CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Nonvalvular Atrial Fibrillation. The ENGAGE AF-TIMI 48 StudyThe ENGAGE AF-TIMI 48 (NCT00781391) study was multi-national, double-blind, non-inferiority study comparing the efficacy and safety of two SAVAYSA treatment 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 warfarin 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 additional risk factors for stroke:a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or2 or more of the following risk factors:- age >= 75 years,- hypertension,- heart failure, or- diabetes mellitus total of 21,105 patients were randomized and followed for median of 2.8 years and treated for 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 present: 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 reduced dose at baseline, and an additional 7% were dose-reduced during the study. The most common reason for dose reduction was CrCL <= 50 mL/min at randomization (19% of patients).Patients were well balanced with respect to demographic and baseline characteristics. 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 Vitamin Antagonist (VKA) (i.e., never took VKA or had not taken VKA for more than months).The mean patient body weight was 84 kg (185 lbs) and 10% of patients had 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 thienopyridine.Patients randomized to the warfarin arm achieved 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 systemic embolic event (SEE) that occurred during treatment or within 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 numerically 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 < 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 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 TreatmentIncludes events during treatment or within days of stopping study treatment)EventsSAVAYSA30 mgIncludes patients dose-reduced to 15 mg for the 30 mg treatment group and 30 mg for the 60 mg treatment group (N 7002)n (%/yr)The event rate (%/yr) is calculated as number of events/subject-year exposure. SAVAYSA60 mg (N 7012)n (%/yr) Warfarin(N 7012)n (%/yr) SAVAYSA 30 mg vs. warfarinHR (CI)97.5% CI for primary endpoint of First Stroke or SEE. 95% CI for Ischemic Stroke, Hemorrhagic Stroke or Systemic Embolism p-valueSAVAYSA 60 mg vs. warfarinHR (CI) p-valueAbbreviations: HR Hazard Ratio versus Warfarin, CI Confidence Interval, = number of events, mITT Modified Intent-to-Treat, = number of patients in mITT population, SEE Systemic Embolic Event, yr year.First Stroke or SEE253 (1.6)182 (1.2)232 (1.5)1.07 (0.87, 1.31)p 0.440.79 (0.63, 0.99)p 0.017 Ischemic Stroke225 (1.4)135 (0.9)144 (0.9)1.54 (1.25, 1.90)0.94 (0.75, 1.19)Hemorrhagic Stroke18 (0.1)39 (0.3)75 (0.5)0.24 (0.14, 0.39)0.52 (0.36, 0.77)Systemic Embolism10 (< 0.1)8 (< 0.1)13 (< 0.1)0.75 (0.33, 1.72)0.62 (0.26, 1.50)Figure 14.1 is 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) (mITTOn-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 CrCL level <= 50 mL/min, low body weight <= 60 kg, or the concomitant use of P-gp inhibitor drug, was 1.79% per year. Patients with any of these characteristics 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% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of 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 strong relationship between the blood levels of edoxaban and its effectiveness in reducing the rate of ischemic stroke. There was 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 eliminated 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 compared to patients with CrCL of 50 to <= 80 mL/min. Given the clear relationship 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 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 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 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 levels, along with 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 Function of Baseline Creatinine Clearance (mITT Population, On-Treatment)STROKE TYPERenal Function SubgroupsRenal function subgroups are based on estimated creatinine clearance in mL/min calculated using the Cockcroft-Gault formula. Treatment Armn (N)Event Rate(%/yr)SAVAYSA 60 mg vs. Warfarin HR(95% CI)Abbreviations: HR Hazard Ratio versus Warfarin, CI Confidence Interval, = number of events, mITT Modified Intent-to-Treat, = number of patients in mITT population, yr year.PRIMARY ENDPOINT(STROKE/SEE)<= 95 (Indicated Population)Warfarin211 (5485)1.80.68 (0.55, 0.84)SAVAYSA 60 mg142 (5417)1.2 <= 5083% 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. Warfarin50 (1356)2.00.90 (0.60, 1.34)SAVAYSA 60 mg45 (1372)1.8 50 to <= 80 Warfarin135 (3053)2.00.53 (0.40, 0.70)SAVAYSA 60 mg71 (3020)1.1 80 to <= 95Warfarin26 (1076)1.01.05 (0.61, 1.82)SAVAYSA 60 mg26 (1025)1.1> 95See Boxed Warning Warfarin21 (1527)0.61.87 (1.10, 3.17)SAVAYSA 60 mg40 (1595)1.0ISCHEMIC STROKE<= 95 (Indicated Population)Warfarin129 (5485)1.10.80 (0.62, 1.04)SAVAYSA 60 mg102 (5417)0.9 <= 50 Warfarin28 (1356)1.11.11 (0.66, 1.84)SAVAYSA 60 mg31 (1372)1.2 50 to <= 80 Warfarin83 (3053)1.20.63 (0.44, 0.89)SAVAYSA 60 mg52 (3020)0.8 80 to <= 95Warfarin18 (1076)0.71.11 (0.58, 2.12)SAVAYSA 60 mg19 (1025)0.8> 95 Warfarin15 (1527)0.42.16 (1.17, 3.97)SAVAYSA 60 mg33 (1595)0.9HEMORRHAGIC STROKE<= 95 (Indicated Population)Warfarin70 (5485)0.60.50 (0.33, 0.75)SAVAYSA 60 mg34 (5417)0.3 <= 50 Warfarin18 (1356)0.70.66 (0.32, 1.36)SAVAYSA 60 mg12 (1372)0.5 50 to <= 80 Warfarin45 (3053)0.70.38 (0.22, 0.67)SAVAYSA 60 mg17 (3020)0.3 80 to <= 95Warfarin7 (1076)0.30.76 (0.24, 2.38)SAVAYSA 60 mg5 (1025)0.2> 95 Warfarin6 (1527)0.20.98 (0.31, 3.05)SAVAYSA 60 mg6 (1595)0.2. prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or. or more of the following risk factors:- age >= 75 years,- hypertension,- heart failure, or- diabetes mellitus - age >= 75 years,. hypertension,. heart failure, or. diabetes mellitus. Figure 14.1. Figure 14.2. Transition to Other Anticoagulants in the ENGAGE AF-TIMI 48 StudyIn 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 (0.2%) of 4529 patients had stroke or SEE compared to (0.2%) of 4506 patients in the warfarin arm.. 14.2Treatment 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 multi-national, double-blind study (Hokusai VTE) (NCT00986154) 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 days [median LMWH/heparin treatment in the SAVAYSA 60 mg group was 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 warfarin 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 concomitant 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, nelfinavir, 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 months up to 12 months, determined by investigator based on patient clinical features. Patients were excluded if they required thrombectomy, insertion of caval filter, use of fibrinolytic agent, or use of other P-gp inhibitors, had creatinine clearance 30 mL/min, significant liver disease, or active bleeding. The primary efficacy outcome was symptomatic VTE, defined as the composite 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 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 temporary risk factors only (e.g., trauma, surgery, immobilization, estrogen therapy). Overall 9.4% had history of cancer, 17.3% of the patients had an age >= 75 years and/or body weight <= 50 kg, and/or 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 = 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 EndpointSAVAYSAIncludes 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, = 733) and 30 (4.2%) of warfarin patients (n 719) had symptomatic recurrent VTE event n/N (%)Warfarinn/N (%)SAVAYSA vs. Warfarin HR (95% CI)Abbreviations: mITT modified intent-to-treat; HR =hazard ratio vs. warfarin; CI =confidence interval; = number of patients in mITT population; = number of eventsAll patients with symptomatic recurrent VTEPrimary Efficacy Endpoint: Symptomatic recurrent VTE (i.e., the composite endpoint of DVT, non-fatal PE and fatal PE) 130/4118 (3.2)146/4122 (3.5)0.89 (0.70,1.13) PE with or without DVT73/4118 (1.8)83/4122 (2.0)- Fatal PE and Death where PE cannot be ruled out24/4118 (0.6)24/4122 (0.6)- Non-fatal PE49/4118 (1.2)59/4122 (1.4)- DVT