SAVAYSA

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 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, 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 ( 5.1 ). (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 ( 2.4 , 5.2 , 14 ). (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 paralysis. Consider these risks when scheduling patients for spinal procedures ( 5.4 ). 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 Administration (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 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 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 necessary [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) ] .

5 WARNINGS AND PRECAUTIONS Bleeding: Serious and potentially fatal bleeding. Promptly evaluate signs and symptoms of blood loss ( 5.3 ) Mechanical Heart Valves or Moderate to Severe Mitral Stenosis: Use is not recommended ( 5.5 ) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: SAVAYSA use not recommended. ( 5.6 ) 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 compared to patients treated with warfarin. In these patients another anticoagulant should be used [see Dosage and Administration (2.1) and 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 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) and Clinical Studies (14.1) ] . 5.3 Risk of Bleeding SAVAYSA increases the risk of bleeding and can cause serious and potentially 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 antithrombotic agents, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) [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 anticoagulant 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 anticoagulation 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 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 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 traumatic or repeated epidural or spinal puncture. 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. 5.5 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) ] . 5.6 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including SAVAYSA, are not recommended for use in patients with triple positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

6 ADVERSE REACTIONS The following clinically significant 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 Nonvalvular Atrial Fibrillation [see Warnings and Precautions (5.2) ] Risk of Bleeding [see Warnings and Precautions (5.3) ] Spinal/Epidural Anesthesia or Puncture [see Warnings and Precautions (5.4) ] 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. 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, Hokusai VTE, and Hokusai VTE Cancer studies including 11,530 patients exposed to SAVAYSA 60 mg and 7124 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 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. Event A subject can be included in multiple sub-categories if he/she had an event for those categories. SAVAYSA 60 mg 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. N = 5417 n (%/year) Warfarin N = 5485 n (%/year) SAVAYSA 60 mg vs. Warfarin HR (95% CI) Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, n = number of patients with events, N = number of patients in Safety population, Major Bleeding 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 compartment 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 transfusion = 1.0 g/dL drop in hemoglobin). 357 (3.1) 431 (3.7) 0.84 (0.73, 0.97) Intracranial Hemorrhage (ICH) ICH includes primary hemorrhagic stroke, subarachnoid hemorrhage, epidural/subdural hemorrhage, and ischemic stroke with major hemorrhagic conversion. 53 (0.5) 122 (1.0) 0.44 (0.32, 0.61) 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) Gastrointestinal Gastrointestinal (GI) bleeds include bleeding from upper and lower GI tract. Lower GI tract bleeding includes rectal bleeds. 205 (1.8) 150 (1.3) 1.40 (1.13, 1.73) Fatal Bleeding Fatal bleed is a bleeding event during the on-treatment period and adjudicated as leading directly to death within 7 days. 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) ---- 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 During or within 2 days of stopping study treatment SAVAYSA N = 5417 n (%/year) Warfarin N = 5485 n (%/year) Major Gastrointestinal (GI) Bleeding GI bleeding was defined by location as upper or lower GI 205 (1.78) 150 (1.27) Upper GI 123 (1.06) 88 (0.74) Lower GI Lower GI bleeding included anorectal bleeding 85 (0.73) 64 (0.54) GUSTO GUSTO – Severe or life-threatening bleeding that caused hemodynamic compromise and requires intervention Severe GI bleeding 16 (0.14) 17 (0.14) Fatal GI bleeding 1 (< 0.1) 2 (< 0.1) 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 following 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 During or within 2 days of stopping study treatment Study Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. 