FDA label 55e8002e-0d6d-3bbd-e063-6394a90ac337

WARNING: (A) PREMATURE DISCONTINUATION OF RIVAROXABAN TABLETS INCREASE THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA WARNING: (A) PREMATURE DISCONTINUATION OF RIVAROXABAN TABLETS INCREASE THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning. (A) Premature discontinuation of rivaroxaban tablets increase the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including rivaroxaban tablets, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if rivaroxaban tablets are discontinued for a reason other than pathological bleeding or completion of a course of therapy. ( 2.2 , 2.3 , 5.1 , 14.1 ) (B) Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with rivaroxaban tablets 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 ) A. Premature discontinuation of rivaroxaban tablets increase the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including rivaroxaban tablets, increases the risk of thrombotic events. If anticoagulation with rivaroxaban tablets is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3 , 2.4) , Warnings and Precautions (5.1) , and Clinical Studies (14.1) ] . B. Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with rivaroxaban tablets who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants a history of traumatic or repeated epidural or spinal punctures a history of spinal deformity or spinal surgery optimal timing between the administration of rivaroxaban tablets 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) ] .

5 WARNINGS AND PRECAUTIONS Risk of bleeding: Rivaroxaban tablets can cause serious and fatal bleeding. ( 5.2 ) Pregnancy-related hemorrhage: Use rivaroxaban tablets with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. ( 5.7 , 8.1 ) Prosthetic heart valves: Rivaroxaban tablets use not recommended. ( 5.8 ) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: Rivaroxaban tablets use not recommended. ( 5.10 ) 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including rivaroxaban tablets, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from rivaroxaban tablets to warfarin in clinical trials in atrial fibrillation patients. If rivaroxaban tablets are discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3 , 2.4) and Clinical Studies (14.1) ] . 5.2 Risk of Bleeding Rivaroxaban tablets increase the risk of bleeding, including in any organ, and can cause serious or fatal bleeding. In deciding whether to prescribe rivaroxaban tablets 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 rivaroxaban tablets in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y 12 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 Bleeding Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of rivaroxaban tablets 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. Rivaroxaban tablets are not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding. Reversal of Anticoagulant Effect A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology (12.3) ] . Protamine sulfate and vitamin K 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 a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended. 5.3 Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning ] . To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban tablets and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban tablets [see Clinical Pharmacology (12.3) ] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban tablets is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of rivaroxaban tablets [see Clinical Pharmacology (12.3) ] . The next rivaroxaban tablets dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of rivaroxaban tablets 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. 5.4 Use in Patients with Renal Impairment Nonvalvular Atrial Fibrillation Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly [see Dosage and Administration (2.1) ] . Consider dose adjustment or discontinuation of rivaroxaban tablets in patients who develop acute renal failure while on rivaroxaban tablets [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 PE In 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 rivaroxaban tablets in these patients. Discontinue rivaroxaban tablets 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 Surgery In 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 rivaroxaban tablets in these patients. Discontinue rivaroxaban tablets 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 Bleeding In 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 rivaroxaban tablets in these patients. Discontinue rivaroxaban tablets in patients who develop acute renal failure while on treatment [see Use in Specific Populations (8.6) ]. Pediatric Patients There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m 2 ); therefore, avoid the use of rivaroxaban in these patients. There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5 th percentile; therefore, avoid the use of rivaroxaban in these patients [see Dosage and Administration (2.2) and Use in Specific Populations (8.6) ] . 