only57/4118 (1.4)63/4122 (1.5)-Index PEIndex PE refers to patients whose presenting diagnosis was PE (with or without concomitant DVT) patients with symptomatic recurrent VTE47/1650 (2.8)65/1669 (3.9)-Index DVTIndex DVT refers to patients whose presenting diagnosis was DVT only patients with symptomatic recurrent VTE83/2468 (3.4)81/2453 (3.3)-Figure 14.3:Kaplan-Meier Cumulative Event Rate Estimates for Adjudicated Recurrent VTE (mITT analysis on treatment). Figure 14.3. The Hokusai VTE Cancer StudyIn the Hokusai VTE Cancer study (NCT02073682), 1050 patients were randomized to receive SAVAYSA 60 mg once daily [30 mg dose reduced per the dose adjustment regimen used in Engage AF-TIMI 48 and Hokusai VTE studies, (see The Hokusai VTE Study )] after at least days of low-molecular-weight heparin treatment or dalteparin (200 IU/kg day 1-30; 150 IU/kg day 31 to the end of treatment). The treatment duration was for minimum of months and up to 12 months.The efficacy of SAVAYSA was based upon the rate of recurrent VTE (mITT) during the overall study period. SAVAYSA was non-inferior to dalteparin for the rate of recurrent VTE. Recurrent VTE occurred in 7.9% (41/522) and 11.3% (59/524) of patients in the SAVAYSA and dalteparin groups, respectively [HR (95% CI): 0.71 (0.48, 1.06)].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 StudyIn 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), < 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/minThe on-treatment period is during treatment or within 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 days of stopping study treatment and this table only includes patients with CrCL <= 95 mL/min. EventA subject can be included in multiple sub-categories if he/she had an event for those categories. SAVAYSA 60 mgIncludes 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. = 5417n (%/year)WarfarinN 5485n (%/year)SAVAYSA 60 mg vs. Warfarin HR (95% CI)Abbreviations: HR Hazard Ratio versus Warfarin, CI Confidence Interval, = number of patients with events, = number of patients in Safety population,Major BleedingA 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 critical site such as retroperitoneal, intracranial, intraocular, intraspinal, intra-articular, pericardial, or intramuscular with compartment syndrome; clinically overt bleeding event that caused fall in hemoglobin of at least 2.0 g/dL (or 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 Stroke33 (0.3)69 (0.6)0.49 (0.32, 0.74) Other ICH20 (0.2)55 (0.5)0.37 (0.22, 0.62) GastrointestinalGastrointestinal (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 BleedingFatal bleed is bleeding event during the on-treatment period and adjudicated as leading directly to death within days. 21 (0.2)42 (0.4)0.51 (0.30, 0.86) ICH19 (0.2)36 (0.3)0.54 (0.31, 0.94) Non-intracranial2 (< 0.1)6 (< 0.1)----The most common site of 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/minDuring or within days of stopping study treatment SAVAYSAN 5417n (%/year)WarfarinN 5485n (%/year)Major Gastrointestinal (GI) BleedingGI bleeding was defined by location as upper or lower GI 205 (1.78)150 (1.27) Upper GI123 (1.06)88 (0.74) Lower GILower GI bleeding included anorectal bleeding 85 (0.73)64 (0.54)GUSTOGUSTO Severe or life-threatening bleeding that caused hemodynamic compromise and requires intervention Severe GI bleeding16 (0.14)17 (0.14)Fatal GI bleeding1 (< 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 48During or within days of stopping study treatment StudyNote: 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 particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.. Figure 6.1. Other Adverse ReactionsThe 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 serious adverse event on treatment for SAVAYSA 60 mg and warfarin in 15 (0.2%) and (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 and fatal ILD cases in the SAVAYSA 60 mg and warfarin groups, respectively.. The Hokusai VTE StudyThe safety of SAVAYSA in the treatment of VTE was assessed in the Hokusai VTE study. The duration of drug exposure for SAVAYSA was <= 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 StudyThe 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); = 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 StudySAVAYSA(N 4118)Warfarin(N 4122)Abbreviations: = number of patients in the modified intent-to-treat population; = number of events; CRNM clinically relevant non-majorClinically Relevant BleedingPrimary Safety Endpoint: Clinically Relevant Bleeding (composite of Major and CRNM). (Major/CRNM), (%)349 (8.5)423 (10.3)Major BleedingA major bleeding event was defined as clinically overt bleeding that met one of the following criteria: associated with 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 critical site or organ: intracranial, intraspinal, intraocular, pericardial, intra- articular, intramuscular with compartment syndrome, retroperitoneal; contributing to death., (%)56 (1.4)66 (1.6) Fatal bleeding2 (<0.1)10 (0.2) Intracranial fatal0 (0.0)6 (0.1)Non-fatal critical organ bleeding13 (0.3)25 (0.6) Intracranial bleeding5 (0.1)12 (0.3)Non-fatal non-critical organ bleeding41 (1.0)33 (0.8)Decrease in Hb >= g/dL40 (1.0)33 (0.8)Transfusion of >= units of RBC28 (0.7)22 (0.5)CRNM BleedingCRNM bleeding was defined as overt bleeding not meeting the criteria for major bleeding event but that was associated with medical intervention, an unscheduled contact (visit or telephone call) with 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 Bleed895 (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 VTESAVAYSA 60 mg(N 4118)n (%)Warfarin(N 4122)n (%)Bleeding ADRsAdjudicated Any Bleeding by location for all bleeding event categories (including Major and CRNM) VaginalGender specific vaginal bleeding percentage is based on number of female subjects in each treatment group 158 (9)126 (7.1) Cutaneous soft tissue245 (5.9)414 (10) Epistaxis195 (4.7)237 (5.7) Gastrointestinal bleeding171 (4.2)150 (3.6) Lower gastrointestinal141 (3.4)126 (3.1) Oral/pharyngeal138 (3.4)162 (3.9) Macroscopic hematuria/urethral91 (2.2)117 (2.8) Puncture site56 (1.4)99 (2.4)Non-Bleeding ADRs Rash147 (3.6)151 (3.7) Abnormal liver function tests322 (7.8)322 (7.8) Anemia72 (1.7)55 (1.3). Bleeding in Patients with VTE in the Hokusai VTE Cancer StudyThe 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, 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 StudySAVAYSA(N 522)Dalteparin(N 524)Abbreviations: = number of patients in the modified intent-to-treat population; = number of events; CRNM clinically relevant non-majorMajor BleedingA major bleeding event was defined as clinically overt bleeding that met one of the following criteria: associated with 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 critical site or organ: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; contributing to death., (%)32 (6.1%)16 (3.1%)Fatal bleeding1 (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 major bleed; however, the adjudicated cause of death was cancer-related death. (0.4%) Intracranial01 (0.2%) Lower gastrointestinal1 (0.2%)1 (0.2%)Non-fatal critical organ bleeding5 (1%)6 (1.1%) Intracranial bleeding2 (0.4%)2 (0.4%)Non-fatal non-critical organ bleeding27 (5.2%)8 (1.5%) Gastrointestinal22 (4.2%)4 (0.8%) Upper gastrointestinal18 (3.4%)3 (0.6%) Lower gastrointestinal3 (0.6%)1 (0.2%)Decrease in Hb >= g/dL28 (5.4%)11 (2.1%)CRNM BleedingCRNM bleeding was defined as overt bleeding not meeting the criteria for major bleeding event but that was associated with medical intervention, an unscheduled contact (visit or telephone call) with physician, temporary cessation of study treatment, or associated with discomfort for the subject such as pain or impairment of activities of daily life., (%)70 (13.4%)48 (9.2%)Any Bleeding, (%)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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. SAVAYSA is contraindicated in patients with:Active pathological bleeding [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].. Active pathological bleeding [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].. Active pathological bleeding (4). Active pathological bleeding (4).

