rivaroxaban; Window for dosing is ± 3 minutes. 
3 Last dose for all anticoagulants = Hour 0 (zero) on Day 6. 
4 To be completed after randomization but prior to administering 1st dose of anticoagulant (Day 1) or andexanet. 
5 To be completed within 5 minutes prior to anticoagulant administration. 
 
Visit: 
INPT 
Day: 
5 
Hour: 
PRE 
0 
1 
2 
3 
4 
5 
6 
7 
8 
12 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
Local Lab:  Serum Chemistry 
X 
 
 
 
 
 
 
 
 
 
 
Local Lab:  Hematology 
X 
 
 
 
 
 
 
 
 
 
 
Local Lab:  Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
Stool (occult blood) 
X 
Administer Anticoagulant 1, 2 
 
X 2 
 
 
 
 
 
 
 
 
X 2 
Central Lab:  Anticoagulant PK (blood) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local Lab:  PT, aPTT, ACT 
X 
 
X 3 
 
Central Lab:  Anti-fXa Activity 
X 
 
X 3 
 
Central Lab:  Thrombin Generation 
X 
 
X 3 
 
Central Lab:  F1+2, TAT, D-dimer, Total TFPI, 
TFPI Activity 
X 
 
X 3 
 
Central Lab:  tPA, PAP, TAFI, Free TFPI, β-TG, 
PF4, sTM 
X 
 
X 3 
 
Central Lab:  Fibrinogen, AT-III, FX 
X 
 
X 3 
 
Concomitant Medication 
X…………………………………………………………….X 
Adverse Events 
X…………………………………………………………….X 
1 qAM for edoxaban; q12h for apixaban and rivaroxaban.  Window for dosing is ± 3 minutes. 
2 Last dose for all anticoagulants = Hour 0 (zero) on Day 6. 
3 These laboratory measurements should be performed 24 hours prior to the end of the andexanet/placebo 
continuous infusion on Day 6.  For Cohorts 1, 3, 5, and 6, collection should be 3 hours after FXa inhibitor dosing.  
For Cohort 2, collection should be 4 hours after the FXa inhibitor dose.  For Cohorts 4 and 7, collection should be 
90 minutes after the FXa inhibitor dose.  For Cohorts 8, 9, and 10, collection should be 8 hours after the FXa 
inhibitor dose. 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 81 
Visit: 
INPT 
Day: 
6 
 
Hours Post 
Anticoagulant Dose 
End of Bolus 
Minutes after the Start 
of Andexanet Infusion 
Hours Post Completion of Andexanet Infusion 
Hour for Cohorts 1, 3, 5, 
6: 
PRE 
0 
1 
2 
3 
End 
Bolus 
(+2 
min) 
End 
Bolus 
(+5 
min) 
45 
min 
90 
min 
110 
min 
End 
Infu-
sion (-2 
min) 
5 
min 0.5 1 1.5 2 2.5 3 3.5 
4.5 
5.5 
6.5 
7.5 
8.5 14.5 
Hour for Cohort 2: 
PRE 
0 
1 
2 
4 
Hour for Cohorts 4, 7: 
PRE 
0 
1 
 
1.5 
Hours for Cohorts 8-10: 
PRE 
0 
1 
2 
8 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
X 4 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse Oximetry 
X 
 
 
 
X 4 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local Lab:  Serum 
Chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Lab:  Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Lab:  Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Stool (occult blood) 
 
X 
Administer 
Anticoagulant 1, 2 
 
X 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Andexanet 
 
 
 
 
X 3 
X…………………..……… ................... X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Lab:  
Anticoagulant PK (blood) 
X 
 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Central Lab:  Andexanet 
PK (blood) 
 
 
 
 
X  
X 
X 
X 
 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local Lab:  PT, aPTT, 
ACT 
X 
 
 
 
X  
X 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
Central Lab:  Anti-fXa 
Activity 
X 
 
 
 
X  
X 
X 
X 
X 
X 
X 
X 
X X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 82 
  
Visit 
INPT 
Day 
6 
 
Hours Post 
Anticoagulant Dose 
End of Bolus 
Minutes after the Start 
of Andexanet Infusion 
Hours Post Completion of Andexanet Infusion 
Hour for Cohorts 
1, 3, 5, 6: PRE 
0 
1 
2 
3 
End 
Bolus 
(+2 
min) 
End 
Bolus 
(+5 
min) 
45 
min 
90 
min 
110 
min 
End 
Infu-
sion (-2 
min) 
5 
min 0.5 1 1.5 2 2.5 3 3.5 
4.5 
5.5 
6.5 
7.5 
8.5 14.5 
Hour for Cohort 2: PRE 
0 
1 
2 
4 
Hour for Cohorts 4, 7: PRE 
0 
1 
 
1.5 
Hours for Cohorts 8-10: PRE 
0 
1 
2 
8 
Central Lab:  Thrombin 
Generation 
X 
 
 
 
X  
X 
X 
X 
X 
X 
X 
X 
X X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Central Lab:  F1+2, TAT, 
D-dimer, Total TFPI, 
TFPI activity 
 
X 
 
 
 
 
X  
 
X 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Central Lab:  tPA, PAP, 
TAFI, 
Free TFPI, β-TG, PF4, 
sTM 
 
 
X 
 
 
 
 
 
X  
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Fibrinogen, AT-III, FX 
X 
 
 
 
X  
X 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
VTE Screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant Medication 
X ------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Adverse Events 
X ------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
1 qAM for edoxaban; q12h for apixaban and rivaroxaban.  Window for dosing is ± 3 minutes. 
2 Last dose for all anticoagulants = Hour 0 (zero) on Day 6. 
3 IV will be in place 90 minutes pre-dose and for at least 3 hours post last dose of andexanet. 
4 To be completed after randomization but prior to administering andexanet as well as at 3 minutes and 10 minutes after the start of bolus administration. 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 83 
Visit: 
INPT 
INPT 
INPT 
Discharge 
Day: 
7 
8 
9 
10 
 
Hours Post 
Last Anticoagulant Dose 
 
 
24 
36 
48 
60 
0 
0 
Physical Examination 
X 
 
 
 
 
X 
Vital Signs (sitting) 
X 
 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
Local Lab:  Serum Chemistry 
X 
 
 
 
 
X 
Local Lab:  Hematology 
X 
 
 
 
 
X 
Local Lab:  Urinalysis 
X 
 
 
 
 
X 
Local Lab:  Serum Pregnancy 
 
 
 
 
 
X 
Stool (occult blood) 
X 
X 
X 
X 
Central Lab:  Anticoagulant PK (blood) 
X 
 
X 
 
X 
X 
Central Lab:  Andexanet PK (blood) 
X 
 
X 
 
X 
 
Local Lab:  PT, aPTT, ACT 
X 
 
X 
 
X 
X 
Central Lab:  Thrombin Generation 
X 
 
 
 
X 
 
Central Lab:  Anti-fXa Activity 
X 
 
X 
 
X 
 
Central Lab:  F1+2, TAT, D-dimer, Total 
TFPI, TFPI activity 
X 
 
X 
 
X 
X 
Central Lab:  tPA, PAP, TAFI, Free TFPI, 
b-TG, PF4, sTM 
X 
 
X 
 
X 
X 
Central Lab:  Fibrinogen, AT-III, FX 
X 
 
X 
 
X 
X 
VTE Screening 
X 
 
 
 
 
X 
Concomitant Medication 
X  
Adverse Events 
X  


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 84 
Visit: 
OPV 
Termination OPV 
Day: 
20 (+3 days) 
36 (+3 days) 
Physical Examination 
 
X 
Vital Signs (sitting) 
X 
X 
12-lead ECG 
 
X 
Local Lab:  Serum Chemistry 
 
X 
Local Lab:  Hematology 
 
X 
Local Lab:  Urinalysis 
 
X 
Local Lab:  Serum Pregnancy 
 
X 
Local Lab:  Urine (drugs of abuse) 
 
X 
Local Lab:  Breathalyzer (Ethanol screen) 
 
X 
Central Lab:  Thrombin Generation 
X 
X 
Central Lab:  F1+2, TAT, D-dimer, Total 
TFPI, TFPI Activity 
X 
X 
Central Lab:  tPA, PAP, TAFI, Free TFPI, 
b-TG, PF4, sTM 
X 
X 
Central Lab:  Fibrinogen, AT-III, FX 
X 
X 
Central Lab:  RVVT 
X 
X 
Central Lab:  Anti-fX, -fXa, -Andexanet 
Antibodies (neutralizing antibodies as 
appropriate) 
X 
X 
VTE Screening 
X 
X 
Concomitant Medication 
X 
X 
Adverse Events 
X 
X 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 85 
APPENDIX B. 
STUDY EVENTS FLOW CHART (PART 2) 
Visit: 
SCREENING 1 ADMISSION 
INPT 
INPT 
INPT 
INPT 
Day: 
≤ -45 
-1 
1 
2 
3 
4 
Hour 
 
 
0 
0 
0 
0 
Informed Consent 
X 
 
 
 
 
 
Review/Complete I/E 
X 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
Physical Examination 
 
X 
 
 
 
 
Vital Signs (sitting) 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
Local Lab:  Serum Chemistry 
X 
 
 
 
 
 
Local Lab:  Hematology 
X 
X 
 
 
 
 
Local Lab:  Urinalysis 
X 
 
 
 
 
 
Local Lab:  Serum Pregnancy 
X 
X 
 
 
 
 
Local Lab:  FSH 
X 
 
 
 
 
 
Local Lab:  Urine (drugs of abuse) 
 
X 
 
 
 
 
Local Lab:  Breathalyzer (Ethanol screen) 
 
X 
 
 
 
 
Local Lab:  Hep B & C, HIV I & II 
X 
 
 
 
 
 
Local Lab:  Factor V Leiden, Protein S&C, 
Anti-thrombin III 
X 
 
 
 
 
 
Stool (occult blood) (if produced) 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
Administer Anticoagulant 2, 3 
 
 
X 
X 
X 
X 
Central Lab:  Anticoagulant PK (blood) 
 
 
X 4 
 
 
 
Local Lab:  PT, aPTT, ACT 
X 
 
 
 
 
 
Central Lab:  Thrombin generation 
 
 
X 4 
 
 
 
Central Lab:  Anti-fXa activity 
 
 
X 4 
 
 
 
Central Lab:  F1+2, TAT, D-dimer, TFPI 
activity 
 
 
X 4 
X 5 
X 5 
X 5 
Central Lab:  Anti-fX, Anti-fXa, Anti-
andexanet Antibodies (Neutralizing 
Antibodies as appropriate) 
 
 
X 4 
 
 
 
VTE Screening 
X 
X 
 
 
 
 
Concomitant Medication 
 
X------------------------------------------------------X 
Adverse Events 
 
X -------------------------------------------------------- X 
1 Screening activities may be done on more than one day. 
2 qAM for edoxaban; q12h for apixaban and rivaroxaban; Window for dosing is ± 3 minutes. 
3 Last dose for all anticoagulants = Hour 0 (zero) on Day 6. 
4 To be completed after randomization but prior to administering 1st dose of anticoagulant (Day 1) or andexanet. 
5 To be completed within 5 minutes prior to anticoagulant administration. 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 86 
 
Visit: 
INPT 
Day: 
5 
Hour: 
PRE 
0 
1 
2 
3 
4 
5 
6 
7 
8 
12 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
Local Lab:  Serum Chemistry 
X 
 
 
 
 
 
 
 
 
 
 
Local Lab:  Hematology 
X 
 
 
 
 
 
 
 
 
 
 
Local Lab:  Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
Stool (occult blood) 
X 
Administer Anticoagulant 1, 2 
 
X 2 
 
 
 
 
 
 
 
 
X 2 
Central Lab:  Anticoagulant PK (blood) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Central Lab:  Anti-fXa Activity 
X 
 
X 3 
 
Central Lab:  Thrombin Generation 
X 
 
X 3 
 
Central Lab:  F1+2, TAT, D-dimer, TFPI Activity 
X 
 
X 3 
 
Concomitant Medication 
X…………………………………………………………….X 
Adverse Events 
X…………………………………………………………….X 
1 qAM for edoxaban; q12h for apixaban and rivaroxaban.  Window for dosing is ± 3 minutes. 
2 Last dose for all anticoagulants = Hour 0 (zero) on Day 6. 
3 These laboratory measurements should be performed 24 hours prior to the end of the andexanet/placebo 
continuous infusion on Day 6.  For Cohorts 1, 3, 5, and 6, collection should be 3 hours after FXa inhibitor dosing.  
For Cohort 2, collection should be 4 hours after the FXa inhibitor dose.  For Cohorts 4 and 7, collection should be 
90 minutes after the FXa inhibitor dose.  For Cohorts 8, 9, and 10, collection should be 8 hours after the FXa 
inhibitor dose. 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 87 
Visit: 
INPT 
Day: 
6 
 
Hours Post 
Anticoagulant Dose 
End of Bolus 
Minutes after the Start 
of Andexanet Infusion 
Hours Post Completion of Andexanet Infusion 
Hour for 
Cohorts 1, 3, 5, 6: PRE 
0 
1 
2 
3 
End 
Bolus 
(+2 
min) 
End 
Bolus 
(+5 
min) 
45 
min 
90 
min 
110 
min 
End 
Infu-
sion (-2 
min) 
5 
min 0.5 1 1.5 2 2.5 3 3.5 
4.5 
5.5 
6.5 
7.5 
8.5 14.5 
Hour for Cohort 2: PRE 
0 
1 
2 
4 
Hour for Cohorts 4, 7: PRE 
0 
1 
 
1.5 
Hours for Cohorts 8-10: PRE 
0 
1 
2 
8 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
X 4 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse Oximetry 
X 
 
 
 
X 4 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local Lab:  Serum 
Chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Lab:  Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Lab:  Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Stool (occult blood) 
 
X 
Administer 
Anticoagulant 1, 2 
 
X 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Andexanet 
 
 
 
 
X 3 
X…………………..……… ................... X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Lab:  
Anticoagulant PK (blood) 
X 
 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Central Lab:  Andexanet 
PK (blood) 
 
 
 
 
X  
X 
X 
X 
 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Central Lab:  Anti-fXa 
Activity 
X 
 
 
 
X  
X 
X 
X 
X 
X 
X 
X 
X X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 88 
Visit 
INPT 
Day 
6 
 
Hours Post 
Anticoagulant Dose 
End of Bolus 
Minutes after the Start 
of Andexanet Infusion 
Hours Post Completion of Andexanet Infusion 
Hour for Cohorts 1, 3, 5, 
6 
PRE 
0 
1 
2 
3 
End 
Bolus 
(+2 
min) 
End 
Bolus 
(+5 
min) 
45 
min 
90 
min 
110 
min 
End 
Infu-
sion (-2 
min) 
5 
min 0.5 1 1.5 2 2.5 3 3.5 
4.5 
5.5 
6.5 
7.5 
8.5 14.5 
Hour for Cohort 2 
PRE 
0 
1 
2 
4 
Hour for Cohorts 4, 7 
PRE 
0 
1 
 
1.5 
Hours for Cohorts 8-10: 
PRE 
0 
1 
2 
8 
Central Lab:  Thrombin 
Generation 
X 
 
 
 
X  
X 
X 
X 
X 
X 
X 
X 
X X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Central Lab:  F1+2, TAT, 
D-dimer, TFPI activity 
 
X 
 
 
 
 
X  
 
X 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
VTE Screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant Medication 
X ------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Adverse Events 
X ------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
1 qAM for edoxaban; q12h for apixaban and rivaroxaban.  Window for dosing is ± 3 minutes. 
2 Last dose for all anticoagulants = Hour 0 (zero) on Day 6. 
3 IV will be in place 90 minutes pre-dose and for at least 3 hours post last dose of andexanet. 
4 To be completed after randomization but prior to administering andexanet as well as at 3 minutes and 10 minutes after the start of bolus administration. 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 89 
Visit: 
INPT 
INPT 
INPT 
Discharge 
Day: 
7 
8 
9 
10 
 
Hours Post Last Anticoagulant Dose 
 
 
24 
36 
48 
60 
0 
0 
Physical Examination 
X 
 
 
 
 
X 
Vital Signs (sitting) 
X 
 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
Local Lab:  Serum Chemistry 
X 
 
 
 
 
X 
Local Lab:  Hematology 
X 
 
 
 
 
X 
Local Lab:  Urinalysis 
X 
 
 
 
 
X 
Local Lab:  Serum Pregnancy 
 
 
 
 
 
X 
Stool (occult blood) 
X 
X 
X 
X 
Central Lab:  Anticoagulant PK (blood) 
X 
 
X 
 
X 
X 
Central Lab:  Andexanet PK (blood) 
X 
 
X 
 
X 
 
Central Lab:  Thrombin Generation 
X 
 
 
 
X 
 
Central Lab:  Anti-fXa Activity 
X 
 
X 
 
X 
 
Central Lab:  F1+2, TAT, D-dimer, TFPI 
activity 
X 
 
X 
 
X 
X 
VTE Screening 
X 
 
 
 
 
X 
Concomitant Medication 
X  
Adverse Events 
X  
Visit: 
OPV 
Termination OPV 
Day: 
20 (+3 days) 
36 (+3 days) 
Physical Examination 
 
X 
Vital Signs (sitting) 
X 
X 
12-lead ECG 
 
X 
Local Lab:  Serum Chemistry 
 
X 
Local Lab:  Hematology 
 
X 
Local Lab:  Urinalysis 
 
X 
Local Lab:  Serum Pregnancy 
 
X 
Local Lab:  Urine (drugs of abuse) 
 
X 
Local Lab:  Breathalyzer (Ethanol screen) 
 
X 
Central Lab:  Thrombin Generation 
X 
X 
Central Lab:  F1+2, TAT, D-dimer,  TFPI 
Activity 
X 
X 
Central Lab:  Anti-fX, -fXa, -Andexanet 
Antibodies (neutralizing antibodies as 
appropriate) 
X 
X 
VTE Screening 
X 
X 
Concomitant Medication 
X 
X 
Adverse Events 
X 
X 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 90 
APPENDIX C. 
WELLS SCORES 
Clinical risk scores [7] for assessing the probability of Pulmonary Embolism (PE) 
Parameter 
Score 
Wells score 1 for Prediction of PE (Wells) 
 
Clinically Suspected DVT 
3 
Alternative Diagnosis Less Likely than PE 
3 
Heart Rate Greater than 100 
1.5 
Immobilization within Past 4 weeks 
1.5 
History of DVT/PE 
1.5 
Haemoptysis 
1 
Malignancy (on treatment, treated in the last 6 months, or 
palliative) 
1 
1 A total score > 6 indicates a high probability of a PE, 2–6 moderate probability and 
< 2 low probability. 
 
Clinical risk scores [8] for assessing the probability of deep vein thrombosis (DVT) 
Parameter 
Score 
Entire Leg Swollen 
1 
Calf Swelling 3 cm > Asymptomatic Side 
1 
Pitting Edema Confined to Symptomatic Leg 
1 
Localized Tenderness Along Distribution of Deep Vein System 
1 
Collateral Superficial Veins (non-varicose) 
1 
Active Cancer (treatment ongoing or within previous 6 months or 
palliative) 
1 
Paralysis, Paresis, or Recent Plaster Immobilization of Legs 
1 
Recent Immobilization > 3 days or Major Surgery within 4 Weeks 
1 
Alternative Diagnosis as Likely or Greater than That of DVT 
-2 
Notes:  Clinical probability:  HIGH (3); MODERATE (1 or 2); LOW (0). 
HIGH > 75% incidence DVT; LOW < 5% incidence. 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 91 
APPENDIX D. 
US PACKAGE INSERT FOR APIXABAN (ELIQUIS) 


FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES  
THE RISK OF THROMBOTIC EVENTS
(B) SPINAL/EPIDURAL HEMATOMA
1	
INDICATIONS AND USAGE
1.1	
Reduction of Risk of Stroke and Systemic Embolism in  
Nonvalvular Atrial Fibrillation
1.2	
Prophylaxis of Deep Vein Thrombosis Following Hip or  
Knee Replacement Surgery
1.3	
Treatment of Deep Vein Thrombosis
1.4	
Treatment of Pulmonary Embolism
1.5	
Reduction in the Risk of Recurrence of DVT and PE
2	
DOSAGE AND ADMINISTRATION
2.1	
Recommended Dose
2.2	
Missed Dose
2.3	
Temporary Interruption for Surgery and Other Interventions
2.4	
Converting from or to ELIQUIS
2.5	
Strong Dual Inhibitors of CYP3A4 and P-glycoprotein
2.6	
Administration Options
3	
DOSAGE FORMS AND STRENGTHS
4	
CONTRAINDICATIONS
5	
WARNINGS AND PRECAUTIONS
5.1	
Increased Risk of Thrombotic Events after Premature Discontinuation
5.2	
Bleeding
5.3	
Spinal/Epidural Anesthesia or Puncture 
5.4	
Patients with Prosthetic Heart Valves
5.5	
Acute PE in Hemodynamically Unstable Patients or Patients who 
Require Thrombolysis or Pulmonary Embolectomy
6	
ADVERSE REACTIONS
6.1	
Clinical Trials Experience
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ELIQUIS safely 
and effectively. See full prescribing information for ELIQUIS.
ELIQUIS® (apixaban) tablets, for oral use
Initial U.S. Approval: 2012
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS  
INCREASES THE RISK OF THROMBOTIC EVENTS 
(B) SPINAL/EPIDURAL HEMATOMA
See full prescribing information for complete boxed warning.
(A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF 
THROMBOTIC EVENTS: Premature discontinuation of any oral anticoagulant, 
including ELIQUIS, increases the risk of thrombotic events. To reduce this 
risk, consider coverage with another anticoagulant if ELIQUIS is discontinued 
for a reason other than pathological bleeding or completion of a course of 
therapy. (2.4, 5.1, 14.1)
(B) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas may 
occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia 
or undergoing spinal puncture. These hematomas may result in long-term 
or permanent paralysis. Consider these risks when scheduling patients for 
spinal procedures. (5.3)
----------------------------- RECENT MAJOR CHANGES------------------------------
Dosage and Administration (2.6)	
7/2016
Warnings and Precautions (5.2)	
7/2016
------------------------------INDICATIONS AND USAGE------------------------------
ELIQUIS is a factor Xa inhibitor indicated:
•	 to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial 
fibrillation. (1.1)
•	 for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary 
embolism (PE), in patients who have undergone hip or knee replacement surgery. (1.2)
•	 for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and 
PE following initial therapy. (1.3, 1.4, 1.5)
---------------------------DOSAGE AND ADMINISTRATION---------------------------
•	 Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation:
•	 The recommended dose is 5 mg orally twice daily. (2.1)
•	 In patients with at least 2 of the following characteristics: age ≥80 years, 
body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, the recommended dose is 
2.5 mg orally twice daily. (2.1)
•	 Prophylaxis of DVT following hip or knee replacement surgery:
•	 The recommended dose is 2.5 mg orally twice daily. (2.1)
•	 Treatment of DVT and PE:
•	 The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 
5 mg taken orally twice daily. (2.1)
•	 Reduction in the risk of recurrent DVT and PE following initial therapy:
•	 The recommended dose is 2.5 mg taken orally twice daily. (2.1)
------------------------- DOSAGE FORMS AND STRENGTHS--------------------------
•	 Tablets: 2.5 mg and 5 mg (3)
--------------------------------CONTRAINDICATIONS--------------------------------
•	 Active pathological bleeding (4)
•	 Severe hypersensitivity to ELIQUIS (apixaban) (4)
---------------------------WARNINGS AND PRECAUTIONS---------------------------
•	 ELIQUIS can cause serious, potentially fatal bleeding. Promptly evaluate signs and 
symptoms of blood loss. (5.2)
•	 Prosthetic heart valves: ELIQUIS use not recommended. (5.4)
--------------------------------ADVERSE REACTIONS--------------------------------
Most common adverse reactions (>1%) are related to bleeding. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 
1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-------------------------------- DRUG INTERACTIONS--------------------------------
•	 Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of apixaban. Reduce 
ELIQUIS dose or avoid coadministration. (2.5, 7.1, 12.3)
•	 Simultaneous use of strong dual inducers of CYP3A4 and P-gp reduces blood levels 
of apixaban: Avoid concomitant use. (7.2, 12.3)
---------------------------USE IN SPECIFIC POPULATIONS---------------------------
•	 Pregnancy: Not recommended. (8.1)
•	 Nursing Mothers: Discontinue drug or discontinue nursing. (8.3)
•	 Severe Hepatic Impairment: Not recommended. (8.7, 12.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 7/2016
7	
DRUG INTERACTIONS
7.1	
Strong Dual Inhibitors of CYP3A4 and P-gp
7.2	
Strong Dual Inducers of CYP3A4 and P-gp
7.3	
Anticoagulants and Antiplatelet Agents
8	
USE IN SPECIFIC POPULATIONS
8.1	
Pregnancy
8.2	
Labor and Delivery
8.3	
Nursing Mothers
8.4	
Pediatric Use
8.5	
Geriatric Use
8.6	
Renal Impairment
8.7	
Hepatic Impairment
10	
OVERDOSAGE
11	
DESCRIPTION
12	
CLINICAL PHARMACOLOGY
12.1	
Mechanism of Action
12.2	
Pharmacodynamics
12.3	
Pharmacokinetics
13	
NONCLINICAL TOXICOLOGY
13.1	
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 	
CLINICAL STUDIES
14.1	
Reduction of Risk of Stroke and Systemic Embolism in  
Nonvalvular Atrial Fibrillation
14.2	
Prophylaxis of Deep Vein Thrombosis Following Hip or  
Knee Replacement Surgery
14.3	
Treatment of DVT and PE and Reduction in the Risk of  
Recurrence of DVT and PE
16	
HOW SUPPLIED/STORAGE AND HANDLING
17	
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.


ELIQUIS® (apixaban)
FULL PRESCRIBING INFORMATION
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE 
RISK OF THROMBOTIC EVENTS
(B) SPINAL/EPIDURAL HEMATOMA
(A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF 
THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including ELIQUIS, 
increases the risk of thrombotic events. If anticoagulation with ELIQUIS is 
discontinued for a reason other than pathological bleeding or completion of 
a course of therapy, consider coverage with another anticoagulant [see 
Dosage and Administration (2.4), Warnings and Precautions (5.1), and Clinical 
Studies (14.1)].
(B) SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients treated with ELIQUIS 
who are receiving neuraxial anesthesia or undergoing spinal puncture. 
These hematomas may result in long-term or permanent paralysis. Consider 
these risks when scheduling patients for spinal procedures. Factors that 
can increase the risk of developing epidural or spinal hematomas in these 
patients include:
•	
use of indwelling epidural catheters
•	
concomitant use of other drugs that affect hemostasis, such as 
nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other 
anticoagulants
•	
a history of traumatic or repeated epidural or spinal punctures
•	
a history of spinal deformity or spinal surgery
•	
optimal timing between the administration of ELIQUIS and neuraxial 
procedures is not known
[see Warnings and Precautions (5.3)]
Monitor patients frequently for signs and symptoms of neurological 
impairment. If neurological compromise is noted, urgent treatment is 
necessary [see Warnings and Precautions (5.3)].
Consider the benefits and risks before neuraxial intervention in patients 
anticoagulated or to be anticoagulated [see Warnings and Precautions (5.3)].
1	
INDICATIONS AND USAGE
1.1	
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial 
Fibrillation
ELIQUIS® (apixaban) is indicated to reduce the risk of stroke and systemic embolism in 
patients with nonvalvular atrial fibrillation.
1.2	
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement 
Surgery
ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may 
lead to pulmonary embolism (PE), in patients who have undergone hip or knee 
replacement surgery.
1.3	
Treatment of Deep Vein Thrombosis
ELIQUIS is indicated for the treatment of DVT.
1.4	
Treatment of Pulmonary Embolism
ELIQUIS is indicated for the treatment of PE.
1.5	
Reduction in the Risk of Recurrence of DVT and PE
ELIQUIS is indicated to reduce the risk of recurrent DVT and PE following initial therapy.
2	
DOSAGE AND ADMINISTRATION 
2.1	
Recommended Dose
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular 
Atrial Fibrillation
The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily.
The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with at least two of 
the following characteristics:
•	
age ≥80 years 
•	
body weight ≤60 kg 
•	
serum creatinine ≥1.5 mg/dL
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose 
should be taken 12 to 24 hours after surgery.
•	
In patients undergoing hip replacement surgery, the recommended duration of 
treatment is 35 days.
•	
In patients undergoing knee replacement surgery, the recommended duration of 
treatment is 12 days.
Treatment of DVT and PE
The recommended dose of ELIQUIS is 10 mg taken orally twice daily for the first 7 days of 
therapy. After 7 days, the recommended dose is 5 mg taken orally twice daily.
Reduction in the Risk of Recurrence of DVT and PE
The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least 
6 months of treatment for DVT or PE [see Clinical Studies (14.3)].
2.2	
Missed Dose
If a dose of ELIQUIS is not taken at the scheduled time, the dose should be taken as 
soon as possible on the same day and twice-daily administration should be resumed. 
The dose should not be doubled to make up for a missed dose.
2.3	
Temporary Interruption for Surgery and Other Interventions
ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive 
procedures with a moderate or high risk of unacceptable or clinically significant bleeding. 
ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive 
procedures with a low risk of bleeding or where the bleeding would be non-critical in 
location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after 
stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should 
be restarted after the surgical or other procedures as soon as adequate hemostasis has 
been established.
2.4	
Converting from or to ELIQUIS
Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS started 
when the international normalized ratio (INR) is below 2.0.
Switching from ELIQUIS to warfarin: ELIQUIS affects INR, so that initial INR measurements 
during the transition to warfarin may not be useful for determining the appropriate 
dose of warfarin. One approach is to discontinue ELIQUIS and begin both a parenteral 
anticoagulant and warfarin at the time the next dose of ELIQUIS would have been taken, 
discontinuing the parenteral anticoagulant when INR reaches an acceptable range.
Switching from ELIQUIS to anticoagulants other than warfarin (oral or parenteral): 
Discontinue ELIQUIS and begin taking the new anticoagulant other than warfarin at the 
usual time of the next dose of ELIQUIS.
Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS: 
Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the usual 
time of the next dose of the anticoagulant other than warfarin.
2.5	
Strong Dual Inhibitors of CYP3A4 and P-glycoprotein
For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose 
by 50% when ELIQUIS is coadministered with drugs that are strong dual inhibitors 
of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, 
itraconazole, ritonavir, clarithromycin) [see Clinical Pharmacology (12.3)].
In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with 
strong dual inhibitors of CYP3A4 and P-gp [see Drug Interactions (7.1)].
2.6	
Administration Options
For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS tablets 
may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, 
or mixed with applesauce and promptly administered orally [see Clinical Pharmacology 
(12.3)]. Alternatively, ELIQUIS tablets may be crushed and suspended in 60 mL of water 
or D5W and promptly delivered through a nasogastric tube [see Clinical Pharmacology 
(12.3)].
Crushed ELIQUIS tablets are stable in water, D5W, apple juice, and applesauce for up 
to 4 hours.
3	
DOSAGE FORMS AND STRENGTHS
•	
2.5  mg, yellow, round, biconvex, film-coated tablets with “893” debossed on 
one side and “2½” on the other side.
•	
5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894” debossed on 
one side and “5” on the other side.
4	
CONTRAINDICATIONS 
ELIQUIS is contraindicated in patients with the following conditions:
•	
Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse 
Reactions (6.1)]
•	
Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) [see 
Adverse Reactions (6.1)]
5	
WARNINGS AND PRECAUTIONS
5.1	
Increased Risk of Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence 
of adequate alternative anticoagulation increases the risk of thrombotic events. 
An increased rate of stroke was observed during the transition from ELIQUIS to warfarin 
in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a reason other 
than pathological bleeding or completion of a course of therapy, consider coverage with 
another anticoagulant [see Dosage and Administration (2.4) and Clinical Studies (14.1)].
5.2	
Bleeding
ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding 
[see Dosage and Administration (2.1) and Adverse Reactions (6.1)].


ELIQUIS® (apixaban)
ELIQUIS® (apixaban)
Concomitant use of drugs affecting hemostasis increases the risk of bleeding. 
These include aspirin and other antiplatelet agents, other anticoagulants, heparin, 
thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine 
reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug 
Interactions (7.3)].
Advise patients of signs and symptoms of blood loss and to report them immediately 
or go to an emergency room. Discontinue ELIQUIS in patients with active pathological 
hemorrhage.
Reversal of Anticoagulant Effect
A specific antidote for ELIQUIS is not available, and there is no established way to 
reverse bleeding in patients taking ELIQUIS. The pharmacodynamic effect of ELIQUIS 
can be expected to persist for at least 24 hours after the last dose, i.e., for about two 
drug half-lives. Use of procoagulant reversal agents, such as prothrombin complex 
concentrate (PCC), activated prothrombin complex concentrate or recombinant 
factor VIIa, may be considered but has not been evaluated in clinical studies [see Clinical 
Pharmacology (12.2)]. When PCCs are used, monitoring for the anticoagulation effect 
of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not 
useful and is not recommended. Activated oral charcoal reduces absorption of apixaban, 
thereby lowering apixaban plasma concentration [see Overdosage (10)].
Hemodialysis does not appear to have a substantial impact on apixaban exposure [see 
Clinical Pharmacology (12.3)]. Protamine sulfate and vitamin K are not expected to 
affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic 
agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is 
no experience with systemic hemostatics (desmopressin and aprotinin) in individuals 
receiving apixaban and they are not expected to be effective as a reversal agent.
5.3	
Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is 
employed, patients treated with antithrombotic agents for prevention of thromboembolic 
complications are at risk of developing an epidural or spinal hematoma which can result 
in long-term or permanent paralysis.
The risk of these events may be increased by the postoperative use of indwelling epidural 
catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling 
epidural or intrathecal catheters should not be removed earlier than 24 hours after the 
last administration of ELIQUIS. The next dose of ELIQUIS should not be administered 
earlier than 5 hours after the removal of the catheter. The risk may also be increased 
by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay 
the administration of ELIQUIS for 48 hours.
Monitor patients frequently for signs and symptoms of neurological impairment (e.g., 
numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological 
compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial 
intervention the physician should consider the potential benefit versus the risk in 
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
5.4	
Patients with Prosthetic Heart Valves
The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart 
valves. Therefore, use of ELIQUIS is not recommended in these patients.
5.5	
Acute PE in Hemodynamically Unstable Patients or Patients who Require 
Thrombolysis or Pulmonary Embolectomy
Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin 
for the initial treatment of patients with PE who present with hemodynamic instability or 
who may receive thrombolysis or pulmonary embolectomy.
6	
ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections 
of the prescribing information.
•	
Increased risk of thrombotic events after premature discontinuation [see Warnings 
and Precautions (5.1)]
•	
Bleeding [see Warnings and Precautions (5.2)]
•	
Spinal/epidural anesthesia or puncture [see Warnings and Precautions (5.3)]
6.1	
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in the clinical trials of a drug cannot be directly compared to rates in the 
clinical trials of another drug and may not reflect the rates observed in practice.
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial 
Fibrillation
The safety of ELIQUIS was evaluated in the ARISTOTLE and AVERROES studies [see 
Clinical Studies (14)], including 11,284 patients exposed to ELIQUIS 5 mg twice daily and 
602 patients exposed to ELIQUIS 2.5 mg twice daily. The duration of ELIQUIS exposure 
was ≥12 months for 9375 patients and ≥24 months for 3369 patients in the two studies. 
In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000 patient-years). 
In AVERROES, the mean duration of exposure was approximately 59 weeks (>3000 
patient-years).
The most common reason for treatment discontinuation in both studies was for bleeding-
related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients 
treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on 
ELIQUIS and aspirin, respectively.
Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES
Tables 1 and 2 show the number of patients experiencing major bleeding during the 
treatment period and the bleeding rate (percentage of subjects with at least one bleeding 
event per 100 patient-years) in ARISTOTLE and AVERROES.
Table 1:	
Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in 
ARISTOTLE*
ELIQUIS 
N=9088 
n (per  
100 pt-year)
Warfarin 
N=9052 
n (per  
100 pt-year)
Hazard Ratio 
(95% CI)
P-value
Major†
327 (2.13)
462 (3.09)
0.69 (0.60, 0.80)
<0.0001
	 Intracranial (ICH)‡
52 (0.33)
125 (0.82)
0.41 (0.30, 0.57)
-
	 	 Hemorrhagic stroke§
38 (0.24)
74 (0.49)
0.51 (0.34, 0.75)
-
	 	 Other ICH
15 (0.10)
51 (0.34)
0.29 (0.16, 0.51)
-
	 Gastrointestinal (GI)¶
128 (0.83)
141 (0.93)
0.89 (0.70, 1.14)
-
	 Fatal**
10 (0.06)
37 (0.24)
0.27 (0.13, 0.53)
-
	 	 Intracranial
4 (0.03)
30 (0.20)
0.13 (0.05, 0.37)
-
	 	 Non-intracranial
6 (0.04)
7 (0.05)
0.84 (0.28, 2.15)
-
*	Bleeding events within each subcategory were counted once per subject, but subjects 
may have contributed events to multiple endpoints. Bleeding events were counted during 
treatment or within 2 days of stopping study treatment (on-treatment period).
†	Defined as clinically overt bleeding accompanied by one or more of the following: 
a decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of packed 
red blood cells, bleeding at a critical site: intracranial, intraspinal, intraocular, pericardial, 
intra-articular, intramuscular with compartment syndrome, retroperitoneal or with 
fatal outcome.
‡	Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid 
bleeding. Any type of hemorrhagic stroke was adjudicated and counted as an intracranial 
major bleed.
§	On-treatment analysis based on the safety population, compared to ITT analysis presented 
in Section 14.
¶	GI bleed includes upper GI, lower GI, and rectal bleeding.
**	Fatal bleeding is an adjudicated death with the primary cause of death as intracranial 
bleeding or non-intracranial bleeding during the on-treatment period.
In ARISTOTLE, the results for major bleeding were generally consistent across most major 
subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate 
risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic 
region, and aspirin use at randomization (Figure 1). Subjects treated with apixaban with 
diabetes bled more (3.0% per year) than did subjects without diabetes (1.9% per year).


