CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Stroke Prevention in Nonvalvular Atrial Fibrillation. The evidence for the efficacy and safety of XARELTO was derived from Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin antagonist for the prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) [NCT00403767], multi-national, double-blind study comparing XARELTO (at dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to 50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more of the following additional risk factors for stroke:oa prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, oro2 or more of the following risk factors: oage >=75 years,ohypertension,oheart failure or left ventricular ejection fraction <=35%, orodiabetes mellitusROCKET AF was non-inferiority study designed to demonstrate that XARELTO preserved more than 50% of warfarins effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation.A total of 14264 patients were randomized and followed on study treatment for median of 590 days. The mean age was 71 years and the mean CHADS2 score was 3.5. The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black. There was history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken vitamin antagonist (VKA) within weeks at time of screening. Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of patients were on aspirin (almost exclusively at dose of 100 mg or less) and few patients were on clopidogrel. Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%). Patients randomized to warfarin had mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.In ROCKET AF, XARELTO was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism [HR (95% CI): 0.88 (0.74, 1.03)], but superiority to warfarin was not demonstrated. There is insufficient experience to determine how XARELTO and warfarin compare when warfarin therapy is well-controlled.Table 12 displays the overall results for the primary composite endpoint and its components.Table 12:Primary Composite Endpoint Results in ROCKET AF Study (Intent-to-Treat Population)XARELTOWarfarinXARELTO vs. WarfarinEventN=7081n (%)Event Rate(per 100 Pt-yrs)N=7090n (%)Event Rate(per 100 Pt-yrs)Hazard Ratio(95% CI)Primary Composite EndpointThe primary endpoint was the time to first occurrence of stroke (any type) or non-CNS systemic embolism. Data are shown for all randomized patients followed to site notification that the study would end. 269 (3.8)2.1306 (4.3)2.40.88 (0.74, 1.03)Stroke253 (3.6)2.0281 (4.0)2.2 Hemorrhagic StrokeDefined as primary hemorrhagic strokes confirmed by adjudication in all randomized patients followed up to site notification 33 (0.5) 0.357 (0.8)0.4 Ischemic Stroke206 (2.9)1.6208 (2.9)1.6 Unknown Stroke Type19 (0.3)0.218 (0.3)0.1Non-CNS Systemic Embolism20 (0.3)0.227 (0.4)0.2Figure is plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms. Figure 4:Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group (Intent-to-Treat Population)Figure shows the risk of stroke or non-CNS systemic embolism across major subgroups.Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Figure 5:Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AFData are shown for all randomized patients followed to site notification that the study would end. (Intent-to-Treat Population)The efficacy of XARELTO was generally consistent across major subgroups.The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin. XARELTO patients were generally switched to warfarin without period of coadministration of warfarin and XARELTO, so that they were not adequately anticoagulated after stopping XARELTO until attaining therapeutic INR. During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking XARELTO vs. in the 4691 patients taking warfarin.Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation. The utility of XARELTO for preventing post-cardioversion stroke and systemic embolism is unknown.. oa prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or. o2 or more of the following risk factors: oage >=75 years,ohypertension,oheart failure or left ventricular ejection fraction <=35%, orodiabetes mellitus. oage >=75 years,. ohypertension,. oheart failure or left ventricular ejection fraction <=35%, or. odiabetes mellitus. Figure 4:Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group (Intent-to-Treat Population). Figure 5:Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AFData are shown for all randomized patients followed to site notification that the study would end. (Intent-to-Treat Population). Figure 4. Figure 5. 14.2Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE). EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism StudiesXARELTO for the treatment of DVT and/or PE was studied in EINSTEIN DVT [NCT00440193] and EINSTEIN PE [NCT00439777], multi-national, open-label, non-inferiority studies comparing XARELTO (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by XARELTO 20 mg once daily with food) to enoxaparin mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0-3.0) was reached. Patients who required thrombectomy, insertion of caval filter, or use of fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigators assessment prior to randomization.A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for mean of 208 days in the XARELTO group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black. About 73% and 92% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for median duration of days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for median duration of days. Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline. Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic conditions (6%), or active cancer (5%).In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI): 1.12 (0.75, 1.68)]. In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.Table 13 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.Table 13:Primary Composite Endpoint ResultsFor the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (3, or 12 months) irrespective of the actual treatment duration. If the same patient had several events, the patient may have been counted for several components. in EINSTEIN DVT and EINSTEIN PE Studies Intent-to-Treat PopulationEventXARELTO 20 mgTreatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: mg/kg twice daily, VKA: individually titrated doses to achieve target INR of 2.5 (range: 2.0-3.0)]Enoxaparin/VKAXARELTO vs. Enoxaparin/VKAHazard Ratio(95% CI)EINSTEIN DVT StudyN=1731n (%)N=1718n (%)Primary Composite Endpoint36 (2.1)51 (3.0)0.68 (0.44, 1.04) Death (PE)1 (<0.1) Death (PE cannot be excluded)3 (0.2)6 (0.3) Symptomatic PE and DVT1 (<0.1)0 Symptomatic recurrent PE only20 (1.2)18 (1.0) Symptomatic recurrent DVT only14 (0.8)28 (1.6)EINSTEIN PE StudyN=2419n (%)N=2413n (%)Primary Composite Endpoint50 (2.1)44 (1.8)1.12 (0.75, 1.68) Death (PE)3 (0.1)1 (<0.1) Death (PE cannot be excluded)8 (0.3)6 (0.2) Symptomatic PE and DVT02 (<0.1) Symptomatic recurrent PE only23 (1.0)20 (0.8) Symptomatic recurrent DVT only18 (0.7)17 (0.7)Figures and are plots of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively. Figure 6:Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) EINSTEIN DVT Study Figure 7:Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) EINSTEIN PE Study. Figure 6:Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) EINSTEIN DVT Study. Figure 7:Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) EINSTEIN PE Study. Figure 6. Figure 7. 14.3Reduction in the Risk of Recurrence of DVT and/or PE. EINSTEIN CHOICE StudyXARELTO for reduction in the risk of recurrence of DVT and of PE was evaluated in the EINSTEIN CHOICE study [NCT02064439], multi-national, double-blind, superiority study comparing XARELTO (10 or 20 mg once daily with food) to 100 mg acetylsalicylic acid (aspirin) once daily in patients who had completed to 12 months of anticoagulant treatment for DVT and/or PE following the acute event. The intended treatment duration in the study was up to 12 months. Patients with an indication for continued therapeutic-dose anticoagulation were excluded.Because the benefit-risk assessment favored the 10 mg dose versus aspirin compared to the 20 mg dose versus aspirin, only the data concerning the 10 mg dose is discussed below.A total of 2275 patients were randomized and followed on study treatment for mean of 290 days for the XARELTO and aspirin treatment groups. The mean age was approximately 59 years. The population was 56% male, 70% Caucasian, 14% Asian and 3% Black. In the EINSTEIN CHOICE study, 51% of patients had DVT only, 33% had PE only, and 16% had PE and DVT combined. Other risk factors included idiopathic VTE (43%), previous episode of DVT/PE (17%), recent surgery or trauma (12%), prolonged immobilization (10%), use of estrogen containing drugs (5%), known thrombophilic conditions (6%), Factor Leiden gene mutation (4%), or active cancer (3%). In the EINSTEIN CHOICE study, XARELTO 10 mg was demonstrated to be superior to aspirin 100 mg for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE.Table 14 displays the overall results for the primary composite endpoint and its components.Table 14:Primary Composite Endpoint and its Components ResultsFor the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (12 months) irrespective of the actual treatment duration. The individual component of the primary endpoint represents the first occurrence of the event. in EINSTEIN CHOICE Study Full Analysis SetEventXARELTO 10 mgN=1,127n (%)Acetylsalicylic Acid (Aspirin)100 mgN=1,131n (%)XARELTO 10 mg vs. Aspirin 100 mgHazard Ratio(95% CI)Primary Composite Endpoint13 (1.2)50 (4.4)0.26 (0.14, 0.47)p<0.0001 Symptomatic recurrent DVT8 (0.7)29 (2.6) Symptomatic recurrent PE5 (0.4)19 (1.7) Death (PE)01 (<0.1) Death (PE cannot be excluded)01 (<0.1)Figure is plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups. Figure 8:Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Full Analysis Set) EINSTEIN CHOICE Study. Figure 8:Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Full Analysis Set) EINSTEIN CHOICE Study. Figure 8. 14.4Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery. XARELTO was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the REgulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE, Controlled, Double-blind, Randomized Study of BAY 59-7939 in the Extended Prevention of VTE in Patients Undergoing Elective Total Hip or Knee Replacement (RECORD 1, 2, and 3) [NCT00329628, NCT00332020, NCT00361894] studies.The two randomized, double-blind, clinical studies (RECORD and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least to hours (about 90% of patients dosed to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD and 2, total of 6727 patients were randomized and 6579 received study drug. The mean age [+- standard deviation (SD)] was 63 +- 12.2 (range 18 to 93) years with 49% of patients >=65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (+- SD) to active XARELTO and enoxaparin was 33.3 +- 7.0 and 33.6 +- 8.3 days, respectively. In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was 33.5 +- 6.9 and 12.4 +- 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration. The efficacy data for RECORD and are provided in Table 15.Table 15:Summary of Key Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery Modified Intent-to-Treat PopulationRECORD 1RECORD 2Treatment Dosage and DurationXARELTO 10 mg once dailyEnoxaparin 40 mg once dailyRRRRelative Risk Reduction; CI confidence interval, p-valueXARELTO 10 mg once dailyEnoxaparinIncludes the placebo-controlled period of RECORD 40 mg once dailyRRR, p-valueNumber of PatientsN=1513N=1473N=834N=835Total VTE17 (1.1%)57 (3.9%)71% (95% CI: 50, 83),p<0.00117 (2.0%)70 (8.4%)76% (95% CI: 59, 86),p<0.001Components of Total VTE Proximal DVT1 (0.1%)31 (2.1%)5 (0.6%)40 (4.8%) Distal DVT12 (0.8%)26 (1.8%)11 (1.3%)43 (5.2%) Non-fatal PE3 (0.2%)1 (0.1%)1 (0.1%)4 (0.5%) Death (any cause)4 (0.3%)4 (0.3%)2 (0.2%)4 (0.5%)Number of PatientsN=1600N=1587N=928N=929Major VTEProximal DVT, nonfatal PE or VTE-related death3 (0.2%)33 (2.1%)91% (95% CI: 71, 97), p<0.0016 (0.7%)45 (4.8%)87% (95% CI: 69, 94), p<0.001Number of PatientsN=2103N=2119N=1178N=1179Symptomatic VTE5 (0.2%)11 (0.5%)3 (0.3%)15 (1.3%)One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared XARELTO 10 mg once daily started at least to hours (about 90% of patients dosed to 10 hours) after wound closure versus enoxaparin. In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively. The mean age (+- SD) of patients in the study was 68 +- 9.0 (range 28 to 91) years with 66% of patients >=65 years. Sixty-eight percent (68%) of patients were female. Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black. The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis). The mean exposure duration (+- SD) to active XARELTO and enoxaparin was 11.9 +- 2.3 and 12.5 +- 3.0 days, respectively. The efficacy data are provided in Table 16.Table 16:Summary of Key Efficacy Analysis Results for Patients Undergoing Total Knee Replacement Surgery Modified Intent-to-Treat PopulationRECORD 3Treatment Dosage and DurationXARELTO 10 mg once dailyEnoxaparin 40 mg once dailyRRRRelative Risk Reduction; CI confidence interval, p-valueNumber of PatientsN=813N=871Total VTE79 (9.7%)164 (18.8%)48%(95% CI: 34, 60),p<0.001Components of events contributing to Total VTE Proximal DVT9 (1.1%)19 (2.2%) Distal DVT74 (9.1%)154 (17.7%) Non-fatal PE04 (0.5%) Death (any cause)02 (0.2%)Number of PatientsN=895N=917Major VTEProximal DVT, nonfatal PE or VTE-related death9 (1.0%)23 (2.5%)60% (95% CI: 14, 81), = 0.024Number of PatientsN=1206N=1226Symptomatic VTE8 (0.7%)24 (2.0%). 