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of SAVAYSA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and lymphatic system disorders: thrombocytopeniaGastrointestinal disorders: abdominal painImmune system disorders: angioedema, hypersensitivityNervous system disorders: dizziness, headacheSkin and subcutaneous tissue disorders: urticaria.

ADVERSE REACTIONS SECTION.

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)] 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 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 StudyIn 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), < 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/minThe on-treatment period is during treatment or within 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 days of stopping study treatment and this table only includes patients with CrCL <= 95 mL/min. EventA subject can be included in multiple sub-categories if he/she had an event for those categories. SAVAYSA 60 mgIncludes 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. = 5417n (%/year)WarfarinN 5485n (%/year)SAVAYSA 60 mg vs. Warfarin HR (95% CI)Abbreviations: HR Hazard Ratio versus Warfarin, CI Confidence Interval, = number of patients with events, = number of patients in Safety population,Major BleedingA 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 critical site such as retroperitoneal, intracranial, intraocular, intraspinal, intra-articular, pericardial, or intramuscular with compartment syndrome; clinically overt bleeding event that caused fall in hemoglobin of at least 2.0 g/dL (or 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 Stroke33 (0.3)69 (0.6)0.49 (0.32, 0.74) Other ICH20 (0.2)55 (0.5)0.37 (0.22, 0.62) GastrointestinalGastrointestinal (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 BleedingFatal bleed is bleeding event during the on-treatment period and adjudicated as leading directly to death within days. 21 (0.2)42 (0.4)0.51 (0.30, 0.86) ICH19 (0.2)36 (0.3)0.54 (0.31, 0.94) Non-intracranial2 (< 0.1)6 (< 0.1)----The most common site of 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/minDuring or within days of stopping study treatment SAVAYSAN 5417n (%/year)WarfarinN 5485n (%/year)Major Gastrointestinal (GI) BleedingGI bleeding was defined by location as upper or lower GI 205 (1.78)150 (1.27) Upper GI123 (1.06)88 (0.74) Lower GILower GI bleeding included anorectal bleeding 85 (0.73)64 (0.54)GUSTOGUSTO Severe or life-threatening bleeding that caused hemodynamic compromise and requires intervention Severe GI bleeding16 (0.14)17 (0.14)Fatal GI bleeding1 (< 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 48During or within days of stopping study treatment StudyNote: 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 particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.. Figure 6.1. Other Adverse ReactionsThe 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 serious adverse event on treatment for SAVAYSA 60 mg and warfarin in 15 (0.2%) and (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 and fatal ILD cases in the SAVAYSA 60 mg and warfarin groups, respectively.. The Hokusai VTE StudyThe safety of SAVAYSA in the treatment of VTE was assessed in the Hokusai VTE study. The duration of drug exposure for SAVAYSA was <= 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 StudyThe 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); = 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 StudySAVAYSA(N 4118)Warfarin(N 4122)Abbreviations: = number of patients in the modified intent-to-treat population; = number of events; CRNM clinically relevant non-majorClinically Relevant BleedingPrimary Safety Endpoint: Clinically Relevant Bleeding (composite of Major and CRNM). (Major/CRNM), (%)349 (8.5)423 (10.3)Major BleedingA major bleeding event was defined as clinically overt bleeding that met one of the following criteria: associated with 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 critical site or organ: intracranial, intraspinal, intraocular, pericardial, intra- articular, intramuscular with compartment syndrome, retroperitoneal; contributing to death., (%)56 (1.4)66 (1.6) Fatal bleeding2 (<0.1)10 (0.2) Intracranial fatal0 (0.0)6 (0.1)Non-fatal critical organ bleeding13 (0.3)25 (0.6) Intracranial bleeding5 (0.1)12 (0.3)Non-fatal non-critical organ bleeding41 (1.0)33 (0.8)Decrease in Hb >= g/dL40 (1.0)33 (0.8)Transfusion of >= units of RBC28 (0.7)22 (0.5)CRNM BleedingCRNM bleeding was defined as overt bleeding not meeting the criteria for major bleeding event but that was associated with medical intervention, an unscheduled contact (visit or telephone call) with 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 Bleed895 (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 VTESAVAYSA 60 mg(N 4118)n (%)Warfarin(N 4122)n (%)Bleeding ADRsAdjudicated Any Bleeding by location for all bleeding event categories (including Major and CRNM) VaginalGender specific vaginal bleeding percentage is based on number of female subjects in each treatment group 158 (9)126 (7.1) Cutaneous soft tissue245 (5.9)414 (10) Epistaxis195 (4.7)237 (5.7) Gastrointestinal bleeding171 (4.2)150 (3.6) Lower gastrointestinal141 (3.4)126 (3.1) Oral/pharyngeal138 (3.4)162 (3.9) Macroscopic hematuria/urethral91 (2.2)117 (2.8) Puncture site56 (1.4)99 (2.4)Non-Bleeding ADRs Rash147 (3.6)151 (3.7) Abnormal liver function tests322 (7.8)322 (7.8) Anemia72 (1.7)55 (1.3). Bleeding in Patients with VTE in the Hokusai VTE Cancer StudyThe 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, 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 StudySAVAYSA(N 522)Dalteparin(N 524)Abbreviations: = number of patients in the modified intent-to-treat population; = number of events; CRNM clinically relevant non-majorMajor BleedingA major bleeding event was defined as clinically overt bleeding that met one of the following criteria: associated with 