ELIQUIS® (apixaban)
ELIQUIS® (apixaban)
Figure 1:	
Major Bleeding Hazard Ratios by Baseline Characteristics – ARISTOTLE Study
Apixaban
Better
Warfarin
Better
n of Events / N of Patients (% per year)
Subgroup
Apixaban
Warfarin
Hazard Ratio (95% CI)
All Patients
327 / 9088 (2.1)
462 / 9052 (3.1)
0.69 (0.60, 0.80)
Prior Warfarin/VKA Status
 
Experienced (57%)
185 / 5196 (2.1)
274 / 5180 (3.2)
0.66 (0.55, 0.80)
 
Naive (43%)
142 / 3892 (2.2)
188 / 3872 (3.0)
0.73 (0.59, 0.91)
Age
 
<65 (30%)
56 / 2723 (1.2)
72 / 2732 (1.5)
0.78 (0.55, 1.11)
 
≥65 and <75 (39%)
120 / 3529 (2.0)
166 / 3501 (2.8)
0.71 (0.56, 0.89)
 
≥75 (31%)
151 / 2836 (3.3)
224 / 2819 (5.2)
0.64 (0.52, 0.79)
Sex
 
Male (65%)
225 / 5868 (2.3)
294 / 5879 (3.0)
0.76 (0.64, 0.90)
 
Female (35%)
102 / 3220 (1.9)
168 / 3173 (3.3)
0.58 (0.45, 0.74)
Weight
 
≤60 kg (11%)
36 / 1013 (2.3)
62 / 965 (4.3)
0.55 (0.36, 0.83)
 
>60 kg (89%)
290 / 8043 (2.1)
398 / 8059 (3.0)
0.72 (0.62, 0.83)
Prior Stroke or TIA
 
Yes (19%)
77 / 1687 (2.8)
106 / 1735 (3.9)
0.73 (0.54, 0.98)
 
No (81%)
250 / 7401 (2.0)
356 / 7317 (2.9)
0.68 (0.58, 0.80)
Diabetes Mellitus
 
Yes (25%)
112 / 2276 (3.0)
114 / 2250 (3.1)
0.96 (0.74, 1.25)
 
No (75%)
215 / 6812 (1.9) 
348 / 6802 (3.1)
0.60 (0.51, 0.71)
CHADS2 Score
 ≤1 (34%)
76 / 3093 (1.4)
126 / 3076 (2.3)
0.59 (0.44, 0.78)
 
2 (36%)
125 / 3246 (2.3)
163 / 3246 (3.0)
0.76 (0.60, 0.96)
 ≥3 (30%)
126 / 2749 (2.9)
173 / 2730 (4.1)
0.70 (0.56, 0.88)
Creatinine Clearance
 
<30 mL/min (1%)
7 / 136 (3.7)
19 / 132 (11.9)
0.32 (0.13, 0.78)
 
30-50 mL/min (15%)
66 / 1357 (3.2)
123 / 1380 (6.0)
0.53 (0.39, 0.71)
 >50-80 mL/min (42%)
157 / 3807 (2.5)
199 / 3758 (3.2)
0.76 (0.62, 0.94)
 
>80 mL/min (41%)
96 / 3750 (1.5)
119 / 3746 (1.8)
0.79 (0.61, 1.04)
Geographic Region
 
US (19%)
83 / 1716 (2.8)
109 / 1693 (3.8)
0.75 (0.56, 1.00)
 
Non-US (81%)
244 / 7372 (2.0)
353 / 7359 (2.9)
0.68 (0.57, 0.80)
Aspirin at Randomization
 
Yes (31%)
129 / 2846 (2.7)
164 / 2762 (3.7)
0.75 (0.60, 0.95)
 
No (69%)
198 / 6242 (1.9)
298 / 6290 (2.8)
0.66 (0.55, 0.79)
 0.125 
0.25 
0.5 
1 
2
Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were pre-specified, if not the groupings. The 95% confidence limits 
that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity 
or heterogeneity among groups should not be over-interpreted.
Table 2:	
Bleeding Events in Patients with Nonvalvular Atrial Fibrillation 
in AVERROES 
ELIQUIS
N=2798
n (%/year)
Aspirin
N=2780
n (%/year)
Hazard Ratio 
(95% CI)
P-value
Major
45 (1.41)
29 (0.92)
1.54 (0.96, 2.45)
0.07
	
Fatal
5 (0.16)
5 (0.16)
0.99 (0.23, 4.29)
-
	
Intracranial
11 (0.34)
11 (0.35)
0.99 (0.39, 2.51)
-
Events associated with each endpoint were counted once per subject, but subjects may have 
contributed events to multiple endpoints.
Other Adverse Reactions
Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and 
anaphylactic reactions, such as allergic edema) and syncope were reported in <1% of 
patients receiving ELIQUIS.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
The safety of ELIQUIS has been evaluated in 1 Phase II and 3 Phase III studies including 
5924 patients exposed to ELIQUIS 2.5 mg twice daily undergoing major orthopedic 
surgery of the lower limbs (elective hip replacement or elective knee replacement) 
treated for up to 38 days.
In total, 11% of the patients treated with ELIQUIS 2.5 mg twice daily experienced adverse 
reactions.
Bleeding results during the treatment period in the Phase III studies are shown in Table 3. 
Bleeding was assessed in each study beginning with the first dose of double-blind 
study drug.
Table 3: 	
Bleeding During the Treatment Period in Patients Undergoing 
Elective Hip or Knee Replacement Surgery
Bleeding 
Endpoint*
ADVANCE-3 
Hip Replacement 
Surgery
ADVANCE-2 
Knee Replacement 
Surgery
ADVANCE-1 
Knee Replacement 
Surgery
ELIQUIS 
2.5 mg po 
bid 
35±3 days
Enoxaparin 
40 mg 
sc qd 
35±3 days
ELIQUIS 
2.5 mg po 
bid 
12±2 days
Enoxaparin 
40 mg 
sc qd 
12±2 days
ELIQUIS 
2.5 mg po 
bid 
12±2 days
Enoxaparin 
30 mg sc 
q12h 
12±2 days
First dose 
12 to 
24 hours 
post 
surgery
First dose 
9 to 
15 hours 
prior 
to surgery
First dose 
12 to 
24 hours 
post 
surgery
First dose 
9 to 
15 hours 
prior 
to surgery
First dose 
12 to 
24 hours 
post 
surgery
First dose 
12 to 
24 hours 
post 
surgery
All treated
N=2673
N=2659
N=1501
N=1508
N=1596
N=1588
Major 
(including 
surgical site) 
22 
(0.82%)†
18 
(0.68%)
9 
(0.60%)‡
14 
(0.93%)
11 
(0.69%) 
22 
(1.39%)
	 Fatal
0
0
0
0
0
1 
(0.06%)
	 Hgb decrease 
≥2 g/dL
13 
(0.49%)
10 
(0.38%)
8 
(0.53%)
9 
(0.60%)
10 
(0.63%)
16 
(1.01%)
	 Transfusion of 
≥2 units RBC
16 
(0.60%)
14 
(0.53%)
5 
(0.33%)
9 
(0.60%)
9 
(0.56%)
18 
(1.13%)
(Continued)


ELIQUIS® (apixaban)
ELIQUIS® (apixaban)
Table 3: 	
Bleeding During the Treatment Period in Patients Undergoing 
Elective Hip or Knee Replacement Surgery
Bleeding 
Endpoint*
ADVANCE-3 
Hip Replacement 
Surgery
ADVANCE-2 
Knee Replacement 
Surgery
ADVANCE-1 
Knee Replacement 
Surgery
ELIQUIS 
2.5 mg po 
bid 
35±3 days
Enoxaparin 
40 mg 
sc qd 
35±3 days
ELIQUIS 
2.5 mg po 
bid 
12±2 days
Enoxaparin 
40 mg 
sc qd 
12±2 days
ELIQUIS 
2.5 mg po 
bid 
12±2 days
Enoxaparin 
30 mg sc 
q12h 
12±2 days
First dose 
12 to 
24 hours 
post 
surgery
First dose 
9 to 
15 hours 
prior 
to surgery
First dose 
12 to 
24 hours 
post 
surgery
First dose 
9 to 
15 hours 
prior 
to surgery
First dose 
12 to 
24 hours 
post 
surgery
First dose 
12 to 
24 hours 
post 
surgery
	 Bleed at 
critical site§
1 
(0.04%)
1 
 (0.04%)
1 
 (0.07%)
2 
(0.13%)
1 
(0.06%)
4 
(0.25%)
Major 
+ CRNM¶
129 
(4.83%)
134 
(5.04%)
53 
(3.53%)
72 
(4.77%)
46 
(2.88%)
68 
(4.28%)
All
313 
(11.71%)
334 
(12.56%)
104 
(6.93%)
126 
(8.36%)
85 
(5.33%)
108 
(6.80%) 
*	All bleeding criteria included surgical site bleeding.
†	Includes 13 subjects with major bleeding events that occurred before the first dose of 
apixaban (administered 12 to 24 hours post surgery).
‡	Includes 5 subjects with major bleeding events that occurred before the first dose of 
apixaban (administered 12 to 24 hours post surgery).
§	Intracranial, intraspinal, intraocular, pericardial, an operated joint requiring re-operation or 
intervention, intramuscular with compartment syndrome, or retroperitoneal. Bleeding into 
an operated joint requiring re-operation or intervention was present in all patients with 
this category of bleeding. Events and event rates include one enoxaparin-treated patient in 
ADVANCE-1 who also had intracranial hemorrhage.
¶	CRNM = clinically relevant nonmajor.
Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement 
surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4.
Table 4:	
Adverse Reactions Occurring in ≥1% of Patients in Either Group 
Undergoing Hip or Knee Replacement Surgery
ELIQUIS, n (%) 
2.5 mg po bid 
 
N=5924
Enoxaparin, n (%) 
40 mg sc qd or 
30 mg sc q12h 
N=5904
Nausea
153 (2.6)
159 (2.7)
Anemia (including postoperative and 
hemorrhagic anemia, and respective laboratory 
parameters)
153 (2.6)
178 (3.0)
Contusion
83 (1.4)
115 (1.9)
Hemorrhage (including hematoma, and vaginal 
and urethral hemorrhage)
67 (1.1)
81 (1.4)
Postprocedural hemorrhage (including 
postprocedural hematoma, wound hemorrhage, 
vessel puncture site hematoma and catheter 
site hemorrhage)
54 (0.9)
60 (1.0)
Transaminases increased (including alanine 
aminotransferase increased and alanine 
aminotransferase abnormal)
50 (0.8)
71 (1.2)
Aspartate aminotransferase increased
47 (0.8)
69 (1.2)
Gamma-glutamyltransferase increased
38 (0.6)
65 (1.1)
Less common adverse reactions in apixaban-treated patients undergoing hip or knee 
replacement surgery occurring at a frequency of ≥0.1% to <1%:
Blood and lymphatic system disorders: thrombocytopenia (including platelet count 
decreases)
Vascular disorders: hypotension (including procedural hypotension)
Respiratory, thoracic, and mediastinal disorders: epistaxis
Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and 
melena), hematochezia
Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase 
increased, blood bilirubin increased
Renal and urinary disorders: hematuria (including respective laboratory parameters)
Injury, poisoning, and procedural complications: wound secretion, incision-site 
hemorrhage (including incision-site hematoma), operative hemorrhage
(Continued)
Less common adverse reactions in apixaban-treated patients undergoing hip or knee 
replacement surgery occurring at a frequency of <0.1%:
Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage 
(including conjunctival hemorrhage), rectal hemorrhage
Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT or PE
The safety of ELIQUIS has been evaluated in the AMPLIFY and AMPLIFY-EXT studies, 
including 2676 patients exposed to ELIQUIS 10 mg twice daily, 3359 patients exposed 
to ELIQUIS 5 mg twice daily, and 840 patients exposed to ELIQUIS 2.5 mg twice daily.
Common adverse reactions (≥1%) were gingival bleeding, epistaxis, contusion, 
hematuria, rectal hemorrhage, hematoma, menorrhagia, and hemoptysis.
AMPLIFY Study
The mean duration of exposure to ELIQUIS was 154 days and to enoxaparin/warfarin 
was 152 days in the AMPLIFY study. Adverse reactions related to bleeding occurred in 
417 (15.6%) ELIQUIS-treated patients compared to 661 (24.6%) enoxaparin/warfarin-
treated patients. The discontinuation rate due to bleeding events was 0.7% in the 
ELIQUIS-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients in 
the AMPLIFY study.
In the AMPLIFY study, ELIQUIS was statistically superior to enoxaparin/warfarin in the 
primary safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55], 
P-value <0.0001).
Bleeding results from the AMPLIFY study are summarized in Table 5.
Table 5:	
Bleeding Results in the AMPLIFY Study 
ELIQUIS 
N=2676 
n (%)
Enoxaparin/Warfarin 
N=2689 
n (%)
Relative Risk  
(95% CI)
Major
	
15 	(0.6)
	
49 	(1.8)
0.31 (0.17, 0.55) 
p<0.0001
CRNM*
	
103 	(3.9)
	
215 	(8.0)
Major + CRNM
	
115 	(4.3)
	
261 	(9.7)
Minor
	
313 	(11.7)
	
505 	(18.8)
All
	
402 	(15.0)
	
676 	(25.1)
*	CRNM = clinically relevant nonmajor bleeding.
Events associated with each endpoint were counted once per subject, but subjects may have 
contributed events to multiple endpoints.
Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6.
Table 6:	
Adverse Reactions Occurring in ≥1% of Patients Treated for 
DVT and PE in the AMPLIFY Study 
ELIQUIS 
N=2676 
n (%)
Enoxaparin/Warfarin 
N=2689 
n (%)
Epistaxis
77 (2.9)
146 (5.4)
Contusion
49 (1.8)
97 (3.6)
Hematuria
46 (1.7)
102 (3.8)
Menorrhagia
38 (1.4)
30 (1.1)
Hematoma
35 (1.3)
76 (2.8)
Hemoptysis
32 (1.2)
31 (1.2)
Rectal hemorrhage
26 (1.0)
39 (1.5)
Gingival bleeding
26 (1.0)
50 (1.9)
AMPLIFY-EXT Study
The mean duration of exposure to ELIQUIS was approximately 330 days and to placebo 
was 312 days in the AMPLIFY-EXT study. Adverse reactions related to bleeding occurred 
in 219 (13.3%) ELIQUIS-treated patients compared to 72 (8.7%) placebo-treated 
patients. The discontinuation rate due to bleeding events was approximately 1% in the 
ELIQUIS-treated patients compared to 0.4% in those patients in the placebo group in the 
AMPLIFY-EXT study.
Bleeding results from the AMPLIFY-EXT study are summarized in Table 7.


ELIQUIS® (apixaban)
ELIQUIS® (apixaban)
7.3	
Anticoagulants and Antiplatelet Agents
Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID 
use increases the risk of bleeding.
APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute 
coronary syndrome patients treated with aspirin or the combination of aspirin and 
clopidogrel, was terminated early due to a higher rate of bleeding with apixaban 
compared to placebo. The rate of ISTH major bleeding was 2.8% per year with apixaban 
versus 0.6% per year with placebo in patients receiving single antiplatelet therapy and 
was 5.9% per year with apixaban versus 2.5% per year with placebo in those receiving 
dual antiplatelet therapy.
In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS 
from 1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin 
increased the bleeding risk from 2.7% per year to 4.6% per year. In this clinical trial, 
there was limited (2.3%) use of dual antiplatelet therapy with ELIQUIS.
8	
USE IN SPECIFIC POPULATIONS
8.1	
Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies of ELIQUIS in pregnant women. 
Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. 
ELIQUIS should be used during pregnancy only if the potential benefit outweighs the 
potential risk to the mother and fetus.
Treatment of pregnant rats, rabbits, and mice after implantation until the end of gestation 
resulted in fetal exposure to apixaban, but was not associated with increased risk for 
fetal malformations or toxicity. No maternal or fetal deaths were attributed to bleeding. 
Increased incidence of maternal bleeding was observed in mice, rats, and rabbits at 
maternal exposures that were 19, 4, and 1 times, respectively, the human exposure of 
unbound drug, based on area under plasma-concentration time curve (AUC) comparisons 
at the maximum recommended human dose (MRHD) of 10 mg (5 mg twice daily).
8.2	
Labor and Delivery
Safety and effectiveness of ELIQUIS during labor and delivery have not been studied in 
clinical trials. Consider the risks of bleeding and of stroke in using ELIQUIS in this setting 
[see Warnings and Precautions (5.2)].
Treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 
21) with apixaban at a dose of 1000 mg/kg (about 5 times the human exposure based 
on unbound apixaban) did not result in death of offspring or death of mother rats during 
labor in association with uterine bleeding. However, increased incidence of maternal 
bleeding, primarily during gestation, occurred at apixaban doses of ≥25 mg/kg, a dose 
corresponding to ≥1.3 times the human exposure.
8.3	
Nursing Mothers
It is unknown whether apixaban or its metabolites are excreted in human milk. 
Rats excrete apixaban in milk (12% of the maternal dose).
Women should be instructed either to discontinue breastfeeding or to discontinue 
ELIQUIS therapy, taking into account the importance of the drug to the mother.
8.4	
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5	
Geriatric Use
Of the total subjects in the ARISTOTLE and AVERROES clinical studies, >69% 
were 65 and older, and >31% were 75 and older. In the ADVANCE-1, ADVANCE-2, 
and ADVANCE-3 clinical studies, 50% of subjects were 65 and older, while 16% 
were 75 and older. In the AMPLIFY and AMPLIFY-EXT clinical studies, >32% of subjects 
were 65 and older and >13% were 75 and older. No clinically significant differences in 
safety or effectiveness were observed when comparing subjects in different age groups.
8.6	
Renal Impairment
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial 
Fibrillation
The recommended dose is 2.5 mg twice daily in patients with at least two of the following 
characteristics [see Dosage and Administration (2.1)]:
•	
age ≥80 years
•	
body weight ≤60 kg
•	
serum creatinine ≥1.5 mg/dL
Patients with End-Stage Renal Disease on Dialysis
Clinical efficacy and safety studies with ELIQUIS did not enroll patients with end-stage 
renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent 
hemodialysis, administration of ELIQUIS at the usually recommended dose [see Dosage 
and Administration (2.1)] will result in concentrations of apixaban and pharmacodynamic 
activity similar to those observed in the ARISTOTLE study [see Clinical Pharmacology 
(12.3)]. It is not known whether these concentrations will lead to similar stroke reduction 
and bleeding risk in patients with ESRD on dialysis as was seen in ARISTOTLE. 
Table 7:	
Bleeding Results in the AMPLIFY-EXT Study 
ELIQUIS 2.5 mg bid 
N=840 
n (%)
ELIQUIS 5 mg bid 
N=811 
n (%)
Placebo
N=826 
n (%)
Major
2 (0.2)
1 (0.1)
4 (0.5)
CRNM*
25 (3.0)
34 (4.2)
19 (2.3)
Major + CRNM
27 (3.2)
35 (4.3)
22 (2.7)
Minor
75 (8.9)
98 (12.1)
58 (7.0)
All
94 (11.2)
121 (14.9)
74 (9.0)
*	CRNM = clinically relevant nonmajor bleeding.
Events associated with each endpoint were counted once per subject, but subjects may have 
contributed events to multiple endpoints.
Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in 
Table 8.
Table 8:	
Adverse Reactions Occurring in ≥1% of Patients Undergoing 
Extended Treatment for DVT and PE in the AMPLIFY-EXT Study 
ELIQUIS 
2.5 mg bid 
N=840 
n (%)
ELIQUIS 
5 mg bid 
N=811 
n (%)
Placebo 
 
N=826 
n (%)
Epistaxis
13 (1.5)
29 (3.6)
9 (1.1)
Hematuria
12 (1.4)
17 (2.1)
9 (1.1)
Hematoma
13 (1.5)
16 (2.0)
10 (1.2)
Contusion
18 (2.1)
18 (2.2)
18 (2.2)
Gingival bleeding
12 (1.4)
9 (1.1)
3 (0.4)
Other Adverse Reactions
Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or AMPLIFY-
EXT studies occurring at a frequency of ≥0.1% to <1%:
Blood and lymphatic system disorders: hemorrhagic anemia
Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, gastrointestinal 
hemorrhage, hematemesis, melena, anal hemorrhage
Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural 
hemorrhage, traumatic hematoma, periorbital hematoma
Musculoskeletal and connective tissue disorders: muscle hemorrhage
Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia, 
menometrorrhagia, genital hemorrhage
Vascular disorders: hemorrhage
Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae
Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage
Investigations: blood urine present, occult blood positive, occult blood, red blood cells 
urine positive
General disorders and administration-site conditions: injection-site hematoma, vessel 
puncture-site hematoma
7	
DRUG INTERACTIONS
Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp 
increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 
and P-gp decrease exposure to apixaban and increase the risk of stroke and other 
thromboembolic events.
7.1	
Strong Dual Inhibitors of CYP3A4 and P-gp
For patients receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should 
be decreased by 50% when coadministered with drugs that are strong dual inhibitors 
of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin) [see 
Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration 
with strong dual inhibitors of CYP3A4 and P-gp [see Dosage and Administration (2.5) and 
Clinical Pharmacology (12.3)].
7.2	
Strong Dual Inducers of CYP3A4 and P-gp
Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp (e.g., 
rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease 
exposure to apixaban [see Clinical Pharmacology (12.3)].


ELIQUIS® (apixaban)
ELIQUIS® (apixaban)
Effect of PCCs on Pharmacodynamics of ELIQUIS
There is no clinical experience to reverse bleeding with the use of 4-factor PCC products 
in individuals who have received ELIQUIS.
Effects of 4-factor PCCs on the pharmacodynamics of apixaban were studied in 
healthy subjects. Following administration of apixaban dosed to steady state, 
endogenous thrombin potential (ETP) returned to pre-apixaban levels 4 hours after 
the initiation of a 30 minute PCC infusion, compared to 45 hours with placebo. 
Mean ETP levels continued to increase and exceeded pre-apixaban levels reaching a 
maximum (34 - 51% increase over pre-apixaban levels) at 21 hours after initiating PCC 
and remained elevated (21 – 27% increase) at the end of the study (69 hours after 
initiation of PCC). The clinical relevance of this increase in ETP is unknown.
Pharmacodynamic Drug Interaction Studies
Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin 
and clopidogrel, prasugrel, enoxaparin, and naproxen were conducted. No 
pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel 
[see Warnings and Precautions (5.2)]. A 50% to 60% increase in anti-FXa activity 
was observed when apixaban was coadministered with enoxaparin or naproxen.
Specific Populations
Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across 
renal function categories.
Hepatic impairment: Changes in anti-FXa activity were similar in patients with mild-to-
moderate hepatic impairment and healthy subjects. However, in patients with moderate 
hepatic impairment, there is no clear understanding of the impact of this degree of 
hepatic function impairment on the coagulation cascade and its relationship to efficacy 
and bleeding. Patients with severe hepatic impairment were not studied.
Cardiac Electrophysiology
Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.
12.3	
Pharmacokinetics
Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in 
exposure for oral doses up to 10 mg.
Absorption
The absolute bioavailability of apixaban is approximately 50% for doses up to 
10 mg of ELIQUIS. Food does not affect the bioavailability of apixaban. Maximum 
concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration of 
ELIQUIS. At doses ≥25 mg, apixaban displays dissolution-limited absorption with 
decreased bioavailability. Following oral administration of 10 mg of apixaban as 
2 crushed 5 mg tablets suspended in 30 mL of water, exposure was similar to that 
after oral administration of 2 intact 5 mg tablets. Following oral administration of 10 mg 
of apixaban as 2 crushed 5 mg tablets mixed with 30 g of applesauce, the Cmax and 
AUC were 20% and 16% lower, respectively, when compared to administration of 
2 intact 5 mg tablets. Following administration of a crushed 5 mg ELIQUIS tablet 
that was suspended in 60 mL D5W and delivered through a nasogastric tube, 
exposure was similar to that seen in other clinical trials involving healthy volunteers 
receiving a single oral 5 mg tablet dose.
Distribution
Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) 
is approximately 21 liters.
Metabolism
Approximately 25% of an orally administered apixaban dose is recovered in urine 
and feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor 
contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and hydroxylation 
at the 3-oxopiperidinyl moiety are the major sites of biotransformation.
Unchanged apixaban is the major drug-related component in human plasma; there are 
no active circulating metabolites.
Elimination
Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% 
of total clearance. Biliary and direct intestinal excretion contributes to elimination of 
apixaban in the feces.
Apixaban has a total clearance of approximately 3.3 L/hour and an apparent half-life of 
approximately 12 hours following oral administration.
Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance protein.
Drug Interaction Studies
In vitro apixaban studies at concentrations significantly greater than therapeutic 
exposures, no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, 
CYP2C9, CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of CYP1A2, 
CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to alter the 
metabolic clearance of coadministered drugs that are metabolized by these enzymes. 
Apixaban is not a significant inhibitor of P-gp.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery, and 
Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT and PE
No dose adjustment is recommended for patients with renal impairment, including those 
with ESRD on dialysis [see Dosage and Administration (2.1)]. Clinical efficacy and safety 
studies with ELIQUIS did not enroll patients with ESRD on dialysis or patients with a CrCl 
<15 mL/min; therefore, dosing recommendations are based on pharmacokinetic and 
pharmacodynamic (anti-FXa activity) data in subjects with ESRD maintained on dialysis 
[see Clinical Pharmacology (12.3)].
8.7	
Hepatic Impairment
No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh 
class A).
Because patients with moderate hepatic impairment (Child-Pugh class B) may have 
intrinsic coagulation abnormalities and there is limited clinical experience with ELIQUIS in 
these patients, dosing recommendations cannot be provided [see Clinical Pharmacology 
(12.2)].
ELIQUIS is not recommended in patients with severe hepatic impairment (Child-Pugh 
class C) [see Clinical Pharmacology (12.2)].
10	
OVERDOSAGE
There is no antidote to ELIQUIS. Overdose of ELIQUIS increases the risk of bleeding [see 
Warnings and Precautions (5.2)].
In controlled clinical trials, orally administered apixaban in healthy subjects at doses 
up to 50 mg daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 
3 days) had no clinically relevant adverse effects.
In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of 
a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively. 
Thus, administration of activated charcoal may be useful in the management of apixaban 
overdose or accidental ingestion.
11	
DESCRIPTION
ELIQUIS (apixaban), a factor Xa (FXa) inhibitor, is chemically described as 
1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Its molecular formula is C25H25N5O4, 
which corresponds to a molecular weight of 459.5. Apixaban has the following 
structural formula:
Apixaban is a white to pale-yellow powder. At physiological pH (1.2–6.8), apixaban does 
not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL.
ELIQUIS tablets are available for oral administration in strengths of 2.5 mg and 5 mg 
of apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline 
cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The 
film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and 
yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).
12	
CLINICAL PHARMACOLOGY
12.1	
Mechanism of Action
Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for 
antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase 
activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits 
platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases 
thrombin generation and thrombus development.
12.2	
Pharmacodynamics
As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time 
(PT), INR, and activated partial thromboplastin time (aPTT). Changes observed in these 
clotting tests at the expected therapeutic dose, however, are small, subject to a high 
degree of variability, and not useful in monitoring the anticoagulation effect of apixaban.
The Rotachrom® Heparin chromogenic assay was used to measure the effect of apixaban 
on FXa activity in humans during the apixaban development program. A concentration-
dependent increase in anti-FXa activity was observed in the dose range tested and was 
similar in healthy subjects and patients with AF.
This test is not recommended for assessing the anticoagulant effect of apixaban.


ELIQUIS® (apixaban)
ELIQUIS® (apixaban)
Race: The results across pharmacokinetic studies in normal subjects showed no 
differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/
African American subjects. No dose adjustment is required based on race/ethnicity.
Hemodialysis in ESRD subjects: Systemic exposure to apixaban administered as a 
single 5 mg dose in ESRD subjects dosed immediately after the completion of a 4-hour 
hemodialysis session (post-dialysis) is 36% higher when compared to subjects with 
normal renal function (Figure 3).
The systemic exposure to apixaban administered 2 hours prior to a 4-hour hemodialysis 
session with a dialysate flow rate of 500 mL/min and a blood flow rate in the range of 
350 to 500 mL/min is 17% higher compared to those with normal renal function. The 
dialysis clearance of apixaban is approximately 18 mL/min. The systemic exposure of 
apixaban is 14% lower on dialysis when compared to not on dialysis.
Protein binding was similar (92%-94%) between healthy controls and ESRD subjects 
during the on-dialysis and off-dialysis periods.
13	
NONCLINICAL TOXICOLOGY
13.1	
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Apixaban was not carcinogenic when administered to mice and 
rats for up to 2 years. The systemic exposures (AUCs) of unbound apixaban in male 
and female mice at the highest doses tested (1500 and 3000 mg/kg/day) were 
9 and 20 times, respectively, the human exposure of unbound drug at the MRHD of 
10 mg/day. Systemic exposures of unbound apixaban in male and female rats at the 
highest dose tested (600 mg/kg/day) were 2 and 4 times, respectively, the human 
exposure.
Mutagenesis: Apixaban was neither mutagenic in the bacterial reverse mutation (Ames) 
assay, nor clastogenic in Chinese hamster ovary cells in vitro, in a 1-month in vivo/in 
vitro cytogenetics study in rat peripheral blood lymphocytes, or in a rat micronucleus 
study in vivo.
Impairment of Fertility: Apixaban had no effect on fertility in male or female rats when 
given at doses up to 600 mg/kg/day, a dose resulting in exposure levels that are 3 and 4 
times, respectively, the human exposure.
Apixaban administered to female rats at doses up to 1000 mg/kg/day from implantation 
through the end of lactation produced no adverse findings in male offspring (F1 
generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure that is 5 times 
the human exposure. Adverse effects in the F1-generation female offspring were limited 
to decreased mating and fertility indices at 1000 mg/kg/day.
14	
CLINICAL STUDIES
14.1	
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular 
Atrial Fibrillation
ARISTOTLE
Evidence for the efficacy and safety of ELIQUIS was derived from ARISTOTLE, a 
multinational, double-blind study in patients with nonvalvular AF comparing the 
effects of ELIQUIS and warfarin on the risk of stroke and non-central nervous system 
(CNS) systemic embolism. In ARISTOTLE, patients were randomized to ELIQUIS 5 mg 
orally twice daily (or 2.5 mg twice daily in subjects with at least 2 of the following 
characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) or 
to warfarin (targeted to an INR range of 2.0–3.0). Patients had to have one or more of the 
following additional risk factors for stroke:
•	
prior stroke or transient ischemic attack (TIA)
•	
prior systemic embolism
•	
age ≥75 years 
•	
arterial hypertension requiring treatment
•	
diabetes mellitus
•	
heart failure ≥New York Heart Association Class 2
•	
left ventricular ejection fraction ≤40%
The primary objective of ARISTOTLE was to determine whether ELIQUIS 5 mg twice 
daily (or 2.5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk 
of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of ELIQUIS 
to warfarin was also examined for the primary endpoint (rate of stroke and systemic 
embolism), major bleeding, and death from any cause.
A total of 18,201 patients were randomized and followed on study treatment for a median 
of 89 weeks. Forty-three percent of patients were vitamin K antagonist (VKA) “naive,” 
defined as having received ≤30 consecutive days of treatment with warfarin or another 
VKA before entering the study. The mean age was 69 years and the mean CHADS2 
score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting 
greater risk) was 2.1. The population was 65% male, 83% Caucasian, 14% Asian, and 
1% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 19% 
of patients. Concomitant diseases of patients in this study included hypertension 88%,
The effects of coadministered drugs on the pharmacokinetics of apixaban are summarized 
in Figure 2 [see also Warnings and Precautions (5.2) and Drug Interactions (7)].
Figure 2:	
Effect of Coadministered Drugs on the Pharmacokinetics of 
Apixaban
Interacting Drug
PK
Fold Change and 90% CI
Strong CYP3A4 and P-gp Inhibitor
Ketoconazole 400 mg
Cmax
AUC
Other CYP3A4 and P-gp Inhibitors
Diltiazem 360 mg
Cmax
AUC
Naproxen 500 mg
Cmax
AUC
Strong CYP3A4 and P-gp Inducer
Rifampin 600 mg
Cmax
AUC
Change Relative to Reference
2.0 
0.5 
1.0 
1.5 
In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, and 
enoxaparin did not meaningfully alter the pharmacokinetics of apixaban.
In studies conducted in healthy subjects, apixaban did not meaningfully alter the 
pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid.
Specific Populations
The effects of level of renal impairment, age, body weight, and level of hepatic impairment 
on the pharmacokinetics of apixaban are summarized in Figure 3.
Figure 3: 	
Effect of Specific Populations on the Pharmacokinetics of 
Apixaban
*	ESRD subjects treated with intermittent hemodialysis; reported PK findings are following 
single dose of apixaban post hemodialysis.
†	Results reflect CrCl of 15 mL/min based on regression analysis.
‡	Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing 
recommendations.
§	No dose adjustment is recommended for nonvalvular atrial fibrillation patients unless at 
least 2 of the following patient characteristics (age ≥80 years, body weight ≤60 kg, or serum 
creatinine ≥1.5 mg/dL) are present.
Gender: A study in healthy subjects comparing the pharmacokinetics in males and 
females showed no meaningful difference.


ELIQUIS® (apixaban)
ELIQUIS® (apixaban)
Figure 4:	
Kaplan-Meier Estimate of Time to First Stroke or Systemic 
Embolism in ARISTOTLE (Intent-to-Treat Population)
All-cause death was assessed using a sequential testing strategy that allowed testing 
for superiority if effects on earlier endpoints (stroke plus systemic embolus and major 
bleeding) were demonstrated. ELIQUIS treatment resulted in a significantly lower rate 
of all-cause death (p = 0.046) than did treatment with warfarin, primarily because of a 
reduction in cardiovascular death, particularly stroke deaths. Non-vascular death rates 
were similar in the treatment arms.
In ARISTOTLE, the results for the primary efficacy endpoint were generally consistent 
across most major subgroups including weight, CHADS2 score (a scale from 0 to 6 
used to predict risk of stroke in patients with AF, with higher scores predicting greater 
risk), prior warfarin use, level of renal impairment, geographic region, and aspirin use at 
randomization (Figure 5).
diabetes 25%, congestive heart failure (or left ventricular ejection fraction ≤40%) 35%, 
and prior myocardial infarction 14%. Patients treated with warfarin in ARISTOTLE had a 
mean percentage of time in therapeutic range (INR 2.0–3.0) of 62%.
ELIQUIS was superior to warfarin for the primary endpoint of reducing the risk of stroke 
and systemic embolism (Table 9 and Figure 4). Superiority to warfarin was primarily 
attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic 
conversion compared to warfarin. Purely ischemic strokes occurred with similar rates 
on both drugs.
ELIQUIS also showed significantly fewer major bleeds than warfarin [see Adverse 
Reactions (6.1)].
Table 9: 	
Key Efficacy Outcomes in Patients with Nonvalvular Atrial 
Fibrillation in ARISTOTLE (Intent-to-Treat Analysis)
ELIQUIS 
N=9120 
n (%/year)
Warfarin 
N=9081 
n (%/year)
Hazard Ratio 
(95% CI)
P-value
Stroke or systemic embolism
212 (1.27)
265 (1.60)
0.79 (0.66, 0.95)
0.01
	
Stroke
199 (1.19)
250 (1.51)
0.79 (0.65, 0.95)
	
	 Ischemic without 
	
	 	 hemorrhage
140 (0.83)
136 (0.82)
1.02 (0.81, 1.29)
	
	 Ischemic with  
	
	 	 hemorrhagic conversion
12 (0.07)
20 (0.12)
0.60 (0.29, 1.23)
	
	 Hemorrhagic
40 (0.24)
78 (0.47)
0.51 (0.35, 0.75)
	
	 Unknown
14 (0.08)
21 (0.13)
0.65 (0.33, 1.29)
	
Systemic embolism
15 (0.09)
17 (0.10)
0.87 (0.44, 1.75)
The primary endpoint was based on the time to first event (one per subject). Component 
counts are for subjects with any event, not necessarily the first.
Figure 5:	
Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics – ARISTOTLE Study
 0.25 
0.5 
1 
2
Apixaban
Better
Warfarin
Better
n of Events / N of Patients (% per year)
Subgroup
Apixaban
Warfarin
Hazard Ratio (95% CI)
All Patients
212 / 9120 (1.3)
265 / 9081 (1.6)
0.79 (0.66, 0.95)
Prior Warfarin/VKA Status
 
Experienced (57%)
102 / 5208 (1.1)
138 / 5193 (1.5)
0.73 (0.57, 0.95)
 
Naive (43%)
110 / 3912 (1.5)
127 / 3888 (1.8)
0.86 (0.66, 1.11)
Age
 
<65 (30%)
51 / 2731 (1.0)
44 / 2740 (0.9)
1.16 (0.77, 1.73)
 
≥65 and <75 (39%)
82 / 3539 (1.3)
112 / 3513 (1.7)
0.72 (0.54, 0.96)
 
≥75 (31%)
79 / 2850 (1.6)
109 / 2828 (2.2)
0.71 (0.53, 0.95)
Sex
 
Male (65%)
132 / 5886 (1.2)
160 / 5899 (1.5)
0.82 (0.65, 1.04)
 
Female (35%)
80 / 3234 (1.3)
105 / 3182 (1.8)
0.74 (0.56, 1.00)
Weight
 
≤60 kg (11%)
34 / 1018 (2.0)
52 / 967 (3.2)
0.63 (0.41, 0.97)
 
>60 kg (89%)
177 / 8070 (1.2)
212 / 8084 (1.4)
0.83 (0.68, 1.01)
Prior Stroke or TIA
 
Yes (19%)
73 / 1694 (2.5)
98 / 1742 (3.2)
0.76 (0.56, 1.03)
 
No (81%)
139 / 7426 (1.0)
167 / 7339 (1.2)
0.82 (0.65, 1.03)
Diabetes Mellitus
 
Yes (25%)
57 / 2284 (1.4)
75 / 2263 (1.9)
0.75 (0.53, 1.05)
 
No (75%)
155 / 6836 (1.2) 
190 / 6818 (1.5)
0.81 (0.65, 1.00)
CHADS2 Score
 ≤1 (34%)
44 / 3100 (0.7)
51 / 3083 (0.9)
0.85 (0.57, 1.27)
 
2 (36%)
74 / 3262 (1.2)
82 / 3254 (1.4)
0.90 (0.66, 1.23)
 ≥3 (30%)
94 / 2758 (2.0)
132 / 2744 (2.8)
0.70 (0.54, 0.91)
Creatinine Clearance
 
<30 mL/min (1%)
6 / 137 (2.8)
10 / 133 (5.1)
0.55 (0.20, 1.53)
 
30-50 mL/min (15%)
48 / 1365 (2.0)
59 / 1382 (2.5)
0.83 (0.57, 1.21)
 >50-80 mL/min (42%)
87 / 3817 (1.2)
116 / 3770 (1.7)
0.74 (0.56, 0.97)
 
>80 mL/min (41%)
70 / 3761 (1.0)
79 / 3757 (1.1)
0.88 (0.64, 1.21)
Geographic Region
 
US (19%)
31 / 1720 (0.9)
39 / 1697 (1.2)
0.79 (0.50, 1.27)
 
Non-US (81%)
181 / 7400 (1.3)
226 / 7384 (1.7)
0.79 (0.65, 0.96)
Aspirin at Randomization
 
Yes (31%)
70 / 2859 (1.3)
94 / 2773 (1.9)
0.72 (0.53, 0.98)
 
No (69%)
142 / 6261 (1.2)
171 / 6308 (1.5)
0.83 (0.67, 1.04)
Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were pre-specified, if not the groupings. The 95% confidence limits that are 
shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity 
among groups should not be over-interpreted.


ELIQUIS® (apixaban)
ELIQUIS® (apixaban)
At the end of the ARISTOTLE study, warfarin patients who completed the study 
were generally maintained on a VKA with no interruption of anticoagulation. ELIQUIS 
patients who completed the study were generally switched to a VKA with a 2-day 
period of coadministration of ELIQUIS and VKA, so that some patients may not have 
been adequately anticoagulated after stopping ELIQUIS until attaining a stable and 
therapeutic INR. During the 30 days following the end of the study, there were 
21 stroke or systemic embolism events in the 6791 patients (0.3%) in the ELIQUIS 
arm compared to 5 in the 6569 patients (0.1%) in the warfarin arm [see Dosage and 
Administration (2.4)].
AVERROES
In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates for 
warfarin therapy were randomized to treatment with ELIQUIS 5 mg orally twice daily (or 
2.5 mg twice daily in selected patients) or aspirin 81 to 324 mg once daily. The primary 
objective of the study was to determine if ELIQUIS was superior to aspirin for preventing 
the composite outcome of stroke or systemic embolism. AVERROES was stopped early 
on the basis of a prespecified interim analysis showing a significant reduction in stroke 
and systemic embolism for ELIQUIS compared to aspirin that was associated with a 
modest increase in major bleeding (Table 10) [see Adverse Reactions (6.1)].
Table 10:	
Key Efficacy Outcomes in Patients with Nonvalvular Atrial 
Fibrillation in AVERROES
ELIQUIS 
N=2807 
n (%/year)
Aspirin 
N=2791 
n (%/year)
Hazard Ratio 
(95% CI)
P-value
Stroke or systemic embolism
51 (1.62)
113 (3.63)
0.45 (0.32, 0.62)
<0.0001
	
Stroke
	
	 Ischemic or 
	
	 	 undetermined
43 (1.37)
97 (3.11)
0.44 (0.31, 0.63)
-
	
	 Hemorrhagic
6 (0.19)
9 (0.28)
0.67 (0.24, 1.88)
-
	
Systemic embolism
2 (0.06)
13 (0.41)
0.15 (0.03, 0.68)
-
MI
24 (0.76)
28 (0.89)
0.86 (0.50, 1.48)
-
All-cause death
111 (3.51)
140 (4.42)
0.79 (0.62, 1.02)
0.068
	
Vascular death
84 (2.65)
96 (3.03)
0.87 (0.65, 1.17)
-
14.2	
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement 
Surgery
The clinical evidence for the effectiveness of ELIQUIS is derived from the ADVANCE-1, 
ADVANCE-2, and ADVANCE-3 clinical trials in adult patients undergoing elective hip 
(ADVANCE-3) or knee (ADVANCE-2 and ADVANCE-1) replacement surgery. A total of 
11,659 patients were randomized in 3 double-blind, multi-national studies. Included 
in this total were 1866 patients age 75 or older, 1161 patients with low body weight 
(≤60 kg), 2528 patients with Body Mass Index ≥33 kg/m2, and 625 patients with severe 
or moderate renal impairment.
In the ADVANCE-3 study, 5407 patients undergoing elective hip replacement surgery 
were randomized to receive either ELIQUIS 2.5 mg orally twice daily or enoxaparin 
40 mg subcutaneously once daily. The first dose of ELIQUIS was given 12 to 24 hours 
post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Treatment 
duration was 32 to 38 days.
In patients undergoing elective knee replacement surgery, ELIQUIS 2.5 mg orally 
twice daily was compared to enoxaparin 40 mg subcutaneously once daily (ADVANCE-2, 
N=3057) or enoxaparin 30 mg subcutaneously every 12 hours (ADVANCE-1, N=3195). 
In the ADVANCE-2 study, the first dose of ELIQUIS was given 12 to 24 hours post surgery, 
whereas enoxaparin was started 9 to 15 hours prior to surgery. In the ADVANCE-1 study, 
both ELIQUIS and enoxaparin were initiated 12 to 24 hours post surgery. Treatment 
duration in both ADVANCE-2 and ADVANCE-1 was 10 to 14 days.
In all 3 studies, the primary endpoint was a composite of adjudicated asymptomatic 
and symptomatic DVT, nonfatal PE, and all-cause death at the end of the double-blind 
intended treatment period. In ADVANCE-3 and ADVANCE-2, the primary endpoint was 
tested for noninferiority, then superiority, of ELIQUIS to enoxaparin. In ADVANCE-1, the 
primary endpoint was tested for noninferiority of ELIQUIS to enoxaparin.
The efficacy data are provided in Tables 11 and 12.
Table 11:	
Summary of Key Efficacy Analysis Results During the Intended 
Treatment Period for Patients Undergoing Elective Hip 
Replacement Surgery*
 ADVANCE-3
Events During 35-Day 
Treatment Period
ELIQUIS 
2.5 mg po bid
Enoxaparin 
40 mg sc qd
Relative Risk 
(95% CI) 
P-value
Number of Patients
N=1949
N=1917
Total VTE†/All-cause death
27 (1.39%) 
(0.95, 2.02)
74 (3.86%) 
(3.08, 4.83)
0.36 
(0.22, 0.54) 
p<0.0001
Number of Patients
N=2708
N=2699
	 All-cause death
3 (0.11%) 
(0.02, 0.35)
1 (0.04%) 
(0.00, 0.24)
	 PE
3 (0.11%) 
(0.02, 0.35)
5 (0.19%) 
(0.07, 0.45)
	 Symptomatic DVT
1 (0.04%) 
(0.00, 0.24)
5 (0.19%) 
(0.07, 0.45)
Number of Patients
N=2196
N=2190
	 Proximal DVT‡
7 (0.32%) 
(0.14, 0.68)
20 (0.91%) 
(0.59, 1.42)
Number of Patients
N=1951
N=1908
	 Distal DVT‡
20 (1.03%) 
(0.66, 1.59)
57 (2.99%) 
(2.31, 3.86)
*	Events associated with each endpoint were counted once per subject but subjects may have 
contributed events to multiple endpoints.
†	Total VTE includes symptomatic and asymptomatic DVT and PE.
‡	Includes symptomatic and asymptomatic DVT.
Table 12:	
Summary of Key Efficacy Analysis Results During the Intended 
Treatment Period for Patients Undergoing Elective Knee 
Replacement Surgery*
ADVANCE-1
ADVANCE-2
Events during 
12-day 
treatment 
period
ELIQUIS 
2.5 mg po 
bid
Enoxaparin 
30 mg sc 
q12h
Relative 
Risk 
(95% CI) 
P-value
ELIQUIS 
2.5 mg po bid
Enoxaparin 
40 mg sc qd
Relative 
Risk 
(95% CI) 
P-value
Number of 
Patients
N=1157
N=1130
N=976
N=997
Total VTE†/All- 
cause death
104 (8.99%) 
(7.47, 10.79)
100 (8.85%) 
(7.33, 10.66)
1.02 
(0.78, 1.32) 
NS
147 (15.06%) 
(12.95, 17.46)
243 (24.37%) 
(21.81, 27.14)
0.62 
(0.51, 0.74) 
p<0.0001
Number of 
Patients
N=1599
N=1596
N=1528
N=1529
	 All-cause 
death
3 (0.19%) 
(0.04, 0.59)
3 (0.19%) 
(0.04, 0.59)
2 (0.13%) 
 (0.01, 0.52)
0 (0%) 
(0.00, 0.31)
	 PE 
16 (1.0%) 
(0.61, 1.64)
7 (0.44%) 
(0.20, 0.93)
4 (0.26%) 
(0.08, 0.70)
0 (0%) 
(0.00, 0.31)
	 Symptomatic 
DVT
3 (0.19%) 
(0.04, 0.59)
7 (0.44%) 
(0.20, 0.93)
3 (0.20%) 
 (0.04, 0.61)
7 (0.46%) 
(0.20, 0.97)
Number of 
Patients
N=1254
N=1207
N=1192
N=1199
	 Proximal 
DVT‡
9 (0.72%) 
(0.36, 1.39)
11 (0.91%) 
(0.49, 1.65)
9 (0.76%) 
(0.38, 1.46)
26 (2.17%) 
(1.47, 3.18)
Number of 
Patients
N=1146
N=1133
N=978
N=1000
	 Distal 
DVT‡
83 (7.24%) 
(5.88, 8.91)
91 (8.03%) 
(6.58, 9.78)
142 (14.52%) 
(12.45, 16.88)
239 (23.9%) 
(21.36, 26.65)
*	Events associated with each endpoint were counted once per subject but subjects may 
have contributed events to multiple endpoints.
†	Total VTE includes symptomatic and asymptomatic DVT and PE.
‡	Includes symptomatic and asymptomatic DVT.
The efficacy profile of ELIQUIS was generally consistent across subgroups of interest for 
this indication (e.g., age, gender, race, body weight, renal impairment).