5.5 Use in Patients with Hepatic Impairment No clinical data are available for adult patients with severe hepatic impairment. Avoid use of rivaroxaban tablets 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) ] . No clinical data are available in pediatric patients with hepatic impairment. 5.6 Use with P-gp and Strong CYP3A Inhibitors or Inducers Avoid concomitant use of rivaroxaban tablets with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions (7.2) ] . Avoid concomitant use of rivaroxaban tablets with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions (7.3) ] . 5.7 Risk of Pregnancy-Related Hemorrhage In pregnant women, rivaroxaban tablets should be used only if the potential benefit justifies the potential risk to the mother and fetus. Rivaroxaban tablets dosing in pregnancy has not been studied. The anticoagulant effect of rivaroxaban tablets cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1) ] . 5.8 Patients with Prosthetic Heart Valves On the basis of the GALILEO study, use of rivaroxaban tablets is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to rivaroxaban tablets experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of rivaroxaban tablets have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of rivaroxaban tablets is not recommended in patients with prosthetic heart valves. 5.9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy Initiation of rivaroxaban tablets 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. 5.10 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including rivaroxaban tablets, 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 I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed in other sections of the labeling: Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation [see Boxed Warning and Warnings and Precautions (5.1) ] Bleeding Risk [see Warnings and Precautions (5.2 , 5.4 , 5.5 , 5.6 , 5.7) ] Spinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions (5.3) ] The most common adverse reaction (>5%) in adult patients was bleeding. ( 6.1 ) The most common adverse reactions (>10%) in pediatric patients were bleeding, cough, vomiting, and gastroenteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact HEC Pharm USA Inc., at 1-800-610-5709 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During clinical development for the approved indications, 34,947 adult patients were exposed to rivaroxaban tablets. Hemorrhage The most common adverse reactions with rivaroxaban tablets were bleeding complications [see Warnings and Precautions (5.2) ] . Nonvalvular Atrial Fibrillation In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for rivaroxaban tablets vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups. Table 5 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial. Table 5: Bleeding Events in ROCKET AF Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. - On Treatment Plus 2 Days Parameter Rivaroxaban Tablets N=7111 n (%/year) Warfarin N=7125 n (%/year) Rivaroxaban Tablets vs. Warfarin HR (95% CI) Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. Major Bleeding Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. 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 Stroke Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. 36 (0.3) 58 (0.5) 0.63 (0.42, 0.96) Other ICH 19 (0.2) 26 (0.2) 0.74 (0.41, 1.34) Gastrointestinal (GI) Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. 221 (2.0) 140 (1.2) 1.61 (1.30, 1.99) Fatal Bleeding Fatal bleeding is adjudicated death with the primary cause of death from bleeding. 