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 critical site or organ: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; contributing to death., (%)32 (6.1%)16 (3.1%)Fatal bleeding1 (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 major bleed; however, the adjudicated cause of death was cancer-related death. (0.4%) Intracranial01 (0.2%) Lower gastrointestinal1 (0.2%)1 (0.2%)Non-fatal critical organ bleeding5 (1%)6 (1.1%) Intracranial bleeding2 (0.4%)2 (0.4%)Non-fatal non-critical organ bleeding27 (5.2%)8 (1.5%) Gastrointestinal22 (4.2%)4 (0.8%) Upper gastrointestinal18 (3.4%)3 (0.6%) Lower gastrointestinal3 (0.6%)1 (0.2%)Decrease in Hb >= g/dL28 (5.4%)11 (2.1%)CRNM BleedingCRNM bleeding was defined as overt bleeding not meeting the criteria for major bleeding event but that was associated with medical intervention, an unscheduled contact (visit or telephone call) with physician, temporary cessation of study treatment, or associated with discomfort for the subject such as pain or impairment of activities of daily life., (%)70 (13.4%)48 (9.2%)Any Bleeding, (%)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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and lymphatic system disorders: thrombocytopeniaGastrointestinal disorders: abdominal painImmune system disorders: angioedema, hypersensitivityNervous system disorders: dizziness, headacheSkin and subcutaneous tissue disorders: urticaria.

BOXED WARNING SECTION.

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 HEMATOMASee 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 reason other than pathological bleeding or completion of 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/MINSAVAYSA 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 reason other than pathological bleeding or completion of 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 HEMATOMAEpidural 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 cathetersconcomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulantsa history of traumatic or repeated epidural or spinal puncturesa history of spinal deformity or spinal surgeryoptimal 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)].. use of indwelling epidural catheters. concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants. history of traumatic or repeated epidural or spinal punctures. history of spinal deformity or spinal surgery. optimal timing between the administration of SAVAYSA and neuraxial procedures is not known.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 and times, respectively, the human exposure (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 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 bacterial reverse mutation (Ames test), in in vitro human lymphocytes micronucleus 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Edoxaban is 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 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 high degree of variability and not useful in monitoring the anticoagulant effect of edoxaban. Following oral administration, peak pharmacodynamic effects are observed within 1-2 hours, which correspond with peak edoxaban concentrations (Cmax).. Cardiac ElectrophysiologyIn 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 SAVAYSAThere is no systematic evaluation of bleeding reversal by 4-factor prothrombin complex concentrate (PCC) products in patients who have received SAVAYSA. Effects of PCC (50 IU/kg) on the pharmacodynamics of edoxaban were studied in healthy subjects following punch biopsy. Following administration of single dose of edoxaban, endogenous thrombin potential (ETP) returned to pre-edoxaban baseline levels in 0.5 hours after the initiation of 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. AspirinCo-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.. AbsorptionFollowing 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.Administration of crushed 60 mg tablet, either mixed into applesauce or suspended in water and given through nasogastric tube, showed similar exposure compared to administration of an intact tablet.. DistributionDisposition is biphasic. The steady-state volume of distribution (Vdss) is 107 (19.9) [mean (SD)]. In vitro plasma protein binding is approximately 55%. There is no clinically relevant accumulation of edoxaban (accumulation ratio 1.14) with once daily dosing.Steady-state concentrations are achieved within days.. MetabolismUnchanged 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 compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.. EliminationEdoxaban is eliminated primarily as unchanged drug in the urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance 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 ImpairmentIn dedicated pharmacokinetic study, patients with mild or moderate hepatic impairment (classified as Child-Pugh 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 ImpairmentIn 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)].. HemodialysisA 4-hour hemodialysis session reduced total edoxaban exposure by less than 7%.. AgeIn population pharmacokinetic analysis, after taking renal function and body weight into account, age had no additional clinically significant effect on edoxaban pharmacokinetics.. WeightIn 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). GenderIn population pharmacokinetic analysis, after accounting for body weight, gender had no additional clinically significant effect on edoxaban pharmacokinetics.. RaceIn population pharmacokinetic analysis, edoxaban exposures in Asian patients and non-Asian patients were similar.. Drug Interactions In vitro Drug Interactions StudiesIn 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 substrate of P-gp transporter.. Impact of Other Drugs on SAVAYSAThe 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. Figure 12.1. Impact of Edoxaban on Other DrugsEdoxaban 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.