ELIQUIS® (apixaban)
ELIQUIS® (apixaban)
Table 14:	
Efficacy Results in the AMPLIFY-EXT Study
Relative Risk (95% CI)
ELIQUIS  
2.5 mg bid 
N=840
ELIQUIS  
5 mg bid 
N=813
Placebo 
 
N=829
ELIQUIS 
2.5 mg bid 
vs Placebo
ELIQUIS 
5 mg bid 
vs Placebo
n (%)
Recurrent VTE or 
all-cause death
32 (3.8)
34 (4.2)
96 (11.6)
0.33 (0.22, 0.48) 
p<0.0001
0.36 (0.25, 0.53) 
p<0.0001
	 DVT*
19 (2.3)
28 (3.4)
72 (8.7)
	 PE*
23 (2.7)
25 (3.1)
37 (4.5)
	 All-cause death
22 (2.6)
25 (3.1)
33 (4.0)
*	Patients with more than one event are counted in multiple rows.
16	
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
ELIQUIS (apixaban) tablets are available as listed in the table below.
Tablet 
Strength
Tablet 
Color/Shape
Tablet 
Markings
Package Size
NDC Code
2.5 mg
Yellow, round, 
biconvex
Debossed with 
“893” on one side 
and “2½” 
on the other side
Bottles of 60
Bottles of 180 
Hospital Unit-Dose 
Blister Package 
of 100
0003-0893-21
0003-0893-41
0003-0893-31
5 mg
Pink, oval, 
biconvex
Debossed with 
“894” on one side 
and “5” 
on the other side
Bottles of 60
Bottles of 180
Hospital Unit-Dose 
Blister Package 
of 100
0003-0894-21
0003-0894-41
0003-0894-31
Storage and Handling
Store at 20°C to 25°C (68°F-77°F); excursions permitted between 15°C and 30°C 
(59°F-86°F) [see USP Controlled Room Temperature].
17	
PATIENT COUNSELING INFORMATION
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Advise patients of the following:
•	
Not to discontinue ELIQUIS without talking to their physician first.
•	
That it might take longer than usual for bleeding to stop, and they may bruise 
or bleed more easily when treated with ELIQUIS. Advise patients about how to 
recognize bleeding or symptoms of hypovolemia and of the urgent need to report 
any unusual bleeding to their physician.
•	
To tell their physicians and dentists they are taking ELIQUIS, and/or any other 
product known to affect bleeding (including nonprescription products, such as 
aspirin or NSAIDs), before any surgery or medical or dental procedure is scheduled 
and before any new drug is taken.
•	
If the patient is having neuraxial anesthesia or spinal puncture, inform the patient 
to watch for signs and symptoms of spinal or epidural hematomas [see Warnings 
and Precautions (5.3)]. If any of these symptoms occur, advise the patient to seek 
emergent medical attention.
•	
To tell their physicians if they are pregnant or plan to become pregnant or are 
breastfeeding or intend to breastfeed during treatment with ELIQUIS [see Use in 
Specific Populations (8.1, 8.3)].
•	
How to take ELIQUIS if they cannot swallow, or require a nasogastric tube [see 
Dosage and Administration (2.6)].
•	
What to do if a dose is missed [see Dosage and Administration (2.2)].
Marketed by: 
Bristol-Myers Squibb Company 
Princeton, New Jersey 08543 USA  
and 
Pfizer Inc 
New York, New York 10017 USA
Rotachrom® is a registered trademark of Diagnostica Stago.
1356615A2 / 1356514A1
14.3	
Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT 
and PE
Efficacy and safety of ELIQUIS for the treatment of DVT and PE, and for the reduction in 
the risk of recurrent DVT and PE following 6 to 12 months of anticoagulant treatment 
was derived from the AMPLIFY and AMPLIFY-EXT studies. Both studies were randomized, 
parallel-group, double-blind trials in patients with symptomatic proximal DVT and/or 
symptomatic PE. All key safety and efficacy endpoints were adjudicated in a blinded 
manner by an independent committee.
AMPLIFY
The primary objective of AMPLIFY was to determine whether ELIQUIS was noninferior 
to enoxaparin/warfarin for the incidence of recurrent VTE (venous thromboembolism) 
or VTE-related death. Patients with an objectively confirmed symptomatic DVT 
and/or PE were randomized to treatment with ELIQUIS 10 mg twice daily orally for 
7 days followed by ELIQUIS 5 mg twice daily orally for 6 months, or enoxaparin 1 mg/kg 
twice daily subcutaneously for at least 5 days (until INR ≥2) followed by warfarin (target 
INR range 2.0-3.0) orally for 6 months. Patients who required thrombectomy, insertion 
of a caval filter, or use of a fibrinolytic agent, and patients with creatinine clearance 
<25 mL/min, significant liver disease, an existing heart valve or atrial fibrillation, or 
active bleeding were excluded from the AMPLIFY study. Patients were allowed to enter 
the study with or without prior parenteral anticoagulation (up to 48 hours).
A total of 5244 patients were evaluable for efficacy and were followed for a mean of 
154 days in the ELIQUIS group and 152 days in the enoxaparin/warfarin group. The 
mean age was 57 years. The AMPLIFY study population was 59% male, 83% Caucasian, 
8% Asian, and 4% Black. For patients randomized to warfarin, the mean percentage of 
time in therapeutic range (INR 2.0-3.0) was 60.9%.
Approximately 90% of patients enrolled in AMPLIFY had an unprovoked DVT or PE at 
baseline. The remaining 10% of patients with a provoked DVT or PE were required 
to have an additional ongoing risk factor in order to be randomized, which included 
previous episode of DVT or PE, immobilization, history of cancer, active cancer, and 
known prothrombotic genotype.
ELIQUIS was shown to be noninferior to enoxaparin/warfarin in the AMPLIFY study for 
the primary endpoint of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-
related death over 6 months of therapy (Table 13).
Table 13:	
Efficacy Results in the AMPLIFY Study 
ELIQUIS 
N=2609 
n
Enoxaparin/Warfarin 
N=2635 
n
Relative Risk
(95% CI)
VTE or VTE-related death*
59 (2.3%)
71 (2.7%)
0.84 (0.60, 1.18)
	 DVT†
22 (0.8%)
35 (1.3%)
	 PE†
27 (1.0%)
25 (0.9%)
	 VTE-related death†
12 (0.4%)
16 (0.6%)
VTE or all-cause death
84 (3.2%)
104 (4.0%)
0.82 (0.61, 1.08)
VTE or CV-related death
61 (2.3%)
77 (2.9%)
0.80 (0.57, 1.11)
*	Noninferior compared to enoxaparin/warfarin (P-value <0.0001).
†	Events associated with each endpoint were counted once per subject, but subjects may 
have contributed events to multiple endpoints.
In the AMPLIFY study, patients were stratified according to their index event of PE (with 
or without DVT) or DVT (without PE). Efficacy in the initial treatment of VTE was consistent 
between the two subgroups.
AMPLIFY-EXT
Patients who had been treated for DVT and/or PE for 6 to 12 months with anticoagulant 
therapy without having a recurrent event were randomized to treatment with ELIQUIS 
2.5 mg orally twice daily, ELIQUIS 5 mg orally twice daily, or placebo for 12 months. 
Approximately one-third of patients participated in the AMPLIFY study prior to enrollment 
in the AMPLIFY-EXT study.
A total of 2482 patients were randomized to study treatment and were followed for a 
mean of approximately 330 days in the ELIQUIS group and 312 days in the placebo 
group. The mean age in the AMPLIFY-EXT study was 57 years. The study population was 
57% male, 85% Caucasian, 5% Asian, and 3% Black.
The AMPLIFY-EXT study enrolled patients with either an unprovoked DVT or PE at baseline 
(approximately 92%) or patients with a provoked baseline event and one additional 
risk factor for recurrence (approximately 8%). However, patients who had experienced 
multiple episodes of unprovoked DVT or PE were excluded from the AMPLIFY-EXT study. 
In the AMPLIFY-EXT study, both doses of ELIQUIS were superior to placebo in the primary 
endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE), or all-cause death 
(Table 14).


ELIQUIS® (apixaban)
MEDICATION GUIDE
ELIQUIS® (ELL eh kwiss) 
(apixaban) 
tablets
What is the most important information I should know about ELIQUIS?
•	 For people taking ELIQUIS for atrial fibrillation:
People with atrial fibrillation (a type of irregular heartbeat) are at an increased risk of forming a 
blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. 
ELIQUIS lowers your chance of having a stroke by helping to prevent clots from forming. If you 
stop taking ELIQUIS, you may have increased risk of forming a clot in your blood.
Do not stop taking ELIQUIS without talking to the doctor who prescribes it for you. 
Stopping ELIQUIS increases your risk of having a stroke.
ELIQUIS may need to be stopped, if possible, prior to surgery or a medical or dental procedure. 
Ask the doctor who prescribed ELIQUIS for you when you should stop taking it. Your doctor will 
tell you when you may start taking ELIQUIS again after your surgery or procedure. If you have 
to stop taking ELIQUIS, your doctor may prescribe another medicine to help prevent a blood clot 
from forming.
•	 ELIQUIS can cause bleeding which can be serious and rarely may lead to death. This is because 
ELIQUIS is a blood thinner medicine that reduces blood clotting.
You may have a higher risk of bleeding if you take ELIQUIS and take other medicines that increase 
your risk of bleeding, including:
•	 aspirin or aspirin-containing products
•	 long-term (chronic) use of nonsteroidal anti-inflammatory drugs (NSAIDs)
•	 warfarin sodium (COUMADIN®, JANTOVEN®)
•	 any medicine that contains heparin
•	 selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors 
(SNRIs)
•	 other medicines to help prevent or treat blood clots
Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not 
sure if your medicine is one listed above.
While taking ELIQUIS:
•	 you may bruise more easily
•	 it may take longer than usual for any bleeding to stop
Call your doctor or get medical help right away if you have any of these signs or symptoms 
of bleeding when taking ELIQUIS:
•	 unexpected bleeding, or bleeding that lasts a long time, such as:
•	 unusual bleeding from the gums
•	 nosebleeds that happen often
•	 menstrual bleeding or vaginal bleeding that is heavier than normal
•	 bleeding that is severe or you cannot control
•	 red, pink, or brown urine
•	 red or black stools (looks like tar)


ELIQUIS® (apixaban)
•	 cough up blood or blood clots
•	 vomit blood or your vomit looks like coffee grounds
•	 unexpected pain, swelling, or joint pain
•	 headaches, feeling dizzy or weak
•	 ELIQUIS is not for patients with artificial heart valves.
•	 Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine 
(anticoagulant) like ELIQUIS, and have medicine injected into their spinal and epidural area, or 
have a spinal puncture have a risk of forming a blood clot that can cause long-term or permanent 
loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is 
higher if:
•	 a thin tube called an epidural catheter is placed in your back to give you certain medicine
•	 you take NSAIDs or a medicine to prevent blood from clotting
•	 you have a history of difficult or repeated epidural or spinal punctures
•	 you have a history of problems with your spine or have had surgery on your spine
If you take ELIQUIS and receive spinal anesthesia or have a spinal puncture, your doctor should 
watch you closely for symptoms of spinal or epidural blood clots or bleeding. Tell your doctor right 
away if you have tingling, numbness, or muscle weakness, especially in your legs and feet.
What is ELIQUIS?
ELIQUIS is a prescription medicine used to:
•	 reduce the risk of stroke and blood clots in people who have atrial fibrillation.
•	 reduce the risk of forming a blood clot in the legs and lungs of people who have just had hip or 
knee replacement surgery.
•	 treat blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism), 
and reduce the risk of them occurring again.
It is not known if ELIQUIS is safe and effective in children.
Who should not take ELIQUIS?
Do not take ELIQUIS if you:
•	 currently have certain types of abnormal bleeding.
•	 have had a serious allergic reaction to ELIQUIS. Ask your doctor if you are not sure.
What should I tell my doctor before taking ELIQUIS?
Before you take ELIQUIS, tell your doctor if you:
•	 have kidney or liver problems
•	 have any other medical condition
•	 have ever had bleeding problems
•	 are pregnant or plan to become pregnant. It is not known if ELIQUIS will harm your unborn baby.
•	 are breastfeeding or plan to breastfeed. It is not known if ELIQUIS passes into your 
breast milk. You and your doctor should decide if you will take ELIQUIS or breastfeed. You should 
not do both.
Tell all of your doctors and dentists that you are taking ELIQUIS. They should talk to the doctor who 
prescribed ELIQUIS for you, before you have any surgery, medical or dental procedure.


ELIQUIS® (apixaban)
Tell your doctor about all the medicines you take, including prescription and over-the-counter 
medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way 
ELIQUIS works. Certain medicines may increase your risk of bleeding or stroke when taken with 
ELIQUIS. See “What is the most important information I should know about ELIQUIS?”
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get 
a new medicine.
How should I take ELIQUIS?
•	 Take ELIQUIS exactly as prescribed by your doctor.
•	 Take ELIQUIS twice every day with or without food.
•	 Do not change your dose or stop taking ELIQUIS unless your doctor tells you to.
•	 If you miss a dose of ELIQUIS, take it as soon as you remember. Do not take more than one dose 
of ELIQUIS at the same time to make up for a missed dose.
•	 If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take 
ELIQUIS.
•	 Your doctor will decide how long you should take ELIQUIS. Do not stop taking it without 
first talking with your doctor. If you are taking ELIQUIS for atrial fibrillation, stopping 
ELIQUIS may increase your risk of having a stroke.
•	 Do not run out of ELIQUIS. Refill your prescription before you run out. When leaving the 
hospital following hip or knee replacement, be sure that you will have ELIQUIS available to avoid 
missing any doses.
•	 If you take too much ELIQUIS, call your doctor or go to the nearest hospital emergency room right 
away.
•	 Call your doctor or healthcare provider right away if you fall or injure yourself, especially if you hit 
your head. Your doctor or healthcare provider may need to check you.
What are the possible side effects of ELIQUIS?
•	 See “What is the most important information I should know about ELIQUIS?”
•	 ELIQUIS can cause a skin rash or severe allergic reaction. Call your doctor or get medical help right 
away if you have any of the following symptoms:
•	 chest pain or tightness
•	 swelling of your face or tongue
•	 trouble breathing or wheezing
•	 feeling dizzy or faint
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of ELIQUIS. For more information, ask your doctor or 
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 
1-800-FDA-1088.
How should I store ELIQUIS?
Store ELIQUIS at room temperature between 68°F to 77°F (20°C to 25°C).
Keep ELIQUIS and all medicines out of the reach of children.


ELIQUIS® (apixaban)
General Information about ELIQUIS
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. 
Do not use ELIQUIS for a condition for which it was not prescribed. Do not give ELIQUIS to other 
people, even if they have the same symptoms that you have. It may harm them.
If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for 
information about ELIQUIS that is written for health professionals.
For more information, call 1-855-354-7847 (1-855-ELIQUIS) or go to www.ELIQUIS.com.
What are the ingredients in ELIQUIS?
Active ingredient: apixaban.
Inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium 
lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, 
titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Marketed by: 
Bristol-Myers Squibb Company 
Princeton, New Jersey 08543 USA 
and 
Pfizer Inc 
New York, New York 10017 USA
COUMADIN® is a registered trademark of Bristol-Myers Squibb Pharma Company. All other trademarks 
are property of their respective companies.
1356615A2 / 1356514A1
1356616A0	
Revised July 2016
	
432US1603587-11-01


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 103 
APPENDIX E. 
US PACKAGE INSERT FOR EDOXABAN (SAVAYSA) 


HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use SAVAYSA™
safely and effectively. See full prescribing information for SAVAYSA.
SAVAYSA (edoxaban) tablets, for oral use
Initial U.S. Approval: 2015
____________________ RECENT MAJOR CHANGES ____________________
Warnings and Precautions (5.3)   9/2016
______________________ INDICATIONS AND USAGE ____________________
SAVAYSA is a factor Xa inhibitor indicated:
To reduce the risk of stroke and systemic embolism (SE) in patients with non-
valvular atrial fibrillation (NVAF) (1.1) 
• Limitation of Use for NVAF
SAVAYSA should not be used in patients with creatinine clearance (CrCL) 
> 95 mL/min because of increased risk of ischemic stroke compared to 
warfarin at the highest dose studied (60 mg) (1.1) 
SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and
pulmonary embolism (PE) following 5 to 10 days of initial therapy with a 
parenteral anticoagulant (1.2) 
___________________ DOSAGE AND ADMINISTRATION __________________
• Treatment of NVAF: 
Assess CrCL before initiating therapy (2.1) 
The recommended dose is 60 mg once daily in patients with CrCL >50 to 
≤95 mL/min. Do not use SAVAYSA in patients with CrCL > 95 mL/min (2.1)
Reduce dose to 30 mg once daily in patients with creatinine clearance 15 to
50 mL/min (2.1)
• Treatment of DVT and PE: 
The recommended dose is 60 mg once daily (2.2) 
The recommended dose is 30 mg once daily for patients with CrCL 15 to 
50 mL/min or body weight less than or equal to 60 kg or who use certain 
P-gp inhibitors (2.2)
__________________ DOSAGE FORMS AND STRENGTHS _________________
• Tablets: 60 mg, 30 mg, and 15 mg (3)
_______________________ CONTRAINDICATIONS _______________________
• Active pathological bleeding (4)
___________________ WARNINGS AND PRECAUTIONS ___________________
•  Bleeding: Serious and potentially fatal bleeding. Promptly evaluate signs and
symptoms of blood loss (5.2)
•  Mechanical heart valves or moderate to severe mitral stenosis: Use is not
recommended (5.5)
________________________ ADVERSE REACTIONS ______________________
Treatment of NVAF: The most common adverse reactions (≥5%) are bleeding
and anemia (6.1)
Treatment of DVT and PE: The most common adverse reactions (≥1%) are
bleeding, rash, abnormal liver function tests and anemia (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at
1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
_______________________ DRUG INTERACTIONS ______________________
•  Anticoagulants: Avoid concomitant use (7.1)
•  Rifampin: Avoid concomitant use (7.2)
___________________ USE IN SPECIFIC POPULATIONS __________________
• Nursing mothers: Discontinue drug or discontinue nursing (8.3)
• Impaired renal function (CrCL 15 to 50 mL/min): Reduce dose (2.1, 2.2, 8.6)
• Moderate or severe hepatic impairment: Not recommended (8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 09/2016
WARNING  (A) REDUCED EFFICACY IN NONVALVULAR ATRIAL 
FIBRILLATION PATIENTS WITH CREATININE CLEARANCE (CRCL) 
> 95 ML/MIN (B) PREMATURE DISCONTINUATION OF SAVAYSA
INCREASES THE RISK OF ISCHEMIC EVENTS
(C) SPINAL/EPIDURAL HEMATOMA
See full prescribing information for complete boxed warning.
(A) REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION
PATIENTS WITH CRCL > 95 ML/MIN: SAVAYSA should not be used in
patients with CrCL > 95 mL/min. In the ENGAGE AF-TIMI 48 study, nonval -
vular atrial fibrillation patients with CrCL > 95 mL/min had an increased
rate of ischemic stroke with SAVAYSA 60 mg once daily compared to
patients treated with warfarin. In these patients another anticoagulant
should be used (5.1).
(B) PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK
OF ISCHEMIC EVENTS: Premature discontinuation of any oral anticoagu-
lant in the absence of adequate alternative anticoagulation increases the
risk of ischemic events. If SAVAYSA is discontinued for a reason other
than pathological bleeding or completion of a course of therapy, consider
coverage with another anticoagulant as described in the transition gui -
dance (2.4, 5.2, 14).
(C) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas may
occur in patients treated with SAVAYSA who are receiving neuraxial anes-
thesia or undergoing spinal puncture. These hematomas may result in
long-term or permanent paralysis. Consider these risks when scheduling
patients for spinal procedures (5.4).
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: (A) REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION
PATIENTS WITH CREATININE CLEARANCE (CRCL) > 95 ML/MIN (B) PREMA-
TURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF ISCHEMIC
EVENTS (C) SPINAL/EPIDURAL HEMATOMA
1
INDICATIONS AND USAGE
1.1 Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular
Atrial Fibrillation
1.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism 
2
DOSAGE AND ADMINISTRATION
2.1 Nonvalvular Atrial Fibrillation
2.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism 
2.3 Administration Information
2.4 Transition to or from SAVAYSA
2.5 Discontinuation for Surgery and Other Interventions
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with 
CrCL > 95 mL/min
5.2 Increased Risk of Stroke with Discontinuation of SAVAYSA in Patients
with Nonvalvular Atrial Fibrillation 
5.3 Risk of Bleeding
5.4 Spinal/Epidural Anesthesia or Puncture
5.5 Patients with Mechanical Heart Valves or Moderate to Severe Mitral
Stenosis
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
7
DRUG INTERACTIONS
7.1 Anticoagulants, Antiplatelets, and Thrombolytics
7.2 P-gp Inducers 
7.3 P-gp Inhibitors 
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
8.8 Low Body Weight Consideration for Patients treated for DVT and/or PE
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Nonvalvular Atrial Fibrillation
14.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed.


FULL PRESCRIBING INFORMATION
  1  INDICATIONS AND USAGE
1.1 Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular
Atrial Fibrillation
SAVAYSA is indicated to reduce the risk of stroke and systemic embolism
(SE) in patients with nonvalvular atrial fibrillation (NVAF).
Limitation of Use for NVAF
SAVAYSA should not be used in patients with CrCL > 95 mL/min because
of an increased risk of ischemic stroke compared to warfarin [see Dosage
and Administration (2.1), Warnings and Precautions (5.1), Clinical Studies
(14.1)]. 
1.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism 
SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and
pulmonary embolism (PE) following 5 to 10 days of initial therapy with a
parenteral anticoagulant.
  2  DOSAGE AND ADMINISTRATION
2.1 Nonvalvular Atrial Fibrillation
The recommended dose of SAVAYSA is 60 mg taken orally once daily [see
Warnings and Precautions (5.1), Clinical Studies (14.1)]. Assess creatinine
clearance, as calculated using the Cockcroft-Gault equation*, before initiat-
ing therapy with SAVAYSA. Do not use SAVAYSA in patients with CrCL 
> 95 mL/min.  
Reduce SAVAYSA dose to 30 mg once daily in patients with CrCL 15 to 
50 mL/min [see Use in Specific Populations (8.6) and Clinical Pharmacol-
ogy (12.3)]. 
    *Cockcroft-Gault CrCL = (140-age) x (weight in kg) x (0.85 if female) /
(72 x creatinine in mg/dL).
2.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism 
The recommended dose of SAVAYSA is 60 mg taken orally once daily fol-
lowing 5 to 10 days of initial therapy with a parenteral anticoagulant [see
Clinical Studies (14.2)].
The recommended dose of SAVAYSA is 30 mg once daily in patients with
CrCL 15 to 50 mL/min, patients who weigh less than or equal to 60 kg, or
patients who are taking certain concomitant P-gp inhibitor medications
based on clinical study data in this indication [see Clinical Studies (14.2)].
2.3 Administration Information
If a dose of SAVAYSA is missed, the dose should be taken as soon as pos-
sible on the same day. Dosing should resume the next day according to the
normal dosing schedule. The dose should not be doubled to make up for a
missed dose.
SAVAYSA can be taken without regard to food [see Clinical Pharmacology
(12.3)].
2.4 Transition to or from SAVAYSA
Transition to SAVAYSA
From
To
Recommendation
Warfarin or 
SAVAYSA
Discontinue warfarin and start SAVAYSA 
other Vitamin K 
when the INR is ≤ 2.5
Antagonists
Oral 
SAVAYSA
Discontinue current oral anticoagulant and
anticoagulants
start SAVAYSA at the time of the next
other than 
scheduled dose of the other oral 
warfarin or other 
anticoagulant
Vitamin K
Antagonists
Low Molecular
SAVAYSA
Discontinue LMWH and start SAVAYSA at 
Weight Heparin
the time of the next scheduled administration
(LMWH)
of LMWH
Unfractionated 
SAVAYSA
Discontinue the infusion and start SAVAYSA
heparin
4 hours later
Transition from SAVAYSA
From
To
Recommendation
Oral option: For patients taking 60 mg of 
SAVAYSA, reduce the dose to 30 mg and 
begin warfarin concomitantly. For patients 
receiving 30 mg of SAVAYSA, reduce the dose
SAVAYSA
Warfarin
to 15 mg and begin warfarin concomitantly.
INR must be measured at least weekly and
just prior to the daily dose of SAVAYSA
to minimize the influence of SAVAYSA 
on INR measurements. Once a stable INR 
≥ 2.0 is achieved, SAVAYSA should be 
discontinued and the warfarin continued
Parenteral option: Discontinue SAVAYSA 
and administer a parenteral anticoagulant and
warfarin at the time of the next scheduled 
SAVAYSA
Warfarin
SAVAYSA dose. Once a stable INR ≥ 2.0 is
achieved the parenteral anticoagulant should
be discontinued and the warfarin continued
SAVAYSA
Non-Vitamin- Discontinue SAVAYSA and start the other
K-Dependent 
oral anticoagulant at the time of the next dose
Oral
of SAVAYSA
anticoagulants
SAVAYSA
Parenteral 
Discontinue SAVAYSA and start the paren-
anticoagulants teral anticoagulant at the time of the next 
dose of SAVAYSA
Abbreviations: INR=International Normalized Ratio
2.5 Discontinuation for Surgery and Other Interventions
Discontinue SAVAYSA at least 24 hours before invasive or surgical proce-
dures because of the risk of bleeding [see Warnings and Precautions (5.3)].
If surgery cannot be delayed, there is an increased risk of bleeding. This
risk of bleeding should be weighed against the urgency of intervention [see
Warnings and Precautions (5.3)]. 
SAVAYSA can be restarted after the surgical or other procedure as soon as
adequate hemostasis has been established noting that the time to onset of
pharmacodynamic effect is 1-2 hours [see Warnings and Precautions
(5.2)]. Administer a parenteral anticoagulant and then switch to oral
SAVAYSA, if oral medication cannot be taken during or after surgical 
intervention.
  3  DOSAGE FORMS AND STRENGTHS
•  60 mg, yellow round shaped, film-coated tablets, debossed with DSC L60
on one side
•  30 mg, pink round shaped, film-coated tablets, debossed with DSC L30
on one side
•  15 mg, orange round shaped, film-coated tablets, debossed with DSC L15
on one side
WARNING (A) REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLA-
TION PATIENTS WITH CREATININE CLEARANCE  (CRCL) > 95 ML/MIN 
(B) PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK
OF ISCHEMIC EVENTS (C) SPINAL/EPIDURAL HEMATOMA
A. REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION
PATIENTS WITH CRCL > 95 ML/MIN 
SAVAYSA should not be used in patients with CrCL > 95 mL/min. In the
ENGAGE AF-TIMI 48 study, nonvalvular atrial fibrillation patients with
CrCL > 95 mL/min had an increased rate of ischemic stroke with SAVAYSA
60 mg once daily compared to patients treated with warfarin. In these
patients another anticoagulant should be used [see Dosage and Adminis-
tration (2.1), Warnings and Precautions (5.1), and Clinical Studies
(14.1)].
B. PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF
ISCHEMIC EVENTS 
Premature discontinuation of any oral anticoagulant in the absence of
adequate alternative anticoagulation increases the risk of ischemic
events. If SAVAYSA is discontinued for a reason other than pathological
bleeding or completion of a course of therapy, consider coverage with
another anticoagulant as described in the transition guidance [see Dosage
and Administration (2.4), Warnings and Precautions (5.2), and Clinical
Studies (14.1)].
C. SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients treated with
SAVAYSA who are receiving neuraxial anesthesia or undergoing spinal
puncture. These hematomas may result in long-term or permanent paraly-
sis. Consider these risks when scheduling patients for spinal procedures.
Factors that can increase the risk of developing epidural or spinal
hematomas in these patients include:
•  use of indwelling epidural catheters
•  concomitant use of other drugs that affect hemostasis, such as non-
steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other
anticoagulants
•  a history of traumatic or repeated epidural or spinal punctures
•  a history of spinal deformity or spinal surgery
•  optimal timing between the administration of SAVAYSA and neuraxial
procedures is not known
[see Warnings and Precautions (5.4)].
Monitor patients frequently for signs and symptoms of neurological
impairment. If neurological compromise is noted, urgent treatment is nec-
essary [see Warnings and Precautions (5.4)].
Consider the benefits and risks before neuraxial intervention in patients
anticoagulated or to be anticoagulated [see Warnings and Precautions
(5.4)].


  4  CONTRAINDICATIONS
SAVAYSA is contraindicated in patients with:
•  Active pathological bleeding [see Warnings and Precautions (5.3) and
Adverse Reactions (6.1)].
  5  WARNINGS AND PRECAUTIONS
5.1 Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with 
CrCL > 95 mL/min 
SAVAYSA should not be used in patients with CrCL > 95 mL/min. In the
randomized ENGAGE AF-TIMI 48 study, NVAF patients with CrCL > 95 mL/min
had an increased rate of ischemic stroke with SAVAYSA 60 mg daily com-
pared to patients treated with warfarin. In these patients another anticoagu-
lant should be used [see Dosage and Administration (2.1), Clinical Studies
(14.1)].
5.2 Increased Risk of Stroke with Discontinuation of SAVAYSA in
Patients with Nonvalvular Atrial Fibrillation  
Premature discontinuation of any oral anticoagulant in the absence of ade-
quate alternative anticoagulation increases the risk of ischemic events. If
SAVAYSA is discontinued for a reason other than pathological bleeding or
completion of a course of therapy, consider coverage with another anti -
coagulant as described in the transition guidance [see Dosage and Admin -
istration (2.4) and Clinical Studies (14.1)].
5.3 Risk of Bleeding
SAVAYSA increases the risk of bleeding and can cause serious and poten-
tially fatal bleeding. Promptly evaluate any signs or symptoms of blood
loss.
Discontinue SAVAYSA in patients with active pathological bleeding.
Concomitant use of drugs affecting hemostasis may increase the risk of
bleeding. These include aspirin and other antiplatelet agents, other anti -
thrombotic agents, fibrinolytic therapy, chronic use of nonsteroidal anti-
inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors and
serotonin norepinephrine reuptake inhibitors [see Drug Interactions (7.1)].
Reversal of Anticoagulant Effect
There is no established way to reverse the anticoagulant effects of
SAVAYSA, which can be expected to persist for approximately 24 hours
after the last dose. The anticoagulant effect of SAVAYSA cannot be reliably
monitored with standard laboratory testing. A specific reversal agent for
edoxaban is not available. Hemodialysis does not significantly contribute to
edoxaban clearance [see Clinical Pharmacology (12.3)]. Protamine sulfate,
vitamin K, and tranexamic acid are not expected to reverse the anticoagu-
lant activity of SAVAYSA. The use of prothrombin complex concentrates
(PCC), or other procoagulant reversal agents such as activated prothrombin
complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) may be
considered but has not been evaluated in clinical outcome studies [see
Clinical Pharmacology (12.2)]. When PCCs are used, monitoring for anti -
coagulation effect of edoxaban using clotting test (PT, INR, or aPTT) or
anti-FXa activity is not useful and is not recommended.
5.4 Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural
puncture is employed, patients treated with antithrombotic agents for pre-
vention of thromboembolic complications are at risk of developing an
epidural or spinal hematoma, which can result in long-term or permanent
paralysis.
The risk of these events may be increased by the postoperative use of
indwelling epidural catheters or the concomitant use of medicinal products
affecting hemostasis. Indwelling epidural or intrathecal catheters should not
be removed earlier than 12 hours after the last administration of SAVAYSA.
The next dose of SAVAYSA should not be administered earlier than 2 hours
after the removal of the catheter. The risk may also be increased by trau-
matic or repeated epidural or spinal puncture. 
Monitor patients frequently for signs and symptoms of neurological impair-
ment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunc-
tion). If neurological compromise is noted, urgent diagnosis and treatment
is necessary. Prior to neuraxial intervention the physician should consider
the potential benefit versus the risk in anticoagulated patients or in patients
to be anticoagulated for thromboprophylaxis.
5.5 Patients with Mechanical Heart Valves or Moderate to Severe Mitral
Stenosis
The safety and efficacy of SAVAYSA has not been studied in patients with
mechanical heart valves or moderate to severe mitral stenosis. The use of
SAVAYSA is not recommended in these patients [see Clinical Studies
(14.1)].
  6  ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in
other sections of the prescribing information.
•  Increased risk of stroke with discontinuation of SAVAYSA in patients with
NVAF [see Warnings and Precautions (5.2)]
•  Spinal/epidural anesthesia or puncture [see Warnings and Precautions
(5.4)]
The most serious adverse reactions reported with SAVAYSA were related to
bleeding [see Warnings and Precautions (5.3)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
The safety of SAVAYSA was evaluated in the ENGAGE AF-TIMI 48 and
Hokusai VTE studies including 11,130 patients exposed to SAVAYSA 60 mg
and 7002 patients exposed to SAVAYSA 30 mg once daily [see Clinical
Studies (14)].
The ENGAGE AF-TIMI 48 Study
In the ENGAGE AF-TIMI 48 study, the median study drug exposure for the
SAVAYSA and warfarin treatment groups was 2.5 years. 
Bleeding was the most common reason for treatment discontinuation.
Bleeding led to treatment discontinuation in 3.9% and 4.1% of patients in
the SAVAYSA 60 mg and warfarin treatment groups, respectively.
In the overall population, Major Bleeding was lower in the SAVAYSA group
compared to the warfarin group [HR 0.80 (0.70, 0.91), p<0.001]. Table 6.1
shows Major Bleeding events (percentage of patients with at least one
bleeding event, per year) for the indicated population (CrCL ≤95 mL/min).
Table 6.1: Adjudicated Bleeding Events for NVAF Patients with CrCL 
≤95 mL/min*
Eventa
SAVAYSA 60 mgb
Warfarin
SAVAYSA 
N = 5417
N = 5485
60 mg vs. Warfarin
n (%/year)
n (%/year)
HR (95% CI)
Major Bleedingc
357 (3.1)
431 (3.7)
0.84 (0.73, 0.97)
Intracranial 
Hemorrhage 
53 (0.5)
122 (1.0)
0.44 (0.32, 0.61)
(ICH)d
Hemorrhagic
Stroke
33 (0.3)
69 (0.6)
0.49 (0.32, 0.74)
Other ICH
20 (0.2)
55 (0.5)
0.37 (0.22, 0.62)
Gastrointestinale
205 (1.8)
150 (1.3)
1.40 (1.13, 1.73)
Fatal Bleedingf
21 (0.2)
42 (0.4)
0.51 (0.30, 0.86)
ICH
19 (0.2)
36 (0.3)
0.54 (0.31, 0.94)
Non-intracranial
2 (<0.1)
6 (<0.1)
----
Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, 
n = number of patients with events, N = number of patients in Safety population,
* The on treatment period is during treatment or within 2 days of stopping
study treatment. The difference in hemorrhagic stroke rate from Table 14.1 
is because Table 14.1 includes events occurring during treatment or within 
3 days of stopping study treatment and this table only includes patients with
CrCL ≤ 95 mL/min.
a A subject can be included in multiple sub-categories if he/she had an event
for those categories.
b Includes all patients with CrCL ≤95 mL/min randomized to receive 60 mg
once daily, including those who were dose-reduced to 30 mg once daily
because of prespecified baseline conditions.
c A Major Bleeding event (the study primary safety endpoint) was defined as
clinically overt bleeding that met one of the following criteria: fatal bleeding;
symptomatic bleeding in a critical site such as retroperitoneal, intracranial,
intraocular, intraspinal, intra-articular, pericardial, or intramuscular with com-
partment syndrome; a clinically overt bleeding event that caused a fall in
hemoglobin of at least 2.0 g/dL (or a fall in hematocrit of at least 6.0% in the
absence of hemoglobin data), when adjusted for transfusions (1 unit of trans-
fusion = 1.0 g/dL drop in hemoglobin).
d ICH includes primary hemorrhagic stroke, subarachnoid hemorrhage,
epidural/subdural hemorrhage, and ischemic stroke with major hemorrhagic
conversion.
e Gastrointestinal (GI) bleeds include bleeding from upper and lower GI tract.
Lower GI tract bleeding includes rectal bleeds.
f Fatal bleed is a bleeding event during the on treatment period and adjudicated
as leading directly to death within 7 days.
The most common site of a Major Bleeding event was the gastrointestinal
(GI) tract. Table 6.2 shows the number of and the rate at which patients
experienced GI bleeding in the SAVAYSA 60 mg and warfarin treatment
groups.