14.5Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding. The efficacy and safety of XARELTO for prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding was evaluated in the MAGELLAN study (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically iLL patients comparing rivaroxabaN with enoxaparin [NCT00571649]). MAGELLAN was multicenter, randomized, double-blind, parallel-group efficacy and safety study comparing XARELTO to enoxaparin, in the prevention of VTE in hospitalized acutely ill medical patients during the in-hospital and post-hospital discharge period. Eligible patients included adults who were at least 40 years of age, hospitalized for an acute medical illness, at risk of VTE due to moderate or severe immobility, and had additional risk factors for VTE. The population at risk of VTE was required to have one or more of the following VTE risk factors, i.e. prolonged immobilization, age >=75 years, history of cancer, history of VTE, history of heart failure, thrombophilia, acute infectious disease contributing to the hospitalization and BMI >=35 kg/m2). The causes for hospitalization included heart failure, active cancer, acute ischemic stroke, acute infectious and inflammatory disease and acute respiratory insufficiency. Patients were randomized to receive either XARELTO 10 mg once daily for 35 +-4 days starting in hospital and continuing post hospital discharge (n=4050) or enoxaparin 40 mg once daily for 10 +-4 days starting in hospital followed by placebo post-discharge (n=4051). The major efficacy outcome in the MAGELLAN trial was composite endpoint that included asymptomatic proximal deep venous thrombosis (DVT) in lower extremity, symptomatic proximal or distal DVT in the lower extremity, symptomatic non-fatal pulmonary embolism (PE), and death related to venous thromboembolism (VTE).A total of 6024 patients were evaluable for the major efficacy outcome analysis (2967 on XARELTO 10 mg once daily and 3057 on enoxaparin/placebo). The mean age was 68.9 years, with 37.1% of the subject population >= 75 years. VTE risk factors included severe immobilization at study entry (99.9%), D-dimer 2x ULN (43.7%), history of heart failure (35.6%), BMI >= 35 kg/m2 (15.2%), chronic venous insufficiency (14.9%), acute infectious disease (13.9%), severe varicosis (12.5%), history of cancer (16.2%), history of VTE (4.5%), hormone replacement therapy (1.1%), and thrombophilia (0.3%), recent major surgery (0.8%) and recent serious trauma (0.2%). The population was 54.7% male, 68.2% White, 20.4% Asian, 1.9% Black and 5.3% Other. Admitting diagnoses for hospitalization were acute infectious diseases (43.8%) followed by congestive heart failure NYHA class III or IV (33.2%), acute respiratory insufficiency (26.4%), acute ischemic stroke (18.5%) and acute inflammatory diseases (3.4%). Table 17 shows the overall results from the prespecified, modified intent-to-treat (mITT) analysis for the efficacy outcomes and their components. This analysis excludes approximately 25% of the patients mainly due to no ultrasonographic assessment (13.5%), inadequate assessment at day 35 (8.1%), or lack of intake of study medication (1.3%).Table 17:Efficacy Results at Day 35 (modified Intent-to-Treat) and at Day 10 (per protocol) in the MAGELLAN StudymITT: modified intent-to-treat; PP: per protocol; DVT: Deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; CI: Confidence Interval; RR: Relative RiskEvents from Day to Day 35, mITT analysis setXARELTO 10 mgN=2967n (%)Enoxaparin 40 mg/placeboN=3057n (%)RR(95% CI)Primary Composite Endpoint at Day 35131 (4.4%)175 (5.7%)0.77(0.62, 0.96) Symptomatic non-fatal PE10 (0.3)14 (0.5) Symptomatic DVT in lower extremity13 (0.4)15 (0.5) Asymptomatic proximal DVT in lower extremity103 (3.5)133 (4.4) VTE related death19 (0.6)30 (1.0)Events from Day to Day 10, PP analysis setXARELTO10 mgN=2938n (%)Enoxaparin 40 mgN=2993n (%)RR(95% CI)Primary Composite Endpoint at Day 1078 (2.7)82 (2.7)0.97(0.71, 1.31) Symptomatic non-fatal PE6 (0.2)2 (<0.1) Symptomatic DVT in lower extremity7 (0.2)6 (0.2) Asymptomatic proximal DVT in lower extremity71 (2.4)71 (2.4) VTE related death3 (0.1)6 (0.2)mITT analysis set plus all-cause mortality N=3096n (%)N=3169n (%)RR(95% CI)Other Composite Endpoint at Day 35266 (8.6)293 (9.2)0.93(0.80, 1.09) Symptomatic non-fatal PE10 (0.3)14 (0.4) Symptomatic DVT in lower extremity13 (0.4)15 (0.5) Asymptomatic proximal DVT in lower extremity103 (3.3)133 (4.2) All-cause mortality159 (5.1)153 (4.8)Patients with bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months (19.4%) all had an excess of bleeding with XARELTO compared with enoxaparin/placebo. Therefore, patients meeting these criteria were excluded from the following analyses presented below.Table 18 provides the efficacy results for the subgroup of patients not at high risk of bleeding.Table 18:Efficacy Results at Day 35 (modified Intent-to-Treat) and at Day 10 (per protocol) in patients not at high risk of bleeding in the MAGELLAN StudyPatients at high risk of bleeding (i.e. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded. mITT: modified intent-to-treat; PP: per protocol; DVT: Deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; CI: Confidence Interval; RR: Relative RiskEvents from Day to Day 35, mITT analysis setXARELTO10 mgN=2419n (%)Enoxaparin 40 mg/placeboN=2506n (%)RR(95% CI)Primary Composite Endpoint at Day 3594 (3.9)143 (5.7)0.68 (0.53, 0.88) Symptomatic non-fatal PE7 (0.3)10 (0.4) Symptomatic DVT in lower extremity9 (0.4)10 (0.4) Asymptomatic proximal DVT in lower extremity73 (3.0)110 (4.4) VTE related death15 (0.6)26 (1.0)Events from Day to Day 10, PP analysis setXARELTO10 mgN=2385n (%)Enoxaparin 40 mgN=2433n (%)RR(95% CI)Primary Composite Endpoint at Day 1058 (2.4)72 (3.0)0.82(0.58, 1.15) Symptomatic non-fatal PE5 (0.2)2 (<0.1) Symptomatic DVT in lower extremity6 (0.3)4 (0.2) Asymptomatic proximal DVT in lower extremity52 (2.2)62 (2.5) VTE related death2 (<0.1)6 (0.2)mITT analysis set plus all-cause mortality N=2504n (%)N=2583n (%)RR(95% CI)Other Composite Endpoint at Day 35184 (7.3)225 (8.7)0.84(0.70, 1.02) Symptomatic non-fatal PE7 (0.3) 10 (0.4) Symptomatic DVT in lower extremity9 (0.4)10 (0.4) Asymptomatic proximal DVT in lower extremity73 (2.9)110 (4.3) All-cause mortality107 (4.3)112 (4.3). 14.6Reduction of Risk of Major Cardiovascular Events in Patients with CAD. The evidence for the efficacy and safety of XARELTO for the reduction in the risk of stroke, myocardial infarction, or cardiovascular death in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) was derived from the double-blind, placebo-controlled Cardiovascular OutcoMes for People using Anticoagulation StrategieS trial (COMPASS) [NCT10776424]. total of 27,395 patients were evenly randomized to rivaroxaban 2.5 mg orally twice daily plus aspirin 100 mg once daily, rivaroxaban mg orally twice daily alone, or aspirin 100 mg once daily alone. Because the mg dose alone was not superior to aspirin alone, only the data concerning the 2.5 mg dose plus aspirin are discussed below.Patients with established CAD or PAD were eligible. Patients with CAD who were younger than 65 years of age were also required to have documentation of atherosclerosis involving at least two vascular beds or to have at least two additional cardiovascular risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate [eGFR] <60 mL per minute, heart failure, or non-lacunar ischemic stroke >=1 month earlier). Patients with PAD were either symptomatic with ankle brachial index <0.90 or had asymptomatic carotid artery stenosis >=50%, previous carotid revascularization procedure, or established ischemic disease of one or both lower extremities. Patients were excluded for use of dual antiplatelet, other non-aspirin antiplatelet, or oral anticoagulant therapies, ischemic, non-lacunar stroke within month, hemorrhagic or lacunar stroke at any time, or eGFR <15 mL/min. The mean age was 68 years and 21% of the subject population were >=75 years. Of the included patients, 91% had CAD (and will be referred to as the COMPASS CAD population), 27% had PAD (and will be referred to as the COMPASS PAD population), and 18% had both CAD and PAD. Of the patients with CAD, 69% had prior MI, 60% had prior percutaneous transluminal coronary angioplasty (PTCA)/atherectomy/ percutaneous coronary intervention (PCI), and 26% had history of coronary artery bypass grafting (CABG) prior to study. Of the patients with PAD, 49% had intermittent claudication, 27% had peripheral artery bypass surgery or peripheral percutaneous transluminal angioplasty, 26% had asymptomatic carotid artery stenosis 50%, and 4% had limb or foot amputation for arterial vascular disease. The mean duration of follow-up was 23 months. Relative to placebo, XARELTO reduced the rate of the primary composite outcome of stroke, myocardial infarction or cardiovascular death: HR 0.76 (95% CI: 0.66, 0.86; p=0.00004). In the COMPASS CAD population, the benefit was observed early with constant treatment effect over the entire treatment period (see Table 19 and Figure 10). benefit-risk analysis of the data from COMPASS was performed by comparing the number of CV events (CV deaths, myocardial infarctions and non-hemorrhagic strokes) prevented to the number of fatal or life-threatening bleeding events (fatal bleeds symptomatic non-fatal bleeds into critical organ) in the XARELTO group versus the placebo group. Compared to placebo, during 10,000 patient-years of treatment, XARELTO would be expected to result in 70 fewer CV events and 12 additional life-threatening bleeds, indicating favorable balance of benefits and risks. The results in the COMPASS CAD population were consistent across major subgroups (see Figure 9).Figure 9: Risk of Primary Efficacy Outcome by Baseline Characteristics in the COMPASS CAD Population (Intent-to-Treat Population)All patients received aspirin 100 mg once daily as background therapy.Table 19:Efficacy results from COMPASS CAD Populationintention to treat analysis set, primary analyses. EventXARELTOTreatment schedule: XARELTO 2.5 mg twice daily vs placebo. All patients received aspirin 100 mg once daily as background therapy.N=8313PlaceboN=8261Hazard Ratio(95% CI) XARELTO vs. placebo.n (%)Event Rate(%/year)n (%)Event Rate(%/year)CHD: coronary heart disease, CI: confidence interval; CV: cardiovascular; MI: myocardial infarctionStroke, MI or CV death347 (4.2)2.2460 (5.6)2.90.74 (0.65, 0.86)- Stroke74 (0.9)0.5130 (1.6)0.80.56 (0.42, 0.75)- MI169 (2.0)1.1195 (2.4)1.20.86 (0.70, 1.05)- CV death139 (1.7)0.9184 (2.2)1.10.75 (0.60, 0.93)Coronary heart disease death, MI, ischemic stroke, acute limb ischemia299 (3.6)1.9411 (5.0)2.60.72 (0.62, 0.83)- Coronary heart disease deathCoronary heart disease death: death due to acute MI, sudden cardiac death, or CV procedure. 80 (1.0)0.5107 (1.3)0.70.74 (0.55, 0.99)- Ischemic stroke56 (0.7)0.3114 (1.4)0.70.49 (0.35, 0.67)- Acute limb ischemiaAcute limb ischemia is defined as limb-threatening ischemia leading to an acute vascular intervention (i.e., pharmacologic, peripheral arterial surgery/reconstruction, peripheral angioplasty/stent, or amputation). 13 (0.2)0.127 (0.3)0.20.48 (0.25, 0.93)CV death,CV death includes CHD death, or death due to other CV causes or unknown death. MI, ischemic stroke, acute limb ischemia349 (4.2)2.2470 (5.7)3.00.73 (0.64, 0.84)All-cause mortality262 (3.2)1.6339 (4.1)2.10.77 (0.65, 0.90)CI: confidence interval Figure 10:Time to first occurrence of primary efficacy outcome (stroke, myocardial infarction, cardiovascular death) in the COMPASS CAD PopulationAll patients received aspirin 100 mg once daily as background therapy.. Figure 10:Time to first occurrence of primary efficacy outcome (stroke, myocardial infarction, cardiovascular death) in the COMPASS CAD PopulationAll patients received aspirin 100 mg once daily as background therapy.. Figure 9. Figure 10. 