DESCRIPTION SECTION.

11 DESCRIPTION. Edoxaban, factor Xa inhibitor, is supplied as edoxaban tosylate monohydrate. 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-methylbenzenesulfonate) monohydrate. Edoxaban tosylate monohydrate has the empirical formula C24H30ClN7O4SC7H8O3SH2O representing molecular weight of 738.27. The chemical structure of edoxaban tosylate monohydrate is:It is white to pale yellowish-white crystalline powder. The solubility of edoxaban tosylate (pKa 6.7) decreases with increasing pH. It is slightly soluble in water, pH to buffer, very slightly soluble at pH to 7; and practically insoluble at pH to 9.SAVAYSA is available for oral administration as 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 monohydrate 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).. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

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)Reduce dose to 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). 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)Reduce dose to 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). 2.1 Nonvalvular Atrial Fibrillation. The recommended dose of SAVAYSA is 60 mg taken orally once daily [see Warnings and Precautions (5.1) and Clinical Studies (14.1)]. Assess creatinine clearance, as calculated using the Cockcroft-Gault equationCockcroft-Gault CrCL (140-age) (weight in kg) (0.85 if female) (72 creatinine in mg/dL)., before initiating 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 Pharmacology (12.3)].. 2.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism. The recommended dose of SAVAYSA is 60 mg taken orally once daily following to 10 days of initial therapy with parenteral anticoagulant [see Clinical Studies (14.2)].Reduce SAVAYSA dose to 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 [see Clinical Studies (14.2)].. 2.3Administration Information. If dose of SAVAYSA is missed, the dose should be taken as soon as possible 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 missed dose.SAVAYSA can be taken without regard to food [see Clinical Pharmacology (12.3)].. 2.4Transition to or from SAVAYSA. Transition to SAVAYSAFromToRecommendationWarfarin or other Vitamin AntagonistsSAVAYSADiscontinue warfarin and start SAVAYSA when the INR is <= 2.5Oral anticoagulants other than warfarin or other Vitamin AntagonistsSAVAYSADiscontinue current oral anticoagulant and start SAVAYSA at the time of the next scheduled dose of the other oral anticoagulantLow Molecular Weight Heparin (LMWH)SAVAYSADiscontinue LMWH and start SAVAYSA at the time of the next scheduled administration of LMWHUnfractionated heparinSAVAYSADiscontinue the infusion and start SAVAYSA hours laterTransition from SAVAYSAFromToRecommendationAbbreviations: INR=International Normalized RatioSAVAYSAWarfarinOral 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 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 stable INR >= 2.0 is achieved, SAVAYSA should be discontinued and the warfarin continuedSAVAYSAWarfarinParenteral option: Discontinue SAVAYSA and administer parenteral anticoagulant and warfarin at the time of the next scheduled SAVAYSA dose. Once stable INR >= 2.0 is achieved the parenteral anticoagulant should be discontinued and the warfarin continuedSAVAYSANon-Vitamin-K-Dependent Oral anticoagulantsDiscontinue SAVAYSA and start the other oral anticoagulant at the time of the next dose of SAVAYSASAVAYSAParenteral anticoagulantsDiscontinue SAVAYSA and start the parenteral anticoagulant at the time of the next dose of SAVAYSA. 2.5Discontinuation for Surgery and Other Interventions. Discontinue SAVAYSA at least 24 hours before invasive or surgical procedures 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 parenteral anticoagulant and then switch to oral SAVAYSA, if oral medication cannot be taken during or after surgical intervention.. 2.6Administration Options. For patients who are unable to swallow whole tablets, SAVAYSA tablets may be crushed and mixed with to ounces of water and immediately administered by mouth or through gastric tube. The crushed tablets may also be mixed into applesauce and immediately administered orally [see Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 60 mg, yellow round shaped, film-coated tablets, debossed with DSC L60 on one side30 mg, pink round shaped, film-coated tablets, debossed with DSC L30 on one side15 mg, orange round shaped, film-coated tablets, debossed with DSC L15 on one side. 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. Tablets: 60 mg, 30 mg, and 15 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Anticoagulants, Antiplatelets, Thrombolytics, and Selective Serotonin Reuptake Inhibitors (SSRIs)/Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): Avoid concomitant use due to increased risk of bleeding. (7.1)Rifampin: Avoid concomitant use (7.2). Anticoagulants, Antiplatelets, Thrombolytics, and Selective Serotonin Reuptake Inhibitors (SSRIs)/Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): Avoid concomitant use due to increased risk of bleeding. (7.1). Rifampin: Avoid concomitant use (7.2). 7.1Anticoagulants, Antiplatelets, Thrombolytics, and SSRIs/SNRIs. Co-administration of anticoagulants, antiplatelet drugs, thrombolytics and SSRIs or SNRIs may increase the risk of bleeding. Promptly evaluate any signs or symptoms 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 Pharmacology (12.3)].As with other anticoagulants the possibility may exist that patients are at an increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets [see Warnings and Precautions (5.3)]. 7.2P-gp Inducers. Avoid the concomitant use of SAVAYSA with rifampin [see Clinical Pharmacology (12.3)].. 7.3P-gp Inhibitors. Treatment of NVAFBased 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 concomitant P-gp inhibitor use [see Dosage and Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].. Treatment of Deep Vein Thrombosis and Pulmonary Embolism[see Clinical Studies (14.2)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including SAVAYSA should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

GERIATRIC USE SECTION.

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 the Hokusai VTE Cancer Study, 539 (52%) patients were 65 years and older and 176 (17%) 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)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. The use of SAVAYSA in patients with moderate or severe hepatic impairment (Child-Pugh 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 Pharmacology (12.3)].

HOW SUPPLIED SECTION.