Table 6.2 Gastrointestinal Bleeding Events for NVAF Patients with 
CrCL ≤95 mL/min*
SAVAYSA
Warfarin
N= 5417
N= 5485
n (%/year)
n (%/year)
Major Gastrointestinal (GI) 
Bleedinga
205 (1.78)
150 (1.27)
- Upper GI
123 (1.06)
88 (0.74)
- Lower GIb
85 (0.73)
64 (0.54)
GUSTOc Severe GI bleeding
16 (0.14)
17 (0.14)
Fatal GI bleeding
1 (<0.1)
2 (<0.1)
* During or within 2 days of stopping study treatment
a GI bleeding was defined by location as upper or lower GI
b Lower GI bleeding included anorectal bleeding
c GUSTO – Severe or life-threatening bleeding that caused hemodynamic com-
promise and requires intervention
The rate of anemia-related adverse events was greater with SAVAYSA 60 mg
than with warfarin (9.6% vs. 6.8%).  
The comparative rates of Major Bleeding on SAVAYSA and warfarin were
generally consistent among subgroups (see Figure 6.1). Bleeding rates
appeared higher in both treatment arms (SAVAYSA and warfarin) in the fol-
lowing subgroups of patients: those receiving aspirin, those in the United
States, those more than 75 years old and those with reduced renal function.    
Figure 6.1: Adjudicated Major Bleeding in the ENGAGE AF-TIMI 48* Study
*During or within 2 days of stopping study treatment
Note: The figure above presents effects in various subgroups all of which are
baseline characteristics and most of which were pre-specified. The 95% confi-
dence limits that are shown do not take into account how many comparisons
were made, nor do they reflect the effect of a particular factor after adjustment
for all other factors. Apparent homogeneity or heterogeneity among groups
should not be over-interpreted.
Other Adverse Reactions
The most common non-bleeding adverse reactions (≥1%) for SAVAYSA 
60 mg versus warfarin were rash (4.2% vs. 4.1%), and abnormal liver func-
tion tests (4.8% vs. 4.6%), respectively.
Interstitial Lung Disease (ILD) was reported as a serious adverse event on
treatment for SAVAYSA 60 mg and warfarin in 15 (0.2%) and 7 (0.1%)
patients, respectively. Many of the cases in both treatment groups were
confounded by the use of amiodarone, which has been associated with ILD,
or by infectious pneumonia. In the overall study period, there were 5 and 0
fatal ILD cases in the SAVAYSA 60 mg and warfarin groups, respectively.
The Hokusai VTE Study
In the Hokusai VTE study, the duration of drug exposure for SAVAYSA was
≤6 months for 1561 (37.9%) of patients, > 6 months for 2557 (62.1%) of
patients and 12 months for 1661 (40.3%) of patients.
Bleeding was the most common reason for treatment discontinuation and
occurred in 1.4% and 1.4% of patients in the SAVAYSA and warfarin arms,
respectively.
Bleeding in Patients with DVT and/or PE in the Hokusai VTE Study
The primary safety endpoint was Clinically Relevant Bleeding, defined as the
composite of Major and Clinically Relevant Non-Major (CRNM) Bleeding
that occurred during or within three days of stopping study treatment. The
incidence of Clinically Relevant Bleeding was lower in SAVAYSA than war-
farin [HR (95% CI): 0.81 (0.71, 0.94); p =0.004].
Table 6.3 shows the number of patients experiencing bleeding events in the
Hokusai VTE Study.
Table 6.3:Bleeding Events in the Hokusai VTE Study
SAVAYSA
Warfarin
(N=4118)
(N=4122)
Clinically Relevant Bleedinga
(Major/CRNM), n (%)
349 (8.5)
423 (10.3)
Major Bleedingb, n (%) 
56 (1.4)
66 (1.6)
Fatal bleeding
2 (<0.1)
10 (0.2)
Intracranial fatal
0 (0.0)
6 (0.1)
Non-fatal critical organ bleeding
13 (0.3)
25 (0.6)
Intracranial bleeding
5 (0.1)
12 (0.3)
Non-fatal non-critical organ bleeding
41 (1.0)
33 (0.8)
Decrease in Hb ≥2g/dL
40 (1.0)
33 (0.8)
Transfusion of ≥2 units of RBC
28 (0.7)
22 (0.5)
CRNM Bleedingc
298 (7.2)
368 (8.9)
Any Bleed
895 (21.7)
1056 (25.6)
Abbreviations: N=number of patients in the modified intent-to-treat population;
n = number of events; CRNM = clinically relevant non-major
a Primary Safety Endpoint: Clinically Relevant Bleeding (composite of Major
and CRNM).
b A Major Bleeding event was defined as clinically overt bleeding that met one
of the following criteria: associated with a fall in hemoglobin level of 2.0 g/dL
or more, or leading to transfusion of two or more units of packed red cells or
whole blood; occurring in a critical site or organ: intracranial, intraspinal,
intraocular, pericardial, intra-articular, intramuscular with compartment syn-
drome, retroperitoneal; contributing to death.
c CRNM bleeding was defined as overt bleeding not meeting the criteria for a
Major Bleeding event but that was associated with a medical intervention, an
unscheduled contact (visit or telephone call) with a physician, temporary ces-
sation of study treatment, or associated with discomfort for the subject such
as pain, or impairment of activities of daily life.
Patients with low body weight (≤60 kg), CrCL ≤50 mL/min, or concomi-
tant use of select P-gp inhibitors were randomized to receive SAVAYSA 30 mg
or warfarin. As compared to all patients who received SAVAYSA or warfarin
in the 60 mg cohort, all patients who received SAVAYSA or warfarin in the
30 mg cohort (n= 1452, 17.6% of the entire study population) were older
(60.1 vs 54.9 years), more frequently female (66.5% vs 37.7%), more 
frequently of Asian race (46.0% vs 15.6%) and had more co-morbidities 
(e.g., history of bleeding, hypertension, diabetes, cardiovascular disease,
cancer). Clinically relevant bleeding events occurred in 58/733 (7.9%) of
the SAVAYSA patients receiving 30 mg once daily and 92/719 (12.8%) of
warfarin patients meeting the above criteria.
In the Hokusai VTE study, among all patients the most common bleeding
adverse reactions (≥1%) are shown in Table 6.4.
Table 6.4: Adverse Reactions Occurring in ≥1% of Patients Treated in 
Hokusai VTE
SAVAYSA 60 mg
Warfarin
(N=4118)
(N=4122)
n (%)
n (%)
Bleeding ADRsa
Vaginalb
158 (9.0)
126 (7.1)
Cutaneous soft tissue
245 (5.9)
414 (10.0)
Epistaxis
195 (4.7)
237 (5.7)
Gastrointestinal bleeding
171 (4.2)
150 (3.6)
Lower gastrointestinal
141 (3.4)
126 (3.1)
Oral/pharyngeal
138 (3.4)
162 (3.9)
Macroscopic hematuria/urethral
91 (2.2)
117 (2.8)
Puncture site
56 (1.4)
99 (2.4)
Non-Bleeding ADRs
Rash
147 (3.6)
151 (3.7)
Abnormal liver function tests
322 (7.8)
322 (7.8)
Anemia
72 (1.7)
55 (1.3)
a Adjudicated Any Bleeding by location for all bleeding event categories (includ-
ing Major and CRNM)
b Gender specific vaginal bleeding percentage is based on number of female
subjects in each treatment group


 7  DRUG INTERACTIONS
7.1 Anticoagulants, Antiplatelets, and Thrombolytics
Co-administration of anticoagulants, antiplatelet drugs, and thrombolytics
may increase the risk of bleeding. Promptly evaluate any signs or symp-
toms of blood loss if patients are treated concomitantly with anticoagulants,
aspirin, other platelet aggregation inhibitors, and/or NSAIDs [see Warnings
and Precautions (5.3)].
Long-term concomitant treatment with SAVAYSA and other anticoagulants
is not recommended because of increased risk of bleeding [see Warnings
and Precautions (5.3)]. Short term co-administration may be needed for
patients transitioning to or from SAVAYSA [see Dosage and Administration
(2.4)]. 
In clinical studies with SAVAYSA concomitant use of aspirin (low dose 
≤100 mg/day) or thienopyridines, and NSAIDs was permitted and resulted
in increased rates of Clinically Relevant Bleeding. Carefully monitor for
bleeding in patients who require chronic treatment with low dose aspirin
and/or NSAIDs [see Warnings and Precautions (5.3) and Clinical Pharma-
cology (12.3)].
7.2 P-gp Inducers 
Avoid the concomitant use of SAVAYSA with rifampin [see Clinical Pharma-
cology (12.3)].
7.3 P-gp Inhibitors 
Treatment of NVAF
Based on clinical experience from the ENGAGE AF-TIMI 48 study, dose
reduction in patients concomitantly receiving P-gp inhibitors resulted in
edoxaban blood levels that were lower than in patients who were given the
full dose. Consequently, no dose reduction is recommended for concomi-
tant P-gp inhibitor use [see Dosage and Administration (2.1), Clinical Phar-
macology (12.3) and Clinical Studies (14.1)].
Treatment of Deep Vein Thrombosis and Pulmonary Embolism
[see Clinical Studies (14.2)]
 8  USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies in pregnant women.
SAVAYSA should be used during pregnancy only if the potential benefit jus-
tifies the potential risk to the fetus.
Human Data
In the Hokusai VTE study there were 10 pregnancy cases reported in patients
receiving SAVAYSA with exposure in the first trimester and estimated dura-
tion of exposure for up to approximately 6 weeks. Among these there were
6 live births (4 full term, 2 pre-term), 1 first-trimester spontaneous abortion,
and 3 cases of elective termination of pregnancy.
Animal Data
Embryo-fetal development studies were conducted in pregnant rats and rab-
bits during the period of organogenesis. In rats, no teratogenic effects were
seen when edoxaban was administered orally at doses up to 300 mg/kg/day,
or 49 times the human dose of 60 mg/day normalized to body surface area.
Increased post-implantation loss occurred at 300 mg/kg/day, but this effect
may be secondary to the maternal vaginal hemorrhage seen at this dose. 
In rabbits, no teratogenic effects were seen at doses up to 600 mg/kg/day
(49 times the human exposure at a dose of 60 mg/day when based on
AUC). Embryo-fetal toxicities occurred at maternally toxic doses, and included
absent or small fetal gallbladder at 600 mg/kg/day, and increased post-
implantation loss, increased spontaneous abortion, and decreased live
fetuses and fetal weight at doses equal to or greater than 200 mg/kg/day,
which is equal to or greater than 20 times the human exposure.
In a rat pre- and post-natal developmental study, edoxaban was adminis-
tered orally during the period of organogenesis and through lactation day 20
at doses up to 30 mg/kg/day, which is up to 3 times the human exposure
when based on AUC. Vaginal bleeding in pregnant rats and delayed avoid-
ance response (a learning test) in female offspring were seen at 30 mg/kg/day.
8.2 Labor and Delivery
Safety and effectiveness of SAVAYSA during labor and delivery have not
been studied in clinical studies. The risks of bleeding should be balanced
with the risk of thrombotic events when considering the use of SAVAYSA in
this setting.
8.3 Nursing Mothers
It is not known if edoxaban is excreted in human milk. Edoxaban was
excreted in the milk of lactating rats. Because many drugs are excreted in
human milk and because of the potential for adverse reactions in nursing
infants from SAVAYSA, a decision should be made to discontinue nursing
or the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established. 
8.5 Geriatric Use
Of the total patients in the ENGAGE AF-TIMI 48 study, 5182 (74%) were 
65 years and older, while 2838 (41%) were 75 years and older. In Hokusai VTE,
1334 (32%) patients were 65 years and older, while 560 (14%) patients
were 75 years and older. In clinical trials the efficacy and safety of SAVAYSA
in elderly (65 years or older) and younger patients were similar [see Adverse
Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].
8.6 Renal Impairment 
Renal clearance accounts for approximately 50% of the total clearance 
of edoxaban. Consequently, edoxaban blood levels are increased in 
patients with poor renal function compared to those with higher renal func-
tion. Reduce SAVAYSA dose to 30 mg once daily in patients with CrCL 
15-50 mL/min. There are limited clinical data with SAVAYSA in patients
with CrCL < 15 mL/min; SAVAYSA is therefore not recommended in these
patients. Hemodialysis does not significantly contribute to SAVAYSA clear-
ance [see Dosage and Administration (2.1, 2.2) and Clinical Pharmacology
(12.3)]. 
As renal function improves and edoxaban blood levels decrease, the risk for
ischemic stroke increases in patients with NVAF [see Indications and Usage
(1.1), Dosage and Administration (2.1), and Clinical Studies (14.1)]. 
8.7 Hepatic Impairment
The use of SAVAYSA in patients with moderate or severe hepatic impair-
ment (Child-Pugh B and C) is not recommended as these patients may have
intrinsic coagulation abnormalities. No dose reduction is required in
patients with mild hepatic impairment (Child-Pugh A) [see Clinical Pharma-
cology (12.3)].
8.8 Low Body Weight Consideration for Patients treated for DVT and/or PE
Based on the clinical experience from the Hokusai VTE study, reduce
SAVAYSA dose to 30 mg in patients with body weight less than or equal to
60 kg [see Dosage and Administration (2.2) and Clinical Studies (14.2)].
10  OVERDOSAGE
A specific reversal agent for edoxaban is not available. Overdose of
SAVAYSA increases the risk of bleeding.
The following are not expected to reverse the anticoagulant effects of 
edoxaban: protamine sulfate, vitamin K, and tranexamic acid [see Warnings
and Precautions (5.3)].
Hemodialysis does not significantly contribute to edoxaban clearance [see
Pharmacokinetics (12.3)].
11  DESCRIPTION
Edoxaban, a factor Xa inhibitor, is supplied as edoxaban tosylate mono -
hydrate. The chemical name is N-(5-Chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-
(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]
pyridine-2-carboxamido)cyclohexyl] oxamide mono (4-methylbenzene -
sulfonate) monohydrate. Edoxaban tosylate monohydrate has the empirical
formula C24H30ClN7O4S•C7H8O3S•H2O representing a molecular weight of
738.27. The chemical structure of edoxaban tosylate monohydrate is:
It is a white to pale yellowish-white crystalline powder. The solubility of
edoxaban tosylate (pKa 6.7) decreases with increasing pH. It is slightly sol-
uble in water, pH 3 to 5 buffer, very slightly soluble at pH 6 to 7; and practi-
cally insoluble at pH 8 to 9. 
SAVAYSA is available for oral administration as a 60 mg, 30 mg, or 15 mg
round shaped, film-coated tablet, debossed with product identification
markings. Each 60 mg tablet contains 80.82 mg edoxaban tosylate mono-
hydrate equivalent to 60 mg of edoxaban. Each 30 mg tablet contains 
40.41 mg edoxaban tosylate monohydrate equivalent to 30 mg of edoxaban.
Each 15 mg tablet contains 20.20 mg edoxaban tosylate monohydrate
equivalent to 15 mg of edoxaban. The inactive ingredients are: mannitol,
pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium
stearate, talc, and carnauba wax. The color coatings contain hypromellose,
titanium dioxide, talc, polyethylene glycol 8000, iron oxide yellow (60 mg
tablets and 15 mg tablets), and iron oxide red (30 mg tablets and 15 mg
tablets).
12  CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Edoxaban is a selective inhibitor of FXa. It does not require antithrombin III
for antithrombotic activity. Edoxaban inhibits free FXa, and prothrombinase
activity and inhibits thrombin-induced platelet aggregation. Inhibition of FXa
in the coagulation cascade reduces thrombin generation and reduces
thrombus formation.
12.2 Pharmacodynamics
As a result of FXa inhibition, edoxaban prolongs clotting time tests such as
prothrombin time (PT), and activated partial thromboplastin time (aPTT).
Changes observed in PT, INR, and aPTT at the expected therapeutic dose,
however, are small, subject to a high degree of variability and not useful in


monitoring the anticoagulant effect of edoxaban. Following oral administra-
tion, peak pharmacodynamic effects are observed within 1-2 hours, which
correspond with peak edoxaban concentrations (Cmax).
Cardiac Electrophysiology
In a thorough QT study in healthy men and women aged 19-45 years, no
QTc interval prolongation was observed with edoxaban (90 mg and 180 mg).
Effect of PCCs on Pharmacodynamics of SAVAYSA
There is no systematic evaluation of bleeding reversal by 4-factor prothrom-
bin complex concentrate (PCC) products in patients who have received
SAVAYSA. 
Effects of PCC (50 IU/kg) on the pharmacodynamics of edoxaban were stud-
ied in healthy subjects following a punch biopsy. Following administration of
a single dose of edoxaban, endogenous thrombin potential (ETP) returned to
pre-edoxaban baseline levels in 0.5 hours after the initiation of a 15 minute
infusion of 50 IU/kg PCC, compared to more than 24 hours with placebo.
Mean ETP levels continued to increase and exceeded pre-edoxaban baseline,
reaching maximum elevations (~40% over pre-edoxaban levels) at 22 hours
after initiating PCC dose, which was the last observation of ETP. The clinical
relevance of this ETP increase is unknown.
Pharmacodynamic Interactions
Aspirin
Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased
bleeding time relative to that seen with either drug alone. 
NSAID (Naproxen) 
Co-administration of naproxen (500 mg) and edoxaban increased bleeding
time relative to that seen with either drug alone. 
12.3 Pharmacokinetics
Edoxaban displays approximately dose-proportional pharmacokinetics for
doses of 15 to 150 mg and 60 to 120 mg following single and repeat doses,
respectively, in healthy subjects.
Absorption
Following oral administration, peak plasma edoxaban concentrations are
observed within 1-2 hours. Absolute bioavailability is 62%. Food does not
affect total systemic exposure to edoxaban. SAVAYSA was administered
with or without food in the ENGAGE AF-TIMI 48 and Hokusai VTE trials. No
data are available regarding the bioavailability upon crushing and/or mixing
of edoxaban tablets into food, liquids, or administration through feeding
tubes.
Distribution
Disposition is biphasic. The steady-state volume of distribution (Vdss) is
107 (19.9) L [mean (SD)]. In vitro plasma protein binding is approximately
55%. There is no clinically relevant accumulation of edoxaban (accumula-
tion ratio 1.14) with once daily dosing. 
Steady-state concentrations are achieved within 3 days.
Metabolism
Unchanged edoxaban is the predominant form in plasma. There is minimal
metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation,
and oxidation by CYP3A4.  
The predominant metabolite M-4, formed by hydrolysis, is human-specific
and active and reaches less than 10% of the exposure of the parent com-
pound in healthy subjects. Exposure to the other metabolites is less than
5% of exposure to edoxaban.
Elimination
Edoxaban is eliminated primarily as unchanged drug in the urine. Renal
clearance (11 L/hour) accounts for approximately 50% of the total clear-
ance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion
account for the remaining clearance. The terminal elimination half-life of
edoxaban following oral administration is 10 to 14 hours.
Specific Populations
Hepatic Impairment
In a dedicated pharmacokinetic study, patients with mild or moderate
hepatic impairment (classified as Child-Pugh A or Child-Pugh B) exhibited
similar pharmacokinetics and pharmacodynamics to their matched healthy
control group. There is no clinical experience with edoxaban in patients
with severe hepatic impairment [see Use in Specific Populations (8.7)].
Renal Impairment
In a dedicated pharmacokinetic study, total systemic exposure to edoxaban
for subjects with CrCL > 50 to < 80 mL/min, CrCL 30 to 50 mL/min, 
CrCL < 30 mL/min, or undergoing peritoneal dialysis, were increased by 32%,
74%, 72%, and 93%, respectively, relative to subjects with CrCL ≥80 mL/min
[see Use in Specific Populations (8.6)].
Hemodialysis
A 4-hour hemodialysis session reduced total edoxaban exposure by less
than 7%.
Age
In a population pharmacokinetic analysis, after taking renal function and
body weight into account, age had no additional clinically significant effect
on edoxaban pharmacokinetics.
Weight
In a population pharmacokinetic analysis, total exposure in patients with
median low body weight (55 kg) was increased by 13% as compared with
patients with median high body weight (84 kg). 
Gender
In a population pharmacokinetic analysis, after accounting for body 
weight, gender had no additional clinically significant effect on edoxaban 
pharmacokinetics.
Race
In a population pharmacokinetic analysis, edoxaban exposures in Asian
patients and non-Asian patients were similar.
Drug Interactions
In vitro Drug Interactions Studies
In vitro studies indicate that edoxaban does not inhibit the major cytochrome
P450 enzymes (CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, or 3A4) and
does not induce CYP1A2, CYP3A4 or the P-gp transporter (MDR1). In vitro
data also indicate that edoxaban does not inhibit the following transporters
at clinically relevant concentrations: P-gp, the organic anion transporters
OAT1 or OAT3; the organic cation transporters OCT1 or OCT2; or the
organic ion transporting polypeptides OATP1B1 or OATP1B3. Edoxaban is a
substrate of P-gp transporter. 
Impact of Other Drugs on SAVAYSA
The effect of co-administered amiodarone, cyclosporine, dronedarone,
erythromycin, ketoconazole, quinidine, verapamil, and rifampin on edoxaban
exposure is shown in Figure 12.1. 
Figure 12.1: Summary of Drug Interaction Study Results
Impact of Edoxaban on Other Drugs
Edoxaban increased the Cmax of concomitantly administered digoxin by
28%; however, the AUC was not affected. Edoxaban had no effect on the
Cmax and AUC of quinidine.
Edoxaban decreased the Cmax and AUC of concomitantly administered 
verapamil by 14% and 16%, respectively.
13  NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Edoxaban was not carcinogenic when administered daily to mice and rats
by oral gavage for up to 104 weeks. The highest dose tested (500 mg/kg/day)
in male and female mice was 3 and 6 times, respectively, the human expo-
sure (AUC) at the human dose of 60 mg/day, and the highest doses tested
in male (600/400 mg/kg/day) and female (200 mg/kg/day) rats were 8 and
14 times, respectively, the human exposure at the human dose of 60 mg/day.
Edoxaban and its human-specific metabolite, M-4, were genotoxic in in vitro
chromosomal aberration tests but were not genotoxic in the in vitro bacte -
rial reverse mutation (Ames test), in in vitro human lymphocytes micro -
nucleus test, in in vivo rat bone marrow micronucleus test, in in vivo rat
liver micronucleus test, and in in vivo unscheduled DNA synthesis tests. 
Edoxaban showed no effects on fertility and early embryonic development
in rats at doses of up to 1000 mg/kg/day (162 times the human dose of 
60 mg/day normalized to body surface area).


14  CLINICAL STUDIES
14.1 Nonvalvular Atrial Fibrillation
The ENGAGE AF-TIMI 48 Study
The ENGAGE AF-TIMI 48 study was a multi-national, double-blind, non-
inferiority study comparing the efficacy and safety of two SAVAYSA treat-
ment arms (60 mg and 30 mg) to warfarin (titrated to INR 2.0 to 3.0) in
reducing the risk of stroke and systemic embolic events in patients with
NVAF. The non-inferiority margin (degree of inferiority of SAVAYSA to war-
farin that was to be ruled out) was set at 38%, reflecting the substantial
effect of warfarin in reducing strokes. The primary analysis included both
ischemic and hemorrhagic strokes. 
To enter the study, patients had to have one or more of the following addi-
tional risk factors for stroke:
•  a prior stroke (ischemic or unknown type), transient ischemic attack (TIA)
or non-CNS systemic embolism, or
•  2 or more of the following risk factors:
  • age ≥75 years,
  • hypertension,
  • heart failure, or
  • diabetes mellitus
A total of 21,105 patients were randomized and followed for a median of 
2.8 years and treated for a median of 2.5 years. Patients in the SAVAYSA
treatment arms had their dose halved (60 mg halved to 30 mg or 30 mg
halved to 15 mg) if one or more of the following clinical factors were pres-
ent: CrCL ≤50 mL/min, low body weight (≤60 kg) or concomitant use of
specific P-gp inhibitors (verapamil, quinidine, dronedarone). Patients on
antiretroviral therapy (ritonavir, nelfinavir, indinavir, saquinavir) as well as
cyclosporine were excluded from the study. Approximately 25% of patients
in all treatment groups received a reduced dose at baseline, and an addi-
tional 7% were dose-reduced during the study. The most common reason
for dose reduction was a CrCL ≤50 mL/min at randomization (19% of patients).
Patients were well balanced with respect to demographic and baseline char-
acteristics. The percentages of patients age ≥75 years and ≥80 years were
approximately 40% and 17%, respectively. The majority of patients were
Caucasian (81%) and male (62%). Approximately 40% of patients had not
taken a Vitamin K Antagonist (VKA) (i.e., never took a VKA or had not taken
a VKA for more than 2 months).
The mean patient body weight was 84 kg (185 lbs) and 10% of patients had
a body weight of ≤60 kg. Concomitant diseases of patients in this study
included hypertension (94%), congestive heart failure (58%), and prior
stroke or transient ischemic attack (28%). At baseline, approximately 30%
of patients were on aspirin and approximately 2% of patients were taking a
thienopyridine.
Patients randomized to the warfarin arm achieved a mean TTR (time in
therapeutic range, INR 2.0 to 3.0) of 65% during the course of the study.  
The primary endpoint of the study was the occurrence of first stroke (either
ischemic or hemorrhagic) or of a systemic embolic event (SEE) that occurred
during treatment or within 3 days from the last dose taken. In the overall
results of the study, shown in Table 14.1, both treatment arms of SAVAYSA
were non-inferior to warfarin for the primary efficacy endpoint of stroke or
SEE. However, the 30 mg (15 mg dose-reduced) treatment arm was numer-
ically less effective than warfarin for the primary endpoint, and was also
markedly inferior in reducing the rate of ischemic stroke. Based on the
planned superiority analysis (ITT, which required p < 0.01 for success), 
statistical superiority of the 60 mg (30 mg dose-reduced) treatment arm
compared to warfarin was not established in the total study population, but
there was a favorable trend [HR (99% CI): 0.87 (0.71, 1.07)].  
Table 14.1: Strokes and Systemic Embolic Events in the ENGAGE AF-TIMI 48
Study (mITT, on Treatmenta)
SAVAYSA
SAVAYSA
Warfarin
SAVAYSA 30 mg
SAVAYSA 60 mg
30 mgb
60 mgb
(N=7012)
vs. warfarin
vs. warfarin
Events
(N=7002)
(N=7012)
n (%/yr)c
HR (CI)d
HR (CI)d
n (%/yr)c
n (%/yr)c
p-value
p-value
First Stroke or SEE
253 (1.6)
182 (1.2)
232 (1.5)
1.07 (0.87, 1.31)
0.79 (0.63, 0.99)
p=0.44
p=0.017 
Ischemic Stroke 
225 (1.4)
135 (0.9)
144 (0.9)
1.54 (1.25, 1.90)
0.94 (0.75, 1.19)
Hemorrhagic Stroke 
18 (0.1)
39 (0.3)
75 (0.5)
0.24 (0.14, 0.39)
0.52 (0.36, 0.77)
Systemic Embolism
10 (<0.1)
8 (<0.1)
13 (<0.1)
0.75 (0.33, 1.72)
0.62 (0.26, 1.50)
Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, 
n = number of events, mITT = Modified Intent-to-Treat, N=number of patients 
in mITT population, SEE = Systemic Embolic Event, yr = year.
a Includes events during treatment or within 3 days of stopping study treatment
b Includes patients dose-reduced to 15 mg for the 30 mg treatment group and
30 mg for the 60 mg treatment group
c The event rate (%/yr) is calculated as number of events/subject-year exposure.
d 97.5% CI for primary endpoint of First Stroke or SEE. 95% CI for Ischemic
Stroke, Hemorrhagic Stroke or Systemic Embolism
Figure 14.1 is a plot of the time from randomization to the occurrence of the
first primary endpoint in all patients randomized to 60 mg SAVAYSA or 
warfarin.  
Figure 14.1: Kaplan-Meier Cumulative Event Rate Estimates for Primary
Endpoint (first occurrence of stroke or SEE) (mITT*)
* On treatment Study Period defined as Initial Dose to Final Dose + three days
The incidence rate of the primary endpoint of stroke or SEE in patients
(N=1776) treated with the 30 mg reduced dose of SAVAYSA because of a
CrCL level ≤50 mL/min, low body weight ≤60 kg, or the concomitant use of
a P-gp inhibitor drug, was 1.79% per year. Patients with any of these charac-
teristics who were randomized to receive warfarin had an incidence rate of
the primary endpoint of 2.21% per year [HR (95% CI): 0.81 (0.58, 1.13)]. 
In all randomized patients during the overall study period, the rates of 
CV death with SAVAYSA and warfarin were 2.74% per year vs. 3.17% per
year, respectively [HR (95% CI): 0.86 (0.77, 0.97)].    
The results in the ENGAGE AF-TIMI 48 study for the primary efficacy endpoint
for most major subgroups are displayed in Figure 14.2.   
Figure 14.2: ENGAGE AF-TIMI 48 Study: Primary Efficacy Endpoint by 
Subgroups (ITT Analysis Set)
Note: The figure above presents effects in various subgroups all of which are
baseline characteristics and most of which were pre-specified. The 95% confi-
dence limits that are shown do not take into account how many comparisons
were made, nor do they reflect the effect of a particular factor after adjustment
for all other factors. Apparent homogeneity or heterogeneity among groups
should not be over-interpreted.
The results of the ENGAGE AF-TIMI 48 study show a strong relationship
between the blood levels of edoxaban and its effectiveness in reducing the
rate of ischemic stroke. There was a 64% increase in the ischemic stroke rate
in patients in the 30 mg treatment arm (including patients with dose reduced
to 15 mg) compared to the 60 mg treatment arm (including patients with
dose reduced to 30 mg). Approximately half of the SAVAYSA dose is elimi-
nated by the kidney, and edoxaban blood levels are lower in patients with 
better renal function, averaging about 30% less in patients with CrCL of 
> 80 mL/min, and 40% less in patients with CrCL > 95 mL/min when com-
pared to patients with a CrCL of > 50 to ≤80 mL/min. Given the clear rela-
tionship of dose and blood levels to effectiveness in the ENGAGE AF-TIMI 48
study, it could be anticipated that patients with better renal function would
show a smaller effect of SAVAYSA compared to warfarin than would patients
with mildly impaired renal function, and this was in fact observed.


Table 14.2 shows the results for the study primary efficacy endpoint of first
stroke or SEE as well as the effects on ischemic and hemorrhagic stroke in
the pre-randomization CrCL subgroups for SAVAYSA 60 mg (including 30 mg
dose-reduced) and warfarin. There was a decreased rate of ischemic stroke
with SAVAYSA 60 mg compared to warfarin in patients with CrCL > 50 to 
≤80 mL/min [HR (95% CI): 0.63 (0.44, 0.89)]. In patients with CrCL > 80 to
≤95 mL/min the results for ischemic stroke slightly favor warfarin with a
confidence interval that crosses 1.0 [HR (95% CI): 1.11 (0.58, 2.12)]. The
rate of ischemic stroke was higher relative to warfarin in the patients with
CrCL > 95 mL/min [HR (95% CI): 2.16 (1.17, 3.97)]. Pharmacokinetic data
indicate that patients with CrCL > 95 mL/min had lower plasma edoxaban lev-
els, along with a lower rate of bleeding relative to warfarin than patients with
CrCL ≤95 mL/min. Consequently, SAVAYSA should not be used in patients
with CrCL > 95 mL/min [see Dosage and Administration (2.1), Warnings and
Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].
In patients with CrCL ≤95 mL/min, the SAVAYSA 60 mg (30 mg dose-
reduced) treatment arm reduced the risk of stroke or SEE when compared to
warfarin [HR (95% CI): 0.68 (0.55, 0.84)].
In the indicated population (CrCL ≤95 mL/min), during the overall study
period, the rates of CV death with SAVAYSA and warfarin were 2.95% per
year vs. 3.59% per year, respectively [HR (95% CI): 0.82 (0.72, 0.93)].
Table 14.2: Primary Endpoint, Ischemic and Hemorrhagic Stroke Results 
in as a Function of Baseline Creatinine Clearance (mITT Population, 
On Treatment)
STROKE TYPE
Event SAVAYSA 60 mg
Renal Function
Treatment
n (N)
Rate
vs. Warfarin
Subgroupsa
Arm
(%/yr)
HR (95% CI)
PRIMARY 
ENDPOINT 
(STROKE/SEE)
≤95 (Indicated 
Population)
Warfarin
211 (5485)
1.8
SAVAYSA 60 mg
142 (5417)
1.2
0.68 (0.55, 0.84)
≤50b
Warfarin
50 (1356)
2.0
SAVAYSA 60 mg
45 (1372)
1.8
0.90 (0.60, 1.34)
> 50 to ≤80 
Warfarin
135 (3053)
2.0
SAVAYSA 60 mg
71 (3020)
1.1
0.53 (0.40, 0.70)
> 80 to ≤95
Warfarin
26 (1076)
1.0
SAVAYSA 60 mg
26 (1025)
1.1
1.05 (0.61, 1.82)
> 95*
Warfarin
21 (1527)
0.6
SAVAYSA 60 mg
40 (1595)
1.0
1.87 (1.10, 3.17)
ISCHEMIC STROKE
≤95 (Indicated 
Population)
Warfarin
129 (5485)
1.1
SAVAYSA 60 mg
102 (5417)
0.9
0.80 (0.62, 1.04)
≤50b
Warfarin
28 (1356)
1.1
SAVAYSA 60 mg
31 (1372)
1.2
1.11 (0.66, 1.84)
> 50 to ≤80 
Warfarin
83 (3053)
1.2
SAVAYSA 60 mg
52 (3020)
0.8
0.63 (0.44, 0.89)
> 80 to ≤95
Warfarin
18 (1076)
0.7
SAVAYSA 60 mg
19 (1025)
0.8
1.11 (0.58, 2.12) 
> 95*
Warfarin
15 (1527)
0.4
SAVAYSA 60 mg
33 (1595)
0.9
2.16 (1.17, 3.97)
HEMORRHAGIC 
STROKE
≤95 (Indicated 
Population)
Warfarin
70 (5485)
0.6
SAVAYSA 60 mg
34 (5417)
0.3
0.50 (0.33, 0.75)
≤50b
Warfarin
18 (1356)
0.7
SAVAYSA 60 mg
12 (1372)
0.5
0.66 (0.32, 1.36)
> 50 to ≤80 
Warfarin
45 (3053)
0.7
SAVAYSA 60 mg
17 (3020)
0.3
0.38 (0.22, 0.67)
(continued)
Table 14.2: Primary Endpoint, Ischemic and Hemorrhagic Stroke Results 
in as a Function of Baseline Creatinine Clearance (mITT Population, 
On Treatment)
STROKE TYPE
Event SAVAYSA 60 mg
Renal Function
Treatment
n (N)
Rate
vs. Warfarin
Subgroupsa
Arm
(%/yr)
HR (95% CI)
HEMORRHAGIC 
STROKE
> 80 to ≤95
Warfarin
7 (1076)
0.3
SAVAYSA 60 mg
5 (1025)
0.2
0.76 (0.24, 2.38)
> 95*
Warfarin
6 (1527)
0.2
SAVAYSA 60 mg
6 (1595)
0.2
0.98 (0.31, 3.05)
Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, 
n = number of events, mITT = Modified Intent-to-Treat, N=number of patients
in mITT population, yr = year.
* See Boxed Warning
a Renal function subgroups are based on estimated creatinine clearance in
mL/min calculated using the Cockcroft-Gault formula.   
b 83% of patients with pre-randomization CrCL ≤50 mL/min in the SAVAYSA
60 mg group were dose-reduced and consequently received SAVAYSA 30 mg
daily. All patients in the warfarin group with CrCL ≤50 mL/min were treated
in the same way as those with higher levels of CrCL.   
Transition to Other Anticoagulants in the ENGAGE AF-TIMI 48 Study
In the ENGAGE AF-TIMI 48 study, the schemes for transitioning from study
medication to open-label warfarin at the end of study were associated with
similar rates of stroke and systemic embolism in the SAVAYSA 60 mg and
warfarin groups [see Dosage and Administration (2.4)]. In the SAVAYSA 
60 mg group 7 (0.2%) of 4529 patients had a stroke or SEE compared to 
7 (0.2%) of 4506 patients in the warfarin arm.
14.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
The Hokusai VTE Study
SAVAYSA for the treatment of patients with deep vein thrombosis (DVT)
and pulmonary embolism (PE) was studied in a multi-national, double-blind
study (Hokusai VTE) which compared the efficacy and safety of SAVAYSA
60 mg orally once daily to warfarin (titrated to INR 2.0 to 3.0) in patients
with acute symptomatic venous thromboembolism (VTE) (DVT or PE with
or without DVT). All patients had VTE confirmed by appropriate diagnostic
imaging at baseline and received initial heparin therapy with low molecular
weight heparin (LMWH) or unfractionated heparin for at least 5 days
[median LMWH/heparin treatment in the SAVAYSA 60 mg group was 
7 days, and in the warfarin group it was 8.0 days] and until INR (sham or
real) was ≥2.0 on two measurements. Blinded drug treatment in the war-
farin arm was started concurrently with initial heparin therapy and in the
SAVAYSA arm after discontinuation of initial heparin. Patients randomized
to SAVAYSA received 30 mg once daily if they met one or more of the 
following criteria: CrCL 30 to 50 mL/min, body weight ≤60 kg, or con -
comitant use of specific P-gp inhibitors (verapamil and quinidine or the
short-term concomitant administration of azithromycin, clarithromycin,
erythromycin, oral itraconazole or oral ketoconazole). The edoxaban dosage
regimen was to be returned to the regular dosage of 60 mg once daily at
any time the subject is not taking the concomitant medication provided no
other criteria for dose reduction are met. Other P-gp inhibitors were not
permitted in the study. Patients on antiretroviral therapy (ritonavir, nelfin -
avir, indinavir, saquinavir) as well as cyclosporine were excluded from the
Hokusai VTE study. The concomitant use of these drugs with SAVAYSA has
not been studied in patients. The treatment duration was from 3 months up
to 12 months, determined by investigator based on patient clinical features.
Patients were excluded if they required thrombectomy, insertion of a caval
filter, use of a fibrinolytic agent, or use of other P-gp inhibitors, had a creat -
inine clearance < 30 mL/min, significant liver disease, or active bleeding.
The primary efficacy outcome was symptomatic VTE, defined as the com-
posite of recurrent DVT, new non-fatal symptomatic PE, and fatal PE during
the 12-month study period. 
A total of 8292 patients were randomized to receive SAVAYSA or warfarin
and were followed for a mean treatment duration of 252 days for SAVAYSA
and 250 days for warfarin. The mean age was approximately 56 years. The
population was 57% male, 70% Caucasian, 21% Asian, and about 4%
Black. The presenting diagnosis was PE (with or without DVT) in 40.7%
and DVT only in 59.3% of patients. At baseline, 27.6% of patients had tem-
porary risk factors only (e.g., trauma, surgery, immobilization, estrogen
therapy). Overall 9.4% had a history of cancer, 17.3% of the patients had
an age ≥75 years and/or a body weight ≤50 kg, and/or a CrCL < 50 mL/min,
and 31.4% of patients had NT-ProBNP ≥500 pg/mL. 


Aspirin was taken as on treatment concomitant antithrombotic medication
by approximately 9% of patients in both groups.
In the warfarin group, the median TTR (time in therapeutic range, INR 2.0
to 3.0) was 65.6%.
A total of 8240 patients (n= 4118 for SAVAYSA and n = 4122 for warfarin)
received study drug and were included in the modified intent-to-treat
(mITT) population. SAVAYSA was demonstrated to be non inferior to 
warfarin for the primary endpoint of recurrent VTE [HR (95% CI): 0.89
(0.70, 1.13)] (Table 14.3, Figure 14.3). 
Table 14.3: Primary Composite Efficacy Endpoint Results in Hokusai VTE
(mITT Overall Study Period)
Primary Endpoint
SAVAYSA a
Warfarin
SAVAYSA vs.
n/N (%)
n/N (%)
Warfarin
HR (95% CI)
All patients with 
130/4118 (3.2)
146/4122 (3.5)
0.89 (0.70,1.13)
symptomatic 
recurrent VTEb
PE with or 
73/4118 (1.8)
83/4122 (2.0)
-
without DVT
Fatal PE and Death
24/4118 (0.6)
24/4122 (0.6)
-
where PE cannot
be ruled out
Non-fatal PE
49/4118 (1.2)
59/4122 (1.4)
-
DVT only
57/4118 (1.4)
63/4122 (1.5)
-
Index PEc patients 
47/1650 (2.8)
65/1669 (3.9)
-
with symptomatic 
recurrent VTE 
Index DVTd patients 
83/2468 (3.4)
81/2453 (3.3)
-
with symptomatic 
recurrent VTE 
Abbreviations: mITT = modified intent-to-treat; HR =hazard ratio vs. warfarin; 
CI =confidence interval; N=number of patients in mITT population; n = number
of events
a Includes patients dose-reduced to 30 mg. Among the 1452 (17.6%) patients
with low body weight (≤60 kg), moderate renal impairment (CrCL ≤50 mL/min),
or concomitant use of P-gp inhibitors in the Hokusai VTE study, 22 (3.0%) of
the SAVAYSA patients (30 mg once daily, n =733) and 30 (4.2%) of warfarin
patients (n= 719) had a symptomatic recurrent VTE event  
b Primary Efficacy Endpoint: Symptomatic recurrent VTE (i.e., the composite
endpoint of DVT, non-fatal PE and fatal PE)
c Index PE refers to patients whose presenting diagnosis was PE (with or with-
out concomitant DVT)
d Index DVT refers to patients whose presenting diagnosis was DVT only 
Figure 14.3: Kaplan-Meier Cumulative Event Rate Estimates for Adjudicated
Recurrent VTE (mITT analysis – on treatment)
16  HOW SUPPLIED/STORAGE AND HANDLING
SAVAYSA (edoxaban) is supplied as round shaped, film-coated, non-scored
tablets containing edoxaban tosylate equivalent to 60, 30 or 15 mg of
SAVAYSA, packaged in bottles and blisters.
NDC 65597-xxx-yy
xxx
yy
Bottle of
Blister of
Strength
Color
Deboss
30
90
500
10 x 10*
10 x 5**
15 mg
orange
DSC 
201
L15
30
-
-
-
-
30 mg
pink
DSC 
202
L30
30
90
50
10
05
60 mg
yellow
DSC 
203
L60
30
90
50
10
05
*10 blister cards of 10 counts  **5 blister cards of 10 counts  
Store at 20-25°C (68-77°F); excursions permitted to 15°-30°C (59°-86°F)
[see USP Controlled Room Temperature].
Keep out of the reach of children.
17  PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication
Guide).
Advise patients of the following:
• they may bleed more easily, may bleed longer, or bruise more easily
when treated with SAVAYSA
• to report any unusual bleeding immediately to their healthcare provider
• to take SAVAYSA exactly as prescribed
• to not discontinue SAVAYSA without talking to the healthcare provider
who prescribed it
• to inform their healthcare providers that they are taking SAVAYSA before
any surgery, medical, or dental procedure is scheduled
• to inform their healthcare providers and dentists if they plan to take, or
are taking any prescription medications, over-the-counter drugs or herbal
products
• to inform their healthcare provider immediately if they become pregnant
or intend to become pregnant or are breastfeeding or intend to breastfeed
during treatment with SAVAYSA
• that if a dose is missed, take SAVAYSA as soon as possible the same day,
and resume the normal dosing schedule the following day. The dose
should not be doubled to make up for a missing dose
• that if they are having neuraxial anesthesia or spinal puncture, advise
patients to watch for signs and symptoms of spinal or epidural hematoma,
such as back pain, tingling, numbness (especially in the lower limbs),
muscle weakness, and stool or urine incontinence. If any of these symp-
toms occur, advise the patient to contact his or her physician immediately
[see Boxed Warning].
SAVAYSA™ is a trademark of Daiichi Sankyo Co., LTD.
Manufactured by:
Daiichi Sankyo Co., LTD.
Tokyo 103-8426
Japan
Distributed by:
Daiichi Sankyo, Inc.
Parsippany, NJ 07054 USA
Copyright© 2015, Daiichi Sankyo, Inc.  
PRINTED IN USA.