27 (0.2) 55 (0.5) 0.50 (0.31, 0.79) ICH 24 (0.2) 42 (0.4) 0.58 (0.35, 0.96) Non-intracranial 3 (0.0) 13 (0.1) 0.23 (0.07, 0.82) Figure 1 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 a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days F1 Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) EINSTEIN DVT and EINSTEIN PE Studies In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with rivaroxaban tablets vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for rivaroxaban tablets-treated patients and 204 days for enoxaparin/VKA-treated patients. Table 6 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. Table 6: Bleeding Events Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Parameter Rivaroxaban Tablets Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: rivaroxaban tablets 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0–3.0)] N=4130 n (%) Enoxaparin/VKA N=4116 n (%) Major bleeding event 40 (1.0) 72 (1.7) Fatal bleeding 3 (<0.1) 8 (0.2) Intracranial 2 (<0.1) 4 (<0.1) Non-fatal critical organ bleeding 10 (0.2) 29 (0.7) Intracranial Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group 3 (<0.1) 10 (0.2) Retroperitoneal 1 (<0.1) 8 (0.2) Intraocular 3 (<0.1) 2 (<0.1) Intra-articular 0 4 (<0.1) Non-fatal non-critical organ bleeding Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥2 units of whole blood or packed red blood cells 27 (0.7) 37 (0.9) Decrease in Hb ≥ 2 g/dL 28 (0.7) 42 (1.0) Transfusion of ≥2 units of whole blood or packed red blood cells 18 (0.4) 25 (0.6) Clinically relevant non-major bleeding 357 (8.6) 357 (8.7) Any bleeding 1169 (28.3) 1153 (28.0) Reduction in the Risk of Recurrence of DVT and/or PE EINSTEIN CHOICE Study In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for rivaroxaban tablets 10 mg, 2% for rivaroxaban tablets 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for rivaroxaban tablets 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients. Table 7 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study. Table 7: Bleeding Events Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. in EINSTEIN CHOICE Parameter Rivaroxaban Tablets Treatment schedule: rivaroxaban tablets 10 mg once daily or aspirin 100 mg once daily. 10 mg N=1127 n (%) Acetylsalicylic Acid (aspirin) 100 mg N=1131 n (%) Major bleeding event 5 (0.4) 3 (0.3) Fatal bleeding 0 1 (<0.1) Non-fatal critical organ bleeding 2 (0.2) 1 (<0.1) Non-fatal non-critical organ bleeding Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells. 3 (0.3) 1 (<0.1) Clinically relevant non-major (CRNM) bleeding Bleeding which was clinically overt, did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. 22 (2.0) 20 (1.8) Any bleeding 151 (13.4) 138 (12.2) In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the rivaroxaban tablets 20 mg group compared to the rivaroxaban tablets 10 mg or aspirin 100 mg groups. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with rivaroxaban tablets. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 8. Table 8: Bleeding Events Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event. in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1–3) Rivaroxaban Tablets 10 mg Enoxaparin Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3) Total treated patients N=4487 n (%) N=4524 n (%) Major bleeding event 14 (0.3) 9 (0.2) Fatal bleeding 1 (<0.1) 0 Bleeding into a critical organ 2 (<0.1) 3 (0.1) Bleeding that required re-operation 7 (0.2) 5 (0.1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 4 (0.1) 1 (<0.1) Any bleeding event Includes major bleeding events 261 (5.8) 251 (5.6) Hip Surgery Studies N=3281 n (%) N=3298 n (%) Major bleeding event 7 (0.2) 3 (0.1) Fatal bleeding 1 (<0.1) 0 Bleeding into a critical organ 1 (<0.1) 1 (<0.1) Bleeding that required re-operation 2 (0.1) 1 (<0.1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 3 (0.1) 1 (<0.1) Any bleeding event 201 (6.1) 191 (5.8) Knee Surgery Study N=1206 n (%) N=1226 n (%) Major bleeding event 7 (0.6) 6 (0.5) Fatal bleeding 0 0 Bleeding into a critical organ 1 (0.1) 2 (0.2) Bleeding that required re-operation 5 (0.4) 4 (0.3) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 1 (0.1) 0 Any bleeding event 60 (5.0) 60 (4.9) Following rivaroxaban tablets 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 Bleeding In 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 rivaroxaban tablets compared with enoxaparin/placebo and are excluded from all MAGELLAN data presented in Table 9. The incidence of bleeding leading to drug discontinuation was 2.5% for rivaroxaban tablets vs. 1.4% for enoxaparin/placebo. Table 9 shows the number of patients experiencing various types of bleeding events in the MAGELLAN study. Table 9: Bleeding Events in MAGELLAN Patients 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 2 Days MAGELLAN Study Patients received either rivaroxaban tablets 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. Rivaroxaban Tablets 10 mg N=3218 n (%) Enoxaparin 40 mg /placebo N=3229 n (%) Major bleeding Defined as clinically overt bleeding associated with a drop in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. 