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-yyStrengthColorDebossyyxxxBottle ofBlister of 309050010 1010 blister cards of 10 counts 10 55 blister cards of 10 counts 15 mgorangeDSC L1520130----30 mgpinkDSC L30202309050100560 mgyellowDSC L602033090501005. Store at 20-25C (68-77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].Keep out of the reach of children.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. SAVAYSA is factor Xa inhibitor indicated:To reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF) (1.1)Limitation of Use for NVAFSAVAYSA 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 to 10 days of initial therapy with parenteral anticoagulant (1.2). Limitation of Use for NVAFSAVAYSA 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). 1.1Reduction 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 NVAFSAVAYSA 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) and Clinical Studies (14.1)].. 1.2Treatment of Deep Vein Thrombosis and Pulmonary Embolism. SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following to 10 days of initial therapy with parenteral anticoagulant.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Advise patients of the following:. Instructions for Patient UseAdvise patients to take SAVAYSA exactly as prescribed.Remind patients to not discontinue SAVAYSA without talking to the healthcare provider who prescribed it.Instruct patients to keep an adequate supply of tablets to ensure continuous dosing of SAVAYSA.Instruct patients who cannot swallow the tablet whole to crush SAVAYSA, combine with to ounces of water or applesauce and ingest immediately.Instruct patients who require gastric tube to crush the SAVAYSA tablet and mix it with to ounces of water before administering immediately via the gastric feeding tube.Inform patients that if dose is missed, they should 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 missing dose.. Advise patients to take SAVAYSA exactly as prescribed.. Remind patients to not discontinue SAVAYSA without talking to the healthcare provider who prescribed it.. Instruct patients to keep an adequate supply of tablets to ensure continuous dosing of SAVAYSA.. Instruct patients who cannot swallow the tablet whole to crush SAVAYSA, combine with to ounces of water or applesauce and ingest immediately.. Instruct patients who require gastric tube to crush the SAVAYSA tablet and mix it with to ounces of water before administering immediately via the gastric feeding tube.. Inform patients that if dose is missed, they should 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 missing dose.. Bleeding RiskAdvise patients that they may bleed more easily, may bleed longer, or bruise more easily when treated with SAVAYSA.Instruct patients to report any unusual bleeding immediately to their healthcare provider.For patients that 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 symptoms occur, advise the patient to contact his or her physician immediately [see Boxed Warning]. Advise patients that they may bleed more easily, may bleed longer, or bruise more easily when treated with SAVAYSA.. Instruct patients to report any unusual bleeding immediately to their healthcare provider.. For patients that 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 symptoms occur, advise the patient to contact his or her physician immediately [see Boxed Warning]. Invasive or Surgical ProceduresRemind patients to inform their healthcare providers that they are taking SAVAYSA before any surgery, medical, or dental procedure is scheduled.. Remind patients to inform their healthcare providers that they are taking SAVAYSA before any surgery, medical, or dental procedure is scheduled.. Concomitant Medication and HerbalsRemind patients 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.. Remind patients 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.. PregnancyRemind patients to inform their healthcare provider immediately if they become pregnant or intend to become pregnant during treatment with SAVAYSA.Inform patients to not breastfeed if they are taking SAVAYSA [see Use in Specific Populations (8.2)]. Remind patients to inform their healthcare provider immediately if they become pregnant or intend to become pregnant during treatment with SAVAYSA.. Inform patients to not breastfeed if they are taking SAVAYSA [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of edoxaban in human milk, or its effects on the breastfeeding infant or on milk production. Edoxaban was present in rat milk. Because of the potential for serious adverse reactions in nursing infants, including hemorrhage, advise patients that breastfeeding is not recommended during treatment with SAVAYSA.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Edoxaban is 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.

NONCLINICAL TOXICOLOGY SECTION.

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 and times, respectively, the human exposure (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 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 bacterial reverse mutation (Ames test), in in vitro human lymphocytes micronucleus 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).

OVERDOSAGE SECTION.

10 OVERDOSAGE. 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)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 65597-201-30Savaysa(edoxaban) tablets15 mg30 TABLETSRx OnlyPRINCIPAL DISPLAY PANELNDC 65597-202-30Savaysa(edoxaban) tablets30 mg30 TABLETSRx OnlyPRINCIPAL DISPLAY PANELNDC 65597-202-05Savaysa(edoxaban) tablets30 mgPackage contains blister packs of 10 tablets eachRx OnlyPRINCIPAL DISPLAY PANELNDC 65597-203-30Savaysa(edoxaban) tablets60 mg30 TABLETSRx OnlyPRINCIPAL DISPLAY PANELNDC 65597-203-90Savaysa(edoxaban) tablets60 mg90 TABLETSRx OnlyPRINCIPAL DISPLAY PANELNDC 65597-203-05Savaysa(edoxaban) tablets60 mgPackage contains blister packs of 10 tablets eachRx Only. PRINCIPAL DISPLAY PANEL NDC 65597-201-30 Savaysa (edoxaban) tablets 15 mg 30 TABLETS Rx Only. PRINCIPAL DISPLAY PANEL NDC 65597-202-30 Savaysa (edoxaban) tablets 30 mg 30 TABLETS Rx Only. PRINCIPAL DISPLAY PANEL NDC 65597-202-05 Savaysa (edoxaban) tablets 30 mg Package contains blister packs of 10 tablets each Rx Only. PRINCIPAL DISPLAY PANEL NDC 65597-203-30 Savaysa (edoxaban) tablets 60 mg 30 TABLETS Rx Only. PRINCIPAL DISPLAY PANEL NDC 65597-203-90 Savaysa (edoxaban) tablets 60 mg 90 TABLETS Rx Only. PRINCIPAL DISPLAY PANEL NDC 65597-203-05 Savaysa (edoxaban) tablets 60 mg Package contains blister packs of 10 tablets each Rx Only.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. As 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 high degree of variability and not useful in monitoring the anticoagulant effect of edoxaban. Following oral administration, peak pharmacodynamic effects are observed within 1-2 hours, which correspond with peak edoxaban concentrations (Cmax).. Cardiac ElectrophysiologyIn 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 SAVAYSAThere is no systematic evaluation of bleeding reversal by 4-factor prothrombin complex concentrate (PCC) products in patients who have received SAVAYSA. Effects of PCC (50 IU/kg) on the pharmacodynamics of edoxaban were studied in healthy subjects following punch biopsy. Following administration of single dose of edoxaban, endogenous thrombin potential (ETP) returned to pre-edoxaban baseline levels in 0.5 hours after the initiation of 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. AspirinCo-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.