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. Figure 6.1 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 function 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 The safety of SAVAYSA in the treatment of VTE was assessed 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 major safety outcome 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 warfarin [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 (N = 4118) Warfarin (N = 4122) Abbreviations: N = number of patients in the modified intent-to-treat population; n = number of events; CRNM = clinically relevant non-major Clinically Relevant Bleeding Primary Safety Endpoint: Clinically Relevant Bleeding (composite of Major and CRNM). (Major/CRNM), n (%) 349 (8.5) 423 (10.3) Major Bleeding 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 syndrome, retroperitoneal; contributing to death. , 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 ≥ 2 g/dL 40 (1.0) 33 (0.8) Transfusion of ≥ 2 units of RBC 28 (0.7) 22 (0.5) CRNM Bleeding 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 cessation of study treatment, or associated with discomfort for the subject such as pain, or impairment of activities of daily life. 298 (7.2) 368 (8.9) Any Bleed 895 (21.7) 1056 (25.6) Patients with low body weight (≤ 60 kg), CrCL ≤ 50 mL/min, or concomitant 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 (N = 4118) n (%) Warfarin (N = 4122) n (%) Bleeding ADRs Adjudicated Any Bleeding by location for all bleeding event categories (including Major and CRNM) Vaginal Gender specific vaginal bleeding percentage is based on number of female subjects in each treatment group 158 (9) 126 (7.1) Cutaneous soft tissue 245 (5.9) 414 (10) 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) Bleeding in Patients with VTE in the Hokusai VTE Cancer Study The safety of SAVAYSA in patients with cancer and VTE was evaluated in the Hokusai VTE Cancer study [see Clinical Studies (14.2) ] . The median duration of SAVAYSA exposure was 211 days (range, 2 to 423). The safety outcome was major bleeding that occurred during or within three days of stopping study treatment. The incidence of major bleeding was higher in the SAVAYSA arm than in the dalteparin arm [HR (95% CI): 2.00 (1.09, 3.66)]. Table 6.5 presents the bleeding results from the Hokusai VTE Cancer study. Table 6.5: Bleeding Events in the Hokusai VTE Cancer Study SAVAYSA (N = 522) Dalteparin (N = 524) Abbreviations: N = number of patients in the modified intent-to-treat population; n = number of events; CRNM = clinically relevant non-major Major Bleeding 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 syndrome, retroperitoneal; contributing to death. , n (%) 32 (6.1%) 16 (3.1%) Fatal bleeding 1 (0.2%) All events in this table, except for the fatal bleeding event on SAVAYSA, are based on adjudicated events. The fatal bleeding event on SAVAYSA was adjudicated as a major bleed; however, the adjudicated cause of death was cancer-related death. 2 (0.4%) Intracranial 0 1 (0.2%) Lower gastrointestinal 1 (0.2%) 1 (0.2%) Non-fatal critical organ bleeding 5 (1%) 6 (1.1%) Intracranial bleeding 2 (0.4%) 2 (0.4%) Non-fatal non-critical organ bleeding 27 (5.2%) 8 (1.5%) Gastrointestinal 22 (4.2%) 4 (0.8%) Upper gastrointestinal 18 (3.4%) 3 (0.6%) Lower gastrointestinal 3 (0.6%) 1 (0.2%) Decrease in Hb ≥ 2 g/dL 28 (5.4%) 11 (2.1%) CRNM Bleeding 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 cessation of study treatment, or associated with discomfort for the subject such as pain or impairment of activities of daily life. , n (%) 70 (13.4%) 48 (9.2%) Any Bleeding, n (%) 137 (26.2%) 104 (19.8%) In patients with GI cancer at randomization, major bleeding occurred in 13.2% (18/136) in the SAVAYSA group and 2.4% (3/125) in the dalteparin group. In patients without GI cancer at randomization, major bleeding occurred in 3.6% (14/386) in the SAVAYSA group and 3.3% (13/399) in the dalteparin group. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SAVAYSA. 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: thrombocytopenia Gastrointestinal disorders: abdominal pain Immune system disorders: angioedema, hypersensitivity Nervous system disorders: dizziness, headache Renal and urinary disorders: anticoagulant-related nephropathy Skin and subcutaneous tissue disorders: urticaria

