1 INDICATIONS AND USAGE Rivaroxaban tablet is a factor Xa inhibitor indicated: • to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation ( 1.1 ) • for treatment of deep vein thrombosis (DVT) ( 1.2 ) • for treatment of pulmonary embolism (PE) ( 1.3 ) • for reduction in the risk of recurrence of DVT or PE ( 1.4 ) • for prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery ( 1.5 ) • for prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients ( 1.6 ) • to reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD) ( 1.7 ) • to 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 ) • for treatment of VTE and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years ( 1.9 ) • for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure ( 1.10 ) 1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation Rivaroxaban tablets are indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of rivaroxaban tablets and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies (14.1)].

1.2 Treatment of Deep Vein Thrombosis Rivaroxaban tablets are indicated for the treatment of deep vein thrombosis (DVT).

1.3 Treatment of Pulmonary Embolism Rivaroxaban tablets are indicated for the treatment of pulmonary embolism (PE).

1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism Rivaroxaban tablets are indicated for the reduction in the risk of recurrence of DVT and/or PE in adult patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

1.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Rivaroxaban tablets are indicated for the prophylaxis of DVT, which may lead to PE in adult patients undergoing knee or hip replacement surgery.

1.6 Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding Rivaroxaban tablets are 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)].

1.7 Reduction of Risk of Major Cardiovascular Events in Patients with Coronary Artery Disease (CAD) Rivaroxaban tablets, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction and stroke) in adult patients with coronary artery disease.

1.8 Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD Rivaroxaban tablets, 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 a vascular etiology) in adult patients with PAD, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD.

1.9 Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients Rivaroxaban tablets are indicated for the treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment.

1.10 Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure Rivaroxaban tablets are indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

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 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* - On Treatment Plus 2 Days Parameter Rivaroxaban Tablets N = 7111 n (%/year) Warfarin N = 7125 n (%/year) Rivaroxaban Tablets vs.

Warfarin HR (95% CI) Major Bleeding † 395 (3.6) 386 (3.5) 1.04 (0.9, 1.2) Intracranial Hemorrhage (ICH) ‡ 55 (0.5) 84 (0.7) 0.67 (0.47, 0.93) Hemorrhagic Stroke § 36 (0.3) 58 (0.5) 0.63 (0.42, 0.96) Other ICH 19 (0.2) 26 (0.2) 0.74 (0.41, 1.34) Gastrointestinal (GI) ¶ 221 (2) 140 (1.2) 1.61 (1.3, 1.99) Fatal Bleeding # 27 (0.2) 55 (0.5) 0.5 (0.31, 0.79) ICH 24 (0.2) 42 (0.4) 0.58 (0.35, 0.96) Non-intracranial 3 (0) 13 (0.1) 0.23 (0.07, 0.82) Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major.

* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories.

These events occurred during treatment or within 2 days of stopping treatment.

† Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.

‡ Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma.

§ Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days.

¶ Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding.

# Fatal bleeding is adjudicated death with the primary cause of death from bleeding.

Figure 1 shows the risk of major bleeding events across major subgroups.

Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup but was a criterion for the CHADS2 score).

The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors.

Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Treatment of Deep Vein Thrombosis (DVT) 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-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* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Parameter Rivaroxaban Tablets † N = 4130 n (%) Enoxaparin/ VKA † N = 4116 n (%) Major bleeding event 40 (1) 72 (1.7) Fatal bleeding 3 (<0.1) 8 (0.2) Intracranial 2 (<0.1) 4 (<0.1) Non-fatal critical organ bleeding 10 (0.2) 29 (0.7) Intracranial ‡ 3 (<0.1) 10 (0.2) Retroperitoneal ‡ 1 (<0.1) 8 (0.2) Intraocular ‡ 3 (<0.1) 2 (<0.1) Intra-articular ‡ 0 4 (<0.1) Non-fatal non-critical organ bleeding § 27 (0.7) 37 (0.9) Decrease in Hb ≥ 2g/dL 28 (0.7) 42 (1) 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) * Bleeding event occurred after randomization and up to 2 days after the last dose of study drug.

Although a patient may have had 2 or more events, the patient is counted only once in a category.

† Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: 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 to 3)] ‡ Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥2 units of whole blood or packed red blood cells 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 * in EINSTEIN CHOICE Parameter Rivaroxaban Tablets † 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 ‡ 3 (0.3) 1 (<0.1) Clinically relevant non-major (CRNM) bleeding § 22 (2) 20 (1.8) Any bleeding 151 (13.4) 138 (12.2) * Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug.