PHARMACOKINETICS SECTION.

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.. AbsorptionFollowing 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.Administration of crushed 60 mg tablet, either mixed into applesauce or suspended in water and given through nasogastric tube, showed similar exposure compared to administration of an intact tablet.. DistributionDisposition is biphasic. The steady-state volume of distribution (Vdss) is 107 (19.9) [mean (SD)]. In vitro plasma protein binding is approximately 55%. There is no clinically relevant accumulation of edoxaban (accumulation ratio 1.14) with once daily dosing.Steady-state concentrations are achieved within days.. MetabolismUnchanged 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 compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.. EliminationEdoxaban is eliminated primarily as unchanged drug in the urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance 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 ImpairmentIn dedicated pharmacokinetic study, patients with mild or moderate hepatic impairment (classified as Child-Pugh 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 ImpairmentIn 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)].. HemodialysisA 4-hour hemodialysis session reduced total edoxaban exposure by less than 7%.. AgeIn population pharmacokinetic analysis, after taking renal function and body weight into account, age had no additional clinically significant effect on edoxaban pharmacokinetics.. WeightIn 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). GenderIn population pharmacokinetic analysis, after accounting for body weight, gender had no additional clinically significant effect on edoxaban pharmacokinetics.. RaceIn population pharmacokinetic analysis, edoxaban exposures in Asian patients and non-Asian patients were similar.. Drug Interactions In vitro Drug Interactions StudiesIn 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 substrate of P-gp transporter.. Impact of Other Drugs on SAVAYSAThe 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. Figure 12.1. Impact of Edoxaban on Other DrugsEdoxaban 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data about SAVAYSA use in pregnant women are insufficient to determine whether there are drug-associated risks for adverse developmental outcomes. In animal developmental studies, no adverse developmental effects were seen when edoxaban was administered orally to pregnant rats and rabbits during organogenesis at up to 16-times and 8-times, respectively, the human exposure, when based on body surface area and AUC, respectively (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskPregnancy confers an increased risk of thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data describe that women with previous history of venous thrombosis are at high risk for recurrence during pregnancy.. Fetal/Neonatal adverse reactionsUse of anticoagulants, including edoxaban, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding [see Warnings and Precautions (5.3)].. Labor or deliveryAll patients receiving anticoagulants, including pregnant women, are at risk for bleeding. SAVAYSA use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of shorter acting anticoagulant as delivery approaches [see Warnings and Precautions (5.3)].. Data. Animal DataEmbryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no malformation was 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 malformation was seen at doses up to 600 mg/kg/day (49 times the human exposure at 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 rat pre- and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day, which is up to times the human exposure when based on AUC. Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome (5.6)04/2020.

RENAL IMPAIRMENT SUBSECTION.

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 function. 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 clearance [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)].

SPL MEDGUIDE SECTION.