<table width="80%" ID="Table6.1"><caption>Table 6.1: Adjudicated Bleeding Events for NVAF Patients with CrCL &#x2264; 95 mL/min<footnote>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 &#x2264; 95 mL/min.</footnote></caption><col width="30%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" align="center">Event<footnote>A subject can be included in multiple sub-categories if he/she had an event for those categories.</footnote></th><th styleCode="Rrule">SAVAYSA 60 mg<footnote>Includes all patients with CrCL &#x2264; 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.</footnote> N = 5417 n (%/year)</th><th styleCode="Rrule">Warfarin N = 5485 n (%/year)</th><th styleCode="Rrule">SAVAYSA 60 mg vs. Warfarin HR (95% CI)</th></tr></thead><tfoot><tr><td align="left" colspan="4">Abbreviations: HR = Hazard Ratio versus Warfarin, CI = Confidence Interval, n = number of patients with events, N = number of patients in Safety population,</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Major Bleeding<footnote>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 compartment 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 transfusion = 1.0 g/dL drop in hemoglobin).</footnote></td><td styleCode="Rrule">357 (3.1)</td><td styleCode="Rrule">431 (3.7)</td><td styleCode="Rrule">0.84 (0.73, 0.97)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Intracranial Hemorrhage (ICH)<footnote>ICH includes primary hemorrhagic stroke, subarachnoid hemorrhage, epidural/subdural hemorrhage, and ischemic stroke with major hemorrhagic conversion.</footnote></td><td styleCode="Rrule">53 (0.5)</td><td styleCode="Rrule">122 (1.0)</td><td styleCode="Rrule">0.44 (0.32, 0.61)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hemorrhagic Stroke</td><td styleCode="Rrule">33 (0.3)</td><td styleCode="Rrule">69 (0.6)</td><td styleCode="Rrule">0.49 (0.32, 0.74)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Other ICH</td><td styleCode="Rrule">20 (0.2)</td><td styleCode="Rrule">55 (0.5)</td><td styleCode="Rrule">0.37 (0.22, 0.62)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Gastrointestinal<footnote>Gastrointestinal (GI) bleeds include bleeding from upper and lower GI tract. Lower GI tract bleeding includes rectal bleeds.</footnote></td><td styleCode="Rrule">205 (1.8)</td><td styleCode="Rrule">150 (1.3)</td><td styleCode="Rrule">1.40 (1.13, 1.73)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatal Bleeding<footnote>Fatal bleed is a bleeding event during the on-treatment period and adjudicated as leading directly to death within 7 days.</footnote></td><td styleCode="Rrule">21 (0.2)</td><td styleCode="Rrule">42 (0.4)</td><td styleCode="Rrule">0.51 (0.30, 0.86)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> ICH</td><td styleCode="Rrule">19 (0.2)</td><td styleCode="Rrule">36 (0.3)</td><td styleCode="Rrule">0.54 (0.31, 0.94)</td></tr><tr><td styleCode="Lrule Rrule"> Non-intracranial</td><td styleCode="Rrule">2 (&lt; 0.1)</td><td styleCode="Rrule">6 (&lt; 0.1)</td><td styleCode="Rrule">----</td></tr></tbody></table>

<table width="75%" ID="Table6.2"><caption>Table 6.2: Gastrointestinal Bleeding Events for NVAF Patients with CrCL &#x2264; 95 mL/min<footnote>During or within 2 days of stopping study treatment</footnote></caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">SAVAYSA N = 5417 n (%/year)</th><th styleCode="Rrule">Warfarin N = 5485 n (%/year)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Major Gastrointestinal (GI) Bleeding<footnote>GI bleeding was defined by location as upper or lower GI</footnote></td><td styleCode="Rrule">205 (1.78)</td><td styleCode="Rrule">150 (1.27)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Upper GI</td><td styleCode="Rrule">123 (1.06)</td><td styleCode="Rrule">88 (0.74)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Lower GI<footnote>Lower GI bleeding included anorectal bleeding</footnote></td><td styleCode="Rrule">85 (0.73)</td><td styleCode="Rrule">64 (0.54)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">GUSTO<footnote>GUSTO &#x2013; Severe or life-threatening bleeding that caused hemodynamic compromise and requires intervention</footnote> Severe GI bleeding</td><td styleCode="Rrule">16 (0.14)</td><td styleCode="Rrule">17 (0.14)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Fatal GI bleeding</td><td styleCode="Rrule">1 (&lt; 0.1)</td><td styleCode="Rrule">2 (&lt; 0.1)</td></tr></tbody></table>

<table width="100%" ID="fig6.1" styleCode="Noautorules"><col width="100%" align="left" valign="top"/><thead><tr><th>Figure 6.1: Adjudicated Major Bleeding in the ENGAGE AF-TIMI 48<footnote>During or within 2 days of stopping study treatment</footnote> Study</th></tr></thead><tfoot><tr><td align="left" valign="top">Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. 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.</td></tr></tfoot><tbody><tr><td><paragraph><renderMultiMedia referencedObject="MM1"/></paragraph></td></tr></tbody></table>