MEDICATION GUIDE
SAVAYSA (sa vaye´ sah)
(edoxaban) TABLETS
What is the most important information I should know about
SAVAYSA?
For people who take SAVAYSA for nonvalvular atrial
fibrillation (a type of irregular heartbeat): 
People with atrial fibrillation are at an increased risk of
forming a blood clot in the heart, which can travel to the brain,
causing a stroke, or to other parts of the body. SAVAYSA
lowers your chance of having a stroke by helping to prevent
clots from forming.
   •  Your doctor should check your kidney function before
you start taking SAVAYSA. People whose kidneys work
really well should not receive SAVAYSA because it may
not work well to prevent stroke. 
   •  Do not stop taking SAVAYSA without first talking to the
doctor who prescribed it for you. Stopping SAVAYSA
increases your risk of having a stroke.
For all people who take SAVAYSA:
•  SAVAYSA can cause bleeding which can be serious, and
sometimes lead to death. This is because SAVAYSA is a
blood thinner medicine that reduces blood clotting. While
taking SAVAYSA you may bruise more easily and bleeding
may take longer to stop. You should call your doctor or get
medical help right away if you experience bleeding that is
severe (for example, coughing up or vomiting blood) or
bleeding that cannot be controlled.  
   You may have a higher risk of bleeding if you take SAVAYSA
and take other medicines that increase your risk of bleeding,
including:
   •  aspirin or aspirin containing products
   •  long-term (chronic) use of non-steroidal anti-inflammatory
drugs (NSAIDs)
   •  long-term (chronic) use of blood thinner medicines, such
as:
   •  warfarin sodium (Coumadin®, Jantoven®)
   •  any medicine that contains heparin
   •  selective serotonin reuptake inhibitors (SSRIs) or
serotonin norepinephrine reuptake inhibitors (SNRIs)
   •  other medicines to prevent or treat blood clots
   Tell your doctor if you take any of these medicines. Ask
your doctor or pharmacist if you are not sure if your
medicine is one listed above.
•  SAVAYSA is not for people with mechanical heart valves
or people who have moderate to severe narrowing
(stenosis) of their mitral valve.
•  Spinal or epidural blood clots (hematoma). People who
take a blood thinner medicine (anticoagulant) like SAVAYSA,
and have medicine injected into their spinal and epidural
area, or have a spinal puncture have a risk of forming a
blood clot that can cause long-term or permanent loss of
the ability to move (paralysis). Your risk of developing a
spinal or epidural blood clot is higher if:
   •  a thin tube called an epidural catheter is placed in your
back to give you certain medicine
   •  you take NSAIDs or a medicine to prevent blood from
clotting
   •  you have a history of difficult or repeated epidural or
spinal punctures
   •  you have a history of problems with your spine or have
had surgery on your spine.
   If you take SAVAYSA and receive spinal anesthesia or have
a spinal puncture, your doctor should watch you closely for
symptoms of spinal or epidural blood clots. Tell your doctor
right away if you have back pain, tingling, numbness
(especially in your legs and feet), muscle weakness, loss of
control of the bowels or bladder (incontinence).
See “What are the possible side effects of SAVAYSA?” for
more information about side effects.
What is SAVAYSA?
SAVAYSA is a prescription medicine used to: 
   •  reduce the risk of stroke and blood clots in people who
have atrial fibrillation not caused by a heart valve
problem.
   •  treat blood clots in the veins of your legs (deep vein
thrombosis) or lungs (pulmonary embolism), after you
have been treated with an injectable blood thinner
medicine for 5 to 10 days.
It is not known if SAVAYSA is safe and effective in children. 
Who should not take SAVAYSA?
Do not take SAVAYSA if you currently have certain types of
abnormal bleeding. 
What should I tell my doctor before taking SAVAYSA?
Before you take SAVAYSA, tell your doctor if you:
•  have liver or kidney problems
•  have ever had bleeding problems
•  have a mechanical heart valve
•  are pregnant or plan to become pregnant. It is not known if
SAVAYSA will harm your unborn baby. Tell your doctor
right away if you become pregnant during treatment with
SAVAYSA. 
•  are breastfeeding or plan to breastfeed. It is not known if
SAVAYSA passes into your breast milk. You and your
doctor should decide if you will take SAVAYSA or
breastfeed. You should not do both.
Tell all of your doctors and dentists that you are taking
SAVAYSA. They should talk to the doctor who prescribed
SAVAYSA for you, before you have any surgery, medical or
dental procedure.
Tell your doctor about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and
herbal supplements. Some of your other medicines may affect
the way SAVAYSA works. Certain medicines may increase
your risk of bleeding or stroke when taken with SAVAYSA. See
“What is the most important information I should know
about SAVAYSA?”
Know the medicines you take. Keep a list of them to show
your doctor and pharmacist when you get a new medicine.


How should I take SAVAYSA?
•  Take SAVAYSA exactly as prescribed by your doctor. 
•  Your doctor will decide how long you should take SAVAYSA.
Do not change your dose or stop taking SAVAYSA unless
your doctor tells you to. If you are taking SAVAYSA for
atrial fibrillation, stopping SAVAYSA may increase your
risk of having a stroke.
•  You can take SAVAYSA with or without food.
•  If you miss a dose of SAVAYSA, take it as soon as you
remember on the same day. Take your next dose at your
usual time the next day. Do not take more than one dose of
SAVAYSA at the same time to make up for a missed dose.
•  Do not run out of SAVAYSA. Refill your prescription
before you run out.
•  If you take too much SAVAYSA, go to the nearest hospital
emergency room or call your doctor right away.
•  Call your doctor right away if you fall or injure yourself,
especially if you hit your head. Your doctor may need to
check you.
What are the possible side effects of SAVAYSA?
SAVAYSA can cause serious side effects. See “What is the
most important information I should know about SAVAYSA?”
Common side effects in people who take SAVAYSA include,
bleeding and low red blood cell count (anemia).
Talk to your doctor if you have any side effect that bothers
you or that does not go away.
Call your doctor for medical advice about side effects. You
may report side effects to FDA at 1-800-FDA-1088.
How should I store SAVAYSA?
•  Store SAVAYSA at room temperature between 68°F to 77°F
(20°C to 25°C).
Keep SAVAYSA and all medicines out of the reach of
children.
General information about the safe and effective use of
SAVAYSA
Medicines are sometimes prescribed for purposes other than
those listed in a Medication Guide. Do not use SAVAYSA for a
condition for which it was not prescribed. Do not give SAVAYSA
to other people, even if they have the same symptoms that
you have. It may harm them.
If you would like more information, talk with your doctor. You
can ask your pharmacist or doctor for information about
SAVAYSA that is written for health professionals.
For more information, call 1-877-437-7763 or go to
www.savaysa.com.
What are the ingredients in SAVAYSA?
Active ingredient: edoxaban tosylate monohydrate
Inactive ingredients: mannitol, pregelatinized starch,
crospovidone, hydroxypropyl cellulose, magnesium stearate,
talc, and carnauba wax. The color coatings contain hypromellose,
titanium dioxide, talc, polyethylene glycol 8000, iron oxide
yellow (15 mg tablets and 60 mg tablets), and iron oxide red
(15 mg tablets and 30 mg tablets).
This Medication Guide has been approved by the U.S. Food
and Drug Administration.
Manufactured by:
Daiichi Sankyo Co., LTD.
Tokyo 103-8426
Japan
Distributed by:
Daiichi Sankyo, Inc.
Parsippany, NJ 07054 USA
Copyright© 2015, Daiichi Sankyo, Inc.  
The brands listed above are trademarks of their respective
owners. 
P1805216-P


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 115 
APPENDIX F. 
US PACKAGE INSERT FOR RIVAROXABAN (XARELTO)


1
XARELTO®
(rivaroxaban) tablets, for oral use
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use 
XARELTO® (rivaroxaban) safely and effectively. See full prescribing 
information for XARELTO.
XARELTO (rivaroxaban) tablets, for oral use
Initial U.S. Approval: 2011
WARNING:  (A) PREMATURE DISCONTINUATION OF XARELTO 
INCREASES THE RISK OF THROMBOTIC EVENTS,  
(B) SPINAL/EPIDURAL HEMATOMA
See full prescribing information for complete boxed warning
(A) Premature discontinuation of XARELTO increases the risk of 
thrombotic events
Premature discontinuation of any oral anticoagulant, including XARELTO, 
increases the risk of thrombotic events. To reduce this risk, consider 
coverage with another anticoagulant if XARELTO is discontinued for a 
reason other than pathological bleeding or completion of a course of 
therapy (2.3, 2.7, 5.1, 14.1).  
(B) Spinal/epidural hematoma
Epidural or spinal hematomas have occurred in patients treated with 
XARELTO who are receiving neuraxial anesthesia or undergoing spinal 
puncture. These hematomas may result in long-term or permanent paralysis 
(5.2, 5.3, 6.2).
Monitor patients frequently for signs and symptoms of neurological 
impairment and if observed, treat urgently. Consider the benefits and risks 
before neuraxial intervention in patients who are or who need to be 
anticoagulated (5.3).
------------------------------RECENT MAJOR CHANGES----------------------------
Warnings and Precautions (5.2, 5.4)	
05/2016
Warnings and Precautions (5.3)	
08/2016
-------------------------------INDICATIONS AND USAGE----------------------------
XARELTO is a factor Xa inhibitor indicated:
•	 to reduce the risk of stroke and systemic embolism in patients with 
nonvalvular atrial fibrillation (1.1)
•	 for the treatment of deep vein thrombosis (DVT), pulmonary embolism 
(PE), and for the reduction in the risk of recurrence of DVT and of PE (1.2, 
1.3, 1.4)
•	 for the prophylaxis of DVT, which may lead to PE in patients undergoing 
knee or hip replacement surgery (1.5)
-------------------------- DOSAGE AND ADMINISTRATION-------------------------
•	 Take 15  mg and 20  mg tablets with food; take 10  mg tablets with or 
without food (2.2)
•	 Nonvalvular Atrial Fibrillation:
o	 For patients with CrCl >50  mL/min: 20  mg orally, once daily with the 
evening meal (2.4)
o	 For patients with CrCl 15 - 50 mL/min: 15 mg orally, once daily with the 
evening meal (2.4)
•	 Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT 
and of PE: 15 mg orally twice daily with food for the first 21 days for the 
initial treatment of acute DVT or PE. After the initial treatment period, 
20  mg orally once daily with food for the remaining treatment and the 
long-term reduction in the risk of recurrence of DVT and of PE. (2.5) 
•	 Prophylaxis of DVT Following Hip or Knee Replacement Surgery: 10 mg 
orally, once daily with or without food (2.6)
------------------------- DOSAGE FORMS AND STRENGTHS-----------------------
Tablets: 10 mg, 15 mg, and 20 mg (3)
-------------------------------- CONTRAINDICATIONS--------------------------------
•	 Active pathological bleeding (4)
•	 Severe hypersensitivity reaction to XARELTO (4)
------------------------ WARNINGS AND PRECAUTIONS---------------------------
•	 Risk of bleeding: XARELTO can cause serious and fatal bleeding. 
Promptly evaluate signs and symptoms of blood loss. (5.2)
•	 Pregnancy-related hemorrhage: Use XARELTO with caution in pregnant 
women due to the potential for obstetric hemorrhage and/or emergent 
delivery. Promptly evaluate signs and symptoms of blood loss. (5.7)
•	 Prosthetic heart valves: XARELTO use not recommended (5.8)
------------------------------- ADVERSE REACTIONS---------------------------------
The most common adverse reaction (>5%) was bleeding. (6.1)
To 
report 
SUSPECTED 
ADVERSE 
REACTIONS, 
contact 
Janssen 
Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1‑800-FDA-1088 or www.
fda.gov/medwatch. 
------------------------------- DRUG INTERACTIONS---------------------------------
•	 Combined P-gp and strong CYP3A4 inhibitors and inducers: Avoid 
concomitant use (7.2, 7.3)
•	 Anticoagulants: Avoid concomitant use (7.4)
------------------------- USE IN SPECIFIC POPULATIONS---------------------------
•	 Nursing mothers: discontinue drug or discontinue nursing (8.3)
•	 Renal impairment: Avoid or adjust dose based on CrCl and Indication (8.7) 
•	 Hepatic impairment: Avoid use in patients with Child-Pugh B and C 
hepatic impairment or with any degree of hepatic disease associated 
with coagulopathy (8.8)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 03/2017
XARELTO® (rivaroxaban) tablets
Revised: 03/2017
070441-170404
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES 
THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
1	 INDICATIONS AND USAGE
1.1	 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular 
Atrial Fibrillation
1.2	 Treatment of Deep Vein Thrombosis
1.3	 Treatment of Pulmonary Embolism
1.4	 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and 
of Pulmonary Embolism
1.5	 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee 
Replacement Surgery
2	 DOSAGE AND ADMINISTRATION
2.1	 Recommended Dosage
2.2	 Important Food Effect Information
2.3	 Switching to and from XARELTO
2.4	 Nonvalvular Atrial Fibrillation
2.5	 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism 
(PE), and Reduction in the Risk of Recurrence of DVT and of PE
2.6	 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee 
Replacement Surgery
2.7	 Discontinuation for Surgery and other Interventions
2.8	 Missed Dose
2.9	 Administration Options
3	 DOSAGE FORMS AND STRENGTHS
4	 CONTRAINDICATIONS
5	 WARNINGS AND PRECAUTIONS
5.1	 Increased Risk of Thrombotic Events after Premature 
Discontinuation
5.2	 Risk of Bleeding
5.3	 Spinal/Epidural Anesthesia or Puncture
5.4	 Use in Patients with Renal Impairment
5.5	 Use in Patients with Hepatic Impairment
5.6	 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers
5.7	 Risk of Pregnancy-Related Hemorrhage
5.8	 Patients with Prosthetic Heart Valves
5.9	 Acute PE in Hemodynamically Unstable Patients or Patients Who 
Require Thrombolysis or Pulmonary Embolectomy
6	 ADVERSE REACTIONS
6.1	 Clinical Trials Experience
6.2	 Postmarketing Experience
7	 DRUG INTERACTIONS
7.1	 General Inhibition and Induction Properties
7.2	 Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug 
Transport Systems
7.3	 Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug 
Transport Systems
7.4	 Anticoagulants and NSAIDs/Aspirin


2
8	 USE IN SPECIFIC POPULATIONS
8.1	 Pregnancy
8.2	 Labor and Delivery
8.3	 Nursing Mothers
8.4	 Pediatric Use
8.5	 Geriatric Use
8.6	 Females of Reproductive Potential
8.7	 Renal Impairment
8.8	 Hepatic Impairment
10	 OVERDOSAGE
11	 DESCRIPTION
12	 CLINICAL PHARMACOLOGY
12.1	 Mechanism of Action
12.2	 Pharmacodynamics
12.3	 Pharmacokinetics
12.6	 QT/QTc Prolongation
13	 NON-CLINICAL TOXICOLOGY
13.1	 Carcinogenesis, Mutagenesis, Impairment of Fertility
14	 CLINICAL STUDIES
14.1	 Stroke Prevention in Nonvalvular Atrial Fibrillation
14.2	 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism 
(PE), and Reduction in the Risk of Recurrence of DVT and of PE
14.3	 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee 
Replacement Surgery
16	 HOW SUPPLIED/STORAGE AND HANDLING
17	 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are 
not listed.
FULL PRESCRIBING INFORMATION
WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO 
INCREASES THE RISK OF THROMBOTIC EVENTS,  
(B) SPINAL/EPIDURAL HEMATOMA
A.	 Premature discontinuation of XARELTO increases the risk of 
thrombotic events
Premature discontinuation of any oral anticoagulant, including 
XARELTO, increases the risk of thrombotic events. If anticoagulation 
with XARELTO is discontinued for a reason other than pathological 
bleeding or completion of a course of therapy, consider coverage with 
another anticoagulant [see Dosage and Administration (2.3, 2.7), 
Warnings and Precautions (5.1), and Clinical Studies (14.1)].
B.	 Spinal/epidural hematoma
Epidural or spinal hematomas have occurred in patients treated with 
XARELTO who are receiving neuraxial anesthesia or undergoing spinal 
puncture. These hematomas may result in long-term or permanent 
paralysis. Consider these risks when scheduling patients for spinal 
procedures. Factors that can increase the risk of developing epidural or 
spinal hematomas in these patients include:
•	 use of indwelling epidural catheters
•	 concomitant use of other drugs that affect hemostasis, such as non-
steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other 
anticoagulants
•	 a history of traumatic or repeated epidural or spinal punctures
•	 a history of spinal deformity or spinal surgery
•	 optimal timing between the administration of XARELTO and neuraxial 
procedures is not known
[see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2)].
Monitor patients frequently for signs and symptoms of neurological 
impairment. If neurological compromise is noted, urgent treatment is 
necessary [see Warnings and Precautions (5.3)].
Consider the benefits and risks before neuraxial intervention in 
patients anticoagulated or to be anticoagulated for thromboprophylaxis 
[see Warnings and Precautions (5.3)].
1	
INDICATIONS AND USAGE
1.1	 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular 
Atrial Fibrillation
XARELTO is indicated to reduce the risk of stroke and systemic embolism in 
patients with nonvalvular atrial fibrillation.
There are limited data on the relative effectiveness of XARELTO and 
warfarin in reducing the risk of stroke and systemic embolism when 
warfarin therapy is well-controlled [see Clinical Studies (14.1)].
1.2	 Treatment of Deep Vein Thrombosis 
XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
1.3	 Treatment of Pulmonary Embolism
XARELTO is indicated for the treatment of pulmonary embolism (PE).
1.4	 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of 
Pulmonary Embolism
XARELTO is indicated for the reduction in the risk of recurrence of deep 
vein thrombosis and of pulmonary embolism following initial 6  months 
treatment for DVT and/or PE.
1.5	 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee 
Replacement Surgery
XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in 
patients undergoing knee or hip replacement surgery.
2	
DOSAGE AND ADMINISTRATION
2.1	 Recommended Dosage
Indication
Dosage
Reduction in Risk of 
Stroke in Nonvalvular 
Atrial Fibrillation (2.4)
CrCl >50 mL/min:
20 mg once daily with the 
evening meal
CrCl 15 to 50 mL/min:
15 mg once daily with the 
evening meal
Treatment of DVT (2.5)
Treatment of PE (2.5)
15 mg twice daily with food, for first 21 days
▼after 21 days, transition to ▼
20  mg once daily with food, for remaining treatment
Reduction in the Risk 
of Recurrence of DVT 
and of PE (2.5)
20 mg once daily with food
Prophylaxis of DVT 
Following Hip or  
Knee Replacement 
Surgery (2.6)
Hip replacement:
10 mg once daily for 35 days
Knee replacement:
10 mg once daily for 12 days
2.2	 Important Food Effect Information
The 15  mg and 20  mg XARELTO tablets should be taken with food, while 
the 10  mg tablet can be taken with or without food [see Clinical 
Pharmacology (12.3)].
In the nonvalvular atrial fibrillation efficacy study XARELTO was taken with 
the evening meal.
2.3	 Switching to and from XARELTO
Switching from Warfarin to XARELTO - When switching patients from 
warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as 
the International Normalized Ratio (INR) is below 3.0 to avoid periods of 
inadequate anticoagulation.
Switching from XARELTO to Warfarin - No clinical trial data are available to 
guide converting patients from XARELTO to warfarin. XARELTO affects INR, 
so INR measurements made during coadministration with warfarin may not 
be useful for determining the appropriate dose of warfarin. One approach 
is to discontinue XARELTO and begin both a parenteral anticoagulant and 
warfarin at the time the next dose of XARELTO would have been taken.
Switching from XARELTO to Anticoagulants other than Warfarin - For 
patients currently taking XARELTO and transitioning to an anticoagulant 
with rapid onset, discontinue XARELTO and give the first dose of the other 
anticoagulant (oral or parenteral) at the time that the next XARELTO dose 
would have been taken [see Drug Interactions (7.4)].
Switching from Anticoagulants other than Warfarin to XARELTO - For 
patients currently receiving an anticoagulant other than warfarin, start 
XARELTO 0 to 2 hours prior to the next scheduled evening administration of 
the drug (e.g., low molecular weight heparin or non-warfarin oral 
anticoagulant) and omit administration of the other anticoagulant. For 
unfractionated heparin being administered by continuous infusion, stop the 
infusion and start XARELTO at the same time.
XARELTO® (rivaroxaban) tablets
XARELTO® (rivaroxaban) tablets