MEDICATION GUIDESAVAYSA (sa vaye sah)(edoxaban) tabletsThis Medication Guide has been approved by the U.S. Food and Drug Administration.Revised.: 09/2021 What is the most important information should know about SAVAYSAFor people who take SAVAYSA for nonvalvular atrial fibrillation (a type of irregular heartbeat):People with nonvalvular atrial fibrillation are at an increased risk of forming blood clot in the heart, which can travel to the brain, causing stroke, or to other parts of the body. SAVAYSA reduces your risk of having 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 stroke.SAVAYSA can cause bleeding which can be serious, and sometimes lead to death. This is because SAVAYSA is blood thinner medicine that reduces blood clotting. During treatment with SAVAYSA, you may bleed more easily, bleed longer, or bruise more easily. 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 higher risk of bleeding if you take SAVAYSA and take other medicines that increase your risk of bleeding, including:aspirin or aspirin containing productslong-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 clotsTell 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.Spinal or epidural blood clots (hematoma). People who take blood thinner medicine (anticoagulant) like SAVAYSA, and have medicine injected into their spinal and epidural area, or have spinal puncture have risk of forming blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing spinal or epidural blood clot is higher if:a thin tube called an epidural catheter is placed in your back to give you certain medicineyou take NSAIDs or medicine to prevent blood from clottingyou have history of difficult or repeated epidural or spinal puncturesyou have history of problems with your spine or have had surgery on your spine.If you take SAVAYSA and receive spinal anesthesia or have 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, or loss of control of the bowels or bladder (incontinence).SAVAYSA is not for people with mechanical heart valves or people who have moderate to severe narrowing (stenosis) of their mitral valve.SAVAYSA is not for use in people with antiphospholipid syndrome (APS), especially with positive triple antibody testing, who have history of blood clots.See What are the possible side effects of SAVAYSA for more information about side effects.What is SAVAYSASAVAYSA is prescription medicine used to: reduce the risk of stroke and blood clots in people who have atrial fibrillation not caused by 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 to 10 days.It is not known if SAVAYSA is safe and effective in children.Who should not take SAVAYSADo not take SAVAYSA if you currently have certain types of abnormal bleeding.Before taking SAVAYSA, tell your doctor about all of your medical conditions, including if you:have liver or kidney problemshave antiphospholipid syndromehave ever had bleeding problemshave mechanical heart valvehave cancer of the stomach or intestine (gastrointestinal cancer) 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. Females who are able to become pregnant: Talk with your healthcare provider about pregnancy planning during treatment with SAVAYSA. Talk with your healthcare provider about your risk for severe uterine bleeding if you are treated with blood thinner medicines, including SAVAYSA.are breastfeeding or plan to breastfeed. It is not known if SAVAYSA passes into your breast milk. Do not breastfeed during treatment with SAVAYSA.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 should know about SAVAYSA Know the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.How should take SAVAYSATake 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 nonvalvular atrial fibrillation, stopping SAVAYSA may increase your risk of having stroke. Take SAVAYSA with or without food.If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take SAVAYSA. If you miss 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 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 SAVAYSASAVAYSA can cause serious side effects. See What is the most important information should know about SAVAYSAThe most common side effects in people who take SAVAYSA for nonvalvular atrial fibrillation include bleeding and low red blood cell count (anemia). The most common side effects in people who take SAVAYSA for deep vein thrombosis and pulmonary embolism include, bleeding, rash, abnormal liver function tests and low red blood cell count (anemia).Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store SAVAYSAStore SAVAYSA at room temperature between 68F to 77F (20C to 25C).Keep SAVAYSA and all medicines out of the reach of children.General information about the safe and effective use of SAVAYSAMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use SAVAYSA for 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. You can ask your pharmacist or doctor for information about SAVAYSA that is written for health professionals.What are the ingredients in SAVAYSAActive 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 (60 mg tablets and 15 mg tablets), and iron oxide red (30 mg tablets and 15 mg tablets). Manufactured by: Daiichi Sankyo Co., LTD., Tokyo 103-8426, Japan Distributed by: Daiichi Sankyo, Inc., Basking Ridge, NJ 07920-2311 USAThe brands listed above are trademarks of their respective owners.Copyright(C) 2021, Daiichi Sankyo, Inc.USMG-SAV-C8-0921-r102For more information, call 1-877-437-7763 or go to https://savaysa.com/.. For people who take SAVAYSA for nonvalvular atrial fibrillation (a type of irregular heartbeat):People with nonvalvular atrial fibrillation are at an increased risk of forming blood clot in the heart, which can travel to the brain, causing stroke, or to other parts of the body. SAVAYSA reduces your risk of having 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 stroke.. 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 stroke.. SAVAYSA can cause bleeding which can be serious, and sometimes lead to death. This is because SAVAYSA is blood thinner medicine that reduces blood clotting. During treatment with SAVAYSA, you may bleed more easily, bleed longer, or bruise more easily. 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 higher risk of bleeding if you take SAVAYSA and take other medicines that increase your risk of bleeding, including:aspirin or aspirin containing productslong-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 clotsTell 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.. 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 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. Spinal or epidural blood clots (hematoma). People who take blood thinner medicine (anticoagulant) like SAVAYSA, and have medicine injected into their spinal and epidural area, or have spinal puncture have risk of forming blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing spinal or epidural blood clot is higher if:a thin tube called an epidural catheter is placed in your back to give you certain medicineyou take NSAIDs or medicine to prevent blood from clottingyou have history of difficult or repeated epidural or spinal puncturesyou have history of problems with your spine or have had surgery on your spine.If you take SAVAYSA and receive spinal anesthesia or have 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, or loss of control of the bowels or bladder (incontinence).. thin tube called an epidural catheter is placed in your back to give you certain medicine. you take NSAIDs or medicine to prevent blood from clotting. you have history of difficult or repeated epidural or spinal punctures. you have history of problems with your spine or have had surgery on your spine.. SAVAYSA is not for people with mechanical heart valves or people who have moderate to severe narrowing (stenosis) of their mitral valve.. SAVAYSA is not for use in people with antiphospholipid syndrome (APS), especially with positive triple antibody testing, who have history of blood clots.. reduce the risk of stroke and blood clots in people who have atrial fibrillation not caused by 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 to 10 days.. have liver or kidney problems. have antiphospholipid syndrome. have ever had bleeding problems. have mechanical heart valve. have cancer of the stomach or intestine (gastrointestinal cancer) 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. Females who are able to become pregnant: Talk with your healthcare provider about pregnancy planning during treatment with SAVAYSA. Talk with your healthcare provider about your risk for severe uterine bleeding if you are treated with blood thinner medicines, including SAVAYSA.. are breastfeeding or plan to breastfeed. It is not known if SAVAYSA passes into your breast milk. Do not breastfeed during treatment with 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 nonvalvular atrial fibrillation, stopping SAVAYSA may increase your risk of having stroke. Take SAVAYSA with or without food.. If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take SAVAYSA. If you miss 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 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.. Store SAVAYSA at room temperature between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

A.REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION PATIENTS WITH CRCL 95 ML/MINSAVAYSA 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)].

STORAGE AND HANDLING SECTION.

Store at 20-25C (68-77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].Keep out of the reach of children.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2)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). Lactation: Advise not to breastfeed. (8.2). 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). 8.1 Pregnancy. Risk SummaryAvailable data about SAVAYSA use in pregnant women are insufficient to determine whether there are drug-associated risks for adverse developmental outcomes. In animal developmental studies, no adverse developmental effects were seen when edoxaban was administered orally to pregnant rats and rabbits during organogenesis at up to 16-times and 8-times, respectively, the human exposure, when based on body surface area and AUC, respectively (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskPregnancy confers an increased risk of thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data describe that women with previous history of venous thrombosis are at high risk for recurrence during pregnancy.. Fetal/Neonatal adverse reactionsUse of anticoagulants, including edoxaban, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding [see Warnings and Precautions (5.3)].. Labor or deliveryAll patients receiving anticoagulants, including pregnant women, are at risk for bleeding. SAVAYSA use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of shorter acting anticoagulant as delivery approaches [see Warnings and Precautions (5.3)].. Data. Animal DataEmbryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no malformation was 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 malformation was seen at doses up to 600 mg/kg/day (49 times the human exposure at 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 rat pre- and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day, which is up to times the human exposure when based on AUC. Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day. 8.2 Lactation. Risk SummaryThere are no data on the presence of edoxaban in human milk, or its effects on the breastfeeding infant or on milk production. Edoxaban was present in rat milk. Because of the potential for serious adverse reactions in nursing infants, including hemorrhage, advise patients that breastfeeding is not recommended during treatment with SAVAYSA.. 8.3 Females and Males of Reproductive Potential. Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including SAVAYSA should be assessed in females of reproductive potential and those with abnormal uterine bleeding.. 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 the Hokusai VTE Cancer Study, 539 (52%) patients were 65 years and older and 176 (17%) 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 function. 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 clearance [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 impairment (Child-Pugh 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 Pharmacology (12.3)].. 8.8Low 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)].

WARNINGS AND PRECAUTIONS SECTION.

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). 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). 5.1Reduced 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)].. 5.2Increased 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 reason other than pathological bleeding or completion of 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)].. 5.3Risk 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 EffectThere 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. 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.. 5.4Spinal/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 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.. 5.5Patients 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)].. 5.6Increased 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 antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin antagonist therapy.