14.7Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PAD. The efficacy and safety of XARELTO 2.5 mg orally twice daily versus placebo on background of aspirin 100 mg once daily in patients with PAD were evaluated in the COMPASS study (n=4996) and will be referred to as the COMPASS PAD population [see Clinical Studies (14.6)].The efficacy and safety of XARELTO were also evaluated for the reduction in the risk of the composite endpoint of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia (ALI), and major amputation of vascular etiology in patients undergoing lower extremity infrainguinal revascularization procedure due to symptomatic peripheral artery disease (PAD) in the double-blinded, placebo-controlled Vascular Outcomes studY of ASA alonG with rivaroxaban in Endovascular or surgical limb Revascularization for peripheral artery disease (PAD) trial (VOYAGER) [NCT02504216]. total of 6,564 patients were equally randomized to XARELTO 2.5 mg orally twice daily vs placebo on background therapy of aspirin 100 mg once daily.Eligible patients included adults who were at least 50 years of age with documented moderate to severe symptomatic lower extremity atherosclerotic PAD who had successful peripheral surgical procedure and/or endovascular procedure with or without clopidogrel (up to maximum of months was allowed; median duration of therapy was 31 days). Patients had either prior history of limb revascularization with ankle brachial index <=0.85 or no prior history of limb revascularization with ankle brachial index <=0.80. Patients in need of dual antiplatelet for >6 months, or any additional antiplatelet other than aspirin and clopidogrel, or oral anticoagulant, as well as patients with history of intracranial hemorrhage, stroke, or transient ischemic attack (TIA), or patients with eGFR <15 mL/min were excluded. The mean age was 67 years and 20% of the subject population was >=75 years. Of the included patients, 35% had surgical revascularization, 47% had endovascular revascularization with clopidogrel, and 18% endovascular revascularization without clopidogrel. The median duration of follow-up was 30.8 months.XARELTO 2.5 mg twice daily was superior to placebo in reducing the rate of the primary composite outcome of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia (ALI), and major amputation of vascular etiology. The primary efficacy outcome and its components are provided in Table 20. The Kaplan-Meier plot for the primary efficacy outcome can be seen in Figure 11. The secondary efficacy outcomes were tested for superiority in prespecified, hierarchical order and the first five of seven endpoints were significantly reduced in the rivaroxaban treatment arm (see Table 20). Compared to placebo during 10,000 patient-years of treatment, XARELTO would be expected to result in 181 fewer primary outcome events and 29 more TIMI major bleeding events, indicating favorable balance of benefits and risks. Figure 11:Time to First Occurrence of Primary Efficacy Outcome (Myocardial Infarction, Ischemic Stroke, Cardiovascular Death, Acute Limb Ischemia, Major Amputation due to Vascular Origins) in VOYAGERAll patients received aspirin 100 mg once daily as background therapy.Figure 12 shows the risk of primary efficacy outcome across major subgroups. Subgroup analyses must be interpreted cautiously, as differences can reflect the play of chance among large number of analyses. The primary efficacy endpoint generally shows homogeneous results across subgroups. Figure 12: Risk of Primary Efficacy Outcome by Baseline Characteristics in VOYAGER (Intent-to-Treat Population)All patients received aspirin 100 mg once daily as background therapy.Table 20 provides the efficacy event rates for the prespecified endpoints in VOYAGER and similar endpoints in the COMPASS PAD population.Table 20: Efficacy Results in VOYAGER (Intent-to-Treat Population) and COMPASS PADVOYAGERCOMPASS PADXARELTON=3286PlaceboN=3278Hazard Ratio (95% CI)XARELTO vs. placebo.p-valueTwo-sided p-valuesXARELTON=2492PlaceboN=2504Hazard Ratio(95% CI)Outcome ComponentsEvent Rate(%/year)Event Rate(%/year)Efficacy endpoints in COMPASS PAD were analysed according to the pre-specified endpoints in VOYAGER when applicable.ALI=acute limb ischemia, CHD=coronary heart disease; CI=confidence interval, CV=cardiovascular; MI=myocardial infarction, VTE=venous thromboembolism.5-Component Outcome (Major thrombotic vascular events)Major thrombotic vascular event is the composite of MI, ischemic stroke, CV death, ALI, and major amputation of vascular etiology. 6.88.00.85 (0.76, 0.96)p=0.00853.44.80.71 (0.57, 0.87) MI1.71.90.88 (0.70, 1.12)1.11.50.76 (0.53, 1.09) Ischemic StrokeIschemic stroke for VOYAGER included stroke of uncertain/unknown etiology whereas COMPASS only included ischemic stroke. 0.91.00.87 (0.63, 1.19)0.50.90.55 (0.33, 0.93) CV deathCV death includes Coronary Heart Disease death, or death due to other CV causes or sudden cardiac arrest and unknown death. 2.52.21.14 (0.93, 1.40)1.41.70.82 (0.59, 1.14) ALI2.03.00.67 (0.55, 0.82)0.40.80.56 (0.32, 0.99) Major amputation of vascular etiologyAdjudicated events in VOYAGER and investigator reported events in COMPASS 1.3 1.50.89 (0.68, 1.16)0.20.60.40 (0.20, 0.79)VOYAGER Secondary Efficacy OutcomesSecondary outcomes for VOYAGER were tested sequentially. MI, ischemic stroke, CHD death,CHD death includes death due to sudden cardiac death, MI, or coronary revascularization procedure ALI, and major amputation due to vascular etiology5.87.30.80 (0.71, 0.91)p=0.00082.84.20.66 (0.53, 0.83)Unplanned index limb revascularization for recurrent limb ischemiaUnplanned index limb revascularization for recurrent limb ischemia was not captured in COMPASS study. 8.49.50.88 (0.79, 0.99)p=0.028N/AN/AN/AHospitalization for coronary or peripheral cause of thrombotic nature 3.54.80.72 (0.62, 0.85)p<0.00011.72.90.58 (0.44, 0.77)MI, ischemic stroke, all-cause mortality, ALI, and major amputation due to vascular etiology8.29.30.89 (0.79, 0.99)p=0.0294.86.00.80 (0.67, 0.96)MI, all-cause stroke, CV death, ALI, and major amputation due to vascular etiology6.98.10.86 (0.76, 0.96)p=0.0103.44.90.70 (0.57, 0.86)All-cause mortality4.03.71.08 (0.92, 1.27)2.83.10.91 (0.72, 1.16)VTE eventsInvestigator reported in VOYAGER and adjudicated events in COMPASS 0.30.50.61 (0.37, 1.00)0.20.30.67 (0.30, 1.49). Figure 11:Time to First Occurrence of Primary Efficacy Outcome (Myocardial Infarction, Ischemic Stroke, Cardiovascular Death, Acute Limb Ischemia, Major Amputation due to Vascular Origins) in VOYAGERAll patients received aspirin 100 mg once daily as background therapy.. Figure 11. Figure 12.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are also discussed in other sections of the labeling:oIncreased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation [see Boxed Warning and Warnings and Precautions (5.1)]oBleeding Risk [see Warnings and Precautions (5.2, 5.4, 5.5, 5.6, 5.7)]oSpinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions (5.3)]. oIncreased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation [see Boxed Warning and Warnings and Precautions (5.1)]. oBleeding Risk [see Warnings and Precautions (5.2, 5.4, 5.5, 5.6, 5.7)]. oSpinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions (5.3)]. The most common adverse reaction (>5%) was bleeding. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 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 clinical practice.During clinical development for the approved indications, 34,947 patients were exposed to XARELTO.. HemorrhageThe most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions (5.2)].. Nonvalvular Atrial FibrillationIn the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.Table shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.Table 2:Bleeding Events in ROCKET AFMajor bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within days of stopping treatment.- On Treatment Plus DaysParameterXARELTON=7111n (%/year)Warfarin N=7125n (%/year)XARELTO vs. WarfarinHR(95% CI)Abbreviations: HR Hazard Ratio, CI Confidence interval, CRNM Clinically Relevant Non-Major.Major BleedingDefined as clinically overt bleeding associated with decrease in hemoglobin of >=2 g/dL, transfusion of >=2 units of packed red blood cells or whole blood, bleeding at critical site, or with fatal outcome. 395 (3.6)386 (3.5)1.04 (0.90, 1.20) Intracranial Hemorrhage (ICH) Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. 55 (0.5)84 (0.7)0.67 (0.47, 0.93) Hemorrhagic StrokeHemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus days. 36 (0.3)58 (0.5)0.63 (0.42, 0.96) Other ICH19 (0.2)26 (0.2)0.74 (0.41, 1.34) Gastrointestinal (GI)Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. 221 (2.0)140 (1.2)1.61 (1.30, 1.99) Fatal BleedingFatal bleeding is adjudicated death with the primary cause of death from bleeding. 27 (0.2)55 (0.5)0.50 (0.31, 0.79) ICH24 (0.2)42 (0.4)0.58 (0.35, 0.96) Non-intracranial3 (0.0)13 (0.1)0.23 (0.07, 0.82)Figure shows the risk of major bleeding events across major subgroups.Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup but was criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Figure 1:Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF On Treatment Plus Days. Figure 1:Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF On Treatment Plus Days. Figure 1. Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE). EINSTEIN DVT and EINSTEIN PE StudiesIn the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/Vitamin antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.Table shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.Table 3:Bleeding EventsBleeding event occurred after randomization and up to days after the last dose of study drug. Although patient may have had or more events, the patient is counted only once in category. in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE StudiesParameterXARELTOTreatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: mg/kg twice daily, VKA: individually titrated doses to achieve target INR of 2.5 (range: 2.0-3.0)]N=4130n (%)Enoxaparin/VKAN=4116n (%)Major bleeding event40 (1.0)72 (1.7) Fatal bleeding3 (<0.1)8 (0.2) Intracranial2 (<0.1)4 (<0.1) Non-fatal critical organ bleeding10 (0.2)29 (0.7) IntracranialTreatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group (<0.1)10 (0.2) Retroperitoneal (<0.1)8 (0.2) Intraocular (<0.1)2 (<0.1) Intra-articular 04 (<0.1) Non-fatal non-critical organ bleedingMajor bleeding which is not fatal or in critical organ, but resulting in decrease in Hb >= g/dL and/or transfusion of >=2 units of whole blood or packed red blood cells 27 (0.7)37 (0.9) Decrease in Hb >= g/dL28 (0.7)42 (1.0) Transfusion of >=2 units of whole blood or packed red blood cells18 (0.4) 25 (0.6)Clinically relevant non-major bleeding357 (8.6)357 (8.7)Any bleeding1169 (28.3)1153 (28.0). Reduction in the Risk of Recurrence of DVT and/or PE. EINSTEIN CHOICE StudyIn the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients.Table shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.Table 4:Bleeding EventsBleeding event occurred after the first dose and up to days after the last dose of study drug. Although patient may have had or more events, the patient is counted only once in category. in EINSTEIN CHOICE ParameterXARELTOTreatment schedule: XARELTO 10 mg once daily or aspirin 100 mg once daily.10 mgN=1127n (%)Acetylsalicylic Acid (aspirin) 100 mgN=1131n (%)Major bleeding event5 (0.4)3 (0.3) Fatal bleeding01 (<0.1) Non-fatal critical organ bleeding2 (0.2)1 (<0.1) Non-fatal non-critical organ bleedingMajor bleeding which is not fatal or in critical organ, but resulting in decrease in Hb >= g/dL and/or transfusion of >= units of whole blood or packed red blood cells. (0.3)1 (<0.1)Clinically relevant non-major (CRNM) bleedingBleeding which was clinically overt, did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. 22 (2.0)20 (1.8)Any bleeding151 (13.4)138 (12.2)In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups.. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement SurgeryIn the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO.The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 5.Table 5:Bleeding EventsBleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event. in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3)XARELTO 10 mgEnoxaparinIncludes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3)Total treated patientsN=4487n (%)N=4524n (%) Major bleeding event14 (0.3)9 (0.2) Fatal bleeding1 (<0.1)0 Bleeding into critical organ2 (<0.1)3 (0.1) Bleeding that required re-operation7 (0.2)5 (0.1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells4 (0.1)1 (<0.1) Any bleeding eventIncludes major bleeding events 261 (5.8)251 (5.6)Hip Surgery StudiesN=3281n (%)N=3298n (%) Major bleeding event7 (0.2)3 (0.1) Fatal bleeding1 (<0.1)0 Bleeding into critical organ1 (<0.1)1 (<0.1) Bleeding that required re-operation2 (0.1)1 (<0.1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells3 (0.1)1 (<0.1) Any bleeding event 201 (6.1)191 (5.8)Knee Surgery StudyN=1206n (%)N=1226n (%) Major bleeding event7 (0.6)6 (0.5) Fatal bleeding00 Bleeding into critical organ1 (0.1)2 (0.2) Bleeding that required re-operation5 (0.4)4 (0.3) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells1 (0.1)0 Any bleeding event 60 (5.0)60 (4.9)Following XARELTO treatment, the majority of major bleeding complications (>=60%) occurred during the first week after surgery.. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of BleedingIn the MAGELLAN study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events. Cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. Patients with bronchiectasis/pulmonary cavitation, active cancer (i.e., undergoing acute, in-hospital cancer treatment), dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months all had an excess of bleeding with XARELTO compared with enoxaparin/placebo and are excluded from all MAGELLAN data presented in Table 6. The incidence of bleeding leading to drug discontinuation was 2.5% for XARELTO vs. 1.4% for enoxaparin/placebo.Table shows the number of patients experiencing various types of bleeding events in the MAGELLAN study.Table 6:Bleeding Events in MAGELLANPatients at high risk of bleeding (i.e. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded. Study-Safety Analysis Set On Treatment Plus Days MAGELLAN StudyPatients received either XARELTO or placebo once daily for 35 +-4 days starting in hospital and continuing post hospital discharge or received enoxaparin or placebo once daily for 10 +-4 days in the hospital. XARELTO 10 mg N=3218n (%)Enoxaparin 40 mg /placeboN=3229n (%)Major bleedingDefined as clinically overt bleeding associated with drop in hemoglobin of >=2 g/dL, transfusion of >=2 units of packed red blood cells or whole blood, bleeding at critical site, or with fatal outcome. Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within days of stopping treatment. 22 (0.7)15 (0.5) Critical site bleeding7 (0.2)4 (0.1) Fatal bleedingFatal bleeding is adjudicated death with the primary cause of death from bleeding. (<0.1)1 (<0.1)Clinically relevant non-major bleeding events (CRNM)93 (2.9)34 (1.1). Reduction of Risk of Major Cardiovascular Events in Patients with CADIn the COMPASS trial overall, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily vs. 1.2% for placebo on background therapy for all patients with aspirin 100 mg once daily. The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar. Table shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.Table 7: Major Bleeding Events in COMPASS On Treatment Plus daysMajor bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within days of stopping treatment in the safety analysis set in COMPASS patients. ParameterXARELTOTreatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily.N=9134n (%/year)PlaceboN=9107n (%/year)XARELTO vs. PlaceboHR (95 CI)CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and HemostasisModified ISTH Major BleedingDefined as i) fatal bleeding, or ii) symptomatic bleeding in critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization. 263 (1.6)144 (0.9)1.8 (1.5, 2.3)1.Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial 12 (<0.1)6 (<0.1)6 (<0.1)8 (<0.1)3 (<0.1)5 (<0.1)1.5 (0.6, 3.7)2.0 (0.5, 8.0)1.2 (0.4, 4.0)oSymptomatic bleeding in critical organ (non-fatal)oICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH58 (0.3)23 (0.1)18 (0.1)6 (<0.1)43 (0.3)21 (0.1)13 (<0.1)9 (<0.1)1.4 (0.9, 2.0)1.1 (0.6, 2.0)1.4 (0.7, 2.8)0.7 (0.2, 1.9)oBleeding into the surgical site requiring reoperation (non-fatal, not in critical organ)7 (<0.1)6 (<0.1)1.2 (0.4, 3.5)oBleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation)188 (1.1)91 (0.5)2.1 (1.6, 2.7)Major GI bleeding117 (0.7)49 (0.3)2.4 (1.7, 3.4). 1.Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial oSymptomatic bleeding in critical organ (non-fatal). oICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH. oBleeding into the surgical site requiring reoperation (non-fatal, not in critical organ). oBleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation). Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PADThe incidence of premature permanent discontinuation due to bleeding events for XARELTO 2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% vs. 1.6% and in COMPASS PAD was 2.7% vs. 1.3%, respectively. Table shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal.Table 8: Major Bleeding EventsMajor bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. in VOYAGER- On Treatment Plus daysXARELTOTreatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily.N=3256PlaceboN=3248XARELTO vs. PlaceboHR (95 CI)Parametern (%)Event rate%/yearn (%)Event rate%/year CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding CriteriaTIMI Major Bleeding (CABG/non-CABG)62 (1.9)0.9644 (1.4)0.671.4 (1.0, 2.1) Fatal bleeding6 (0.2)0.096 (0.2)0.091.0 (0.3, 3.2) Intracranial bleeding13 (0.4)0.2017 (0.5)0.260.8 (0.4, 1.6) Clinically overt signs of hemorrhage associated with drop in hemoglobin of >=5 g/dL or drop in hematocrit of >=15%46 (1.4)0.7124 (0.7)0.361.9 (1.2, 3.2). Other Adverse ReactionsNon-hemorrhagic adverse reactions reported in >=1% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 9.Table 9:Other Adverse ReactionsAdverse reaction with Relative Risk >1.5 for XARELTO versus comparator Reported by >=1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE StudiesBody SystemAdverse ReactionEINSTEIN DVT StudyXARELTO 20 mgN=1718n (%)Enoxaparin/VKAN=1711n (%)Gastrointestinal disorders Abdominal pain46 (2.7)25 (1.5)General disorders and administration site conditions Fatigue24 (1.4)15 (0.9)Musculoskeletal and connective tissue disorders Back pain50 (2.9)31 (1.8) Muscle spasm23 (1.3)13 (0.8)Nervous system disorders Dizziness38 (2.2)22 (1.3)Psychiatric disorders Anxiety24 (1.4)11 (0.6) Depression20 (1.2)10 (0.6) Insomnia28 (1.6)18 (1.1)EINSTEIN PE StudyXARELTO 20 mgN=2412n (%)Enoxaparin/VKAN=2405n (%)Skin and subcutaneous tissue disorders Pruritus53 (2.2)27 (1.1)Non-hemorrhagic adverse reactions reported in >=1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 10.Table 10:Other Adverse Drug ReactionsAdverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication Reported by >=1% of XARELTO-Treated Patients in RECORD 1-3 StudiesBody SystemAdverse ReactionXARELTO10 mgN=4487n (%)EnoxaparinIncludes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3)N=4524n (%)Injury, poisoning and procedural complications Wound secretion125 (2.8)89 (2.0)Musculoskeletal and connective tissue disorders Pain in extremity74 (1.7)55 (1.2) Muscle spasm52 (1.2)32 (0.7)Nervous system disorders Syncope55 (1.2)32 (0.7)Skin and subcutaneous tissue disorders Pruritus96 (2.1)79 (1.8) Blister63 (1.4)40 (0.9). 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of XARELTO. 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: agranulocytosis, thrombocytopeniaHepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury)Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedemaNervous system disorders: hemiparesisSkin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS).

BOXED WARNING SECTION.

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA. WARNING:(A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMASee full prescribing information for complete boxed warning.(A) Premature discontinuation of XARELTO increases the risk of thrombotic eventsPremature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if XARELTO is discontinued for reason other than pathological bleeding or completion of course of therapy. (2.2, 2.3, 5.1, 14.1)(B) Spinal/epidural hematomaEpidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. (5.2, 5.3, 6.2)Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently. Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated. (5.3). WARNING:(A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA. A.Premature discontinuation of XARELTO increases the risk of thrombotic eventsPremature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for reason other than pathological bleeding or completion of course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1), and Clinical Studies (14.1)].. A.Premature discontinuation of XARELTO increases the risk of thrombotic events. B.Spinal/epidural hematomaEpidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:ouse of indwelling epidural cathetersoconcomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulantsoa history of traumatic or repeated epidural or spinal puncturesoa history of spinal deformity or spinal surgeryooptimal timing between the administration of XARELTO and neuraxial procedures is not known[see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2)].Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.3)].Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.3)].. B.Spinal/epidural hematoma. ouse of indwelling epidural catheters. oconcomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants. oa history of traumatic or repeated epidural or spinal punctures. oa history of spinal deformity or spinal surgery. ooptimal timing between the administration of XARELTO and neuraxial procedures is not known.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Rivaroxaban was not carcinogenic when administered by oral gavage to mice or rats for up to years. The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/day) were 1- and 2-times, respectively, the human exposure of unbound drug at the human dose of 20 mg/day. Systemic exposures of unbound drug in male and female rats at the highest dose tested (60 mg/kg/day) were 2- and 4-times, respectively, the human exposure.Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in V79 Chinese hamster lung cells in vitro or in the mouse micronucleus test in vivo.No impairment of fertility was observed in male or female rats when given up to 200 mg/kg/day of rivaroxaban orally. This dose resulted in exposure levels, based on the unbound AUC, at least 13 times the exposure in humans given 20 mg rivaroxaban daily.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. XARELTO is selective inhibitor of FXa. It does not require cofactor (such as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.. 12.2 Pharmacodynamics. Dose-dependent inhibition of FXa activity was observed in humans. Neoplastin(R) prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest(R) are also prolonged dose-dependently. Anti-factor Xa activity is also influenced by rivaroxaban.. Specific Populations. Renal ImpairmentThe relationship between systemic exposure and pharmacodynamic activity of rivaroxaban was altered in subjects with renal impairment relative to healthy control subjects [see Use in Specific Populations (8.6)].Table 11:Percentage Increase in Rivaroxaban PK and PD Measures in Subjects with Renal Impairment Relative to Healthy Subjects from Clinical Pharmacology Studies MeasureParameterCreatinine Clearance (mL/min)50-7930-4915-29ESRD (on dialysis)Separate stand-alone study.ESRD (post-dialysis)PT Prothrombin time; FXa Coagulation factor Xa; AUC Area under the plasma concentration-time curve; AUEC Area under the effect-time curveExposureAUC4452644756FXa InhibitionAUEC50861004933PT ProlongationAUEC33116144112158. Hepatic ImpairmentAnti-Factor Xa activity was similar in subjects with normal hepatic function and in mild hepatic impairment (Child-Pugh class). There is no clear understanding of the impact of hepatic impairment beyond this degree on the coagulation cascade and its relationship to efficacy and safety.. 12.3 Pharmacokinetics. AbsorptionThe absolute bioavailability of rivaroxaban is dose-dependent. For the 2.5 mg and 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. XARELTO 2.5 mg and 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with food [see Dosage and Administration (2.1)].The maximum concentrations (Cmax) of rivaroxaban appear to hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of XARELTO (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or XARELTO (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban (see Figure 3).Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.In study with 44 healthy subjects, both mean AUC and Cmax values for 20 mg rivaroxaban administered orally as crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by liquid meal, only mean AUC was comparable to that after the whole tablet, and Cmax was 18% lower.. DistributionPlasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L.. MetabolismApproximately 51% of an orally administered [14C]-rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites.. ExcretionIn Phase study, following the administration of [14C]-rivaroxaban, approximately one-third (36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces. Unchanged drug is excreted into urine, mainly via active tubular secretion and to lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxabans affinity for influx transporter proteins is unknown.Rivaroxaban is low-clearance drug, with systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is to hours in healthy subjects aged 20 to 45 years.. Specific PopulationsThe effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of rivaroxaban are summarized in Figure 2. Figure 2:Effect of Specific Populations on the Pharmacokinetics of Rivaroxaban[See Dosage and Administration (2.1)]. Figure 2:Effect of Specific Populations on the Pharmacokinetics of Rivaroxaban. GenderGender did not influence the pharmacokinetics or pharmacodynamics of XARELTO.. RaceHealthy Japanese subjects were found to have 20 to 40% on average higher exposures compared to other ethnicities including Chinese. However, these differences in exposure are reduced when values are corrected for body weight.. ElderlyThe terminal elimination half-life is 11 to 13 hours in the elderly subjects aged 60 to 76 years [see Use in Specific Populations (8.5)].. Renal ImpairmentThe safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in study in healthy subjects [CrCl >=80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Figure 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Use in Specific Populations (8.6)].. Hemodialysis in ESRD subjects: Systemic exposure to rivaroxaban administered as single 15 mg dose in ESRD subjects dosed hours after the completion of 4-hour hemodialysis session (post-dialysis) is 56% higher when compared to subjects with normal renal function (see Table 11). The systemic exposure to rivaroxaban administered hours prior to 4-hour hemodialysis session with dialysate flow rate of 600 mL/min and blood flow rate in the range of 320 to 400 mL/min is 47% higher compared to those with normal renal function. The extent of the increase is similar to the increase in patients with CrCl 15 to 50 mL/min taking XARELTO 15 mg. Hemodialysis had no significant impact on rivaroxaban exposure. Protein binding was similar (86% to 89%) in healthy controls and ESRD subjects in this study.. Hepatic ImpairmentThe safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Figure 2). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B) (see Figure 2). Increases in pharmacodynamic effects were also observed [see Use in Specific Populations (8.7)].. Figure 2. Drug InteractionsIn vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A nor induces CYP1A2, 2B6, 2C19, or 3A. In vitro data also indicates low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters.The effects of coadministered drugs on the pharmacokinetics of rivaroxaban exposure are summarized in Figure [see Drug Interactions (7)]. Figure 3:Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban. Figure 3:Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban. AnticoagulantsIn drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban (see Figure 3).. NSAIDs/AspirinIn ROCKET AF, concomitant aspirin use (almost exclusively at dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban (see Figure 3).. ClopidogrelIn two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.. Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport SystemsIn pharmacokinetic trial, XARELTO was administered as single dose in subjects with mild (CrCl 50 to 79 mL/min) or moderate renal impairment (CrCl 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A inhibitor). Compared to XARELTO administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported 76% and 99% increase in AUCinf and 56% and 64% increase in Cmax, respectively. Similar trends in pharmacodynamic effects were also observed.. Figure 3. 12.6QT/QTc Prolongation. In thorough QT study in healthy men and women aged 50 years and older, no QTc prolonging effects were observed for XARELTO (15 mg and 45 mg, single-dose).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. XARELTO is contraindicated in patients with:oactive pathological bleeding [see Warnings and Precautions (5.2)]osevere hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see Adverse Reactions (6.2)]. oactive pathological bleeding [see Warnings and Precautions (5.2)]. osevere hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see Adverse Reactions (6.2)]. oActive pathological bleeding (4)oSevere hypersensitivity reaction to XARELTO (4). oActive pathological bleeding (4). oSevere hypersensitivity reaction to XARELTO (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Rivaroxaban, factor Xa (FXa) inhibitor, is the active ingredient in XARELTO(R) Tablets with the chemical name 5-Chloro-N-((5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-ylmethyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89. The structural formula is:Rivaroxaban is pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.Each XARELTO tablet contains 2.5 mg, 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for XARELTO 2.5 mg is Opadry(R) Light Yellow, containing ferric oxide yellow, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 10 mg tablets is Opadry(R) Pink and for XARELTO 15 mg tablets is Opadry(R) Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is Opadry(R) II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oNonvalvular Atrial Fibrillation: 15 or 20 mg, once daily with food (2.1)oTreatment of DVT and/or PE: 15 mg orally twice daily with food for the first 21 days followed by 20 mg orally once daily with food for the remaining treatment (2.1)oReduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE: 10 mg once daily with or without food, after at least months of standard anticoagulant treatment (2.1)oProphylaxis of DVT Following Hip or Knee Replacement Surgery: 10 mg orally once daily with or without food (2.1)oProphylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding: 10 mg once daily, with or without food, in hospital and after hospital discharge for total recommended duration of 31 to 39 days (2.1)oCAD or PAD: 2.5 mg orally twice daily with or without food, in combination with aspirin (75-100 mg) once daily (2.1). oNonvalvular Atrial Fibrillation: 15 or 20 mg, once daily with food (2.1). oTreatment of DVT and/or PE: 15 mg orally twice daily with food for the first 21 days followed by 20 mg orally once daily with food for the remaining treatment (2.1). oReduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE: 10 mg once daily with or without food, after at least months of standard anticoagulant treatment (2.1). oProphylaxis of DVT Following Hip or Knee Replacement Surgery: 10 mg orally once daily with or without food (2.1). oProphylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding: 10 mg once daily, with or without food, in hospital and after hospital discharge for total recommended duration of 31 to 39 days (2.1). oCAD or PAD: 2.5 mg orally twice daily with or without food, in combination with aspirin (75-100 mg) once daily (2.1). 2.1Recommended Dosage. Table 1:Recommended DosageIndicationRenal ConsiderationsCalculate CrCl based on actual weight. [See Warnings and Precautions (5.4) and Use in Specific Populations (8.6)]DosageFood/TimingSee Clinical Pharmacology (12.3) Reduction in Risk of Stroke in Nonvalvular Atrial FibrillationCrCl >50 mL/min20 mg once dailyTake with evening mealCrCl <=50 mL/minPatients with CrCl <30 mL/min were not studied, but administration of XARELTO is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Use in Specific Populations (8.6)] 15 mg once dailyTake with evening mealTreatment of DVT and/or PECrCl >=15 mL/min 15 mg twice daily after 21 days, transition to 20 mg once daily Take with food, at the same time each dayCrCl <15 mL/minAvoid UseReduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PECrCl >=15 mL/min 10 mg once daily, after at least months of standard anticoagulant treatmentTake with or without foodCrCl <15 mL/minAvoid UseProphylaxis of DVT Following:1.Hip Replacement SurgerySee Dosage and Administration (2.3) CrCl >=15 mL/min 10 mg once daily for 35 days, 6-10 hours after surgery once hemostasis has been establishedTake with or without foodCrCl <15 mL/minAvoid UseoKnee Replacement SurgeryCrCl >=15 mL/min 10 mg once daily for 12 days, 6-10 hours after surgery once hemostasis has been establishedTake with or without foodCrCl <15 mL/minAvoid UseProphylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of BleedingCrCl >=15 mL/min 10 mg once daily, in hospital and after hospital discharge, for total recommended duration of 31 to 39 daysTake with or without foodCrCl <15 mL/minAvoid UseReduction of Risk of Major Cardiovascular Events (CV Death, MI, and Stroke) in CADNo dose adjustment needed based on CrCl2.5 mg twice daily, plus aspirin (75-100 mg) once dailyTake with or without foodReduction of Risk of Major Thrombotic Vascular Events in PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PADNo dose adjustment needed based on CrCl2.5 mg twice daily, plus aspirin (75-100 mg) once daily.Take with or without foodWhen starting therapy after successful lower extremity revascularization procedure, initiate once hemostasis has been established.. 1.Hip Replacement SurgerySee Dosage and Administration (2.3) oKnee Replacement Surgery. 2.2Switching to and from XARELTO. Switching from Warfarin to XARELTO When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.. Switching from XARELTO to Warfarin No clinical trial data are available to guide converting patients from XARELTO to warfarin. XARELTO affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue XARELTO and begin both parenteral anticoagulant and warfarin at the time the next dose of XARELTO would have been taken.. Switching from XARELTO to Anticoagulants other than Warfarin For patients currently taking XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO dose would have been taken [see Drug Interactions (7.4)].. Switching from Anticoagulants other than Warfarin to XARELTO For patients currently receiving an anticoagulant other than warfarin, start XARELTO to hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO at the same time.. 2.3Discontinuation for Surgery and other Interventions. If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see Warnings and Precautions (5.2)]. In deciding whether procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention. XARELTO should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short [see Warnings and Precautions (5.1)]. If oral medication cannot be taken during or after surgical intervention, consider administering parenteral anticoagulant.. 2.4Missed Dose. oFor patients receiving 2.5 mg twice daily: if dose is missed, the patient should take single 2.5 mg XARELTO dose as recommended at the next scheduled time.oFor patients receiving 15 mg twice daily: The patient should take XARELTO immediately to ensure intake of 30 mg XARELTO per day. Two 15 mg tablets may be taken at once. oFor patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed XARELTO dose immediately. The dose should not be doubled within the same day to make up for missed dose.. oFor patients receiving 2.5 mg twice daily: if dose is missed, the patient should take single 2.5 mg XARELTO dose as recommended at the next scheduled time.. oFor patients receiving 15 mg twice daily: The patient should take XARELTO immediately to ensure intake of 30 mg XARELTO per day. Two 15 mg tablets may be taken at once. oFor patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed XARELTO dose immediately. The dose should not be doubled within the same day to make up for missed dose.. 2.5Administration Options. For patients who are unable to swallow whole tablets, XARELTO tablets (all strengths) may be crushed and mixed with applesauce immediately prior to use and administered orally. After the administration of crushed XARELTO 15 mg or 20 mg tablet, the dose should be immediately followed by food. Administration with food is not required for the 2.5 mg or 10 mg tablets [see Clinical Pharmacology (12.3)].. Administration via nasogastric (NG) tube or gastric feeding tube: After confirming gastric placement of the tube, XARELTO tablets (all strengths) may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube. Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of XARELTO distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. After the administration of crushed XARELTO 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding. Enteral feeding is not required following administration of the 2.5 mg or 10 mg tablets [see Clinical Pharmacology (12.3)].Crushed XARELTO tablets (all strengths) are stable in water and in applesauce for up to hours. An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from water suspension of crushed XARELTO tablet to PVC or silicone nasogastric (NG) tubing.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. o2.5 mg tablets: Round, light yellow, and film-coated with triangle pointing down above 2.5 marked on one side and Xa on the other sideo10 mg tablets: Round, light red, biconvex and film-coated with triangle pointing down above 10 marked on one side and Xa on the other sideo15 mg tablets: Round, red, biconvex, and film-coated with triangle pointing down above 15 marked on one side and Xa on the other sideo20 mg tablets: Triangle-shaped, dark red, and film-coated with triangle pointing down above 20 marked on one side and Xa on the other side. o2.5 mg tablets: Round, light yellow, and film-coated with triangle pointing down above 2.5 marked on one side and Xa on the other side. o10 mg tablets: Round, light red, biconvex and film-coated with triangle pointing down above 10 marked on one side and Xa on the other side. o15 mg tablets: Round, red, biconvex, and film-coated with triangle pointing down above 15 marked on one side and Xa on the other side. o20 mg tablets: Triangle-shaped, dark red, and film-coated with triangle pointing down above 20 marked on one side and Xa on the other side. Tablets: 2.5 mg, 10 mg, 15 mg, and 20 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oAvoid combined P-gp and strong CYP3A inhibitors and inducers (7.2, 7.3)oAnticoagulants: Avoid concomitant use (7.4). oAvoid combined P-gp and strong CYP3A inhibitors and inducers (7.2, 7.3). oAnticoagulants: Avoid concomitant use (7.4). 7.1General Inhibition and Induction Properties. Rivaroxaban is substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.. 7.2Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems. Interaction with Combined P-gp and Strong CYP3A InhibitorsAvoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].Although clarithromycin is combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology (12.3)].. Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal ImpairmentXARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].. 7.3Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems. Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. Johns wort) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].. 7.4Anticoagulants and NSAIDs/Aspirin. Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology (12.3)]. Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions (5.2)].