3
2.4	 Nonvalvular Atrial Fibrillation
For patients with creatinine clearance (CrCl) >50 mL/min, the recommended 
dose of XARELTO is 20 mg taken orally once daily with the evening meal. 
For patients with CrCl 15  to  50  mL/min, the recommended dose is 15  mg 
once daily with the evening meal [see Use in Specific Populations (8.7)].
2.5	 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), 
and Reduction in the Risk of Recurrence of DVT and of PE
The recommended dose of XARELTO for the initial treatment of acute DVT 
and/or PE is 15 mg taken orally twice daily with food for the first 21 days. 
After this initial treatment period, the recommended dose of XARELTO is 
20  mg taken orally once daily with food, at approximately the same time 
each day. The recommended dose of XARELTO for reduction in the risk of 
recurrence of DVT or PE is 20  mg taken orally once daily with food at 
approximately the same time each day [see Clinical Studies (14.2)].
2.6	 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee 
Replacement Surgery
The recommended dose of XARELTO is 10 mg taken orally once daily with 
or without food. The initial dose should be taken 6 to 10 hours after surgery 
provided that hemostasis has been established [see Dosage and 
Administration (2.7)].
•	 For patients undergoing hip replacement surgery, treatment duration of 
35 days is recommended.
•	 For patients undergoing knee replacement surgery, treatment duration of 
12 days is recommended.
2.7	 Discontinuation for Surgery and other Interventions
If anticoagulation must be discontinued to reduce the risk of bleeding with 
surgical or other procedures, XARELTO should be stopped at least 24 hours 
before the procedure to reduce the risk of bleeding [see Warnings and 
Precautions (5.2)]. In deciding whether a procedure should be delayed until 
24 hours after the last dose of XARELTO, the increased risk of bleeding 
should be weighed against the urgency of intervention. XARELTO should be 
restarted after the surgical or other procedures as soon as adequate 
hemostasis has been established, noting that the time to onset of 
therapeutic effect is short [see Warnings and Precautions (5.1)]. If oral 
medication cannot be taken during or after surgical intervention, consider 
administering a parenteral anticoagulant.
2.8	 Missed Dose
If a dose of XARELTO is not taken at the scheduled time, administer the 
dose as soon as possible on the same day as follows:
•	 For patients receiving 15  mg twice daily: The patient should take 
XARELTO immediately to ensure intake of 30 mg XARELTO per day. In this 
particular instance, two 15 mg tablets may be taken at once. The patient 
should continue with the regular 15  mg twice daily intake as 
recommended on the following day.
•	 For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient 
should take the missed XARELTO dose immediately.
2.9	 Administration Options
For patients who are unable to swallow whole tablets, 10 mg, 15 mg or 
20 mg XARELTO tablets may be crushed and mixed with applesauce 
immediately prior to use and administered orally. After the administration of 
a crushed XARELTO 15 mg or 20 mg tablet, the dose should be immediately 
followed by food [see Dosage and Administration (2.2, 2.4, 2.5) and Clinical 
Pharmacology (12.3)].
Administration via nasogastric (NG) tube or gastric feeding tube: After 
confirming gastric placement of the tube, 10 mg, 15 mg or 20 mg XARELTO 
tablets may be crushed and suspended in 50 mL of water and administered 
via an NG tube or gastric feeding tube. Since rivaroxaban absorption is 
dependent on the site of drug release, avoid administration of XARELTO 
distal to the stomach which can result in reduced absorption and thereby, 
reduced drug exposure. After the administration of a crushed XARELTO 
15 mg or 20 mg tablet, the dose should then be immediately followed by 
enteral feeding [see Clinical Pharmacology (12.3)]. 
Crushed 10 mg, 15 mg or 20 mg XARELTO tablets are stable in water and in 
applesauce for up to 4 hours. An in vitro compatibility study indicated that 
there is no adsorption of rivaroxaban from a water suspension of a crushed 
XARELTO tablet to PVC or silicone nasogastric (NG) tubing.
3	
DOSAGE FORMS AND STRENGTHS
•	 10  mg tablets: Round, light red, biconvex and film-coated with a triangle 
pointing down above a “10” marked on one side and “Xa” on the other side
•	 15 mg tablets: Round, red, biconvex, and film-coated with a triangle pointing 
down above a “15” marked on one side and “Xa” on the other side
•	 20  mg tablets: Triangle-shaped, dark red, and film-coated with a triangle 
pointing down above a “20” marked on one side and “Xa” on the other side
4	
CONTRAINDICATIONS
XARELTO is contraindicated in patients with:
•	 active pathological bleeding [see Warnings and Precautions (5.2)]
•	 severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) 
[see Adverse Reactions (6.2)]
5	
WARNINGS AND PRECAUTIONS
5.1	 Increased Risk of Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including XARELTO, in 
the absence of adequate alternative anticoagulation increases the risk of 
thrombotic events. An increased rate of stroke was observed during the 
transition from XARELTO to warfarin in clinical trials in atrial fibrillation 
patients. If XARELTO is discontinued for a reason other than pathological 
bleeding or completion of a course of therapy, consider coverage with 
another anticoagulant [see Dosage and Administration (2.3, 2.7) and Clinical 
Studies (14.1)].
5.2	 Risk of Bleeding
XARELTO increases the risk of bleeding and can cause serious or fatal 
bleeding. In deciding whether to prescribe XARELTO to patients at 
increased risk of bleeding, the risk of thrombotic events should be weighed 
against the risk of bleeding.
Promptly evaluate any signs or symptoms of blood loss and consider the 
need for blood replacement. Discontinue XARELTO in patients with active 
pathological hemorrhage. The terminal elimination half-life of rivaroxaban 
is 5 to 9 hours in healthy subjects aged 20 to 45 years.
Concomitant use of other drugs that impair hemostasis increases the risk 
of bleeding. These include aspirin, P2Y12 platelet inhibitors, other 
antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory 
drugs (NSAIDs) [see Drug Interactions (7.4)], selective serotonin reuptake 
inhibitors, and serotonin norepinephrine reuptake inhibitors.
Concomitant use of drugs that are known combined P-gp and strong 
CYP3A4 inhibitors increases rivaroxaban exposure and may increase 
bleeding risk [see Drug Interactions (7.2)].
Reversal of Anticoagulant Effect
A specific antidote for rivaroxaban is not available. Because of high plasma 
protein binding, rivaroxaban is not expected to be dialyzable [see Clinical 
Pharmacology (12.3)]. Protamine sulfate and vitamin K are not expected to 
affect the anticoagulant activity of rivaroxaban. Partial reversal of prothrombin 
time prolongation has been seen after administration of prothrombin complex 
concentrates (PCCs) in healthy volunteers. The use of other procoagulant 
reversal agents like activated prothrombin complex concentrate (APCC) or 
recombinant factor VIIa (rFVIIa) has not been evaluated.
5.3	 Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture 
is employed, patients treated with anticoagulant agents for prevention of 
thromboembolic complications are at risk of developing an epidural or 
spinal hematoma which can result in long-term or permanent paralysis 
[see Boxed Warning].
To reduce the potential risk of bleeding associated with the concurrent use 
of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal 
puncture, consider the pharmacokinetic profile of rivaroxaban [see Clinical 
Pharmacology (12.3)]. Placement or removal of an epidural catheter or 
lumbar puncture is best performed when the anticoagulant effect of 
rivaroxaban is low; however, the exact timing to reach a sufficiently low 
anticoagulant effect in each patient is not known.
An indwelling epidural or intrathecal catheter should not be removed 
before at least 2 half-lives have elapsed (i.e., 18 hours in young patients 
aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), 
after the last administration of XARELTO [see Clinical Pharmacology (12.3)]. 
The next XARELTO dose should not be administered earlier than 6  hours 
after the removal of the catheter. If traumatic puncture occurs, delay the 
administration of XARELTO for 24 hours.
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Should the physician decide to administer anticoagulation in the context of 
epidural or spinal anesthesia/analgesia or lumbar puncture, monitor 
frequently to detect any signs or symptoms of neurological impairment, 
such as midline back pain, sensory and motor deficits (numbness, tingling, 
or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct 
patients to immediately report if they experience any of the above signs or 
symptoms. If signs or symptoms of spinal hematoma are suspected, initiate 
urgent diagnosis and treatment including consideration for spinal cord 
decompression even though such treatment may not prevent or reverse 
neurological sequelae.
5.4	 Use in Patients with Renal Impairment
Nonvalvular Atrial Fibrillation
Periodically assess renal function as clinically indicated (i.e., more 
frequently in situations in which renal function may decline) and adjust 
therapy accordingly [see Dosage and Administration (2.4)]. Consider dose 
adjustment or discontinuation of XARELTO in patients who develop acute 
renal failure while on XARELTO [see Use in Specific Populations (8.7)].
Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and 
Reduction in the Risk of Recurrence of DVT and of PE
Avoid the use of XARELTO in patients with CrCl <30  mL/min due to an 
expected increase in rivaroxaban exposure and pharmacodynamic effects 
in this patient population [see Use in Specific Populations (8.7)].
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement 
Surgery
Avoid the use of XARELTO in patients with CrCl <30  mL/min due to an 
expected increase in rivaroxaban exposure and pharmacodynamic effects 
in this patient population. Observe closely and promptly evaluate any signs 
or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients 
who develop acute renal failure while on XARELTO should discontinue the 
treatment [see Use in Specific Populations (8.7)].
5.5	 Use in Patients with Hepatic Impairment
No clinical data are available for patients with severe hepatic impairment.
Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe 
(Child-Pugh C) hepatic impairment or with any hepatic disease associated 
with coagulopathy since drug exposure and bleeding risk may be 
increased [see Use in Specific Populations (8.8)].
5.6	 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers
Avoid concomitant use of XARELTO with known combined P-gp and strong 
CYP3A4 inhibitors [see Drug Interactions (7.2)].
Avoid concomitant use of XARELTO with drugs that are known combined 
P-gp and strong CYP3A4 inducers [see Drug Interactions (7.3)].
5.7	 Risk of Pregnancy-Related Hemorrhage
In pregnant women, XARELTO should be used only if the potential benefit 
justifies the potential risk to the mother and fetus. XARELTO dosing in 
pregnancy has not been studied. The anticoagulant effect of XARELTO 
cannot be monitored with standard laboratory testing nor readily reversed. 
Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a 
drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
5.8	 Patients with Prosthetic Heart Valves
The safety and efficacy of XARELTO have not been studied in patients with 
prosthetic heart valves. Therefore, use of XARELTO is not recommended in 
these patients.
5.9	 Acute PE in Hemodynamically Unstable Patients or Patients Who 
Require Thrombolysis or Pulmonary Embolectomy
Initiation of XARELTO is not recommended acutely as an alternative to 
unfractionated heparin in patients with pulmonary embolism who present 
with hemodynamic instability or who may receive thrombolysis or 
pulmonary embolectomy.
6	
ADVERSE REACTIONS
The following adverse reactions are also discussed in other sections of the 
labeling:
•	 Increased risk of stroke after discontinuation in nonvalvular atrial 
fibrillation [see Boxed Warning and Warnings and Precautions (5.1)]
•	 Bleeding risk [see Warnings and Precautions (5.2, 5.4, 5.5, 5.6, 5.7)]
•	 Spinal/epidural hematoma [see Boxed Warning and Warnings and 
Precautions (5.3)]
6.1	 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, 
adverse reaction rates observed in the clinical trials of a drug cannot be 
directly compared to rates in the clinical trials of another drug and may not 
reflect the rates observed in clinical practice.
During clinical development for the approved indications, 16326 patients 
were exposed to XARELTO. These included 7111 patients who received 
XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 
for 12  months and 2512 for 24  months) to reduce the risk of stroke and 
systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 4728 
patients who received either XARELTO 15  mg orally twice daily for three 
weeks followed by 20 mg orally once daily (EINSTEIN DVT, EINSTEIN PE) or 
20  mg orally once daily (EINSTEIN Extension) to treat DVT, PE, and to 
reduce the risk of recurrence of DVT and of PE; and 4487 patients who 
received XARELTO 10 mg orally once daily for prophylaxis of DVT following 
hip or knee replacement surgery (RECORD 1-3).
Hemorrhage
The most common adverse reactions with XARELTO were bleeding 
complications [see Warnings and Precautions (5.2)].
Nonvalvular Atrial Fibrillation
In the ROCKET AF trial, the most frequent adverse reactions associated 
with permanent drug discontinuation were bleeding events, with incidence 
rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of 
discontinuations for non-bleeding adverse events was similar in both 
treatment groups.
Table 1 shows the number of patients experiencing various types of 
bleeding events in the ROCKET AF trial.
Table 1:  Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days
Parameter
XARELTO
N=7111
n (%/year)
Warfarin
N=7125
n (%/year)
XARELTO vs. Warfarin
HR 
(95% CI)
Major Bleeding†
395 (3.6)
386 (3.5)
1.04 (0.90, 1.20)
Intracranial  
Hemorrhage (ICH)‡
55 (0.5)
84 (0.7)
0.67 (0.47, 0.93)
Hemorrhagic Stroke§
36 (0.3)
58 (0.5)
0.63 (0.42, 0.96)
Other ICH
19 (0.2)
26 (0.2)
0.74 (0.41, 1.34)
Gastrointestinal (GI)¶
221 (2.0)
140 (1.2)
1.61 (1.30, 1.99)
Fatal Bleeding# 
27 (0.2)
55 (0.5)
0.50 (0.31, 0.79)
ICH
24 (0.2)
42 (0.4)
0.58 (0.35, 0.96)
Non-intracranial
3 (0.0)
13 (0.1)
0.23 (0.07, 0.82)
Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = 
Clinically Relevant Non-Major.
*	Major bleeding events within each subcategory were counted once per 
patient, but patients may have contributed events to multiple 
subcategories. These events occurred during treatment or within 2 days 
of stopping treatment.
†	 Defined as clinically overt bleeding associated with a decrease in 
hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells 
or whole blood, bleeding at a critical site, or with a fatal outcome.
‡	 Intracranial bleeding events included intraparenchymal, intraventricular, 
subdural, subarachnoid and/or epidural hematoma.
§	 Hemorrhagic stroke in this table specifically refers to non-traumatic 
intraparenchymal and/or intraventricular hematoma in patients on 
treatment plus 2 days.
¶	 Gastrointestinal bleeding events included upper GI, lower GI, and rectal 
bleeding.
#	 Fatal bleeding is adjudicated death with the primary cause of death from 
bleeding.
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Figure 1 shows the risk of major bleeding events across major subgroups.
Figure 1:  Risk of Major Bleeding Events by Baseline Characteristics in 
ROCKET AF – On Treatment Plus 2 Days
Note: The figure above presents effects in various subgroups all of which 
are baseline characteristics and all of which were pre-specified (diabetic 
status was not pre-specified in the subgroup, but was a criterion for 
the CHADS2 score). The 95% confidence limits that are shown do not 
take into account how many comparisons were made, nor do they reflect 
the effect of a particular factor after adjustment for all other factors. 
Apparent homogeneity or heterogeneity among groups should not be 
over-interpreted.
Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and 
to Reduce the Risk of Recurrence of DVT and of PE
EINSTEIN DVT and EINSTEIN PE Studies
In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical 
studies, the most frequent adverse reactions leading to permanent drug 
discontinuation were bleeding events, with XARELTO vs. enoxaparin/
Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. 
The mean duration of treatment was 208 days for XARELTO-treated patients 
and 204 days for enoxaparin/VKA-treated patients.
Table 2 shows the number of patients experiencing major bleeding events 
in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.
Table 2:  Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and 
EINSTEIN PE Studies
Parameter
XARELTO†
 N=4130
n (%)
Enoxaparin/
VKA†
N=4116
n (%)
Major bleeding event
40 (1.0)
72 (1.7)
Fatal bleeding
3 (<0.1)
8 (0.2)
Intracranial
2 (<0.1)
4 (<0.1)
Non-fatal critical organ bleeding
10 (0.2)
29 (0.7)
Intracranial‡
3 (<0.1)
10 (0.2)
Retroperitoneal‡
1 (<0.1)
8 (0.2)
Intraocular‡
3 (<0.1)
2 (<0.1)
Intra-articular‡
0
4 (<0.1)
Non-fatal non-critical organ bleeding§
27 (0.7)
37 (0.9)
Decrease in Hb ≥ 2 g/dL
28 (0.7)
42 (1.0)
Transfusion of ≥2 units of whole blood or 
packed red blood cells
18 (0.4) 
25 (0.6)
Clinically relevant non-major bleeding
357 (8.6)
357 (8.7)
Any bleeding
1169 (28.3)
1153 (28.0)
*	Bleeding event occurred after randomization and up to 2 days after the 
last dose of study drug. Although a patient may have had 2 or more 
events, the patient is counted only once in a category.
†	 Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 
15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/
VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to 
achieve a target INR of 2.5 (range: 2.0-3.0)]
‡	 Treatment-emergent major bleeding events with at least >2 subjects in 
any pooled treatment group
§	 Major bleeding which is not fatal or in a critical organ, but resulting in a 
decrease in Hb ≥ 2 g/dL and/or transfusion of ≥2 units of whole blood or 
packed red blood cells
EINSTEIN Extension Study
In the EINSTEIN Extension clinical study, the most frequent adverse 
reactions associated with permanent drug discontinuation were bleeding 
events, with incidence rates of 1.8% for XARELTO vs. 0.2% for placebo 
treatment groups. The mean duration of treatment was 190 days for both 
XARELTO and placebo treatment groups.
Table 3 shows the number of patients experiencing bleeding events in the 
EINSTEIN Extension study.
Table 3:  Bleeding Events* in EINSTEIN Extension Study
Parameter
XARELTO†
20 mg
N=598
n (%)
Placebo†
N=590
n (%)
Major bleeding event‡
4 (0.7)
0
Decrease in Hb ≥2 g/dL
4 (0.7)
0
Transfusion of ≥2 units of whole blood or 
packed red blood cells
2 (0.3)
0
Gastrointestinal
3 (0.5)
0
Menorrhagia
1 (0.2)
0
Clinically relevant non-major bleeding
32 (5.4)
7 (1.2)
Any bleeding
104 (17.4)
63 (10.7)
*	Bleeding event occurred after the first dose and up to 2 days after the 
last dose of study drug. Although a patient may have had 2 or more 
events, the patient is counted only once in a category.
†	 Treatment schedule: XARELTO 20 mg once daily; matched placebo once daily
‡ 	There were no fatal or critical organ bleeding events.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement 
Surgery
In the RECORD clinical trials, the overall incidence rate of adverse reactions 
leading to permanent treatment discontinuation was 3.7% with XARELTO.
The rates of major bleeding events and any bleeding events observed in 
patients in the RECORD clinical trials are shown in Table 4.
Table 4:  Bleeding Events* in Patients Undergoing Hip or Knee 
Replacement Surgeries (RECORD 1‑3)
XARELTO 
10 mg
Enoxaparin†
Total treated patients
N=4487
n (%)
N=4524
n (%)
Major bleeding event
14 (0.3)
9 (0.2)
Fatal bleeding
1 (<0.1)
0
Bleeding into a critical organ
2 (<0.1)
3 (0.1)
Bleeding that required re-operation
7 (0.2)
5 (0.1)
Extra-surgical site bleeding requiring 
transfusion of >2 units of whole blood  
or packed cells
4 (0.1)
1 (<0.1)
Any bleeding event‡
261 (5.8)
251 (5.6)
Hip Surgery Studies
N=3281
n (%)
N=3298
n (%)
Major bleeding event
7 (0.2)
3 (0.1)
Fatal bleeding
1 (<0.1)
0
Bleeding into a critical organ
1 (<0.1)
1 (<0.1)
Bleeding that required re-operation
2 (0.1)
1 (<0.1)
Extra-surgical site bleeding requiring 
transfusion of >2 units of whole blood  
or packed cells
3 (0.1)
1 (<0.1)
Any bleeding event‡
201 (6.1)
191 (5.8)
Knee Surgery Study
N=1206
n (%)
N=1226
n (%)
Major bleeding event
7 (0.6)
6 (0.5)
Fatal bleeding
0
0
Bleeding into a critical organ
1 (0.1)
2 (0.2)
Bleeding that required re-operation
5 (0.4)
4 (0.3)
Extra-surgical site bleeding requiring 
transfusion of >2 units of whole blood  
or packed cells
1 (0.1)
0
Any bleeding event‡
60 (5.0)
60 (4.9)
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*	Bleeding events occurring any time following the first dose of double-
blind study medication (which may have been prior to administration of 
active drug) until two days after the last dose of double-blind study 
medication. Patients may have more than one event.
†	 Includes the placebo-controlled period for RECORD 2, enoxaparin dosing 
was 40 mg once daily (RECORD 1-3)
‡	 Includes major bleeding events 
Following XARELTO treatment, the majority of major bleeding complications 
(≥60%) occurred during the first week after surgery.
Other Adverse Reactions
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated 
patients in the EINSTEIN Extension study are shown in Table 5.
Table 5:  Other Adverse Reactions* Reported by ≥1% of XARELTO-Treated 
Patients in EINSTEIN Extension Study
System Organ Class
Preferred Term
XARELTO
N=598
n (%)
Placebo
N=590
n (%)
Gastrointestinal disorders
Abdominal pain upper
10 (1.7)
1 (0.2)
Dyspepsia
8 (1.3)
4 (0.7)
Toothache
6 (1.0)
0
General disorders and administration site 
conditions
Fatigue
6 (1.0)
3 (0.5)
Infections and infestations
Sinusitis
7 (1.2)
3 (0.5)
Urinary tract infection
7 (1.2)
3 (0.5)
Musculoskeletal and connective tissue 
disorders
Back pain
22 (3.7)
7 (1.2)
Osteoarthritis
10 (1.7)
5 (0.8)
Respiratory, thoracic and mediastinal 
disorders
Oropharyngeal pain
6 (1.0)
2 (0.3)
*	Adverse reaction (with Relative Risk >1.5 for XARELTO versus placebo) 
occurred after the first dose and up to 2 days after the last dose of study 
drug. Incidences are based on the number of patients, not the number of 
events. Although a patient may have had 2 or more clinical adverse 
reactions, the patient is counted only once in a category. The same 
patient may appear in different categories.
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated 
patients in RECORD 1-3 studies are shown in Table 6.
Table 6:  Other Adverse Drug Reactions* Reported by ≥1% of XARELTO-
Treated Patients in RECORD 1-3 Studies
System/Organ Class
Adverse Reaction
XARELTO
10 mg
N=4487
n (%)
Enoxaparin†
N=4524
n (%)
Injury, poisoning and procedural 
complications
Wound secretion
125 (2.8)
89 (2.0)
Musculoskeletal and connective tissue 
disorders
Pain in extremity
74 (1.7)
55 (1.2)
Muscle spasm
52 (1.2)
32 (0.7)
Nervous system disorders
Syncope
55 (1.2)
32 (0.7)
Skin and subcutaneous tissue disorders
Pruritus
96 (2.1)
79 (1.8)
Blister
63 (1.4)
40 (0.9)
*	Adverse reaction occurring any time following the first dose of double-
blind medication, which may have been prior to administration of active 
drug, until two days after the last dose of double-blind study medication
†	 Includes the placebo-controlled period of RECORD 2, enoxaparin dosing 
was 40 mg once daily (RECORD 1-3)
Other clinical trial experience: In an investigational study of acute 
medically ill patients being treated with XARELTO 10 mg tablets, cases of 
pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis 
were observed.
6.2	 Postmarketing Experience
The following adverse reactions have been identified during post-approval 
use of rivaroxaban. Because these reactions are reported voluntarily from 
a population of uncertain size, it is not always possible to reliably estimate 
their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia
Gastrointestinal disorders: retroperitoneal hemorrhage
Hepatobiliary 
disorders: 
jaundice, 
cholestasis, 
hepatitis 
(including 
hepatocellular injury)
Immune 
system 
disorders: 
hypersensitivity, 
anaphylactic 
reaction, 
anaphylactic shock, angioedema
Nervous system disorders: cerebral hemorrhage, subdural hematoma, 
epidural hematoma, hemiparesis
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome
7	
DRUG INTERACTIONS
7.1	 General Inhibition and Induction Properties 
Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-
binding cassette G2 (ABCG2) transporters. Combined P-gp and strong 
CYP3A4 inhibitors increase exposure to rivaroxaban and may increase the 
risk of bleeding. Combined P-gp and strong CYP3A4 inducers decrease 
exposure to rivaroxaban and may increase the risk of thromboembolic 
events.
7.2	 Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport 
Systems
Interaction with Combined P-gp and Strong CYP3A4 Inhibitors 
Avoid concomitant administration of XARELTO with known combined P-gp 
and strong CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) [see 
Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].
Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, 
pharmacokinetic data suggests that no precautions are necessary with 
concomitant administration with XARELTO as the change in exposure is 
unlikely to affect the bleeding risk [see Clinical Pharmacology (12.3)].
Interaction with Combined P-gp and Moderate CYP3A4 Inhibitors in 
Patients with Renal Impairment
XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are 
receiving concomitant combined P-gp and moderate CYP3A4 inhibitors 
(e.g., erythromycin) unless the potential benefit justifies the potential risk 
[see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].
7.3	 Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport 
Systems
Avoid concomitant use of XARELTO with drugs that are combined P-gp and 
strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s 
wort) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].
7.4	 Anticoagulants and NSAIDs/Aspirin
Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic 
NSAID use may increase the risk of bleeding [see Clinical Pharmacology 
(12.3)].
Avoid concurrent use of XARELTO with other anticoagulants due to 
increased bleeding risk unless benefit outweighs risk. Promptly evaluate 
any signs or symptoms of blood loss if patients are treated concomitantly 
with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings 
and Precautions (5.2)].
8	
USE IN SPECIFIC POPULATIONS
8.1	 Pregnancy
Pregnancy Category C
There are no adequate or well-controlled studies of XARELTO in pregnant 
women, and dosing for pregnant women has not been established. Use 
XARELTO with caution in pregnant patients because of the potential for 
pregnancy related hemorrhage and/or emergent delivery with an 
anticoagulant that is not readily reversible. The anticoagulant effect of 
XARELTO cannot be reliably monitored with standard laboratory testing. 
Animal reproduction studies showed no increased risk of structural 
malformations, but increased post-implantation pregnancy loss occurred in 
rabbits. XARELTO should be used during pregnancy only if the potential 
benefit justifies the potential risk to mother and fetus [see Warnings and 
Precautions (5.7)].
Rivaroxaban crosses the placenta in animals. Animal reproduction studies 
have shown pronounced maternal hemorrhagic complications in rats and 
an increased incidence of post-implantation pregnancy loss in rabbits. 
XARELTO® (rivaroxaban) tablets
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7
Rivaroxaban increased fetal toxicity (increased resorptions, decreased 
number of live fetuses, and decreased fetal body weight) when pregnant 
rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period 
of organogenesis. This dose corresponds to about 4 times the human 
exposure of unbound drug, based on AUC comparisons at the highest 
recommended human dose of 20  mg/day. Fetal body weights decreased 
when pregnant rats were given oral doses of 120  mg/kg. This dose 
corresponds to about 14 times the human exposure of unbound drug.
8.2	 Labor and Delivery
Safety and effectiveness of XARELTO during labor and delivery have not 
been studied in clinical trials. However, in animal studies maternal bleeding 
and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg 
(about 6 times maximum human exposure of the unbound drug at the 
human dose of 20 mg/day).
8.3	 Nursing Mothers
It is not known if rivaroxaban is excreted in human milk. Rivaroxaban 
and/or its metabolites were excreted into the milk of rats. Because many 
drugs are excreted in human milk and because of the potential for serious 
adverse reactions in nursing infants from rivaroxaban, a decision should be 
made whether to discontinue nursing or discontinue XARELTO, taking into 
account the importance of the drug to the mother.
8.4	 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5	 Geriatric Use
Of the total number of patients in the RECORD 1-3 clinical studies 
evaluating XARELTO, about 54% were 65 years and over, while about 15% 
were >75 years. In ROCKET AF, approximately 77% were 65 years and over 
and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension 
clinical studies approximately 37% were 65 years and over and about 16% 
were >75  years. In clinical trials the efficacy of XARELTO in the elderly 
(65  years or older) was similar to that seen in patients younger than 
65 years. Both thrombotic and bleeding event rates were higher in these 
older patients, but the risk-benefit profile was favorable in all age groups 
[see Clinical Pharmacology (12.3) and Clinical Studies (14)].
8.6	 Females of Reproductive Potential
Females of reproductive potential requiring anticoagulation should discuss 
pregnancy planning with their physician.
8.7	 Renal Impairment
In pharmacokinetic studies, compared to healthy subjects with normal 
creatinine clearance, rivaroxaban exposure increased by approximately 44 
to 64% in subjects with renal impairment. Increases in pharmacodynamic 
effects were also observed [see Clinical Pharmacology (12.3)].
Nonvalvular Atrial Fibrillation
In the ROCKET AF trial, patients with CrCl 30  to 50  mL/min were 
administered XARELTO 15 mg once daily resulting in serum concentrations 
of rivaroxaban and clinical outcomes similar to those in patients with better 
renal function administered XARELTO 20  mg once daily. Patients with 
CrCl 15  to  30 mL/min were not studied, but administration of XARELTO 
15  mg once daily is also expected to result in serum concentrations of 
rivaroxaban similar to those in patients with normal renal function [see 
Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
Patients with End-Stage Renal Disease on Dialysis
Clinical efficacy and safety studies with XARELTO did not enroll patients 
with end-stage renal disease (ESRD) on dialysis. In patients with ESRD 
maintained on intermittent hemodialysis, administration of XARELTO 15 mg 
once daily will result in concentrations of rivaroxaban and pharmacodynamic 
activity similar to those observed in the ROCKET AF study [see Clinical 
Pharmacology (12.2, 12.3)]. It is not known whether these concentrations 
will lead to similar stroke reduction and bleeding risk in patients with ESRD 
on dialysis as was seen in ROCKET AF.
Treatment of DVT and/or PE, and Reduction in the Risk of Recurrence of 
DVT and of PE 
In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening 
were excluded from the studies. Avoid the use of XARELTO in patients with 
CrCl <30 mL/min.
Prophylaxis of DVT Following Hip or Knee Replacement Surgery
The combined analysis of the RECORD 1-3 clinical efficacy studies did not 
show an increase in bleeding risk for patients with CrCl 30 to 50  mL/min 
and reported a possible increase in total venous thromboemboli in this 
population. Observe closely and promptly evaluate any signs or symptoms 
of blood loss in patients with CrCl 30  to  50 mL/min. Avoid the use of 
XARELTO in patients with CrCl <30 mL/min.
8.8	 Hepatic Impairment
In a pharmacokinetic study, compared to healthy subjects with normal liver 
function, AUC increases of 127% were observed in subjects with moderate 
hepatic impairment (Child-Pugh B).
The safety or PK of XARELTO in patients with severe hepatic impairment 
(Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3)].
Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and 
severe (Child-Pugh C) hepatic impairment or with any hepatic disease 
associated with coagulopathy.
10	
OVERDOSAGE
Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and 
initiate appropriate therapy if bleeding complications associated with 
overdosage occur. A specific antidote for rivaroxaban is not available. 
Rivaroxaban systemic exposure is not further increased at single doses 
>50 mg due to limited absorption. The use of activated charcoal to reduce 
absorption in case of XARELTO overdose may be considered. Due to the 
high plasma protein binding, rivaroxaban is not dialyzable [see Warnings 
and Precautions (5.2) and Clinical Pharmacology (12.3)]. Partial reversal 
of laboratory anticoagulation parameters may be achieved with use of 
plasma products.
11	
DESCRIPTION
Rivaroxaban, a FXa inhibitor, is the active ingredient in XARELTO Tablets 
with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)
phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular 
formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89. 
The structural formula is:
Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, 
white to yellowish powder. Rivaroxaban is only slightly soluble in organic 
solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble 
in water and aqueous media.
Each XARELTO tablet contains 10 mg, 15 mg, or 20 mg of rivaroxaban. The 
inactive ingredients of XARELTO are: croscarmellose sodium, hypromellose, 
lactose monohydrate, magnesium stearate, microcrystalline cellulose, and 
sodium lauryl sulfate. Additionally, the proprietary film coating mixture used 
for XARELTO 10 mg tablets is Opadry® Pink and for XARELTO 15 mg tablets 
is Opadry® Red, both containing ferric oxide red, hypromellose, polyethylene 
glycol 3350, and titanium dioxide, and for XARELTO 20  mg tablets is 
Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, 
polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.
12	
CLINICAL PHARMACOLOGY
12.1	 Mechanism of Action
XARELTO is a selective inhibitor of FXa. It does not require a cofactor (such 
as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and 
prothrombinase activity. Rivaroxaban has no direct effect on platelet 
aggregation, but indirectly inhibits platelet aggregation induced by 
thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.
12.2	 Pharmacodynamics
Dose-dependent inhibition of FXa activity was observed in humans. 
Neoplastin® prothrombin time (PT), activated partial thromboplastin time 
(aPTT) and HepTest® are also prolonged dose-dependently. Anti-factor Xa 
activity is also influenced by rivaroxaban.
Specific Populations
Renal Impairment
The relationship between systemic exposure and pharmacodynamic activity of 
rivaroxaban was altered in subjects with renal impairment relative to healthy 
control subjects [see Use in Specific Populations (8.7)].
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Table 7:  Percentage Increase in Rivaroxaban PK and PD Measures in 
Subjects with Renal Impairment Relative to Healthy Subjects 
from Clinical Pharmacology Studies 
Measure
Parameter
Creatinine Clearance (mL/min)
50-79 30-49 15-29
ESRD (on 
dialysis)*
ESRD 
(post-
dialysis)*
Exposure
AUC
44
52
64
47
56
FXa Inhibition 
AUEC
50
86
100
49
33
PT Prolongation AUEC
33
116
144
112
158
*Separate stand-alone study.
PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the 
plasma concentration-time curve; AUEC = Area under the effect-time curve
Hepatic Impairment
Anti-Factor Xa activity was similar in subjects with normal hepatic function and 
in mild hepatic impairment (Child-Pugh A class). There is no clear understanding 
of the impact of hepatic impairment beyond this degree on the coagulation 
cascade and its relationship to efficacy and safety.
12.3	 Pharmacokinetics
Absorption
The absolute bioavailability of rivaroxaban is dose-dependent. For the 
10 mg dose, it is estimated to be 80% to 100% and is not affected by food. 
XARELTO 10 mg tablets can be taken with or without food. For the 20 mg 
dose in the fasted state, the absolute bioavailability is approximately 66%. 
Coadministration of XARELTO with food increases the bioavailability of the 
20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively 
with food). XARELTO 15 mg and 20 mg tablets should be taken with food 
[see Dosage and Administration (2.2)].
The maximum concentrations (Cmax) of rivaroxaban appear 2 to 4 hours after 
tablet intake. The pharmacokinetics of rivaroxaban were not affected by 
drugs altering gastric pH. Coadministration of XARELTO (30 mg single dose) 
with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid 
aluminum hydroxide/magnesium hydroxide (10  mL) or XARELTO (20  mg 
single dose) with the PPI omeprazole (40 mg once daily) did not show an 
effect on the bioavailability and exposure of rivaroxaban (see Figure 3).
Absorption of rivaroxaban is dependent on the site of drug release in the GI 
tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was 
reported when rivaroxaban granulate is released in the proximal small 
intestine. Exposure is further reduced when drug is released in the distal small 
intestine, or ascending colon. Avoid administration of rivaroxaban distal to the 
stomach  which can result in reduced absorption and related drug exposure.
In a study with 44 healthy subjects, both mean AUC and Cmax values for 
20 mg rivaroxaban administered orally as a crushed tablet mixed in 
applesauce were comparable to that after the whole tablet. However, for 
the crushed tablet suspended in water and administered via an NG tube 
followed by a liquid meal, only mean AUC was comparable to that after the 
whole tablet, and Cmax was 18% lower.
Distribution
Plasma protein binding of rivaroxaban in human plasma is approximately 
92% to 95%, with albumin being the main binding component. The steady-
state volume of distribution in healthy subjects is approximately 50 L.
Metabolism
Approximately 51% of an orally administered [14C]-rivaroxaban dose was 
recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative 
degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major 
sites of biotransformation. Unchanged rivaroxaban was the predominant 
moiety in plasma with no major or active circulating metabolites.
Excretion
In a Phase 1 study, following the administration of [14C]-rivaroxaban, approximately 
one-third (36%) was recovered as unchanged drug in the urine and 7% was 
recovered as unchanged drug in feces. Unchanged drug is excreted into 
urine, mainly via active tubular secretion and to a lesser extent via 
glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the 
efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). 
Rivaroxaban’s affinity for influx transporter proteins is unknown.
Rivaroxaban is a low-clearance drug, with a systemic clearance of 
approximately 10  L/hr in healthy volunteers following intravenous 
administration. The terminal elimination half-life of rivaroxaban is 5 to 
9 hours in healthy subjects aged 20 to 45 years.
Specific Populations
The effects of level of renal impairment, age, body weight, and level of 
hepatic impairment on the pharmacokinetics of rivaroxaban are 
summarized in Figure 2.
Figure 2:  Effect of Specific Populations on the Pharmacokinetics of 
Rivaroxaban
Gender
Gender did not influence the pharmacokinetics or pharmacodynamics of 
XARELTO.
Race
Healthy Japanese subjects were found to have 20  to 40% on average 
higher exposures compared to other ethnicities including Chinese. 
However, these differences in exposure are reduced when values are 
corrected for body weight.
Elderly
The terminal elimination half-life is 11  to  13 hours in the elderly subjects 
aged 60 to 76 years [see Use in Specific Populations (8.5)].
Renal Impairment
The safety and pharmacokinetics of single-dose XARELTO (10  mg) were 
evaluated in a study in healthy subjects [CrCl ≥80  mL/min (n=8)] and in 
subjects with varying degrees of renal impairment (see Figure 2). 
Compared to healthy subjects with normal creatinine clearance, 
rivaroxaban exposure increased in subjects with renal impairment. 
Increases in pharmacodynamic effects were also observed [see Use in 
Specific Populations (8.7)].
Hemodialysis in ESRD subjects: Systemic exposure to rivaroxaban 
administered as a single 15 mg dose in ESRD subjects dosed 3 hours after the 
completion of a 4-hour hemodialysis session (post-dialysis) is 56% higher 
when compared to subjects with normal renal function (see Table 7). The 
systemic exposure to rivaroxaban administered 2 hours prior to a 4-hour 
hemodialysis session with a dialysate flow rate of 600 mL/min and a blood flow 
rate in the range of 320 to 400 mL/min is 47% higher compared to those with 
normal renal function. The extent of the increase is similar to the increase in 
patients with CrCl 15 to 50 mL/min taking XARELTO 15 mg. Hemodialysis had no 
significant impact on rivaroxaban exposure. Protein binding was similar (86% 
to 89%) in healthy controls and ESRD subjects in this study. 
Hepatic Impairment
The safety and pharmacokinetics of single-dose XARELTO (10  mg) were 
evaluated in a study in healthy subjects (n=16) and subjects with varying 
degrees of hepatic impairment (see Figure 2). No patients with severe 
hepatic impairment (Child-Pugh C) were studied. Compared to healthy 
subjects with normal liver function, significant increases in rivaroxaban 
exposure were observed in subjects with moderate hepatic impairment 
(Child-Pugh B) (see Figure 2). Increases in pharmacodynamic effects were 
also observed [see Use in Specific Populations (8.8)].
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Drug Interactions
In vitro studies indicate that rivaroxaban neither inhibits the major 
cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A4 nor 
induces CYP1A2, 2B6, 2C19, or 3A4. In vitro data also indicates a low 
rivaroxaban inhibitory potential for P-gp and ABCG2 transporters.
The effects of coadministered drugs on the pharmacokinetics of 
rivaroxaban exposure are summarized in Figure 3 [see Drug Interactions (7) 
for dosing recommendations].
Figure 3:  Effect of Coadministered Drugs on the Pharmacokinetics of 
Rivaroxaban
Anticoagulants
In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) 
and XARELTO (10 mg) given concomitantly resulted in an additive effect on 
anti-factor Xa activity. In another study, single doses of warfarin (15 mg) and 
XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. 
Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban 
(see Figure 3).
NSAIDs/Aspirin
In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 
100 mg or less) during the double-blind phase was identified as an 
independent risk factor for major bleeding. NSAIDs are known to increase 
bleeding, and bleeding risk may be increased when NSAIDs are used 
concomitantly with XARELTO. Neither naproxen nor aspirin affected the 
pharmacokinetics of rivaroxaban (see Figure 3).
Clopidogrel
In two drug interaction studies where clopidogrel (300  mg loading dose 
followed by 75  mg daily maintenance dose) and XARELTO (15  mg single 
dose) were coadministered in healthy subjects, an increase in bleeding 
time to 45 minutes was observed in approximately 45% and 30% of subjects 
in these studies, respectively. The change in bleeding time was 
approximately twice the maximum increase seen with either drug alone. 
There was no change in the pharmacokinetics of either drug.
Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450  3A4 
Enzymes and Drug Transport Systems
In a pharmacokinetic trial, XARELTO was administered as a single dose in 
subjects with mild (CrCl = 50 to 79 mL/min) or moderate renal impairment 
(CrCl = 30 to 49 mL/min) receiving multiple doses of erythromycin 
(a combined P-gp and moderate CYP3A4 inhibitor). Compared to 
XARELTO administered alone in subjects with normal renal function 
(CrCl >80 mL/min), subjects with mild and moderate renal impairment 
concomitantly receiving erythromycin reported a 76% and 99% increase in 
AUCinf and a 56% and 64% increase in Cmax, respectively. Similar trends in 
pharmacodynamic effects were also observed.
12.6	 QT/QTc Prolongation
In a thorough QT study in healthy men and women aged 50 years and older, 
no QTc prolonging effects were observed for XARELTO (15 mg and 45 mg, 
single-dose).
13	
NON-CLINICAL TOXICOLOGY
13.1	 Carcinogenesis, Mutagenesis, Impairment of Fertility
Rivaroxaban was not carcinogenic when administered by oral gavage to 
mice or rats for up to 2 years. The systemic exposures (AUCs) of unbound 
rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/
day) were 1- and 2-times, respectively, the human exposure of unbound 
drug at the human dose of 20 mg/day. Systemic exposures of unbound drug 
in male and female rats at the highest dose tested (60  mg/kg/day) were 
2- and 4-times, respectively, the human exposure.
Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in 
V79 Chinese hamster lung cells in vitro or in the mouse micronucleus test 
in vivo.
No impairment of fertility was observed in male or female rats when given 
up to 200 mg/kg/day of rivaroxaban orally. This dose resulted in exposure 
levels, based on the unbound AUC, at least 13  times the exposure in 
humans given 20 mg rivaroxaban daily.
14	
CLINICAL STUDIES
14.1	 Stroke Prevention in Nonvalvular Atrial Fibrillation
The evidence for the efficacy and safety of XARELTO was derived from 
ROCKET AF, a multi-national, double-blind study comparing XARELTO (at a 
dose of 20  mg once daily with the evening meal in patients with 
CrCl  >50  mL/min and 15  mg once daily with the evening meal in patients 
with CrCl 30 to 50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce 
the risk of stroke and non-central nervous system (CNS) systemic 
embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to 
have one or more of the following additional risk factors for stroke:
•	 a prior stroke (ischemic or unknown type), transient ischemic attack 
(TIA) or non‑CNS systemic embolism, or
•	 2 or more of the following risk factors:
o	 age ≥75 years,
o	 hypertension,
o	 heart failure or left ventricular ejection fraction ≤35%, or
o	 diabetes mellitus
ROCKET AF was a non-inferiority study designed to demonstrate that 
XARELTO preserved more than 50% of warfarin’s effect on stroke and non-
CNS systemic embolism as established by previous placebo-controlled 
studies of warfarin in atrial fibrillation.
A total of 14264 patients were randomized and followed on study treatment 
for a median of 590 days. The mean age was 71 years and the mean CHADS2 
score was 3.5. The population was 60% male, 83% Caucasian, 13% Asian 
and 1.3% Black. There was a history of stroke, TIA, or non-CNS systemic 
embolism in 55% of patients, and 38% of patients had not taken a vitamin K 
antagonist (VKA) within 6 weeks at time of screening. Concomitant diseases 
of patients in this study included hypertension 91%, diabetes 40%, 
congestive heart failure 63%, and prior myocardial infarction 17%. At 
baseline, 37% of patients were on aspirin (almost exclusively at a dose of 
100 mg or less) and few patients were on clopidogrel. Patients were enrolled 
in Eastern Europe (39%); North America (19%); Asia, Australia, and New 
Zealand (15%); Western Europe (15%); and Latin America (13%). Patients 
randomized to warfarin had a mean percentage of time in the INR target 
range of 2.0 to 3.0 of 55%, lower during the first few months of the study.
In ROCKET AF, XARELTO was demonstrated non-inferior to warfarin for the 
primary composite endpoint of time to first occurrence of stroke (any type) 
or non-CNS systemic embolism [HR  (95% CI): 0.88 (0.74, 1.03)], but 
superiority to warfarin was not demonstrated. There is insufficient 
experience to determine how XARELTO and warfarin compare when 
warfarin therapy is well-controlled.
Table 8 displays the overall results for the primary composite endpoint and 
its components.
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Table 8:  Primary Composite Endpoint Results in ROCKET AF Study  
(Intent-to-Treat Population)
XARELTO
Warfarin
XARELTO 
vs. 
Warfarin
Event
N=7081
n (%)
Event Rate
(per 100 
Pt-yrs)
N=7090
n (%)
Event Rate
(per 100 
Pt-yrs)
Hazard 
Ratio
(95% CI)
Primary Composite 
Endpoint* 
269 (3.8)
2.1
306 (4.3)
2.4
0.88 
(0.74, 1.03)
Stroke 
253 (3.6)
2.0
 281 (4.0)
2.2
Hemorrhagic 
Stroke†
33 (0.5) 
0.3 
57 (0.8)
0.4
Ischemic Stroke
206 (2.9)
1.6
208 (2.9) 
1.6 
Unknown Stroke 
Type
19 (0.3)
0.2
18 (0.3) 
0.1
Non-CNS Systemic 
Embolism
20 (0.3) 
0.2
27 (0.4)
0.2
*	The primary endpoint was the time to first occurrence of stroke (any 
type) or non-CNS systemic embolism. Data are shown for all randomized 
patients followed to site notification that the study would end.
†	 Defined as primary hemorrhagic strokes confirmed by adjudication in all 
randomized patients followed up to site notification
Figure 4 is a plot of the time from randomization to the occurrence of the 
first primary endpoint event in the two treatment arms.
Figure 4:  Time to First Occurrence of Stroke (any type) or Non-CNS Systemic 
Embolism by Treatment Group (Intent-to-Treat Population)
Figure 5 shows the risk of stroke or non-CNS systemic embolism across 
major subgroups.
Figure 5:  Risk of Stroke or Non-CNS Systemic Embolism by Baseline 
Characteristics in ROCKET AF* (Intent-to-Treat Population)
* Data are shown for all randomized patients followed to site notification 
that the study would end.
Note: The figure above presents effects in various subgroups all of which 
are baseline characteristics and all of which were pre-specified (diabetic 
status was not pre-specified in the subgroup, but was a criterion for the 
CHADS2 score). The 95% confidence limits that are shown do not take into 
account how many comparisons were made, nor do they reflect the effect 
of a particular factor after adjustment for all other factors. Apparent 
homogeneity or heterogeneity among groups should not be over-interpreted.
The efficacy of XARELTO was generally consistent across major subgroups.
The protocol for ROCKET AF did not stipulate anticoagulation after study 
drug discontinuation, but warfarin patients who completed the study were 
generally maintained on warfarin. XARELTO patients were generally 
switched to warfarin without a period of coadministration of warfarin and 
XARELTO, so that they were not adequately anticoagulated after stopping 
XARELTO until attaining a therapeutic INR. During the 28 days following the 
end of the study, there were 22 strokes in the 4637 patients taking XARELTO 
vs. 6 in the 4691 patients taking warfarin.
Few patients in ROCKET AF underwent electrical cardioversion for atrial 
fibrillation. The utility of XARELTO for preventing post-cardioversion stroke 
and systemic embolism is unknown.
14.2	 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), 
and Reduction in the Risk of Recurrence of DVT and of PE
EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism 
Studies
XARELTO for the treatment of DVT and/or PE and for the reduction in the 
risk of recurrence of DVT and of PE was studied in EINSTEIN DVT and 
EINSTEIN PE, multi-national, open-label, non-inferiority studies comparing 
XARELTO (at an initial dose of 15 mg twice daily with food for the first three 
weeks, followed by XARELTO 20  mg once daily with food) to enoxaparin 
1 mg/kg twice daily for at least five days with VKA and then continued with 
VKA only after the target INR (2.0-3.0) was reached. Patients who required 
thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and 
patients with creatinine clearance <30 mL/min, significant liver disease, or 
active bleeding were excluded from the studies. The intended treatment 
duration was 3, 6, or 12 months based on investigator’s assessment prior 
to randomization.
A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients 
were randomized and followed on study treatment for a mean of 208 days 
in the XARELTO group and 204  days in the enoxaparin/VKA group. The 
mean age was approximately 57 years. The population was 55% male, 70% 
Caucasian, 9% Asian and about 3% Black. About 73% and 92% of 
XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, 
respectively, received initial parenteral anticoagulant treatment for a 
median duration of 2 days. Enoxaparin/VKA-treated patients in the 
EINSTEIN DVT and EINSTEIN PE studies received initial parenteral 
anticoagulant treatment for a median duration of 8 days. Aspirin was taken 
as on treatment concomitant antithrombotic medication by approximately 
12% of patients in both treatment groups. Patients randomized to VKA had 
an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 
of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the 
lower values occurring during the first month of the study.
In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an 
idiopathic DVT/PE at baseline. Other risk factors included previous episode 
of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use 
of estrogen-containing drug (8%), known thrombophilic conditions (6%), or 
active cancer (5%).
In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated 
to be non-inferior to enoxaparin/VKA for the primary composite endpoint of 
time to first occurrence of recurrent DVT or non-fatal or fatal PE [EINSTEIN 
DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI): 1.12 (0.75, 1.68)]. 
In each study the conclusion of non-inferiority was based on the upper limit 
of the 95% confidence interval for the hazard ratio being less than 2.0.
Table 9 displays the overall results for the primary composite endpoint and 
its components for EINSTEIN DVT and EINSTEIN PE studies.
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11
Table 9:  Primary Composite Endpoint Results* in EINSTEIN DVT and 
EINSTEIN PE Studies – Intent-to-Treat Population
Event
XARELTO 
20 mg†
Enoxaparin/
VKA†
XARELTO vs. 
Enoxaparin/VKA 
Hazard Ratio
(95% CI)
EINSTEIN DVT Study
N=1731
n (%)
N=1718
n (%)
Primary Composite  
Endpoint 
36 (2.1)
51 (3.0)
0.68 (0.44, 1.04)
Death (PE)
1 (<0.1) 
0
Death (PE cannot be 
excluded)
3 (0.2)
6 (0.3) 
Symptomatic PE and DVT
1 (<0.1)
0
Symptomatic recurrent  
PE only
20 (1.2)
18 (1.0)
Symptomatic recurrent 
DVT only
14 (0.8)
28 (1.6)
EINSTEIN PE Study
N=2419
n (%)
N=2413
n (%)
Primary Composite  
Endpoint 
50 (2.1)
44 (1.8)
1.12 (0.75, 1.68)
Death (PE)
3 (0.1)
1 (<0.1)
Death (PE cannot be 
excluded)
8 (0.3)
6 (0.2)
Symptomatic PE and DVT
0
2 (<0.1)
Symptomatic recurrent  
PE only
23 (1.0)
20 (0.8)
Symptomatic recurrent 
DVT only
18 (0.7)
17 (0.7)
*	For the primary efficacy analysis, all confirmed events were considered 
from randomization up to the end of intended treatment duration (3, 6 or 
12  months) irrespective of the actual treatment duration. If the same 
patient had several events, the patient may have been counted for 
several components.
†	 Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 
15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/
VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to 
achieve a target INR of 2.5 (range: 2.0-3.0)]
Figures 6 and 7 are plots of the time from randomization to the occurrence 
of the first primary efficacy endpoint event in the two treatment groups in 
EINSTEIN DVT and EINSTEIN PE studies, respectively.
Figure 6:  Time to First Occurrence of the Composite of Recurrent DVT 
or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat 
Population) – EINSTEIN DVT Study
Days from Randomization
Number of Patients at Risk
Enoxaparin/VKA (N= 1718)
XARELTO (N= 1731)
0
0.0
0.5
1.0
1.5
2.0
Cumulative Event Rate (%)
2.5
3.0
3.5
4.0
1616
1668
1581
1648
1565
1635
1368
1424
1358
1412
1301
1369
380
400
362
369
342
364
325
345
297
309
264
266
30
60
90
120
150
180
210
240
270
300
330
360
HR (95% CI):
0.68 (0.44, 1.04)
Enoxaparin/VKA
XARELTO
Figure 7:  Time to First Occurrence of the Composite of Recurrent DVT  
or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat 
Population) – EINSTEIN PE Study
Days from Randomization
Number of Patients at Risk
Enoxaparin/VKA (N= 2413)
XARELTO (N= 2419)
0
0.0
0.5
1.0
1.5
2.0
Cumulative Event Rate (%)
2.5
3.0
3.5
4.0
2316
2350
2295
2321
2280
2311
2155
2180
2146
2167
2113
2133
835
837
787
794
773
785
746
757
722
725
675
672
30
60
90
120
150
180
210
240
270
300
330
360
HR (95% CI):
1.12 (0.75, 1.68)
Enoxaparin/VKA
XARELTO
EINSTEIN Extension Study
XARELTO for reduction in the risk of recurrence of DVT and of PE was 
studied in the EINSTEIN Extension study, a multi-national, double-blind, 
superiority study comparing XARELTO (20  mg once daily with food) to 
placebo in patients who had completed 6 to 14 months of treatment for DVT 
and/or PE following the acute event. The intended treatment duration was 6 
or 12 months based on investigator’s assessment prior to randomization.
A total of 1196 patients were randomized and followed on study treatment 
for a mean of 190 days for both XARELTO and placebo treatment groups. 
The mean age was approximately 58 years. The population was 58% male, 
78% Caucasian, 8% Asian and about 2% Black. Aspirin was taken as 
on-treatment concomitant antithrombotic medication by approximately 12% 
of patients in both treatment groups. In the EINSTEIN Extension study 
about 60% of patients had a history of proximal index DVT without PE event 
and 29% of patients had a PE without symptomatic DVT event. About 59% 
of patients had an idiopathic DVT/PE. Other risk factors included previous 
episode of DVT/PE (16%), immobilization (14%), known thrombophilic 
conditions (8%), or active cancer (5%). 
In the EINSTEIN Extension study XARELTO was demonstrated to be 
superior to placebo for the primary composite endpoint of time to first 
occurrence of recurrent DVT or non-fatal or fatal PE [HR (95% CI): 0.18 
(0.09, 0.39)].
Table 10 displays the overall results for the primary composite endpoint and 
its components.
Table 10:  Primary Composite Endpoint Results* in EINSTEIN Extension 
Study – Intent-to-Treat Population
Event
XARELTO 
20 mg
N=602
n (%)
Placebo
N=594
n (%)
XARELTO vs. 
Placebo
Hazard Ratio
(95% CI)
Primary Composite Endpoint 
8 (1.3)
42 (7.1)
0.18 (0.09, 0.39)
p-value = <0.0001
Death (PE)
0
1 (0.2)
Death (PE cannot be excluded)
1 (0.2)
0
Symptomatic recurrent PE
2 (0.3)
13 (2.2)
Symptomatic recurrent DVT
5 (0.8)
31 (5.2)
*	For the primary efficacy analysis, all confirmed events were considered 
from randomization up to the end of intended treatment duration (6 or 
12 months) irrespective of the actual treatment duration.
Figure 8 is a plot of the time from randomization to the occurrence of the 
first primary efficacy endpoint event in the two treatment groups.
XARELTO® (rivaroxaban) tablets
XARELTO® (rivaroxaban) tablets


12
Figure 8:  Time to First Occurrence of the Composite of Recurrent DVT  
or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat 
Population) – EINSTEIN Extension Study
Days from Randomization
Number of Patients at Risk
Placebo (N= 594)
XARELTO (N= 602)
0
0
1
2
3
4
5
6
Cumulative Event Rate (%)
7
8
9
10
582
590
570
583
559
577
522
552
468
503
453
491
164
171
138
138
134
133
110
114
93
92
85
81
30
60
90
120
150
180
210
240
270
300
330
360
HR (95% CI):
0.18 (0.09, 0.39)
Placebo
XARELTO
14.3	 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee 
Replacement Surgery
XARELTO was studied in 9011 patients (4487  XARELTO-treated, 4524 
enoxaparin-treated patients) in the RECORD 1, 2, and 3 studies.
The two randomized, double-blind, clinical studies (RECORD 1 and 2) in 
patients undergoing elective total hip replacement surgery compared 
XARELTO 10  mg once daily starting at least 6  to 8  hours (about 90% of 
patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg 
once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 
6727 patients were randomized and 6579 received study drug. The mean 
age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 
49% of patients ≥65  years and 55% of patients were female. More than 
82% of patients were White, 7% were Asian, and less than 2% were Black. 
The studies excluded patients undergoing staged bilateral total hip 
replacement, patients with severe renal impairment defined as an 
estimated creatinine clearance <30  mL/min, or patients with significant 
liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure 
duration (± SD) to active XARELTO and enoxaparin was 33.3  ±  7.0 and 
33.6 ± 8.3 days, respectively. In RECORD 2, the mean exposure duration to 
active XARELTO and enoxaparin was 33.5  ±  6.9 and 12.4  ±  2.9 days, 
respectively. After Day 13, oral placebo was continued in the enoxaparin 
group for the remainder of the double-blind study duration. The efficacy 
data for RECORD 1 and 2 are provided in Table 11.
Table 11:  Summary of Key Efficacy Analysis Results for Patients 
Undergoing Total Hip Replacement Surgery - Modified  
Intent-to-Treat Population
RECORD 1
RECORD 2
Treatment 
Dosage and 
Duration
XARELTO 
10 mg 
once daily
Enoxaparin 
40 mg  
once daily
 