22 (0.7) 15 (0.5) Critical site bleeding 7 (0.2) 4 (0.1) Fatal bleeding Fatal bleeding is adjudicated death with the primary cause of death from bleeding. 3 (<0.1) 1 (<0.1) Clinically relevant non-major bleeding events (CRNM) 93 (2.9) 34 (1.1) Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban tablets-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 12. Table 12: Other Adverse Reactions Adverse reaction with Relative Risk >1.5 for rivaroxaban tablets versus comparator Reported by ≥1% of Rivaroxaban Tablets-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies Body System Adverse Reaction EINSTEIN DVT Study Rivaroxaban Tablets 20 mg N=1718 n (%) Enoxaparin/VKA N=1711 n (%) Gastrointestinal disorders Abdominal pain 46 (2.7) 25 (1.5) General disorders and administration site conditions Fatigue 24 (1.4) 15 (0.9) Musculoskeletal and connective tissue disorders Back pain 50 (2.9) 31 (1.8) Muscle spasm 23 (1.3) 13 (0.8) Nervous system disorders Dizziness 38 (2.2) 22 (1.3) Psychiatric disorders Anxiety 24 (1.4) 11 (0.6) Depression 20 (1.2) 10 (0.6) Insomnia 28 (1.6) 18 (1.1) EINSTEIN PE Study Rivaroxaban Tablets 20 mg N=2412 n (%) Enoxaparin/VKA N=2405 n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1) Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban tablets-treated patients in RECORD 1–3 studies are shown in Table 13. Table 13: Other Adverse Drug Reactions Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication Reported by ≥1% of Rivaroxaban Tablets-Treated Patients in RECORD 1–3 Studies Body System Adverse Reaction Rivaroxaban Tablets 10 mg N=4487 n (%) Enoxaparin Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3) N=4524 n (%) Injury, poisoning and procedural complications Wound secretion 125 (2.8) 89 (2.0) Musculoskeletal and connective tissue disorders Pain in extremity 74 (1.7) 55 (1.2) Muscle spasm 52 (1.2) 32 (0.7) Nervous system disorders Syncope 55 (1.2) 32 (0.7) Skin and subcutaneous tissue disorders Pruritus 96 (2.1) 79 (1.8) Blister 63 (1.4) 40 (0.9) Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients The safety assessment is based on data from the EINSTEIN Junior Phase 3 study in 491 patients from birth to less than 18 years of age. Patients were randomized 2:1 to receive body weight-adjusted doses of rivaroxaban or comparator (unfractionated heparin, low molecular weight heparin, fondaparinux or VKA). Discontinuation due to bleeding events occurred in 6 (1.8%) patients in the rivaroxaban group and 3 (1.9%) patients in the comparator group. Table 14 shows the number of patients experiencing bleeding events in the EINSTEIN Junior study. In female patients who had experienced menarche, ages 12 to <18 years of age, menorrhagia occurred in 23 (27%) female patients in the rivaroxaban group and 5 (10%) female patients in the comparator group. Table 14: Bleeding Events in EINSTEIN Junior Study – Safety Analysis Set - Main Treatment Period These events occurred after randomization until 3 months of treatment (1 month for patients <2 years with central venous catheter-related VTE (CVC-VTE). Patients may have more than one event. Parameter Rivaroxaban Treatment schedule: body weight-adjusted doses of rivaroxaban; randomized 2:1 (Rivaroxaban: Comparator). N=329 n (%) Comparator Group Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA. N=162 n (%) Major bleeding Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. 0 2 (1.2) Clinically relevant non-major bleeding Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. 10 (3.0) 1 (0.6) Trivial bleeding 113 (34.3) 44 (27.2) Any bleeding 119 (36.2) 45 (27.8) Non-bleeding adverse reactions reported in ≥5% of rivaroxaban-treated patients are shown in Table 15. Table 15: Other Adverse Reactions Adverse reaction with Relative Risk >1.5 for rivaroxaban versus comparator. Reported in Rivaroxaban-Treated Patients by ≥5% in EINSTEIN Junior Study Adverse Reaction Rivaroxaban N=329 n (%) Comparator Group N=162 n (%) Pain in extremity 23 (7) 7 (4.3) Fatigue The following terms were combined: fatigue, asthenia. 