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 XARELTO should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of adult patients in clinical trials for the approved indications of XARELTO (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. In pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3)].Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. XARELTO(R) (rivaroxaban) Tablets are available in the strengths and packages listed below:o10 mg tablets are round, light red, biconvex film-coated tablets marked with triangle pointing down above 10 on one side, and Xa on the other side. The tablets are supplied in the packages listed: NDC 55154-1422-0Overbagged with 10 tablets per bago15 mg tablets are round, red, biconvex film-coated tablets with triangle pointing down above 15 marked on one side and Xa on the other side. The tablets are supplied in the packages listed: NDC 55154-1424-8Bottle containing approximately 2070 tabletso20 mg tablets are triangle-shaped, dark red film-coated tablets with triangle pointing down above 20 marked on one side and Xa on the other side. The tablets are supplied in the packages listed: NDC 55154-1423-8Bottle containing approximately 4440 tablets. o10 mg tablets are round, light red, biconvex film-coated tablets marked with triangle pointing down above 10 on one side, and Xa on the other side. The tablets are supplied in the packages listed: o15 mg tablets are round, red, biconvex film-coated tablets with triangle pointing down above 15 marked on one side and Xa on the other side. The tablets are supplied in the packages listed: o20 mg tablets are triangle-shaped, dark red film-coated tablets with triangle pointing down above 20 marked on one side and Xa on the other side. The tablets are supplied in the packages listed: Store at room temperature between 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].Keep out of the reach of children.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. XARELTO is factor Xa inhibitor indicated:oto reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation (1.1)ofor treatment of deep vein thrombosis (DVT) (1.2)ofor treatment of pulmonary embolism (PE) (1.3)ofor reduction in the risk of recurrence of DVT or PE (1.4)ofor the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery (1.5)ofor prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients (1.6)oto reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD) (1.7)oto reduce the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after recent lower extremity revascularization due to symptomatic PAD (1.8). oto reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation (1.1). ofor treatment of deep vein thrombosis (DVT) (1.2). ofor treatment of pulmonary embolism (PE) (1.3). ofor reduction in the risk of recurrence of DVT or PE (1.4). ofor the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery (1.5). ofor prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients (1.6). oto reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD) (1.7). oto reduce the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after recent lower extremity revascularization due to symptomatic PAD (1.8). 1.1Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation. XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies (14.1)]. 1.2Treatment of Deep Vein Thrombosis. XARELTO is indicated for the treatment of deep vein thrombosis (DVT).. 1.3Treatment of Pulmonary Embolism. XARELTO is indicated for the treatment of pulmonary embolism (PE).. 1.4Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism. XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least months.. 1.5Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery. XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.. 1.6Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding. XARELTO is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding [see Warnings and Precautions (5.2) and Clinical Studies (14.5)].. 1.7Reduction of Risk of Major Cardiovascular Events in Patients with Coronary Artery Disease (CAD). XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in patients with coronary artery disease.. 1.8Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD. XARELTO, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of vascular etiology) in patients with PAD, including patients who have recently undergone lower extremity revascularization procedure due to symptomatic PAD.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Instructions for Patient UseoAdvise patients to take XARELTO only as directed.oRemind patients to not discontinue XARELTO without first talking to their healthcare professional.oAdvise patients with atrial fibrillation to take XARELTO once daily with the evening meal.oAdvise patients for initial treatment of DVT and/or PE to take XARELTO 15 mg or 20 mg tablets with food at approximately the same time every day [see Dosage and Administration (2.1)].oAdvise patients who are at continued risk of recurrent DVT and/or PE after at least months of initial treatment, to take XARELTO 10 mg once daily with or without food [see Dosage and Administration (2.1)].oAdvise patients who cannot swallow the tablet whole to crush XARELTO and combine with small amount of applesauce followed by food [see Dosage and Administration (2.5)].oFor patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush the XARELTO tablet and mix it with small amount of water before administering via the tube [see Dosage and Administration (2.5)].oIf dose is missed, advise the patient to take XARELTO as soon as possible on the same day and continue on the following day with their recommended daily dose regimen [see Dosage and Administration (2.4)].. oAdvise patients to take XARELTO only as directed.. oRemind patients to not discontinue XARELTO without first talking to their healthcare professional.. oAdvise patients with atrial fibrillation to take XARELTO once daily with the evening meal.. oAdvise patients for initial treatment of DVT and/or PE to take XARELTO 15 mg or 20 mg tablets with food at approximately the same time every day [see Dosage and Administration (2.1)].. oAdvise patients who are at continued risk of recurrent DVT and/or PE after at least months of initial treatment, to take XARELTO 10 mg once daily with or without food [see Dosage and Administration (2.1)].. oAdvise patients who cannot swallow the tablet whole to crush XARELTO and combine with small amount of applesauce followed by food [see Dosage and Administration (2.5)].. oFor patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush the XARELTO tablet and mix it with small amount of water before administering via the tube [see Dosage and Administration (2.5)].. oIf dose is missed, advise the patient to take XARELTO as soon as possible on the same day and continue on the following day with their recommended daily dose regimen [see Dosage and Administration (2.4)].. Bleeding RisksoAdvise patients to report any unusual bleeding or bruising to their physician. Inform patients that it might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily when they are treated with XARELTO [see Warnings and Precautions (5.2)].oIf patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to contact his or her physician immediately [see Boxed Warning].. oAdvise patients to report any unusual bleeding or bruising to their physician. Inform patients that it might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily when they are treated with XARELTO [see Warnings and Precautions (5.2)].. oIf patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to contact his or her physician immediately [see Boxed Warning].. Invasive or Surgical ProceduresInstruct patients to inform their healthcare professional that they are taking XARELTO before any invasive procedure (including dental procedures) is scheduled.. Concomitant Medication and HerbalsAdvise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential interactions [see Drug Interactions (7)].. Pregnancy and Pregnancy-Related HemorrhageoAdvise patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with XARELTO [see Use in Specific Populations (8.1)].oAdvise pregnant women receiving XARELTO to immediately report to their physician any bleeding or symptoms of blood loss [see Warnings and Precautions (5.7)].. oAdvise patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with XARELTO [see Use in Specific Populations (8.1)].. oAdvise pregnant women receiving XARELTO to immediately report to their physician any bleeding or symptoms of blood loss [see Warnings and Precautions (5.7)].. LactationAdvise patients to discuss with their physician the benefits and risks of XARELTO for the mother and for the child if they are nursing or intend to nurse during anticoagulant treatment [see Use in Specific Populations (8.2)].. Females and Males of Reproductive PotentialAdvise patients who can become pregnant to discuss pregnancy planning with their physician [see Use in Specific Populations (8.3)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryRivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition (see Data).. Data. Animal DataFollowing single oral administration of mg/kg of radioactive [14C]-rivaroxaban to lactating rats between Day to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. XARELTO is selective inhibitor of FXa. It does not require cofactor (such as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.

NONCLINICAL TOXICOLOGY SECTION.

13 NON-CLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Rivaroxaban was not carcinogenic when administered by oral gavage to mice or rats for up to years. The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/day) were 1- and 2-times, respectively, the human exposure of unbound drug at the human dose of 20 mg/day. Systemic exposures of unbound drug in male and female rats at the highest dose tested (60 mg/kg/day) were 2- and 4-times, respectively, the human exposure.Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in V79 Chinese hamster lung cells in vitro or in the mouse micronucleus test in vivo.No impairment of fertility was observed in male or female rats when given up to 200 mg/kg/day of rivaroxaban orally. This dose resulted in exposure levels, based on the unbound AUC, at least 13 times the exposure in humans given 20 mg rivaroxaban daily.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel XARELTO(R) TABLETS10 mg10 Tablets. bag label.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Dose-dependent inhibition of FXa activity was observed in humans. Neoplastin(R) prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest(R) are also prolonged dose-dependently. Anti-factor Xa activity is also influenced by rivaroxaban.. Specific Populations. Renal ImpairmentThe relationship between systemic exposure and pharmacodynamic activity of rivaroxaban was altered in subjects with renal impairment relative to healthy control subjects [see Use in Specific Populations (8.6)].Table 11:Percentage Increase in Rivaroxaban PK and PD Measures in Subjects with Renal Impairment Relative to Healthy Subjects from Clinical Pharmacology Studies MeasureParameterCreatinine Clearance (mL/min)50-7930-4915-29ESRD (on dialysis)Separate stand-alone study.ESRD (post-dialysis)PT Prothrombin time; FXa Coagulation factor Xa; AUC Area under the plasma concentration-time curve; AUEC Area under the effect-time curveExposureAUC4452644756FXa InhibitionAUEC50861004933PT ProlongationAUEC33116144112158. Hepatic ImpairmentAnti-Factor Xa activity was similar in subjects with normal hepatic function and in mild hepatic impairment (Child-Pugh class). There is no clear understanding of the impact of hepatic impairment beyond this degree on the coagulation cascade and its relationship to efficacy and safety.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe absolute bioavailability of rivaroxaban is dose-dependent. For the 2.5 mg and 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. XARELTO 2.5 mg and 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with food [see Dosage and Administration (2.1)].The maximum concentrations (Cmax) of rivaroxaban appear to hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of XARELTO (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or XARELTO (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban (see Figure 3).Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.In study with 44 healthy subjects, both mean AUC and Cmax values for 20 mg rivaroxaban administered orally as crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by liquid meal, only mean AUC was comparable to that after the whole tablet, and Cmax was 18% lower.. DistributionPlasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L.. MetabolismApproximately 51% of an orally administered [14C]-rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites.. ExcretionIn Phase study, following the administration of [14C]-rivaroxaban, approximately one-third (36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces. Unchanged drug is excreted into urine, mainly via active tubular secretion and to lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxabans affinity for influx transporter proteins is unknown.Rivaroxaban is low-clearance drug, with systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is to hours in healthy subjects aged 20 to 45 years.. Specific PopulationsThe effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of rivaroxaban are summarized in Figure 2. Figure 2:Effect of Specific Populations on the Pharmacokinetics of Rivaroxaban[See Dosage and Administration (2.1)]. Figure 2:Effect of Specific Populations on the Pharmacokinetics of Rivaroxaban. GenderGender did not influence the pharmacokinetics or pharmacodynamics of XARELTO.. RaceHealthy Japanese subjects were found to have 20 to 40% on average higher exposures compared to other ethnicities including Chinese. However, these differences in exposure are reduced when values are corrected for body weight.. ElderlyThe terminal elimination half-life is 11 to 13 hours in the elderly subjects aged 60 to 76 years [see Use in Specific Populations (8.5)].. Renal ImpairmentThe safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in study in healthy subjects [CrCl >=80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Figure 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Use in Specific Populations (8.6)].. Hemodialysis in ESRD subjects: Systemic exposure to rivaroxaban administered as single 15 mg dose in ESRD subjects dosed hours after the completion of 4-hour hemodialysis session (post-dialysis) is 56% higher when compared to subjects with normal renal function (see Table 11). The systemic exposure to rivaroxaban administered hours prior to 4-hour hemodialysis session with dialysate flow rate of 600 mL/min and blood flow rate in the range of 320 to 400 mL/min is 47% higher compared to those with normal renal function. The extent of the increase is similar to the increase in patients with CrCl 15 to 50 mL/min taking XARELTO 15 mg. Hemodialysis had no significant impact on rivaroxaban exposure. Protein binding was similar (86% to 89%) in healthy controls and ESRD subjects in this study.. Hepatic ImpairmentThe safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Figure 2). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B) (see Figure 2). Increases in pharmacodynamic effects were also observed [see Use in Specific Populations (8.7)].. Figure 2. Drug InteractionsIn vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A nor induces CYP1A2, 2B6, 2C19, or 3A. In vitro data also indicates low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters.The effects of coadministered drugs on the pharmacokinetics of rivaroxaban exposure are summarized in Figure [see Drug Interactions (7)]. Figure 3:Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban. Figure 3:Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban. AnticoagulantsIn drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban (see Figure 3).. NSAIDs/AspirinIn ROCKET AF, concomitant aspirin use (almost exclusively at dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban (see Figure 3).. ClopidogrelIn two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.. Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport SystemsIn pharmacokinetic trial, XARELTO was administered as single dose in subjects with mild (CrCl 50 to 79 mL/min) or moderate renal impairment (CrCl 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A inhibitor). Compared to XARELTO administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported 76% and 99% increase in AUCinf and 56% and 64% increase in Cmax, respectively. Similar trends in pharmacodynamic effects were also observed.. Figure 3.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe limited available data on XARELTO in pregnant women are insufficient to inform drug-associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to pregnant woman [see Warnings and Precautions (5.2, 5.7)].Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. 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 is risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.. Fetal/Neonatal Adverse ReactionsBased on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.. Labor or DeliveryAll patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see Warnings and Precautions (5.7)]. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting. Data. Human DataThere are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.. Animal DataRivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of >=10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.7, 1.8)08/2021Dosage and Administration (2.1)08/2021.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. In pharmacokinetic studies, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3)].. Nonvalvular Atrial Fibrillation. Patients with Chronic Kidney Disease not on DialysisIn the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl <30 mL/min were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment [see Clinical Pharmacology (12.3)].. Patients with End-Stage Renal Disease on DialysisClinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study [see Clinical Pharmacology (12.2, 12.3)]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF.. Treatment of DVT and/or PE and Reduction in the Risk of Recurrence of DVT and/or PEIn the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.. Prophylaxis of DVT Following Hip or Knee Replacement SurgeryThe combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported possible increase in total venous thromboemboli in this population. In the RECORD 1-3 trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of BleedingPatients with CrCl values <30 mL/min at screening were excluded from the MAGELLAN study. In patients with CrCl <30 mL/min dose of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid use of XARELTO in patients with CrCl <15 mL/min.. Reduction of Risk of Major Cardiovascular Events in Patients with CAD and Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients After Recent Lower Extremity Revascularization due to Symptomatic PAD. Patients with Chronic Kidney Disease not on DialysisPatients with CrCl <15 mL/min at screening were excluded from COMPASS and VOYAGER, and limited data are available for patients with CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)], whose efficacy and safety outcomes were similar to those with preserved renal function.. Patients with End-Stage Renal Disease on DialysisNo clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS or VOYAGER. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study [see Clinical Pharmacology (12.2, 12.3)]. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEXARELTO(R) (zah-REL-toe)(rivaroxaban)tabletsThis Medication Guide has been approved by the U.S. Food and Drug AdministrationRevised: 08/2021 What is the most important information should know about XARELTOXARELTO may cause serious side effects, including:oIncreased risk of blood clots if you stop taking XARELTO. People with atrial fibrillation (a type of irregular heart beat) that is not caused by heart valve problem (non-valvular) 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. XARELTO lowers your chance of having stroke by helping to prevent clots from forming. If you stop taking XARELTO, you may have increased risk of forming clot in your blood. Do not stop taking XARELTO without talking to the doctor who prescribes it for you. Stopping XARELTO increases your risk of having stroke. If you have to stop taking XARELTO, your doctor may prescribe another blood thinner medicine to prevent blood clot from forming.oIncreased risk of bleeding. XARELTO can cause bleeding which can be serious and may lead to death. This is because XARELTO is blood thinner medicine (anticoagulant) that lowers blood clotting. During treatment with XARELTO you are likely to bruise more easily, and it may take longer for bleeding to stop. You may have higher risk of bleeding if you take XARELTO and have certain other medical problems. You may have higher risk of bleeding if you take XARELTO and take other medicines that increase your risk of bleeding, including:Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above. Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding: oaspirin or aspirin containing productsolong-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs)owarfarin sodium (Coumadin(R), Jantoven(R))oany medicine that contains heparinoclopidogrel (Plavix(R))oselective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)oother medicines to prevent or treat blood clotsounexpected bleeding or bleeding that lasts long time, such as: onose bleeds that happen oftenounusual bleeding from the gumsomenstrual bleeding that is heavier than normal or vaginal bleedingobleeding that is severe or you cannot controlored, pink or brown urineobright red or black stools (looks like tar)ocough up blood or blood clotsovomit blood or your vomit looks like coffee groundsoheadaches, feeling dizzy or weakopain, swelling, or new drainage at wound sites oSpinal or epidural blood clots (hematoma). People who take blood thinner medicine (anticoagulant) like XARELTO, 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: If you take XARELTO 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:oa thin tube called an epidural catheter is placed in your back to give you certain medicineoyou take NSAIDs or medicine to prevent blood from clottingoyou have history of difficult or repeated epidural or spinal puncturesoyou have history of problems with your spine or have had surgery on your spine oback painotinglingonumbnessomuscle weakness (especially in your legs and feet)oloss of control of the bowels or bladder (incontinence)XARELTO is not for use in people with artificial heart valves.XARELTO is not for use in people with antiphospholipid syndrome (APS), especially with positive triple antibody testing. What is XARELTOXARELTO is prescription medicine used to: oreduce the risk of stroke and blood clots in people who have medical condition called atrial fibrillation that is not caused by heart valve problem. With atrial fibrillation, part of the heart does not beat the way it should. This can lead to the formation of blood clots, which can travel to the brain, causing stroke, or to other parts of the body.otreat blood clots in the veins of your legs (deep vein thrombosis or DVT) or lungs (pulmonary embolism or PE)oreduce the risk of blood clots happening again in people who continue to be at risk for DVT or PE after receiving treatment for blood clots for at least months.ohelp prevent blood clot in the legs and lungs of people who have just had hip or knee replacement surgery.ohelp prevent blood clots in certain people hospitalized for an acute illness and after discharge who are at risk of getting blood clots because of the loss of or decreased ability to move around (mobility) and other risks for getting blood clots and who do not have high risk of bleeding. XARELTO is used with low dose aspirin to: oreduce the risk of serious heart problems, heart attack and stroke in people with coronary artery disease (a condition where the blood supply to the heart is reduced or blocked).oreduce the risk of sudden decrease in blood flow to the legs, major amputation, serious heart problems or stroke in people with peripheral artery disease (a condition where the blood flow to the legs is reduced) and includes people who have recently had procedure to improve blood flow to the legs.It is not known if XARELTO is safe and effective in children.Do not take XARELTO if you:ocurrently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO if you currently have unusual bleeding.oare allergic to rivaroxaban or any of the ingredients in XARELTO. See the end of this Medication Guide for complete list of ingredients in XARELTO.Before taking XARELTO, tell your doctor about all of your medical conditions, including if you:ohave or ever had bleeding problemsohave liver or kidney problemsohave antiphospholipid syndrome (APS)oare pregnant or plan to become pregnant. It is not known if XARELTO will harm your unborn baby. oTell your doctor right away if you become pregnant during treatment with XARELTO. Taking XARELTO while you are pregnant may increase the risk of bleeding in you or in your unborn baby. oIf you take XARELTO during pregnancy tell your doctor right away if you have any signs or symptoms of bleeding or blood loss. See What is the most important information should know about XARELTO for signs and symptoms of bleeding. oare breastfeeding or plan to breastfeed. XARELTO can pass into your breast milk. Talk to your doctor about the best way to feed your baby during treatment with XARELTO.Tell all of your doctors and dentists that you are taking XARELTO. They should talk to the doctor who prescribed XARELTO for you before you have any surgery, medical or dental procedure. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way XARELTO works, causing side effects. Certain medicines may increase your risk of bleeding. See What is the most important information should know about XARELTO Especially tell your doctor if you take: oketoconazoleoerythromycinophenytoinoSt. Johns wortoritonavirocarbamazepineorifampinHow should take XARELTOoTake XARELTO exactly as prescribed by your doctor.oDo not change your dose or stop taking XARELTO unless your doctor tells you to. Your doctor may change your dose if needed.oYour doctor will decide how long you should take XARELTO.oXARELTO may need to be stopped for one or more days before any surgery or medical or dental procedure. Your doctor will tell you when to stop taking XARELTO and when to start taking XARELTO again after your surgery or procedure.oIf you need to stop taking XARELTO for any reason, talk to the doctor who prescribed XARELTO to you to find out when you should stop taking it. Do not stop taking XARELTO without first talking to the doctor who prescribes it to you.oIf you have difficulty swallowing XARELTO tablets whole, talk to your doctor about other ways to take XARELTO. oDo not run out of XARELTO. Refill your prescription of XARELTO before you run out. When leaving the hospital following hip or knee replacement, be sure that you will have XARELTO available to avoid missing any doses.oIf you take too much XARELTO, go to the nearest hospital emergency room or call your doctor right away.If you take XARELTO for:oAtrial fibrillation that is not caused by heart valve problem:oTake XARELTO time day with your evening meal.oIf you miss dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time. oBlood clots in the veins of your legs or lungs:oTake XARELTO or times day as prescribed by your doctor.oFor the 10 mg dose, take XARELTO with or without food.oFor the 15 mg and 20 mg doses, take XARELTO with food at the same time each day.oIf you miss dose: oIf you take the 15 mg dose of XARELTO times day (a total of 30 mg of XARELTO in day): Take XARELTO as soon as you remember on the same day. You may take doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.oIf you take XARELTO time day: Take XARELTO as soon as you remember on the same day. Take your next dose at your regularly scheduled time.oHip or knee replacement surgery:oTake XARELTO time day with or without food.oIf you miss dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.oBlood clots in people hospitalized for an acute illness:oTake XARELTO time day, with or without food, while you are in the hospital and after you are discharged as prescribed by your doctor.oIf you miss dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.oReducing the risk of serious heart problems, heart attack and stroke in coronary artery disease:oTake XARELTO 2.5 mg times day with or without food.oIf you miss dose of XARELTO, take your next dose at your regularly scheduled time.oTake aspirin 75 to 100 mg once daily as instructed by your doctor.oReducing the risk of sudden decrease in blood flow to the legs, major amputation, serious heart problems or stroke in people with peripheral artery disease including those who have recently had procedure to improve blood flow to the legs:oTake XARELTO 2.5 mg times day with or without food.oIf you miss dose of XARELTO, take your next dose at your regularly scheduled time.oTake aspirin 75 to 100 mg once daily as instructed by your doctor.What are the possible side effects of XARELTOXARELTO may cause serious side effects:oSee What is the most important information should know about XARELTOThe most common side effect of XARELTO was bleeding.Call your doctor for medical advice about side effects. You may report side effects to FDA at 800-FDA-1088.How should store XARELTOoStore XARELTO at room temperature between 68F to 77F (20C to 25C).Keep XARELTO and all medicines out of the reach of children.General information about the safe and effective use of XARELTO.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use XARELTO for condition for which it was not prescribed. Do not give XARELTO 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 XARELTO that is written for health professionals.What are the ingredients in XARELTOActive ingredient: rivaroxaban Inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.The proprietary film coating mixture for XARELTO 2.5 mg tablets is Opadry(R) Light Yellow and contains: ferric oxide yellow, hypromellose, polyethylene glycol 3350, and titanium dioxide.The proprietary film coating mixture for XARELTO 10 mg tablets is Opadry(R) Pink and contains: ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.The proprietary film coating mixture for XARELTO 15 mg tablets is Opadry(R) Red and contains: ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.The proprietary film coating mixture for XARELTO 20 mg tablets is Opadry(R) II Dark Red and contains: ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.Manufactured by: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany(C) 2011-2021 Janssen Pharmaceutical Companies Trademarks are property of their respective owners.For more information go to www.XARELTO-US.com or call 1-800-526-7736.Distributed by:Cardinal HealthDublin, OH 43017L79611120L79620720L49750740920. oIncreased risk of blood clots if you stop taking XARELTO. People with atrial fibrillation (a type of irregular heart beat) that is not caused by heart valve problem (non-valvular) 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. XARELTO lowers your chance of having stroke by helping to prevent clots from forming. If you stop taking XARELTO, you may have increased risk of forming clot in your blood. Do not stop taking XARELTO without talking to the doctor who prescribes it for you. Stopping XARELTO increases your risk of having stroke. If you have to stop taking XARELTO, your doctor may prescribe another blood thinner medicine to prevent blood clot from forming.. oIncreased risk of bleeding. XARELTO can cause bleeding which can be serious and may lead to death. This is because XARELTO is blood thinner medicine (anticoagulant) that lowers blood clotting. During treatment with XARELTO you are likely to bruise more easily, and it may take longer for bleeding to stop. You may have higher risk of bleeding if you take XARELTO and have certain other medical problems. You may have higher risk of bleeding if you take XARELTO and take other medicines that increase your risk of bleeding, including:Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above. Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding: oaspirin or aspirin containing productsolong-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs)owarfarin sodium (Coumadin(R), Jantoven(R))oany medicine that contains heparinoclopidogrel (Plavix(R))oselective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)oother medicines to prevent or treat blood clotsounexpected bleeding or bleeding that lasts long time, such as: onose bleeds that happen oftenounusual bleeding from the gumsomenstrual bleeding that is heavier than normal or vaginal bleedingobleeding that is severe or you cannot controlored, pink or brown urineobright red or black stools (looks like tar)ocough up blood or blood clotsovomit blood or your vomit looks like coffee groundsoheadaches, feeling dizzy or weakopain, swelling, or new drainage at wound sites oaspirin or aspirin containing products. olong-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs). owarfarin sodium (Coumadin(R), Jantoven(R)). oany medicine that contains heparin. oclopidogrel (Plavix(R)). oselective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). oother medicines to prevent or treat blood clots. ounexpected bleeding or bleeding that lasts long time, such as: onose bleeds that happen oftenounusual bleeding from the gumsomenstrual bleeding that is heavier than normal or vaginal bleeding. onose bleeds that happen often. ounusual bleeding from the gums. omenstrual bleeding that is heavier than normal or vaginal bleeding. obleeding that is severe or you cannot control. ored, pink or brown urine. obright red or black stools (looks like tar). ocough up blood or blood clots. ovomit blood or your vomit looks like coffee grounds. oheadaches, feeling dizzy or weak. opain, swelling, or new drainage at wound sites. oSpinal or epidural blood clots (hematoma). People who take blood thinner medicine (anticoagulant) like XARELTO, 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: If you take XARELTO 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:oa thin tube called an epidural catheter is placed in your back to give you certain medicineoyou take NSAIDs or medicine to prevent blood from clottingoyou have history of difficult or repeated epidural or spinal puncturesoyou have history of problems with your spine or have had surgery on your spine oa thin tube called an epidural catheter is placed in your back to give you certain medicine. oyou take NSAIDs or medicine to prevent blood from clotting. oyou have history of difficult or repeated epidural or spinal punctures. oyou have history of problems with your spine or have had surgery on your spine. oback pain. otingling. onumbness. omuscle weakness (especially in your legs and feet). oloss of control of the bowels or bladder (incontinence). What is XARELTOXARELTO is prescription medicine used to: oreduce the risk of stroke and blood clots in people who have medical condition called atrial fibrillation that is not caused by heart valve problem. With atrial fibrillation, part of the heart does not beat the way it should. This can lead to the formation of blood clots, which can travel to the brain, causing stroke, or to other parts of the body.. otreat blood clots in the veins of your legs (deep vein thrombosis or DVT) or lungs (pulmonary embolism or PE). oreduce the risk of blood clots happening again in people who continue to be at risk for DVT or PE after receiving treatment for blood clots for at least months.. ohelp prevent blood clot in the legs and lungs of people who have just had hip or knee replacement surgery.. ohelp prevent blood clots in certain people hospitalized for an acute illness and after discharge who are at risk of getting blood clots because of the loss of or decreased ability to move around (mobility) and other risks for getting blood clots and who do not have high risk of bleeding.. XARELTO is used with low dose aspirin to: oreduce the risk of serious heart problems, heart attack and stroke in people with coronary artery disease (a condition where the blood supply to the heart is reduced or blocked).. oreduce the risk of sudden decrease in blood flow to the legs, major amputation, serious heart problems or stroke in people with peripheral artery disease (a condition where the blood flow to the legs is reduced) and includes people who have recently had procedure to improve blood flow to the legs.. ocurrently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO if you currently have unusual bleeding.. oare allergic to rivaroxaban or any of the ingredients in XARELTO. See the end of this Medication Guide for complete list of ingredients in XARELTO.. ohave or ever had bleeding problems. ohave liver or kidney problems. ohave antiphospholipid syndrome (APS). oare pregnant or plan to become pregnant. It is not known if XARELTO will harm your unborn baby. oTell your doctor right away if you become pregnant during treatment with XARELTO. Taking XARELTO while you are pregnant may increase the risk of bleeding in you or in your unborn baby. oIf you take XARELTO during pregnancy tell your doctor right away if you have any signs or symptoms of bleeding or blood loss. See What is the most important information should know about XARELTO for signs and symptoms of bleeding. oTell your doctor right away if you become pregnant during treatment with XARELTO. Taking XARELTO while you are pregnant may increase the risk of bleeding in you or in your unborn baby. oIf you take XARELTO during pregnancy tell your doctor right away if you have any signs or symptoms of bleeding or blood loss. See What is the most important information should know about XARELTO for signs and symptoms of bleeding. oare breastfeeding or plan to breastfeed. XARELTO can pass into your breast milk. Talk to your doctor about the best way to feed your baby during treatment with XARELTO.. oketoconazole. oerythromycin. ophenytoin. oSt. Johns wort. oritonavir. ocarbamazepine. orifampin. oTake XARELTO exactly as prescribed by your doctor.. oDo not change your dose or stop taking XARELTO unless your doctor tells you to. Your doctor may change your dose if needed.. oYour doctor will decide how long you should take XARELTO.. oXARELTO may need to be stopped for one or more days before any surgery or medical or dental procedure. Your doctor will tell you when to stop taking XARELTO and when to start taking XARELTO again after your surgery or procedure.. oIf you need to stop taking XARELTO for any reason, talk to the doctor who prescribed XARELTO to you to find out when you should stop taking it. Do not stop taking XARELTO without first talking to the doctor who prescribes it to you.. oIf you have difficulty swallowing XARELTO tablets whole, talk to your doctor about other ways to take XARELTO. oDo not run out of XARELTO. Refill your prescription of XARELTO before you run out. When leaving the hospital following hip or knee replacement, be sure that you will have XARELTO available to avoid missing any doses.. oIf you take too much XARELTO, go to the nearest hospital emergency room or call your doctor right away.. oAtrial fibrillation that is not caused by heart valve problem:oTake XARELTO time day with your evening meal.oIf you miss dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time. oTake XARELTO time day with your evening meal.. oIf you miss dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time. oBlood clots in the veins of your legs or lungs:oTake XARELTO or times day as prescribed by your doctor.oFor the 10 mg dose, take XARELTO with or without food.oFor the 15 mg and 20 mg doses, take XARELTO with food at the same time each day.oIf you miss dose: oIf you take the 15 mg dose of XARELTO times day (a total of 30 mg of XARELTO in day): Take XARELTO as soon as you remember on the same day. You may take doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.oIf you take XARELTO time day: Take XARELTO as soon as you remember on the same day. Take your next dose at your regularly scheduled time.. oTake XARELTO or times day as prescribed by your doctor.. oFor the 10 mg dose, take XARELTO with or without food.. oFor the 15 mg and 20 mg doses, take XARELTO with food at the same time each day.. oIf you miss dose: oIf you take the 15 mg dose of XARELTO times day (a total of 30 mg of XARELTO in day): Take XARELTO as soon as you remember on the same day. You may take doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.oIf you take XARELTO time day: Take XARELTO as soon as you remember on the same day. Take your next dose at your regularly scheduled time.. oIf you take the 15 mg dose of XARELTO times day (a total of 30 mg of XARELTO in day): Take XARELTO as soon as you remember on the same day. You may take doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.. oIf you take XARELTO time day: Take XARELTO as soon as you remember on the same day. Take your next dose at your regularly scheduled time.. oHip or knee replacement surgery:oTake XARELTO time day with or without food.oIf you miss dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.. oTake XARELTO time day with or without food.. oIf you miss dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.. oBlood clots in people hospitalized for an acute illness:oTake XARELTO time day, with or without food, while you are in the hospital and after you are discharged as prescribed by your doctor.oIf you miss dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.. oTake XARELTO time day, with or without food, while you are in the hospital and after you are discharged as prescribed by your doctor.. oIf you miss dose of XARELTO, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.. oReducing the risk of serious heart problems, heart attack and stroke in coronary artery disease:oTake XARELTO 2.5 mg times day with or without food.oIf you miss dose of XARELTO, take your next dose at your regularly scheduled time.oTake aspirin 75 to 100 mg once daily as instructed by your doctor.. oTake XARELTO 2.5 mg times day with or without food.. oIf you miss dose of XARELTO, take your next dose at your regularly scheduled time.. oTake aspirin 75 to 100 mg once daily as instructed by your doctor.. oReducing the risk of sudden decrease in blood flow to the legs, major amputation, serious heart problems or stroke in people with peripheral artery disease including those who have recently had procedure to improve blood flow to the legs:oTake XARELTO 2.5 mg times day with or without food.oIf you miss dose of XARELTO, take your next dose at your regularly scheduled time.oTake aspirin 75 to 100 mg once daily as instructed by your doctor.. oTake XARELTO 2.5 mg times day with or without food.. oIf you miss dose of XARELTO, take your next dose at your regularly scheduled time.. oTake aspirin 75 to 100 mg once daily as instructed by your doctor.. oSee What is the most important information should know about XARELTO. oStore XARELTO at room temperature between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

A.Premature discontinuation of XARELTO increases the risk of thrombotic eventsPremature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for reason other than pathological bleeding or completion of course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1), and Clinical Studies (14.1)].. A.Premature discontinuation of XARELTO increases the risk of thrombotic events.

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oRenal impairment: Avoid or adjust dose (8.6)oHepatic impairment: Avoid use in Child-Pugh and hepatic impairment or hepatic disease associated with coagulopathy (8.7). oRenal impairment: Avoid or adjust dose (8.6). oHepatic impairment: Avoid use in Child-Pugh and hepatic impairment or hepatic disease associated with coagulopathy (8.7). 8.1 Pregnancy. Risk SummaryThe limited available data on XARELTO in pregnant women are insufficient to inform drug-associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to pregnant woman [see Warnings and Precautions (5.2, 5.7)].Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. 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 is risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.. Fetal/Neonatal Adverse ReactionsBased on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.. Labor or DeliveryAll patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see Warnings and Precautions (5.7)]. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting. Data. Human DataThere are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.. Animal DataRivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of >=10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about times maximum human exposure of the unbound drug at the human dose of 20 mg/day).. 8.2 Lactation. Risk SummaryRivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition (see Data).. Data. Animal DataFollowing single oral administration of mg/kg of radioactive [14C]-rivaroxaban to lactating rats between Day to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.. 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 XARELTO 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 number of adult patients in clinical trials for the approved indications of XARELTO (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients [see Clinical Pharmacology (12.3) and Clinical Studies (14)].. 8.6 Renal Impairment. In pharmacokinetic studies, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3)].. Nonvalvular Atrial Fibrillation. Patients with Chronic Kidney Disease not on DialysisIn the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl <30 mL/min were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment [see Clinical Pharmacology (12.3)].. Patients with End-Stage Renal Disease on DialysisClinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study [see Clinical Pharmacology (12.2, 12.3)]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF.. Treatment of DVT and/or PE and Reduction in the Risk of Recurrence of DVT and/or PEIn the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.. Prophylaxis of DVT Following Hip or Knee Replacement SurgeryThe combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported possible increase in total venous thromboemboli in this population. In the RECORD 1-3 trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of BleedingPatients with CrCl values <30 mL/min at screening were excluded from the MAGELLAN study. In patients with CrCl <30 mL/min dose of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid use of XARELTO in patients with CrCl <15 mL/min.. Reduction of Risk of Major Cardiovascular Events in Patients with CAD and Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients After Recent Lower Extremity Revascularization due to Symptomatic PAD. Patients with Chronic Kidney Disease not on DialysisPatients with CrCl <15 mL/min at screening were excluded from COMPASS and VOYAGER, and limited data are available for patients with CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)], whose efficacy and safety outcomes were similar to those with preserved renal function.. Patients with End-Stage Renal Disease on DialysisNo clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS or VOYAGER. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study [see Clinical Pharmacology (12.2, 12.3)]. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS. 8.7 Hepatic Impairment. In pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3)].Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oRisk of bleeding: XARELTO can cause serious and fatal bleeding. An agent to reverse the activity of rivaroxaban is available. (5.2)oPregnancy-related hemorrhage: Use XARELTO with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. (5.7, 8.1)oProsthetic heart valves: XARELTO use not recommended (5.8)oIncreased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: XARELTO use not recommended. (5.10). oRisk of bleeding: XARELTO can cause serious and fatal bleeding. An agent to reverse the activity of rivaroxaban is available. (5.2). oPregnancy-related hemorrhage: Use XARELTO with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. (5.7, 8.1). oProsthetic heart valves: XARELTO use not recommended (5.8). oIncreased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: XARELTO use not recommended. (5.10). 5.1Increased Risk of Thrombotic Events after Premature Discontinuation. Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO is discontinued for reason other than pathological bleeding or completion of course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.2, 2.3) and Clinical Studies (14.1)].. 5.2Risk of Bleeding. XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is to hours in healthy subjects aged 20 to 45 years.Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.4)], selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions (7.2)].. Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of BleedingAcutely ill medical patients with the following conditions are at increased risk of bleeding with the use of XARELTO for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e. undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy. XARELTO is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.. Reversal of Anticoagulant EffectAn agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology (12.3)]. Protamine sulfate and vitamin are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.. 5.3Spinal/Epidural Anesthesia or Puncture. When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].To reduce the potential risk of bleeding associated with the concurrent use of XARELTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however, the exact timing to reach sufficiently low anticoagulant effect in each patient is not known.An indwelling epidural or intrathecal catheter should not be removed before at least half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO [see Clinical Pharmacology (12.3)]. The next XARELTO dose should not be administered earlier than hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for 24 hours.Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.. 5.4Use in Patients with Renal Impairment. Nonvalvular Atrial FibrillationPeriodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly [see Dosage and Administration (2.1)]. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations (8.6)]. Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PEIn patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients. Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations (8.6)].. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement SurgeryIn patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients. Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations (8.6)]. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of BleedingIn patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations (8.6)]. 5.5Use in Patients with Hepatic Impairment. No clinical data are available for patients with severe hepatic impairment.Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations (8.7)].. 5.6Use with P-gp and Strong CYP3A Inhibitors or Inducers. Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions (7.2)].Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions (7.3)].. 5.7Risk of Pregnancy-Related Hemorrhage. In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)].. 5.8Patients with Prosthetic Heart Valves. On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of XARELTO have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO is not recommended in patients with prosthetic heart valves.. 5.9Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy. Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.. 5.10Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome. Direct-acting oral anticoagulants (DOACs), including XARELTO, 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, and anti-beta 2-glycoprotein antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin antagonist therapy.