RRR*,
p-value
XARELTO 
10 mg 
once daily
Enoxaparin† 
40 mg  
once daily
RRR*,
p-value
Number of 
Patients
N=1513
N=1473
N=834
N=835
Total VTE 
17 (1.1%)
57 (3.9%)
71% (95%  
CI: 50, 83),
p<0.001
17 (2.0%)
70 (8.4%)
76% (95%  
CI: 59, 86),
p<0.001
Components of Total VTE 
Proximal DVT
1 (0.1%)
31 (2.1%)
5 (0.6%)
40 (4.8%)
Distal DVT
12 (0.8%)
26 (1.8%)
11 (1.3%)
43 (5.2%)
Non-fatal PE
3 (0.2%)
1 (0.1%)
1 (0.1%)
4 (0.5%)
Death (any 
cause)
4 (0.3%)
4 (0.3%)
2 (0.2%)
4 (0.5%)
Number of 
Patients
N=1600
N=1587
N=928
N=929
Major VTE‡ 
3 (0.2%)
33 (2.1%)
91% (95% 
CI: 71, 97), 
p<0.001
6 (0.7%)
45 (4.8%)
87% (95% 
CI: 69, 94), 
p<0.001
Number of 
Patients
N=2103
N=2119
N=1178
N=1179
Symptomatic 
VTE
5 (0.2%)
11 (0.5%)
3 (0.3%)
15 (1.3%)
*	Relative Risk Reduction; CI = confidence interval 
†	 Includes the placebo-controlled period of RECORD 2
‡	 Proximal DVT, nonfatal PE or VTE-related death
One randomized, double-blind, clinical study (RECORD 3) in patients undergoing 
elective total knee replacement surgery compared XARELTO 10 mg once daily 
started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after 
wound closure versus enoxaparin. In RECORD 3, the enoxaparin regimen was 
40  mg once daily started 12  hours preoperatively. The mean age (± SD) of 
patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients 
≥65  years. Sixty-eight percent (68%) of patients were female. Eighty-one 
percent (81%) of patients were White, less than 7% were Asian, and less than 
2%  were Black. The study excluded patients with severe renal impairment 
defined as an estimated creatinine clearance <30  mL/min or patients with 
significant liver disease (hepatitis or cirrhosis). The mean exposure duration 
(± SD) to active XARELTO and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, 
respectively. The efficacy data are provided in Table 12.
Table 12:  Summary of Key Efficacy Analysis Results for Patients 
Undergoing Total Knee Replacement Surgery - Modified  
Intent-to-Treat Population
RECORD 3
Treatment Dosage and 
Duration
XARELTO 
10 mg once 
daily
Enoxaparin 
40 mg  
once daily
RRR*, 
p-value
Number of Patients
N=813
N=871
Total VTE 
79 (9.7%)
164 (18.8%)
48%
(95% CI: 34, 60),
p<0.001
Components of events contributing to Total VTE
Proximal DVT
9 (1.1%)
19 (2.2%)
Distal DVT
74 (9.1%)
154 (17.7%)
Non-fatal PE
0
4 (0.5%)
Death (any cause)
0
2 (0.2%)
Number of Patients
N=895
N=917
Major VTE†
9 (1.0%)
23 (2.5%)
60% 
(95% CI: 14, 81), 
p = 0.024
Number of Patients
N=1206
N=1226
Symptomatic VTE
8 (0.7%)
24 (2.0%)
*	Relative Risk Reduction; CI = confidence interval
†	 Proximal DVT, nonfatal PE or VTE-related death
16	
HOW SUPPLIED/STORAGE AND HANDLING
XARELTO (rivaroxaban) Tablets are available in the strengths and packages 
listed below:
•	 10 mg tablets are round, light red, biconvex film-coated tablets marked 
with a triangle pointing down above a “10” on one side, and “Xa” on the 
other side. The tablets are supplied in the packages listed:
NDC 50458-580-30	
Bottle containing 30 tablets
NDC 50458-580-10	
Blister package containing 100 tablets (10 blister 
cards containing 10 tablets each)
•	 15 mg tablets are round, red, biconvex film-coated tablets with a triangle 
pointing down above a “15” marked on one side and “Xa” on the other 
side. The tablets are supplied in the packages listed:
NDC 50458-578-30	
Bottle containing 30 tablets
NDC 50458-578-90	
Bottle containing 90 tablets
NDC 50458-578-10 	 Blister package containing 100 tablets (10 blister 
cards containing 10 tablets each)
•	 20  mg tablets are triangle-shaped, dark red film-coated tablets with a 
triangle pointing down above a “20” marked on one side and “Xa” on the 
other side. The tablets are supplied in the packages listed:
NDC 50458-579-30	
Bottle containing 30 tablets
NDC 50458-579-90	
Bottle containing 90 tablets
NDC 50458-579-10 	 Blister package containing 100 tablets (10 blister 
cards containing 10 tablets each)
•	 Starter Pack for treatment of deep vein thrombosis and treatment of 
pulmonary embolism:
NDC 50458-584-51	 30-day starter blister pack containing 51 tablets: 
42 tablets of 15 mg and 9 tablets of 20 mg
XARELTO® (rivaroxaban) tablets
XARELTO® (rivaroxaban) tablets


13
Store at 25°C (77°F) or room temperature; excursions permitted to 15°-30°C 
(59°-86°F) [see USP Controlled Room Temperature].
Keep out of the reach of children.
17	
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide).
Instructions for Patient Use
•	 Advise patients to take XARELTO only as directed. 
•	 Remind patients to not discontinue XARELTO without first talking to their 
healthcare professional. 
•	 Advise patients with atrial fibrillation to take XARELTO once daily with 
the evening meal.
•	 Advise patients with DVT and/or PE to take XARELTO 15  mg or 20  mg 
tablets with food at approximately the same time every day [see Dosage 
and Administration (2.5)].
•	 Advise patients who cannot swallow the tablet whole to crush XARELTO 
and combine with a small amount of applesauce followed by food [see 
Dosage and Administration (2.9)].
•	 For patients requiring an NG tube or gastric feeding tube, instruct the 
patient or caregiver to crush the XARELTO tablet and mix it with a small 
amount of water before administering via the tube [see Dosage and 
Administration (2.9)].
•	 If a dose is missed, advise the patient to take XARELTO as soon as 
possible on the same day and continue on the following day with their 
recommended daily dose regimen.
Bleeding Risks
•	 Advise patients to report any unusual bleeding or bruising to their 
physician. Inform patients that it might take them longer than usual to 
stop bleeding, and that they may bruise and/or bleed more easily when 
they are treated with XARELTO [see Warnings and Precautions (5.2)].
•	 If patients have had neuraxial anesthesia or spinal puncture, and 
particularly, if they are taking concomitant NSAIDs or platelet inhibitors, 
advise patients to watch for signs and symptoms of spinal or epidural 
hematoma, such as back pain, tingling, numbness (especially in the 
lower limbs), muscle weakness, and stool or urine incontinence. If any of 
these symptoms occur, advise the patient to contact his or her physician 
immediately  [see Boxed Warning].
Invasive or Surgical Procedures
Instruct patients to inform their healthcare professional that they are taking 
XARELTO before any invasive procedure (including dental procedures) is 
scheduled.
Concomitant Medication and Herbals
Advise patients to inform their physicians and dentists if they are taking, or 
plan to take, any prescription or over-the-counter drugs or herbals, so their 
healthcare professionals can evaluate potential interactions [see Drug 
Interactions (7)].
Pregnancy and Pregnancy-Related Hemorrhage
•	 Advise patients to inform their physician immediately if they become 
pregnant or intend to become pregnant during treatment with XARELTO 
[see Use in Specific Populations (8.1)].
•	 Advise pregnant women receiving XARELTO to immediately report to 
their physician any bleeding or symptoms of blood loss [see Warnings 
and Precautions (5.7)].
Nursing
Advise patients to discuss with their physician if they are nursing or intend to 
nurse during anticoagulant treatment [see Use in Specific Populations (8.3)].
Females of Reproductive Potential
Advise patients who can become pregnant to discuss pregnancy planning 
with their physician [see Use in Specific Populations (8.6)].
Active Ingredient Made in Germany
Finished Product Manufactured by:
Janssen Ortho, LLC
Gurabo, PR 00778
or
Bayer Pharma AG
51368 Leverkusen, Germany
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
Licensed from:
Bayer HealthCare AG
51368 Leverkusen, Germany
© Janssen Pharmaceuticals, Inc. 2011 
070441-170404 
XARELTO® (rivaroxaban) tablets
XARELTO® (rivaroxaban) tablets


14
MEDICATION GUIDE
XARELTO® (zah-REL-toe)
(rivaroxaban)
tablets
Read this Medication Guide before you start taking 
XARELTO and each time you get a refill. There may be new 
information. This Medication Guide does not take the place 
of talking with your doctor about your medical condition or 
your treatment.
What is the most important information I should know 
about XARELTO? 
•	 For people taking XARELTO for atrial fibrillation:
People with atrial fibrillation (an irregular heart beat) are at 
an increased risk of forming a blood clot in the heart, which 
can travel to the brain, causing a stroke, or to other parts of 
the body. XARELTO lowers your chance of having a stroke 
by helping to prevent clots from forming. If you stop taking 
XARELTO, you may have increased risk of forming a clot in 
your blood.
Do not stop taking XARELTO without talking to the doctor 
who prescribes it for you. Stopping XARELTO increases 
your risk of having a stroke.
If you have to stop taking XARELTO, your doctor may 
prescribe another blood thinner medicine to prevent a 
blood clot from forming.
•	 XARELTO can cause bleeding which can be serious, and 
rarely may lead to death. This is because XARELTO is a 
blood thinner medicine that reduces blood clotting. While 
you take XARELTO you are likely to bruise more easily and 
it may take longer for bleeding to stop.
You may have a higher risk of bleeding if you take 
XARELTO and take other medicines that increase your risk 
of bleeding, including:
•	 aspirin or aspirin containing products
•	 non-steroidal anti-inflammatory drugs (NSAIDs)
•	 warfarin sodium (Coumadin®, Jantoven®)
•	 any medicine that contains heparin
•	 clopidogrel (Plavix®)
•	 selective serotonin reuptake inhibitors (SSRIs) or 
serotonin norepinephrine reuptake inhibitors (SNRIs)
•	 other medicines to prevent or treat blood clots
Tell your doctor if you take any of these medicines. Ask 
your doctor or pharmacist if you are not sure if your 
medicine is one listed above.
Call your doctor or get medical help right away if you 
develop any of these signs or symptoms of bleeding:
•	 unexpected bleeding or bleeding that lasts a long time, 
such as:
	nose bleeds that happen often
	unusual bleeding from the gums
	menstrual bleeding that is heavier than normal or 
vaginal bleeding
•	 bleeding that is severe or you cannot control
•	 red, pink or brown urine
•	 bright red or black stools (looks like tar)
•	 cough up blood or blood clots
•	 vomit blood or your vomit looks like “coffee grounds”
•	 headaches, feeling dizzy or weak
•	 pain, swelling, or new drainage at wound sites
•	 Spinal or epidural blood clots (hematoma). People who 
take a blood thinner medicine (anticoagulant) like 
XARELTO, and have medicine injected into their spinal and 
epidural area, or have a spinal puncture have a risk of 
forming a blood clot that can cause long-term or 
permanent loss of the ability to move (paralysis). Your risk 
of developing a ­spinal or epidural blood clot is higher if:
	a thin tube called an epidural catheter is placed in your 
back to give you certain medicine
	you take NSAIDs or a medicine to prevent blood from 
clotting
	you have a history of difficult or repeated epidural or 
spinal punctures
	you have a history of problems with your spine or have 
had surgery on your spine
If you take XARELTO and receive spinal anesthesia or 
have a spinal puncture, your doctor should watch you 
closely for symptoms of spinal or epidural blood clots. Tell 
your doctor right away if you have back pain, tingling, 
numbness, muscle weakness (especially in your legs 
and feet), loss of control of the bowels or bladder 
(incontinence). 
•	 XARELTO is not for patients with artificial heart valves.
See “What are the possible side effects of XARELTO?” for 
more information about side effects.
What is XARELTO?
•	 XARELTO is a prescription medicine used to:
	reduce the risk of stroke and blood clots in people who 
have a medical condition called atrial fibrillation. With 
atrial fibrillation, part of the heart does not beat the way 
it should. This can lead to the formation of blood clots, 
which can travel to the brain, causing a stroke, or to 
other parts of the body.
	treat blood clots in the veins of your legs (deep vein 
thrombosis) or lungs (pulmonary embolism) and reduce 
the risk of them occurring again 
	reduce the risk of forming a blood clot in the legs 
and lungs of people who have just had hip or knee 
replacement surgery
It is not known if XARELTO is safe and effective in children.
Who should not take XARELTO?
Do not take XARELTO if you:
•	 currently have certain types of abnormal bleeding. Talk to 
your doctor before taking XARELTO if you currently have 
unusual bleeding.
•	 are allergic to rivaroxaban or any of the ingredients in 
XARELTO. See the end of this leaflet for a complete list of 
ingredients in XARELTO.
XARELTO® (rivaroxaban) tablets
XARELTO® (rivaroxaban) tablets


15
What should I tell my doctor before taking XARELTO?
Before you take XARELTO, tell your doctor if you:
•	 have ever had bleeding problems
•	 have liver or kidney problems
•	 have any other medical condition
•	 are pregnant or plan to become pregnant. It is not known 
if XARELTO will harm your unborn baby. Tell your doctor 
right away if you become pregnant while taking XARELTO. 
If you take XARELTO during pregnancy tell your doctor 
right away if you have any bleeding or symptoms of 
blood loss.
•	 are breastfeeding or plan to breastfeed. It is not known if 
XARELTO passes into your breast milk. You and your 
doctor should decide if you will take XARELTO or 
breastfeed.
Tell all of your doctors and dentists that you are taking 
XARELTO. They should talk to the doctor who prescribed 
XARELTO for you before you have any surgery, medical or 
dental procedure.
Tell your doctor about all the medicines you take, including 
prescription and nonprescription medicines, vitamins, and 
herbal supplements. Some of your other medicines may 
affect the way XARELTO works. Certain medicines may 
increase your risk of bleeding. See “What is the most 
important information I should know about XARELTO?”
Especially tell your doctor if you take:
•	 ketoconazole (Nizoral®)
•	 itraconazole (Onmel™, Sporanox®)
•	 ritonavir (Norvir®)
•	 lopinavir/ritonavir (Kaletra®)
•	 indinavir (Crixivan®)
•	 carbamazepine (Carbatrol®, Equetro®, Tegretol®, 
Tegretol®-XR, Teril™, Epitol®)
•	 phenytoin (Dilantin-125®, Dilantin®)
•	 phenobarbital (Solfoton™)
•	 rifampin (Rifater®, Rifamate®, Rimactane®, Rifadin®)
•	 St. John’s wort (Hypericum perforatum)
Ask your doctor if you are not sure if your medicine is one 
listed above.
Know the medicines you take. Keep a list of them to show 
your doctor and pharmacist when you get a new medicine.
How should I take XARELTO?
•	 Take XARELTO exactly as prescribed by your doctor. 
•	 Do not change your dose or stop taking XARELTO unless 
your doctor tells you to.
•	 Your doctor will tell you how much XARELTO to take and 
when to take it.
•	 Your doctor may change your dose if needed.
•	 If you take XARELTO for:
	atrial fibrillation: 
▪	 Take XARELTO 1 time a day with your evening meal. 
▪	 If you miss a dose of XARELTO, take it as soon as you 
remember on the same day. Take your next dose at 
your regularly scheduled time.
	blood clots in the veins of your legs or lungs:
▪	 Take XARELTO once or twice a day as prescribed by 
your doctor.
▪	 Take XARELTO with food at the same time each day.
▪	 If you miss a dose of XARELTO:
•	 and take XARELTO 2 times a day: Take XARELTO as 
soon as you remember on the same day. You may 
take 2 doses at the same time to make up for the 
missed dose. Take your next dose at your regularly 
scheduled time.
•	 and take XARELTO 1 time a day: Take XARELTO as 
soon as you remember on the same day. Take your 
next dose at your regularly scheduled time.
	hip or knee replacement surgery: 
▪	 Take XARELTO 1 time a day with or without food.
▪	 If you miss a dose of XARELTO, take it as soon as you 
remember on the same day. Take your next dose at 
your regularly scheduled time.
•	 If you have difficulty swallowing the tablet whole, talk to 
your doctor about other ways to take XARELTO.
•	 Your doctor will decide how long you should take 
XARELTO. Do not stop taking XARELTO without talking with 
your doctor first. 
•	 Your doctor may stop XARELTO for a short time before any 
surgery, medical or dental procedure. Your doctor will tell 
you when to start taking XARELTO again after your surgery 
or procedure.
•	 Do not run out of XARELTO. Refill your prescription of 
XARELTO before you run out. When leaving the hospital 
following a hip or knee replacement, be sure that you will 
have XARELTO available to avoid missing any doses.
•	 If you take too much XARELTO, go to the nearest hospital 
emergency room or call your doctor right away. 
What are the possible side effects of XARELTO?
•	 See “What is the most important information I should 
know about XARELTO?”
Tell your doctor if you have any side effect that bothers you 
or that does not go away.
Call your doctor for medical advice about side effects. You 
may report side effects to FDA at 1‑800-FDA-1088.
How should I store XARELTO?
•	 Store XARELTO at room temperature between 68°F to 77°F 
(20° to 25°C).
Keep XARELTO and all medicines out of the reach of 
children.
XARELTO® (rivaroxaban) tablets
XARELTO® (rivaroxaban) tablets


16
General information about XARELTO.
Medicines are sometimes prescribed for purposes other 
than those listed in a Medication Guide. Do not use 
XARELTO for a condition for which it was not prescribed. Do 
not give XARELTO to other people, even if they have the 
same condition. It may harm them.
This Medication Guide summarizes the most important 
infor­mation about XARELTO. If you would like more 
information, talk with your doctor. You can ask your 
pharmacist or doctor for information about XARELTO that 
is written for health professionals.
For more information call 1-800-526-7736 or go to 
www.XARELTO-US.com.
What are the ingredients in XARELTO?
Active ingredient: rivaroxaban
Inactive ingredients: croscarmellose sodium, hypromellose, 
lactose monohydrate, magnesium stearate, microcrystalline 
cellulose, and sodium lauryl sulfate. 
The proprietary film coating mixture for XARELTO 10 mg tablets 
is Opadry® Pink and contains: ferric oxide red, hypromellose, 
polyethylene glycol 3350, and titanium dioxide.
The proprietary film coating mixture for XARELTO 15 mg tablets 
is Opadry® Red and contains: ferric oxide red, hypromellose, 
polyethylene glycol 3350, and titanium dioxide.
The proprietary film coating mixture for XARELTO 20 mg tablets 
is Opadry® II Dark Red and contains: ferric oxide red, 
polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), 
talc, and titanium dioxide.
This Medication Guide has been approved by the U.S. Food 
and Drug Administration.
Finished Product Manufactured by:
Janssen Ortho, LLC
Gurabo, PR 00778
or
Bayer Pharma AG
51368 Leverkusen, Germany
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
Licensed from:
Bayer HealthCare AG
51368 Leverkusen, Germany
Revised: May 2016
© Janssen Pharmaceuticals, Inc. 2011
Trademarks are property of their respective owners.
070441-170404
XARELTO® (rivaroxaban) tablets


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 131 
APPENDIX G. 
PROTOCOL SUMMARY OF CHANGES (AMENDMENT 4 VS. AMENDMENT 5) 
First Section 
of Occurrence 
(& 
throughout 
document) 
Old Text (from Amendment 3) 
New Text (Strikethrough indicates deleted text / bold 
italics added text) 
Rationale for 
Revision 
Substantial 
(S) OR 
Non-
substantial 
(NS) 
Change 
Synopsis 
(Efficacy 
Endpoints) 
 
Several exploratory efficacy endpoints will be 
evaluated.  These include the following markers of pro- 
or anticoagulant activity:  TFPI (total and free antigen, 
TFPI activity), PT, aPTT, ACT, FX, fibrinogen, tPA, 
PAP, TAFI, b-TG, PF4, and sTM. 
 
For Parts 1 and 2 of the study tissue factor pathway 
inhibitor (TFPI) activity, a marker of endogenous 
anticoagulation will be evaluated for the purpose of 
monitoring the potential procoagulant activity of 
andexanet (due to andexanet-TFPI interaction). 
 
For Part 1 of the study the following markers will 
also be examined: PT, aPTT, ACT, FX, fibrinogen, 
tPA, PAP, TAFI, TFPI (total and free antigen), b-TG, 
PF4, and sTM. 
Updated data 
indicate that 
deleted 
exploratory 
biomarker 
endpoints 
carry little 
clinical 
meaning in the 
context of 
andexanet 
administration. 
NS 
 
 
 
 
 
 
 
 
 
 
Synopsis 
(Safety 
Endpoints) 
 
Coagulation markers:  D-dimer, F1+2, TAT, and 
RVVT 
 
Coagulation markers:  D-dimer, F1+2, and TAT. 
RVVT will be collected in Part 1 only. 
Samples carry 
minimal 
clinical 
meaning. 
NS 
6.0 
Enrollment 
and Study 
Procedures 
A detailed description of the subject visits and clinical 
evaluations can be found in Appendix B:  Schedule of 
Activities. 
A detailed description of the subject visits and clinical 
evaluations can be found in Appendix B:  Schedule of 
Activities (Part 1) and Appendix B:  Schedule of Activities 
(Part 2). 
Added 
Appendix B to 
describe the 
Schedule of 
Activities for 
Part 2 
NS 
6.4.2.  
Days 2 to 4 
• 
Collect F1+2, TAT, D-dimer, and total TFPI and TFPI 
activity samples within 5 minutes before FXa inhibitor 
administration (see Appendix B). 
 
• 
Collect F1+2, TAT, D-dimer, and TFPI activity 
samples within 5 minutes before FXa inhibitor 
administration (see Appendix B, Appendix B).  TFPI 
(total and free antigen) collected in Part 1 only. 
Total TFPI 
collected in 
Part 1 and not 
in Part 2 
NS 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 132 
First Section 
of Occurrence 
(& 
throughout 
document) 
Old Text (from Amendment 3) 
New Text (Strikethrough indicates deleted text / bold 
italics added text) 
Rationale for 
Revision 
Substantial 
(S) OR 
Non-
substantial 
(NS) 
Change 
 
6.9.  
Early 
Termination 
Visit 
• 
Collect local laboratory samples for hematology, 
serum chemistry, and coagulation tests (PT, aPTT, 
and ACT). 
• 
Collect local laboratory samples for hematology 
and serum chemistry.   Coagulation tests (PT, 
aPTT, and ACT) collected in Part 1 only. 
PT, aPTT and 
ACT collected 
in Part 1 only 
NS 
7.1.  
Blood 
Collection 
Up to approximately 815 mL of blood will be drawn from 
each subject over the 6 to 10 week course of the study.  
Approximately 650 mL of blood (comparable to the amount 
of blood drawn over ~10 minutes during a single Red Cross 
blood donation—480 mL) will be drawn over the 10 day 
domiciled period of the study, and the remaining amount of 
blood will be drawn during Screening (~31 mL) or the 
~5 week post-discharge follow up period (~134 mL). 
Up to approximately 815ml in Part 1 and 709 mL in Part 2 
of blood will be drawn from each subject over the 6 to 
10 week course of the study.  Approximately 650 mL in 
Part 1 and 555 mL in Part 2 of blood (comparable to the 
amount of blood drawn over ~10 minutes during a single 
Red Cross blood donation—480 mL) will be drawn over the 
10 day domiciled period of the study, and the remaining 
amount of blood will be drawn during Screening (~31 mL) 
or the ~5 week post-discharge follow up period (~134mL in 
Part 1 and ~123 mL in Part 2). 
Removal of 
exploratory 
biomarker lab 
reduces the 
amount of 
blood 
collected in 
Part 2 
NS 
7.3.1. 
Coagulation 
Assays 
 
Part 2 
• 
Anti-fXa activity and thrombin generation will be 
measured using plasma samples collected at the 
site to assess the ability of observed andexanet 
blood levels to reverse the anticoagulant effect of 
apixaban, edoxaban, and rivaroxaban.   
• 
PT, aPTT, and ACT will be measured/analyzed 
locally at the study site at screening only. 
• 
F1+2, TAT, D-dimer (fibrin degradation 
fragment), and TFPI activity will be assessed in 
Clarified the 
coagulation 
assays 
collected in 
Part 2. 
NS 
 
 
 
 
 
 
 
 
 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
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italics added text) 
Rationale for 
Revision 
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(S) OR 
Non-
substantial 
(NS) 
Change 
plasma samples collected at the site and shipped to 
an outside laboratory for analysis.   
 
 
 


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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
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italics added text) 
Rationale for 
Revision 
Substantial 
(S) OR 
Non-
substantial 
(NS) 
Change 
10.5.1.3. 
Exploratory 
Efficacy 
Endpoints 
Several exploratory efficacy endpoints will be evaluated.  
These include the following markers of pro- or 
anticoagulant activity: 
• 
TFPI (total and free antigen, TFPI activity) 
• 
PT 
• 
aPTT 
• 
ACT 
• 
FX 
• 
fibrinogen 
• 
tPA 
• 
PAP 
• 
TAFI 
• 
b-TG 
• 
PF4 
• 
sTM 
For Parts 1 and 2, of the study TFPI activity, a marker of 
endogenous anticoagulation, will be evaluated for the 
purpose of monitoring the potential procoagulant activity 
of andexanet (due to andexanet-TFPI interactions). 
Several exploratory efficacy endpoints will be evaluated.  
These include the following markers of pro- or 
anticoagulant activity: 
 TFPI (total and free antigen, TFPI activity) 
For Part 1 of the study the following additional markers 
will also be examined: 
 PT 
 aPTT 
 ACT 
 FX 
 fibrinogen 
 tPA 
 PAP 
 TAFI 
 b-TG 
 PF4 
 sTM 
 TFPI (total and free antigen) 
Updated data 
indicate that 
deleted 
exploratory 
biomarker 
endpoints 
carry little 
clinical 
meaning in the 
context of 
andexanet 
administration. 
NS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.5.2.2. 
Laboratory-
Based 
Endpoints 
Immunogenicity will be evaluated by measurement of 
antibodies to andexanet, FX, and FXa, as well as RVVT.  In 
addition, neutralizing antibodies for any confirmed antibody 
response will be measured for andexanet. Furthermore, 
potential neutralizing antibody activity against FX/FXa will 
be assessed by a clotting based modified Bethesda assay. 
Immunogenicity will be evaluated by measurement of 
antibodies to andexanet, FX, and FXa, as well as RVVT.  In 
addition, neutralizing antibodies for any confirmed antibody 
response will be measured for andexanet. Furthermore, 
potential neutralizing antibody activity against FX/FXa will 
be assessed by a clotting based modified Bethesda assay. 
In Part 1 of the study, Russell’s Viper Venon Time 
(RVVT) was included as an additional assessment. 
Removal of 
RVVT 
collection in 
Part 2. 
NS 
 
 
 
 
 
 
 
 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
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of Occurrence 
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document) 
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New Text (Strikethrough indicates deleted text / bold 
italics added text) 
Rationale for 
Revision 
Substantial 
(S) OR 
Non-
substantial 
(NS) 
Change 
 
10.6.2.3. 
Exploratory 
Efficacy 
Analyses 
Plots of the value and change from baseline over time for 
TFPI (total and free antigen, TFPI activity), PT, aPTT, 
ACT, FX, fibrinogen, tPA, PAP, TAFI, b-TG, PF4, and 
sTM will be evaluated by treatment in placebo-controlled 
cohort.  If data permitted, the comparison between 
treatment groups may be made at an appropriate time 
Plots of the value and change from baseline over time for 
TFPI (total and free antigen, TFPI activity), PT, aPTT, 
ACT, FX, fibrinogen, tPA, PAP, TAFI, b-TG, PF4, and 
sTM will be evaluated by treatment in placebo-controlled 
cohorts from all parts of the study.  For Part 1 of the 
study, the additional exploratory endpoints of TFPI (total 
and free antigen), PT, aPTT, ACT, FX, fibrinogen, tPA, 
PAP, TAFI, b-TG, P44 and sTM were also collected and 
will be presented.  If data permitted, the comparison 
between treatment groups may be made at an appropriate 
time 
Removal of 
TFPI (TFPI 
activity), PT, 
aPTT, ACT, 
FX, 
fibrinogen, 
tPA, PAP, 
TAFI, b-TG, 
PF4, and sTM 
in Part 2. 
NS 
10.6.4.4. 
Analysis of 
Laboratory 
Parameters 
Clinical laboratory parameters including hematology, 
chemistry, urinalyses, and coagulation markers (D-dimer, 
F1+2, PT, aPTT, and ACT) will be summarized by 
treatment group and by time point. 
Clinical laboratory parameters including hematology, 
chemistry, urinalyses, and coagulation markers (D-dimer, 
TAT and F1+2, PT, aPTT, and ACT) will be summarized 
by treatment group and by time point for the cohorts that 
the data was collected.. 
Clarified that 
TAT is 
included in 
analysis. 
NS 
13.0 
Appendices 
APPENDIX A. STUDY EVENTS FLOW CHART 
APPENDIX B. 
WELLS SCORES 
APPENDIX C. US PACKAGE INSERT FOR APIXABAN 
(ELIQUIS)  
APPENDIX D. US PACKAGE INSERT FOR EDOXABAN 
(SAVAYSA)  
APPENDIX E. 
US PACKAGE INSERT FOR RIVAROXABAN 
(XARELTO)  
APPENDIX A. 
STUDY EVENTS FLOW CHART (PART 1) 
APPENDIX B. 
STUDY EVENTS FLOW CHART (PART 2) 
APPENDIX BC 
WELLS SCORES 
APPENDIX CD 
US PACKAGE INSERT FOR APIXABAN 
(ELIQUIS)  
APPENDIX DE 
US PACKAGE INSERT FOR EDOXABAN 
(SAVAYSA)  
APPENDIX E F 
US PACKAGE INSERT FOR 
RIVAROXABAN (XARELTO) 
Added 
Appendix B 
Study Events 
Flow Chart 
(Part 2). 
NS 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 136 
First Section 
of Occurrence 
(& 
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document) 
Old Text (from Amendment 3) 
New Text (Strikethrough indicates deleted text / bold 
italics added text) 
Rationale for 
Revision 
Substantial 
(S) OR 
Non-
substantial 
(NS) 
Change 
Appendix 
B. Study 
Events 
Flow Chart 
(Screening 
– Inpatient 
Day 4)  
Visit: 
SCREE 
NING 1 
ADMI 
SSION 
INPT INPT INPT INPT 
Day: 
≤ -45 
-1 
1 
2 
3 
4 
Hour 
 
 
0 
0 
0 
0 
Local Lab:  
PT, aPTT, 
ACT 
X 
X 
 
 
 
 
Central Lab:  
F1+2, TAT, 
D-dimer, 
total TFPI, 
TFPI 
activity 
 
 
X 4 
X 5 
X 5 
X 5 
Central Lab:  
tPA, PAP, 
TAFI, free 
TFPI, b-TG, 
PF4, sTM 
 
 
X 4 
 
 
 
Central Lab:  
Fibrinogen, 
AT-III, FX 
 
 
X 4 
 
 
 
Central Lab:  
RVVT 
 
 
X 4 
 
 
 
 
Visit: 
SCREE 
NING 1 
ADMI 
SSION 
INPT INPT INPT INPT 
Day: 
≤ -45 
-1 
1 
2 
3 
4 
Hour 
 
 
0 
0 
0 
0 
Local Lab:  
PT, aPTT, 
ACT 
X 
X 
 
 
 
 
Central Lab:  
F1+2, TAT, 
D-dimer, 
total TFPI, 
TFPI 
activity 
 
 
X 4 
X 5 
X 5 
X 5 
Central Lab:  
tPA, PAP, 
TAFI, free 
TFPI, b-TG, 
PF4, sTM 
 
 
X 4 
 
 
 
Central Lab:  
Fibrinogen, 
AT-III, FX 
 
 
X 4 
 
 
 
Central Lab:  
RVVT 
 
 
X 4 
 
 
 
 
Updated data 
indicate that 
deleted 
exploratory 
biomarker 
endpoints 
carry little 
clinical 
meaning in the 
context of 
andexanet 
administration. 
NS 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 137 
First Section 
of Occurrence 
(& 
throughout 
document) 
Old Text (from Amendment 3) 
New Text (Strikethrough indicates deleted text / bold 
italics added text) 
Rationale for 
Revision 
Substantial 
(S) OR 
Non-
substantial 
(NS) 
Change 
Appendix 
B. Study 
Events 
Flow Chart 
(Day 5) 
 
Visit: 
INPT 
Day: 
5 
Hour: 
PRE 0 1 2 3 4 5 6 7 8 12 
Local Lab:  PT, aPTT, ACT 
X 
 
X 3 
 
Central Lab:  F1+2, TAT, D-
dimer, Total TFPI, TFPI 
Activity 
X 
 
X 3 
 
Central Lab:  tPA, PAP, 
TAFI, Free TFPI, β-TG, PF4, 
sTM 
X 
 
X 3 
 
Central Lab:  Fibrinogen, 
AT-III, FX 
X 
 
X 3 
 
 
Visit: 
INPT 
Day: 
5 
Hour: 
PRE 0 1 2 3 4 5 6 7 8 12 
Local Lab:  PT, aPTT, ACT 
X 
 
X 3 
 
Central Lab:  F1+2, TAT, D-
dimer, Total TFPI, TFPI 
Activity 
X 
 
X 3 
 
Central Lab:  tPA, PAP, 
TAFI, Free TFPI, β-TG, PF4, 
sTM 
X 
 
X 3 
 
Central Lab:  Fibrinogen, 
AT-III, FX 
X 
 
X 3 
 
Updated data 
indicate that 
deleted 
exploratory 
biomarker 
endpoints 
carry little 
clinical 
meaning in the 
context of 
andexanet 
administration. 
NS 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 138 
First Section 
of Occurrence 
(& 
throughout 
document) 
Old Text (from Amendment 3) 
New Text (Strikethrough indicates deleted text / bold 
italics added text) 
Rationale for 
Revision 
Substantial 
(S) OR 
Non-
substantial 
(NS) 
Change 
Appendix 
B. Study 
Events 
Flow Chart 
(Day 6) 
Visit: 
INPT 
Day: 
6 
 
Hours Post 
Anticoagulant 
Dose 
End of Bolus 
Minutes after the 
Start of Andexanet 
Infusion 
Hours Post Completion of Andexanet Infusion 
Hour for 
Cohorts 1, 3, 
5, 6: 
PRE 0 1 2 3 
End 
Bolus 
(+2 
min) 
End 
Bolus 
(+5 
min) 
45 
min 
90 
min 
110 
min 
End 
Infu-
sion 
(-2 
min) 
5 
min 0.5 1 1.5 2 2.5 3 3.5 4.5 5.5 6.5 7.5 8.5 14.5 
Hour for 
Cohort 2: 
PRE 0 1 2 4 
Hour for 
Cohorts 4, 7: 
PRE 0 1  1.5 
Hours for 
Cohorts 8-10: 
PRE 0 1 2 8 
Local Lab:  PT, 
aPTT, ACT 
X 
 
 
 
X  
X 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
Central Lab:  
F1+2, TAT, D-
dimer, Total 
TFPI, TFPI 
activity 
 
X 
 
 
 
 
X  
 
X 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Central Lab:  
tPA, PAP, 
TAFI, 
Free TFPI, β-
TG, PF4, sTM 
 
 
X 
 
 
 
 
 
X  
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Fibrinogen, 
AT-III, FX 
X 
 
 
 
X  
X 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Updated data 
indicate that 
deleted 
exploratory 
biomarker 
endpoints 
carry little 
clinical 
meaning in the 
context of 
andexanet 
administration. 
NS 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 139 
First Section 
of Occurrence 
(& 
throughout 
document) 
Old Text (from Amendment 3) 
New Text (Strikethrough indicates deleted text / bold 
italics added text) 
Rationale for 
Revision 
Substantial 
(S) OR 
Non-
substantial 
(NS) 
Change 
Appendix 
B. Study 
Events 
Flow Chart 
(Day 7-10) 
Visit: 
INPT 
INPT 
INPT 
Discharge 
Day: 
7 
8 
9 
10 
 
Hours Post 
Last Anticoagulant Dose 
 
 
24 
36 
48 
60 
0 
0 
Local Lab:  
PT, aPTT, 
ACT 
X 
 
X 
 
X 
X 
Central 
Lab:  F1+2, 
TAT, D-
dimer, 
Total TFPI, 
TFPI 
activity 
X 
 
X 
 
X 
X 
Central 
Lab:  tPA, 
PAP, TAFI, 
Free TFPI, 
b-TG, PF4, 
sTM 
X 
 
X 
 
X 
X 
Central 
Lab:  
Fibrinogen, 
AT-III, FX 
X 
 
X 
 
X 
X 
 
Visit: 
INPT 
INPT 
INPT 
Discharge 
Day: 
7 
8 
9 
10 
 
Hours Post 
Last Anticoagulant Dose 
 
 
24 
36 
48 
60 
0 
0 
Local Lab:  
PT, aPTT, 
ACT 
X 
 
X 
 
X 
X 
Central 
Lab:  F1+2, 
TAT, D-
dimer, 
Total TFPI, 
TFPI 
activity 
X 
 
X 
 
X 
X 
Central 
Lab:  tPA, 
PAP, 
TAFI, Free 
TFPI, 
b-TG, PF4, 
sTM 
X 
 
X 
 
X 
X 
Central 
Lab:  
Fibrinogen, 
AT-III, FX 
X 
 
X 
 
X 
X 
Updated data 
indicate that 
deleted 
exploratory 
biomarker 
endpoints 
carry little 
clinical 
meaning in the 
context of 
andexanet 
administration. 
NS 
Appendix 
B. Study 
Events 
Flow Chart 
(Day 20 and 
Visit: 
OPV 
Termination OPV 
Day: 
20 (+3 days) 
36 (+3 days) 
Visit: 
OPV 
Termination OPV 
Day: 
20 (+3 days) 
36 (+3 days) 
Updated data 
indicate that 
deleted 
exploratory 
biomarker 
NS 


Clinical Study 16-508 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol Amendment 5 
Confidential 
19 February 2019 
Page 140 
First Section 
of Occurrence 
(& 
throughout 
document) 
Old Text (from Amendment 3) 
New Text (Strikethrough indicates deleted text / bold 
italics added text) 
Rationale for 
Revision 
Substantial 
(S) OR 
Non-
substantial 
(NS) 
Change 
36) 
Central Lab:  F1+2, 
TAT, D-dimer, Total 
TFPI, TFPI Activity 
X 
X 
Central Lab:  tPA, 
PAP, TAFI, Free TFPI, 
b-TG, PF4, sTM 
X 
X 
Central Lab:  
Fibrinogen, AT-III, FX 
X 
X 
Central Lab:  RVVT 
X 
X 
Central Lab:  F1+2, 
TAT, D-dimer, Total 
TFPI, TFPI Activity 
X 
X 
Central Lab:  tPA, PAP, 
TAFI, Free TFPI, b-TG, 
PF4, sTM 
X 
X 
Central Lab:  
Fibrinogen, AT-III, FX 
X 
X 
Central Lab:  RVVT 
X 
X 
endpoints 
carry little 
clinical 
meaning in the 
context of 
andexanet 
administration. 
 