23 (7) 7 (4.3) A clinically relevant adverse reaction in rivaroxaban-treated patients was vomiting (10.6% in the rivaroxaban group vs 8% in the comparator group). Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease (CHD) after the Fontan Procedure The data below are based on Part B of the UNIVERSE study which was designed to evaluate the safety and efficacy of rivaroxaban for thromboprophylaxis in 98 children with CHD after the Fontan procedure who took at least one dose of study drug. Patients in Part B were randomized 2:1 to receive either body weight-adjusted doses of rivaroxaban or aspirin (approximately 5 mg/kg). Discontinuation due to bleeding events occurred in 1 (1.6%) patient in the rivaroxaban group and no patients in the aspirin group. Table 16 shows the number of patients experiencing bleeding events in the UNIVERSE study. Table 16: Bleeding Events in UNIVERSE Study - Safety Analysis Set - On Treatment Plus 2 Days Parameter Rivaroxaban Treatment schedule: body weight-adjusted doses of rivaroxaban or aspirin (approximately 5 mg/kg); randomized 2:1 (Rivaroxaban: Aspirin). N=64 n (%) Aspirin N=34 n (%) Major Bleeding Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. 1 (1.6) 0 Epistaxis leading to transfusion 1 (1.6) 0 Clinically relevant non-major (CRNM) bleeding Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. 4 (6.3) 3 (8.8) Trivial bleeding 21 (32.8) 12 (35.3) Any bleeding 23 (35.9) 14 (41.2) Non-bleeding adverse reactions reported in ≥5% of rivaroxaban-treated patients are shown in Table 17. Table 17: Other Adverse Reactions Adverse reaction with Relative Risk >1.5 for rivaroxaban versus aspirin. Reported by ≥5% of rivaroxaban-Treated Patients in UNIVERSE Study (Part B) Adverse Reaction Rivaroxaban N=64 n (%) Aspirin N=34 n (%) Cough 10 (15.6) 3 (8.8) Vomiting 9 (14.1) 3 (8.8) Gastroenteritis The following terms were combined: Gastroenteritis: gastroenteritis, gastroenteritis viral Rash: rash, rash maculo-papular, viral rash 8 (12.5) 1 (2.9) Rash 6 (9.4) 2 (5.9) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of rivaroxaban tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury) Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: hemiparesis Renal disorders: Anticoagulant-related nephropathy Respiratory, thoracic and mediastinal disorders: Eosinophilic pneumonia Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) Injury, poisoning and procedural complications: Atraumatic splenic rupture

<table width="90%" ID="table5"><caption>Table 5: Bleeding Events in ROCKET AF <footnote ID="K5809">Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment.</footnote>- On Treatment Plus 2 Days </caption><col align="left" valign="top" width="25%"/><col align="center" valign="top" width="25%"/><col align="center" valign="top" width="25%"/><col align="center" valign="top" width="25%"/><thead><tr><th align="center" styleCode="Lrule Rrule">Parameter</th><th styleCode="Rrule">Rivaroxaban Tablets N=7111 n (%/year) </th><th styleCode="Rrule">Warfarin N=7125 n (%/year) </th><th styleCode="Rrule">Rivaroxaban Tablets vs. Warfarin HR (95% CI) </th></tr></thead><tfoot><tr><td align="left" colspan="4" valign="top">Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Major Bleeding <footnote ID="K5868">Defined as clinically overt bleeding associated with a decrease in hemoglobin of &#x2265;2 g/dL, a transfusion of &#x2265;2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.</footnote></td><td styleCode="Rrule">395 (3.6)</td><td styleCode="Rrule">386 (3.5)</td><td styleCode="Rrule">1.04 (0.90, 1.20)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Intracranial Hemorrhage (ICH) <footnote ID="K5884">Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma.</footnote></td><td styleCode="Rrule">55 (0.5)</td><td styleCode="Rrule">84 (0.7)</td><td styleCode="Rrule">0.67 (0.47, 0.93)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hemorrhagic Stroke <footnote ID="K5900">Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days.</footnote></td><td styleCode="Rrule">36 (0.3)</td><td styleCode="Rrule">58 (0.5)</td><td styleCode="Rrule">0.63 (0.42, 0.96)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Other ICH</td><td styleCode="Rrule">19 (0.2)</td><td styleCode="Rrule">26 (0.2)</td><td styleCode="Rrule">0.74 (0.41, 1.34)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gastrointestinal (GI) <footnote ID="K5930">Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding.</footnote></td><td styleCode="Rrule">221 (2.0)</td><td styleCode="Rrule">140 (1.2)</td><td styleCode="Rrule">1.61 (1.30, 1.99)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatal Bleeding <footnote ID="K5946">Fatal bleeding is adjudicated death with the primary cause of death from bleeding.</footnote></td><td styleCode="Rrule">27 (0.2)</td><td styleCode="Rrule">55 (0.5)</td><td styleCode="Rrule">0.50 (0.31, 0.79)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">ICH</td><td styleCode="Rrule">24 (0.2)</td><td styleCode="Rrule">42 (0.4)</td><td styleCode="Rrule">0.58 (0.35, 0.96)</td></tr><tr><td styleCode="Lrule Rrule">Non-intracranial</td><td styleCode="Rrule">3 (0.0)</td><td styleCode="Rrule">13 (0.1)</td><td styleCode="Rrule">0.23 (0.07, 0.82)</td></tr></tbody></table>

<table width="90%" ID="fig1" styleCode="Noautorules"><col align="left" valign="middle" width="100%"/><tfoot><tr><td align="left" colspan="1" valign="top">Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.</td></tr></tfoot><tbody><tr><td><content styleCode="bold">Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF &#x2013; On Treatment Plus 2 Days</content></td></tr><tr><td><paragraph><renderMultiMedia referencedObject="img_3b827ecb-f179-2c5f-e063-6394a90a6345"/></paragraph></td></tr></tbody></table>

<table width="90%" ID="table6"><caption>Table 6: Bleeding Events <footnote ID="K6059">Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category.</footnote>in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies </caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th align="center" styleCode="Lrule Rrule" valign="bottom">Parameter</th><th styleCode="Rrule" valign="bottom">Rivaroxaban Tablets <footnote ID="foot6b">Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: rivaroxaban tablets 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0&#x2013;3.0)]</footnote> N=4130 n (%) </th><th styleCode="Rrule" valign="bottom">Enoxaparin/VKA <footnoteRef IDREF="foot6b"/> N=4116 n (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Major bleeding event</td><td styleCode="Rrule">40 (1.0)</td><td styleCode="Rrule">72 (1.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatal bleeding</td><td styleCode="Rrule">3 (&lt;0.1)</td><td styleCode="Rrule">8 (0.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Intracranial</td><td styleCode="Rrule">2 (&lt;0.1)</td><td styleCode="Rrule">4 (&lt;0.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Non-fatal critical organ bleeding</td><td styleCode="Rrule">10 (0.2)</td><td styleCode="Rrule">29 (0.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Intracranial <footnote ID="foot6c">Treatment-emergent major bleeding events with at least &gt;2 subjects in any pooled treatment group</footnote></td><td styleCode="Rrule">3 (&lt;0.1)</td><td styleCode="Rrule">10 (0.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Retroperitoneal <footnoteRef IDREF="foot6c"/></td><td styleCode="Rrule">1 (&lt;0.1)</td><td styleCode="Rrule">8 (0.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Intraocular <footnoteRef IDREF="foot6c"/></td><td styleCode="Rrule">3 (&lt;0.1)</td><td styleCode="Rrule">2 (&lt;0.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Intra-articular <footnoteRef IDREF="foot6c"/></td><td styleCode="Rrule">0</td><td styleCode="Rrule">4 (&lt;0.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Non-fatal non-critical organ bleeding <footnote ID="K6205">Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb &#x2265; 2 g/dL and/or transfusion of &#x2265;2 units of whole blood or packed red blood cells </footnote></td><td styleCode="Rrule">27 (0.7)</td><td styleCode="Rrule">37 (0.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decrease in Hb &#x2265; 2 g/dL</td><td styleCode="Rrule">28 (0.7)</td><td styleCode="Rrule">42 (1.0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Transfusion of &#x2265;2 units of whole blood or packed red blood cells</td><td styleCode="Rrule">18 (0.4)</td><td styleCode="Rrule">25 (0.6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Clinically relevant non-major bleeding</td><td styleCode="Rrule">357 (8.6)</td><td styleCode="Rrule">357 (8.7)</td></tr><tr><td styleCode="Lrule Rrule">Any bleeding</td><td styleCode="Rrule">1169 (28.3)</td><td styleCode="Rrule">1153 (28.0)</td></tr></tbody></table>