SAP_000.pdf: 
NCT03310021  
 
Statistical Analysis Plan: Part 1 
 
A Phase 2 Randomized, Double‐Blinded, Placebo‐Controlled Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of 
Andexanet Alfa Administered to Healthy Japanese and Caucasian Subjects 
 
Document Date: 29‐July‐2018 




Portola Pharmaceuticals, Inc. 
5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
 
 
 
                                                                         Study 16-508 Appendix 16.1.9 
Confidential 
Final SAP version 1.0 
Page 2 
 
TABLE OF CONTENTS 
Page 
STATISTICAL ANALYSIS PLAN: PART 1 ............................................................................................ 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
1.0 
INTRODUCTION ................................................................................................................................ 7 
1.1. 
RESPONSIBILITIES ...................................................................................................................... 7 
1.2. 
TIMING OF ANALYSES .............................................................................................................. 7 
2.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................... 8 
2.1. 
OBJECTIVES .................................................................................................................................. 8 
2.2. 
ENDPOINTS.................................................................................................................................... 8 
2.3. 
PK PARAMETERS ....................................................................................................................... 10 
2.4. 
SAFETY ENDPOINTS ................................................................................................................. 10 
3.0 
STUDY DESIGN ................................................................................................................................ 11 
3.2 
SAMPLE SIZE JUSTIFICATION ............................................................................................... 12 
3.3 
ESTIMATED DURATION OF SUBJECT PARTICIPATION AND FOLLOW-UP ............. 13 
4.0 
ANALYSIS POPULATIONS ........................................................................................................... 14 
4.1. 
PK ANALYSIS POPULATION .................................................................................................. 14 
4.2. 
EFFICACY ANALYSIS POPULATION ................................................................................... 14 
4.3. 
SAFETY ANALYSIS POPULATION ........................................................................................ 14 
5.0 
GENERAL ASPECTS OF THE STATISTICAL ANALYSIS ................................................... 15 
5.1. 
KEY DEFINITIONS ..................................................................................................................... 15 
5.2. 
VISIT WINDOWS AND TIME POINTS ................................................................................... 15 
5.3. 
MULTIPLICITY ISSUES............................................................................................................. 15 
5.4. 
SUBGROUP ANALYSES............................................................................................................ 15 
5.5. 
MISSING DATA ........................................................................................................................... 15 
6.0 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................................... 18 
6.1. 
SUBJECT DISPOSITION ............................................................................................................ 18 
6.2. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................... 18 
6.3. 
MEDICAL HISTORY................................................................................................................... 19 
6.4. 
PRIOR AND CONCOMITANT MEDICATION ....................................................................... 19 
6.5. 
PROTOCOL DEVIATIONS ........................................................................................................ 19 
7.0 
EFFICACY ANALYSES ................................................................................................................... 21 
7.1. 
PRIMARY EFFICACY ENDPOINT .......................................................................................... 21 
7.2. 
SECONDARY EFFICACY ENDPOINTS.................................................................................. 21 
7.3. 
EXPLORATORY EFFICACY ASSESSMENTS .ERROR! BOOKMARK NOT DEFINED. 
8.0 
PHARMACOKINETIC ANALYSES ............................................................................................. 23 
9.0 
SAFETY 
24 
9.1. 
EXTENT OF EXPOSURE ........................................................................................................... 24 
9.2. 
ADVERSE EVENTS .................................................................................................................... 24 


Portola Pharmaceuticals, Inc. 
5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
 
 
 
                                                                         Study 16-508 Appendix 16.1.9 
Confidential 
Final SAP version 1.0 
Page 3 
 
9.3. 
CLINICAL LABORATORY ASSESSMENTS ......................................................................... 24 
9.4. 
ELECTROCARDIOGRAM (ECG) ............................................................................................. 25 
9.5. 
VITAL SIGNS AND OXYGEN SATURATION ...................................................................... 26 
9.6. 
PHYSICAL EXAMINATION...................................................................................................... 26 
9.7. 
VENOUS THROMBOEMBOLISM (VTE) ................................................................................ 26 
10.0 
ANALYSIS CONVENTIONS .......................................................................................................... 27 
11.0 
REFERENCES.................................................................................................................................... 29 
12.0 
TABLES, LISTINGS, AND FIGURES .......................................................................................... 30 
 
 


Portola Pharmaceuticals, Inc. 
5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
 
 
 
                                                                         Study 16-508 Appendix 16.1.9 
Confidential 
Final SAP version 1.0 
Page 4 
 
LIST OF ABBREVIATIONS 
 
Term 
Definition 
ACT 
Activated clotting time 
AE 
Adverse event 
ALQ 
Above Limit of Quatification 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATA 
Anti-test article antibodies 
AT-III 
Antithrombin-III 
AUC 
Area under the curve 
BID 
Twice a day  
BLQ 
Below Limit of Quatification 
BP 
Blood pressure 
-TG 
Beta thromboglobulin 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CK 
Creatine kinase 
CL 
Clearance 
Cmax/min 
Maximum/minimum observed concentration 
Cr 
Creatinine 
CRF 
Case report form 
CRO 
Contract research organization 
DVT 
Deep venous thrombosis 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
e-CRF 
Electronic case report form 
EOB 
End of Bolus 
EOI 
End of Infusion 
F1+2 
Prothrombin fragment 1+2 
FDA 
(US) Food and Drug Administration 
Fg 
Fibrinogen 


Portola Pharmaceuticals, Inc. 
5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
 
 
 
                                                                         Study 16-508 Appendix 16.1.9 
Confidential 
Final SAP version 1.0 
Page 5 
 
FSH 
Follicle-stimulating hormone 
FX 
Factor X 
fXa 
Factor Xa 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HCO3 
Bicarbonate 
HIV 
Human Immunodeficiency Virus 
HPLC 
High performance liquid chromatography 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
ICF 
Informed Consent Form 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISC 
Independent Safety Committee 
IV 
Intravenous 
LCMS 
Liquid chromatography mass spectrometry 
LLN 
Lower limit of normal 
LMWH 
Low molecular weight heparin 
LOQ 
Limit of Quantification 
λz 
Terminal or elimination rate constant 
MI 
Myocardial infarction 
Min 
Minute 
mL 
Milliliter 
Ng 
Nanogram 
NOAEL 
No observable adverse effect level 
PAP 
Plasmin-antiplasmin complex 
PD 
Pharmacodynamic 
PE 
Pulmonary embolism 
PF4 
Platelet Factor 4 
PK 
Pharmacokinetic 
PI 
Principal Investigator 
PO 
Orally 
PT 
Prothrombin time 


Portola Pharmaceuticals, Inc. 
5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
 
 
 
                                                                         Study 16-508 Appendix 16.1.9 
Confidential 
Final SAP version 1.0 
Page 6 
 
Q 
Every 
QD 
Once daily 
RAST 
Radioallergosorbent 
RR 
Respiratory rate 
RVVT 
Russell’s Viper Venom Time 
SAD 
Single ascending dose  
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
sTM 
Soluble thrombomodulin 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Half-life 
TAFI 
Thrombin activatable fibrinolysis inhibitor 
TAT 
Thrombin-antithrombin complex 
TFPI 
Tissue factor pathway inhibitor 
tmax 
Time to maximum observed concentration 
tPA 
Tissue plasminogen activator 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
VS 
Vital signs 
Vss 
Volume at steady state 
VTE 
Venous thromboembolism 
WBC 
White blood cells 


Portola Pharmaceuticals, Inc. 
5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
 
 
 
                                                                         Study 16-508 Appendix 16.1.9 
Confidential 
Final SAP version 1.0 
Page 7 
 
1.0 INTRODUCTION 
The purpose of this plan is to prospectively outline in detail the data derivations, statistical methods 
and presentations of data so that valid conclusions can be reached to address the study objectives 
outlined in the protocol (Part 1). This SAP addresses only the Part 1 objectives of the study. A 
separate SAP will be developed for Part 2 before the unblinding of subjects in that part.  However, 
the results from both parts may be reported in a single Clinical Study Report. 
The planned analyses identified in this statistical analysis plan (SAP) may be included in 
regulatory submissions and/or future manuscripts.  Exploratory analyses, not identified in this 
SAP, may be performed to support the andexanet alfa clinical development program.  Any post-
hoc or unplanned analyses that are performed but not identified in this SAP will be clearly 
identified in the clinical study report (CSR). 
1.1. 
Responsibilities  
WCCTG will perform the statistical analyses for all clinical data collected.  WCCTG is responsible 
for production and quality control of all tables, figures and listings. 
1.2. 
Timing of Analyses 
Two analyses will be performed on unblinded data during the study.  The final analysis after final 
data lock, and an unblinded interim analysis following completion of Part 1, as detailed in this 
SAP.  


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2.0 STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
 Objectives 
The objectives of this study are to assess the following in healthy subjects dosed to steady state 
with direct oral FXa inhibitors (apixaban, rivaroxaban, and edoxaban): 
Efficacy Objectives 
Primary Efficacy Objective 
• To compare andexanet and placebo with respect to reversal of each FXa inhibitor as 
measured by anti-fXa activity. 
Secondary Efficacy Objectives 
• To assess andexanet and placebo with respect to reversal of each FXa inhibitor as measured 
by free fraction of the inhibitor.  
• To assess andexanet and placebo with respect to reversal of each FXa inhibitor as measured 
by restoration of thrombin generation. 
• To assess the pharmacodynamics of andexanet in Japanese subjects and Caucasian 
subjects, as measured by anti-fXa activity, free fraction of the FXa inhibitor (apixaban), 
and restoration of thrombin generation.  
Safety Objective 
• To evaluate the safety of andexanet in Japanese subjects.  
Pharmacokinetics Objectives 
• To evaluate the pharmacokinetics of andexanet in Japanese subjects. 
• To compare the pharmacokinetics of andexanet in Japanese subjects to the 
pharmacokinetics of andexanet in Caucasian subjects.  
2.2. 
Endpoints 
2.2.1        Efficacy Endpoints  
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in anti-FXa activity from baseline to the end 
of infusion (EOI) nadir. The nadir is defined as the smallest value for anti-FXa activity of 110 
minutes after the start of the andexanet infusion (approximately 10 minutes prior to the end of the 


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continuous infusion), End of Infusion (-2 mins), and the 5-minute time point after the end of the 
continuous infusion.  
Baseline is defined as the value observed for Day 6 pre-Andexanet treatment (i.e., 3 hours post 
last dose of Apixaban or Edoxaban, for Cohorts 1, 3, and 5. For Cohort 2, 4 hours post last dose 
of Rivaroxaban, and for Cohort 4, 1.5 hours post last dose of Edoxaban). The primary analysis will 
be performed on all individual cohorts separately. 
Secondary Efficacy Endpoints 
• The percent change from baseline in anti-FXa activity at its end of bolus (EOB) nadir, 
where the EOB nadir is defined as the smallest value for anti-fXa activity at the +2 minute 
or +5 minute time point after the completion of the andexanet bolus. 
• The change and percent change from baseline in free FXa inhibitors concentration (ng/mL) 
at its EOB nadir, where EOB nadir is defined as the smallest value for free FXa inhibitors 
at the +2 minute or +5 minute time point after the completion of the andexanet bolus. 
• The change and percent change from baseline in free FXa inhibitors concentration (ng/mL) 
at its EOI nadir, where EOI nadir is defined as the smallest value for free FXa inhibitors 
between 110 minutes after the start of the andexanet infusion and ending 5 minutes after 
the end of the andexanet infusion (inclusive).   
• The change in thrombin generation from baseline to its EOB peak, where EOB peak is 
defined as the largest value for thrombin generation between the +2 minute time point and 
the +5 time point after the end of the andexanet bolus (inclusive). 
• The percentage of cases with thrombin generation above the lower limit of the normal 
range at its EOB peak, between the +2 minute time point and the +5 time point after the 
end of the andexanet bolus (inclusive). The lower limit of normal range is defined as overall 
mean for thrombin generation prior to start of treatment (i.e., Day 1) minus the standard 
deviation.  The mean should be calculated based on all cases (overall) as well as combined 
for all cohorts according to the race (i.e., Japanese, Caucasian).  
• The change in thrombin generation from baseline to its EOI peak, where EOI peak is 
defined as the largest value for thrombin generation between 110 minutes after the start of 
the andexanet infusion and ending 5 minutes after the end of the andexanet infusion 
(inclusive). 
• The percent of cases with thrombin generation above the lower limit of the normal range 
at its EOI peak, where EOI peak is defined as the largest value for thrombin generation 
between 110 minutes after the start of the andexanet infusion and ending 5 minutes after 


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the end of the andexanet infusion.  The lower limit of normal range is defined as Mean –
1SD of thrombin generation at Day 1 prior to start of treatment combined for all cohorts 
according to the race (i.e., Japanese, Caucasian) and overall. 
Only subjects with both a baseline and a post-baseline assessment are to be included in within and 
between-cohort comparisons. 
2.3. 
PK Parameters 
Andexanet:  Plasma samples for andexanet will be collected at multiple time points on Day 6 
through Day 9. From these, following non-compartmental PK parameters based on the total 
administered andexanet dose will be computed:  Cmax, Tmax, AUC(0-last), AUC(0-∞), t1/2, CL, Vss, 
and λz.  
Factor Xa inhibitors:  Plasma concentrations of both unbound and total fXa inhibitors will be 
measured in this study.  Samples for fXa inhibitors (total and unbound) will be collected on Day 
1 (pre-dose only), multiple time points on Day 5 through Day 8 and once on Day 9 and Day 10. 
The following noncompartmental PK parameters will be computed for total plasma apixaban, 
rivaroxaban, edoxaban, and the edoxaban metabolite D21-2393:  Cmax, Cbolus (end of bolus + 2 
minutes), Tmax, CL/F, AUC(0-last), AUC(0-τ), t1/2, and λz.  
 
2.4. 
Safety Endpoints 
The following safety parameters will be analyzed:  
• Adverse events, physical exam, vital signs, oxygen saturation, ECG, clinical laboratory 
values Serial clinical assessments for venous thromboembolic events.  
• Antibodies to andexanet, FX, FXa, and HCPs; neutralizing antibodies to andexanet, 
FX/FXa.  
• Coagulation markers:  F1+2, TAT, D-dimer, TFPI antigen (total and free antigen), TFPI 
activity  
• Other coagulation and fibrinolysis markers: ATIII, FX, fibrinogen, tPA, PAP, TAFI, b-TG, 
PF4, and sTM, as well as RVVT. 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be evaluated: PT, aPTT, ACT.  


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3.0 STUDY DESIGN  
This is a single-center, randomized, double blind, and placebo-controlled trial designed to evaluate 
the efficacy, safety, and PK of andexanet in healthy Japanese subjects taking direct FXa inhibitors 
at therapeutic doses.  Reversal of anticoagulation will be evaluated by measuring anti-fXa activity, 
unbound FXa inhibitor plasma levels, and thrombin generation.  
A total of 10 cohorts will be studied in two parts.  Part 1 which is the focus of this SAP consists of 
Cohorts 1-5 will evaluate the efficacy (as assessed by anti-fXa activity reversal), safety, and PK 
of andexanet in Japanese subjects, and evaluate for similarities between analogous data from 
Caucasian subjects. 
3.1 Study Treatments and Dose Administration 
At least 51 subjects are enrolled in part 1 of this study. 
Table 1:      Drug/Dosing Assignments for ALL Cohorts 
Cohort 
fXa Inhibitor 
Andexanet 
N(Active/Placebo) 
1 
Apixaban  
5 mg BID 
400 mg bolus+4 mg/min 120 minute 
infusion/placebo (andexanet dosing at 3 
hours post-apixaban) 
Japanese 9 (6/3) 
2  
Rivaroxaban  
15 mg BID 
800 mg bolus+ 8 mg/min 120 minute 
infusion/placebo (andexanet dosing at 4 
hours post-rivaroxaban) 
Japanese 9 (6/3) 
3 
Edoxaban 
60 mg QD 
800 mg bolus+8 mg/min 120 minutes 
infusion /placebo (andexanet dosing at 3 
hours post-edoxaban) 
Japanese 12 (8/4) 
4 
Edoxaban 
60 mg QD 
800 mg bolus+8 mg/min 120 minute 
infusion/placebo (andexanet dosing at 90 
minutes post-edoxaban) 
Japanese 12 (8/4) 
5 
Apixaban 
5 mg BID 
400 mg bolus+4 mg/min 120 minute 
infusion/placebo (andexanet dosing at 3 
hours post-apixaban) 
Caucasian 9 (6/3) 
 
 


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3.2  Sample Size Justification 
For all cohorts, subjects will be randomized in a 2:1 ratio of treatment with andexanet or placebo, 
respectively.  If enrolled subjects discontinue early from the study or have missing data for any 
reason, the Sponsor may elect to add up to 3 additional subjects (with newly blinded treatment 
assignments) within the discontinued subject’s assigned cohort.   
Apixaban 5 mg BID (Cohort 1 and Cohort 5)  
The mean (SD) of the primary endpoint in Study 14-503 Part 2 which assessed the reversal of 
apixaban 5 mg BID anticoagulation with andexanet administered as an IV bolus followed by a 2-
hour infusion were -92.3% (SD = 2.8%) and -32.7% (SD = 5.6%) for andexanet and placebo arms, 
respectively.  Based on these results, the percent changes from baseline in anti-fXa activity in this 
study are assumed to be -90% (SD = 5%) and -35% (SD = 10%) for andexanet and placebo arms, 
respectively.  The standard deviations in both arms are assumed larger than the observed values in 
the previous study to provide adequate power for the comparison.  Under these assumptions, a 
total number of 9 subjects (6 active and 3 placebo) will provide at least 90% power to detect the 
difference at a significance level of 0.05 (two-sided) using the two sample exact Wilcoxon rank 
sum test.   
Rivaroxaban 15 mg BID (Cohort 2)  
The mean (SD) of the primary endpoint in Study 14-504 Part 2 which assessed the reversal of 
rivaroxaban 20 mg QD anticoagulation with andexanet administered as an IV bolus followed by a 
2-hour infusion were -96.7% (SD = 1.8%) and -44.8% (SD = 11.7%) for andexanet and placebo 
arms, respectively.  Based on these results, the percent changes from baseline in antifXa activity 
are assumed to be -90% (SD = 5%) and -45% (SD = 15%) for andexanet and placebo arms, 
respectively.  Under these assumptions, a total number of 9 subjects (6 active and 3 placebo) will 
provide at least 90% power to detect the difference at a significance level of 0.05 (two-sided) using 
the two sample exact Wilcoxon rank sum test.  
Edoxaban 60 mg QD (Cohort 3:  andexanet dosing at 3 hours post-edoxaban) 
 In Cohort 2 of Study 12-502 Module 4 which assessed the reversal of edoxaban anticoagulation 
with andexanet, the mean (SD) of the percent change from baseline anti-fXa activity at the end of 
infusion was -70.28% (SD = 5.64%) for the andexanet arm.  In Cohort 1 and Cohort 2 of the same 
study, the mean (SD) of the percent change from baseline at 2 hours after the end of bolus was -
40.31% (SD = 12.25%) for placebo.  Based on these results, the percent changes from baseline in 
anti-fXa activity for andexanet and placebo are assumed as -70% (SD = 6%) and -40% (SD = 
15%), respectively.  Under these assumptions, a total number of 12 subjects (8 active and 4 
placebo) will provide at least 90% power to detect the difference at a significance level of 0.05 
(two-sided) using the two sample exact Wilcoxon rank sum test.  


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Edoxaban 60 mg QD (Cohort 4:  andexanet dosing at 90 minutes post-edoxaban)  
There are no actual data of andexanet administration at 90 minutes after edoxaban dosing.  Based 
on the result predicted by the PK-PD model developed using the data of Study 12-502, the percent 
changes from baseline in anti-fXa activity for andexanet and placebo are assumed as -70% (SD = 
15%) and -30% (SD = 15%), respectively.  Under these assumptions, a total number of 12 subjects 
(8 active and 4 placebo) will provide at least 90% power to detect the difference at a significance 
level of 0.05 (two-sided) using the two sample exact Wilcoxon rank sum test.  
3.3 Estimated Duration of Subject Participation and Follow-up 
For each individual subject, the study duration will be approximately 6–12 weeks, depending on 
the length of Screening.  The study periods are as follows: 
 • Screening:  Days -45 to -1 
 • Anticoagulant Dosing:  Days 1 to 6 
 • Andexanet Dosing:  Day 6  
 • Safety Follow-Up:  Days 7 to 36 (+3)  
Study subjects will be domiciled from Day -1 to Day 10, and then discharged from the inpatient 
facility on Day 10 to continue outpatient follow-up through Day 36 (+3). 
 


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4.0 ANALYSIS POPULATIONS 
The results from this study will be presented using the following populations: 
4.1. 
PK Analysis Population 
The PK analysis population will consist of all subjects who have received a complete dose of 
andexanet and have missing data for no more than 3 plasma concentration timepoints. For 
calculation of the primary PK parameter, AUC(0-∞), a minimum of 3 time points after Tmax with 
evaluable concentration data will be required.  
4.2. 
Efficacy Analysis Population 
The Efficacy Analysis Population will include all randomized subjects who received andexanet or 
placebo during the double-blind treatment period and had at least one evaluable post-baseline 
efficacy assessment as well as the required baseline sample assessment. Efficacy populations will 
be defined for each efficacy endpoint separately based on available data. For the efficacy analysis, 
subjects will be presented in the treatment group to which they were randomized.  Subjects will be 
included in the efficacy analysis set on change or percent change from baseline if they have a 
baseline value and at least one measurement post-baseline for the time point under consideration.   
4.3. 
Safety Analysis Population 
The safety analysis population will include all enrolled subjects who received any amount of study 
drug (andexanet or placebo) treatment.  All subjects in the safety population will be associated 
with the treatment actually received.  


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5.0 GENERAL ASPECTS OF THE STATISTICAL ANALYSIS 
5.1. 
Key Definitions 
The Study Day is the day relative to the date of administration of the fXa inhibitor (Day 1). 
Unless otherwise specified, Baseline is the pre-study drug measurement on Day 6, or Day 5 if the 
Day 6 data are not available. 
The treatment period is defined as Days 1-6 for those subjects dosed with either andexanet or 
placebo. 
5.2. 
Visit Windows and Time Points 
There are no plans to derive visit windows, and visits will be used in the analyses as reported on 
the eCRF.     
The time points selected for the PD analysis are exact time points.  However, for analysis purposes, 
the time point windows may be used for assigning the actual time points to the scheduled nominal 
time points.  
5.3. 
Multiplicity Issues 
For this early phase study, although andexanet and placebo are compared via a number of efficacy 
endpoints across a number of cohorts and time points, no multiplicity adjustment will be made to 
account for the potential inflation of the type 1 error rate. 
5.4. 
Subgroup Analyses 
Due to the small size of this study, no inferential subgroup analyses are planned.   
5.5. 
Missing Data 
For the PK evaluation, plasma concentration values for sample data points with missing data 
occurring prior to the last quantifiable data point, which will be assumed to be the point of 
clearance, will be interpolated.   
In calculation of the concentration summaries and PK parameters, BLQ values will be treated as 
follows: 
• BLQ values in samples drawn prior to administration of study drug will be set to zero. 
• Post-dose BLQ values in samples drawn prior to the first measurable concentration will be 
set to LLOQ/2. 
• BLQ values that occur between two measurable concentration values will be treated as 
missing and excluded from the PK parameter calculation 
• BLQ values that occur at the end of the concentration-time profile will be treated as zero   


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In calculation of PD summaries, BLQ values will be set to LLOQ/2. For values above the limit of 
quantitation (ALQ), the values will be set to the upper limit of quantification. 
In listings, BLQ values will be presented as “BLQ”. The ALQ values will be presented as >ALQ. 
For calculation of the geometric mean, values below 1, the log value will be set as zero.  Data may 
be excluded from the descriptive or inferential analyses if the result is based on unscheduled visits. 
In this case data will be presented in data listings with a flag for exclusion.   
For the efficacy evaluation, primary comparison requires data for both pre-andexanet/placebo (i.e., 
baseline) and post-andexanet/placebo nadir or peak.  
Baseline is defined as the value observed for Day 6 pre-Andexanet treatment (i.e., 3 hours post 
last dose of Apixaban or Edoxaban for Cohorts 1, 3, and 5; 4 hours post last dose of Rivaroxaban 
for Cohort 2, and 1.5 hours post last dose of Edoxaban for Cohort 4).  If data at the Day 6 baseline 
is missing, the Day 5 data at the match time point will be used.  If both Day 6 and Day 5 
measurement are missing, baseline will be considered as missing. 
For nadir or peak for the primary efficacy analysis, missing values will not be imputed. If baseline 
data and/or nadir is missing, the subject will be considered non-evaluable and excluded from the 
primary comparison.  
For sensitivity analysis, if baseline is missing, the change and percent changed will be imputed as 
zero.  If post bolus value is missing, missing value will be imputed with nadir value observed prior 
to the 110 minutes after start of infusion.  If the value for the infusion is missing, missing value 
will be replaced with the nadir value for post EOI. If all values are missing for Bolus and infusion, 
change and percent change will be replaced with zero. 
For prior and concomitant medication summaries, if the medication start date is completely 
missing then the medication will be considered to be both prior and concomitant unless it can be 
determined that the medication end date occurred prior to andexanet administration. If the 
medication start date is partially missing and the partial date is not sufficient to determine if the 
medication was taken after andexanet administration then the medication will be considered to be 
both prior and concomitant for the study unless the partial date is clearly after the date of andexanet 
administration (in which case it will be considered concomitant only) or the medication end date 
is prior to andexanet administration (in which case it is prior only). 
For reporting AEs, the start dates and start times are important for the: 
• Treatment emergent algorithm. 
• Designation of unique AE occurrences. 
• Designation of relatedness to study drug. 
 


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Completely missing or partially missing adverse event onset dates/times will be imputed as follows 
after due diligence to obtain accurate adverse event information has failed. 
If the adverse event start date is completely missing then the adverse event will be considered 
treatment emergent unless it can be determined that the adverse event end date occurred prior to 
administration of study medication.  If this is the case, the adverse event will not be considered 
treatment emergent. 
If the adverse event start date is partially missing and the partial date is not sufficient to determine 
if the event occurred after the administration of study medication, then the adverse event will be 
considered treatment emergent unless it can be determined that the adverse event end date occurred 
prior to the start of the study.  In the unlikely event of a missing laboratory result, the result will 
be treated as missing for the laboratory abnormality summary. 


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6.0 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
6.1. 
Subject Disposition 
Summary tables for subject disposition will be presented for all enrolled subjects (presented in 
table and listing summaries as All Subjects) by Cohort from both parts of the study.  The subject 
disposition summary will include subjects who received the FXa inhibitor, subjects randomized, 
subjects who received andexanet or placebo, subjects completing andexanet/placebo treatment, 
and subjects discontinued from the Study.  In addition, disposition will be presented for the entire 
population grouped by andexanet and placebo. The primary reason for premature discontinuation 
from the study will be summarized for the Safety Population.  A listing will be presented on subject 
disposition. 
Summary statistics for FXa inhibitor doses will be presented by cohort.  The number and 
percentage of subjects with interrupted or discontinued andexanet/placebo treatment will be 
reported by cohort. 
6.2. 
Demographic and Baseline Characteristics 
Baseline and demographic characteristics will be summarized for the safety and efficacy 
populations of each part of the study.  Data will be summarized by treatment, overall for Andexanet 
and Placebo, and overall for Japanese patients using descriptive statistics such as frequencies, 
means, medians, standard deviations, minimums, and maximums.  No inferential statistical 
analyses of these data are planned.  
All Subjects in the Safety Population will be used to summarize the demographic and baseline 
characteristics with respect to height (cm), weight (kg), BMI (kg/m2), sex, age (years) at entry into 
the study, race and ethnicity.  Age will be calculated as: 
[Date of Informed Consent – Date of Birth] / 365.25 rounded down to the nearest integer. 
Age will be reported in years and summarized with descriptive statistics:  n, arithmetic mean, 
standard deviation, median, range (i.e., minimum and maximum values).  The number and percent 
of each gender, race, and ethnicity category will be presented using counts and percentages.  Race 
will be presented using the following categories:   
• American Indian or Alaskan Native 
• Asian (including Japanese ethnicity, defined as having four ethnic Japanese grandparents. 
Subjects may not have lived outside of Japan for more than 10 years.) 


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• Black or African American 
• Native Hawaiian or Other Pacific Islander 
• White 
• Other/Unknown 
Ethnicity will be presented using the following 4 categories:  
• Hispanic or Latino 
• Not Hispanic or Latino 
• Unknown 
• Not Reported 
 
6.3. 
Medical History 
Medical and surgical history and concomitant diseases will be coded according to the most recent 
version of MedDRA.  Frequency tables of the number and percentage of subjects by system organ 
class and preferred term will be provided for the Safety Population only. 
6.4. 
Prior and Concomitant Medication 
Medications will be separated into prior and concomitant medications.  Prior medications are taken 
before the date of start of andexanet (or matching placebo).  Concomitant medications are those 
taken from the start of andexanet or matching placebo through the end of the study.  
Medications will be coded according to the most recent version of the WHO Drug Dictionary.  
Listings will present the Anatomical Therapeutic Chemical classification system (ATC) Class 
Level 2, Class Level 3, generic name, and the investigator term. 
Prior medication and concomitant medication will be summarised for the Safety Population by 
Cohort from both parts.  Frequency tables of the number and percentage of subjects by ATC Class 
Level 2 and ATC Class Level 3 will be provided.  
6.5. 
Protocol Deviations 
Protocol deviations will be listed and summarized.  Specific protocol deviations include the 
following: 
• Those who entered the study even though they did not satisfy the entry criteria. 
• Those who developed withdrawal criteria during the study but were not withdrawn. 


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• Those who received the wrong treatment or incorrect or incomplete dose. 
• Those who received an excluded concomitant treatment. 
Details around protocol deviations specific to the primary efficacy endpoint are as follows: 
The percent change from baseline in anti-FXa activity to the EOI nadir will be defined by a specific 
evaluation period beginning 110 minutes after the start of the andexanet infusion and the 5- minute 
time point after the end of the continuous infusion (inclusive).  Samples drawn outside these 
windows may be considered significant protocol deviations, especially if they impact the integrity 
of the data. 


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7.0 EFFICACY ANALYSES 
7.1. 
Primary Efficacy Endpoint 
 
Anti- FXa Activity at EOI 
The primary efficacy endpoint is the percent change in anti-FXa activity from baseline to the nadir 
level.  The nadir is defined as the smallest value for anti-FXa activity of 110 minutes after the start 
of the andexanet infusion (approximately 10 minutes prior to the end of the continuous infusion), 
End of Infusion (-2 mins), and the 5-minute time point after the end of the continuous infusion.  
The primary analysis will be performed on all individual cohorts separately. Summary statistics 
will be provided for baseline, absolute value, change from baseline, and %change from baseline 
for each time point during evaluation period. Only subjects with both a baseline and a post-baseline 
assessment are to be included in within-cohort and between-cohort comparisons. 
A two-sided Wilcoxon Rank Sum test will be used to compare the anti-FXa activity between 
andexanet and placebo at a significance level of 5%.  Besides the p-value from the above test, the 
Hodges-Lehman estimate and 95% confidence interval will be derived for the difference in percent 
change from baseline between the treatments. 
The above analyses will be based on the Efficacy Population.   
7.2. 
Secondary Efficacy Endpoints 
 
Anti- FXa Activity at EOB 
Summary statistics similar to those provided for the EOI nadir analysis for anti-FXa activity will 
be provided for the EOB nadir endpoint where the EOB nadir is defined as the smallest value 
between the +2 minute and +5 minute timepoint after the end of the andexanet bolus. The summary 
statistics will be provided for baseline, absolute value, change from baseline, and %change from 
baseline for each time point during evaluation period. Only subjects with both a baseline and a 
post-baseline assessment are to be included in within-cohort and between-cohort comparisons. 
Unbound (Free) Plasma Fraction of FXa Inhibitor at EOB and EOI 
To characterize the difference in percent change in free FXa inhibitor concentration (ng/mL) from 
baseline to the EOB nadir level, where the EOB nadir is defined as the smallest value for free FXa 
inhibitors at the +2 minute or +5 minute time point after the completion of the andexanet bolus, a 
summary statistics for baseline, absolute value, change from baseline and %change from baseline 
will be provided at nadir and each time point during evaluation period. This analysis will be 
performed on all individual cohorts separately. A similar analysis will be performed after defining 


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the EOI nadir as the smallest value between the 110 minute timepoint after the start of the 
andexanet infusion and the 5-minute time point after the end of the continuous infusion. 
 
Thrombin generation at EOB and EOI 
The change in thrombin generation from baseline to its EOB peak, where the EOB peak is defined 
as the largest value for thrombin generation between the +2 minute time point and the +5 minute 
time point after the end of the andexanet bolus (inclusive), a summary statistics for baseline, 
absolute value, change from baseline will be provided at peak and each time point during 
evaluation period. This analysis will be performed on all individual cohorts separately. A similar 
analysis will be performed after defining the EOI nadir as the smallest value between the 110 
minute timepoint after the start of the andexanet infusion and the 5-minute time point after the end 
of the continuous infusion. 
The occurrence of thrombin generation above the lower limit of the normal range at its EOI peak, 
where EOI peak is defined as the largest value for thrombin generation between 110 minutes after 
the start of the andexanet infusion and ending 5 minutes after the end of the andexanet infusion, 
and the lower limit of normal range is defined as Mean–1SD of thrombin generation at Day 1 will 
be presented. A similar analysis will be performed for the occurrence of thrombin generation above 
the lower limit of the normal range at its EOB peak. 
 


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8.0 PHARMACOKINETIC ANALYSES 
For Part 1 of the study, the plasma concentration results will be summarized by Day (for FXa 
inhibitors) and Cohort using descriptive statistics (N, mean, SD, coefficient of variation (CV%), 
geometric mean, geometric CV%, median, Min, and Max) and presented for the Pharmacokinetic 
Population.  Individual Subject-level plasma concentration data will be listed. 
Noncompartmental PK analysis will be used for individual plasma concentration time values for 
all subjects. The andexanet dose used for this noncompartmental PK analysis will be the total 
(bolus plus infusion) dose administered to subjects. Descriptive statistics for all PK parameters 
determined this way will be presented by Cohort (N, mean, SD, coefficient of variation (CV%), 
geometric mean, geometric CV%, median, Min, and Max). The primary andexanet PK evaluation 
will be on the PK parameter of AUC(0-∞) based on the PK population.  Analysis of PK parameters 
for FXa inhibitors will use AUC(0-24) instead of AUC(0-last) or AUC(0-∞). 
For andexanet PK comparison between Japanese and Caucasian subjects, a two-sided 90% 
confidence interval will be calculated for the geometric mean ratio of the andexanet AUC(0-∞) 
between Cohorts 1 and 5, derived by exponentiating the limits of a 90% confidence interval for 
the mean difference of the log-transformed data based on an Analysis of Covariance (ANCOVA) 
model with race (Japanese vs. Caucasian) as a categorical variable and with and without body 
weight as a continuous covariate.  The limits of this confidence interval will be used to make 
preliminary assessments of the effect of race on the PK of andexanet.  A similar analysis will be 
performed for Cmax and AUC(0-last).  Values excluded from the pharmacokinetic analysis will be 
flagged and concentration values reported as below the level of quantification (BLQ) will be listed 
with the lower limit of quantification (LLQ) in parenthesis. 
BLQ values will be set to zero prior to calculation of descriptive statistics for plasma concentration 
except for the geometric mean calculation where the log value will be assumed to be 0.  Actual 
elapsed time from dosing will be used to estimate all individual plasma pharmacokinetic 
parameters.  


Portola Pharmaceuticals, Inc. 
5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
 
 
 
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9.0 SAFETY 
The following sections describe how the safety endpoints will be analyzed.  Safety analyses will 
be performed on the Safety Population. Safety analyses will be performed for the period during 
and after andexanet/placebo has been administered.  Subjects who received one or more doses of 
fXa inhibitor but discontinued prior to receiving study drug will be listed. 
9.1. 
Extent of Exposure 
The exposure of FXa inhibitor will be presented by cohort and treatment using summary statistics.  
Dosing information for each drug (andexanet or placebo) and each subject will be listed, including 
dose assigned and total dose received.  Interruptions or discontinuation of dosing will be listed by 
treatment received.  The primary reason for study drug discontinuation will also be summarized 
by treatment received. 
9.2. 
Adverse Events 
Treatment-Emergent Adverse Events (TEAEs) will be summarized by treatment, system organ 
class, and preferred term defined by the Medical Dictionary for Regulatory Activities (MedDRA, 
version 20.0 or later). Treatment-Emergent Adverse Events are defined as any adverse event that 
occurred or worsened after andexanet/placebo dosing. 
The number of events, the number of subjects, and the percentage of subjects who experienced at 
least one TEAE will be presented by cohort and treatment group.  TEAEs that are considered by 
the investigator to be related to study medication, TEAEs that lead to early withdrawals, and 
serious TEAEs will be summarized in the same manner. Number and percentage of subjects in 
various severity categories (mild, moderate, severe, life-threatening, and fatal) will also be 
presented by cohort and treatment group. 
The treatment groups will be compared in regards to safety endpoints descriptively.  No inferential 
comparison will be conducted.  
Besides the treatment emergent adverse events, an overall summary of pre-treatment adverse 
events, defined as those adverse events occurring after first dose of the FXa inhibitor but before 
exposure to andexanet or placebo., occurring on FXa inhibitor alone will also be provided for each 
cohort. 
9.3. 
Clinical Laboratory Assessments 
Clinical laboratory parameters including hematology, chemistry, urinalyses, will be summarized 
by cohort, treatment group and by time point.  
Clotting times (PT, aPTT, and ACT) will be summarized by cohort, treatment group and by time 
point. 


Portola Pharmaceuticals, Inc. 
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Andexanet Alfa 
 
 
 
 
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Coagulation markers (F1+2, TAT, D-dimer, TFPI activity, total TFPI, and free TFPI) will be 
summarized by cohort, treatment group and by time point, and presented graphically. 
Baseline values, the values at each subsequent visit, and changes from baseline will be summarized 
for each of the quantitative laboratory assessments by treatment.  
Hematology, chemistry and urinalysis values outside of normal ranges and/or with potential 
clinical importance (PCI) will be listed by subject, visit and treatment.  
The antibodies (anti-andexanet, anti-fX, anti-fXa, and/or neutralizing antibodies) will be 
summarized by visit and treatment. A listing for subjects will also be provided.  
9.4. 
Electrocardiogram (ECG) 
A resting supine 12-lead ECG will be conducted at the Screening Visit, prior to the first study 
treatment, and post study treatment visits, and the results will be evaluated by the Investigator.  
ECG parameters that will be summarized include: 
• Summary (mean) Heart Rate (beats per minute) 
• Summary (mean) RR Duration (msec) 
• Summary (mean) PR Duration (msec) 
• Summary (mean) QRS Duration (msec) 
• Summary (mean) QT Duration (msec) 
• QTcF—Fridericia’s Correction Formula 
 
 
The qualitative assessment of the overall ECG test results will be defined as: 
• Normal 
• Abnormal, not clinically significant  
• Abnormal, clinically significant 
• An outlier analysis will also be performed based on the proportion of subjects with 
treatment emergent values that meet the following criteria: 
− QTcF > 500 msec at any time point  
− QTcF increased by > 60 msec at any time point 
− PR > 220 msec at any time point 
 
 
These abnormal values will be flagged in the listings. 


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5.3.5.1 Study Reports of Controlled Clinical Studies 
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9.5. 
Vital Signs and Oxygen Saturation 
Vital signs include: 
• Respiratory Rate (breaths per minute) 
• Temperature (°F) 
• Systolic Blood Pressure (mm Hg) 
• Diastolic Blood Pressure (mm Hg) 
• Heart Rate (beats per minute) 
• Oxygen Saturation (%) 
 
An analysis of abnormal values will be performed based on the proportion of subjects with 
treatment emergent values that meet the following criteria: 
• SBP > 160 mmHg or < 90 mmHg 
• DBP > 95 mmHg or < 50 mmHg 
• HR < 45 or > 100 
• O2 Saturation < 92% 
 
These abnormal values will be flagged in the listings sorted by subject number and parameter.  All 
data (including unscheduled visits) will also be listed. 
9.6. 
Physical Examination 
Physical exam results will be presented in a listing that will be sorted, subject, parameter, and 
study visit. 
9.7. 
Venous Thromboembolism (VTE) 
Any report of VTE or pulmonary embolism from the Wells Score will be listed.  This listing will 
be sorted by subject number and relative day. 


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10.0 
ANALYSIS CONVENTIONS 
Post-text tables and listings will be prepared in accordance with the current ICH Guidelines [1].  
The information and explanatory notes to be provided in the “footer” or bottom of each table and 
listing will include the following information: 
1. Date and time of output generation. 
2. SAS program name, including the path that generates the output. 
3. Any other output specific details that require further elaboration. 
 
In general, tables will be formatted with a column displaying findings for all subjects combined.  
Row entries in tables are made only if data exists for at least one subject (i.e., a row with all zeros 
will not appear).  The only exception to this rule applies to tables that list the termination status of 
subjects (e.g., reasons for not completing the study).  In this case, zeros will appear for study 
termination reasons that no subject satisfied.  The summary tables clearly indicate the number of 
subjects to which the data apply and unknown or not performed are distinguished from missing 
data 
Supportive individual Subject Data Listings will be sorted and presented, subject number and visit 
date, if applicable.  Listings will also include the number of days relative to the initial exposure to 
the study drug, if applicable. 
Specific algorithms are discussed for imputing missing or partially missing dates, if deemed 
appropriate, under specific data topics.  Imputed or derived data are flagged in the individual 
subject data listings.  Imputed data will not be incorporated into any raw or primary datasets.  The 
imputed data will be retained in the derived/analysis datasets along with flags of imputations. 
The total duration for a subject on study will be calculated as the difference between the date of 
initial exposure to the study drug and the last day of observation plus one day.  All calculations for 
defining the duration on study will follow the algorithm: 
Duration = [Study Completion or Withdraw Date – Initial Drug Administration Date + 1].  
 
This section details general conventions to be used for the statistical analyses.  The following 
conventions will be applied to all data presentations and analyses: 
• Summary statistics will consist of the number and percentage of responses in each level for 
categorical variables, and the sample size (n) mean, median, standard deviation (SD), 
minimum, and maximum values for continuous variables. 
• All mean and median values will be formatted to one more decimal place than the measured 
value.  Standard deviation values will be formatted to two more decimal places than the 
measured value.  Minimum and maximum values will be presented with the same number 
of decimal places as the measured value. 


Portola Pharmaceuticals, Inc. 
5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
 
 
 
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Confidential 
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• The number and percentage of responses will be presented in the form XX (XX.X%). 
• If presented, p-values will be rounded to 4 decimal places.  All p-values that round to 0.000 
will be presented as ‘< 0.001’ and p-values that round to 1.00 will be presented as 
‘> 0.999’.  Probability values ≤ 0.05 will be considered to be statistically significant. 
• All summary tables will include the analysis population sample size (i.e., number of 
subjects). 
• Baseline values will be defined as those values recorded closest to, but prior to, the first 
study treatment on Day 6 (day of initiation of andexanet or placebo dosing). 
• Change from baseline will be calculated as follows:  
 
Change = Post-baseline value − baseline value 
• Date variables will be formatted as DDMMMYYYY for presentation. 
• SAS Version 9.3 [2] or higher will be the statistical software package used for all data 
analyses. 
• The cohort, study treatment, and subject number will be included in all data listings.  All 
listings will be sorted by study cohort, subject number, treatment, and visit date, as 
applicable. 


Portola Pharmaceuticals, Inc. 
5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
 
 
 
                                                                         Study 16-508 Appendix 16.1.9 
Confidential 
Final SAP version 1.0 
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11.0 
REFERENCES 
1. ICH E3: Structure and Content of Clinical Study Reports 
2.  SAS Institute Inc., SAS Version 9.3 software, Cary, NC. 
 


Portola Pharmaceuticals, Inc. 
5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
 
 
 
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12.0 
TABLES, LISTINGS, AND FIGURES 
(To be added after TLF Shells are completed.)