Although a patient may have had 2 or more events, the patient is counted only once in a category.

† Treatment schedule: Rivaroxaban tablets 10 mg once daily or aspirin 100 mg once daily.

‡ Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2g/dL and/or transfusion of ≥2 units of whole blood or packed red blood cells.

§ 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.

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 * in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1 to 3) Rivaroxaban Tablets 10 mg Enoxaparin † Total treated patients N = 4487 n (%) N = 4524 n (%) Major bleeding event 14 (0.3) 9 (0.2) Fatal bleeding 1 (<0.1) 0 Bleeding into a critical organ 2 (<0.1) 3 (0.1) Bleeding that required re-operation 7 (0.2) 5 (0.1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 4 (0.1) 1 (<0.1) Any bleeding event ‡ 261 (5.8) 251 (5.6) Hip Surgery Studies N = 3281 n (%) N = 3298 n (%) Major bleeding event 7 (0.2) 3 (0.1) Fatal bleeding 1 (<0.1) 0 Bleeding into a critical organ 1 (<0.1) 1 (<0.1) Bleeding that required re-operation 2 (0.1) 1 (<0.1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 3 (0.1) 1 (<0.1) Any bleeding event ‡ 201 (6.1) 191 (5.8) Knee Surgery Study N = 1206 n (%) N = 1226 n (%) Major bleeding event 7 (0.6) 6 (0.5) Fatal bleeding 0 0 Bleeding into a critical organ 1 (0.1) 2 (0.2) Bleeding that required re-operation 5 (0.4) 4 (0.3) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 1 (0.1) 0 Any bleeding event ‡ 60 (5) 60 (4.9) * Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication.

Patients may have more than one event.

† Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1 to 3) ‡ Includes major bleeding events 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 * Study-Safety Analysis Set - On Treatment Plus 2 Days MAGELLAN Study ¶ Rivaroxaban Tablets 10 mg N=3218 n (%) Enoxaparin 40 mg/placebo N=3229 n (%) Major bleeding ‡† 22 (0.7) 15 (0.5) Critical site bleeding 7 (0.2) 4 (0.1) Fatal bleeding § 3 (<0.1) 1 (<0.1) Clinically relevant non-major bleeding events (CRNM) 93 (2.9) 34 (1.1) * 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.

† Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories.

These events occurred during treatment or within 2 days of stopping treatment.

‡ Defined as clinically overt bleeding associated with a 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.

§ Fatal bleeding is adjudicated death with the primary cause of death from bleeding.

¶ 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.

Reduction of Risk of Major Cardiovascular Events in Patients with CAD In the COMPASS trial overall, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for rivaroxaban tablets 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 10 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.

Table 10: Major Bleeding Events in COMPASS - On Treatment Plus 2 Days* Parameter Rivaroxaban Tablets † N=9134 n (%/year) Placebo † N=9107 n (%/year) Rivaroxaban Tablets vs.

Placebo HR (95 % CI) Modified ISTH Major Bleeding ‡ 263 (1.6) 144 (0.9) 1.8 (1.5, 2.3) - 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 (0.5, 8) 1.2 (0.4, 4) - Symptomatic bleeding in critical organ (non-fatal) ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH 58 (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) 1.1 (0.6, 2) 1.4 (0.7, 2.8) 0.7 (0.2, 1.9) - Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) 7 (<0.1) 6 (<0.1) 1.2 (0.4, 3.5) - Bleeding 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 bleeding 117 (0.7) 49 (0.3) 2.4 (1.7, 3.4) * 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 in the safety analysis set in COMPASS patients.

† Treatment schedule: Rivaroxaban tablets 2.5 mg twice daily or placebo.

All patients received background therapy with aspirin 100 mg once daily.

‡ Defined as i) fatal bleeding, or ii) symptomatic bleeding in a 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.

CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD The incidence of premature permanent discontinuation due to bleeding events for rivaroxaban tablets 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 11 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 11: Major Bleeding Events* in VOYAGER-On Treatment Plus 2 Days Rivaroxaban Tablets † N=3256 Placebo † N=3248 Rivaroxaban Tablets vs.

Placebo HR (95 % CI) Parameter n (%) Event rate %/year n (%) Event rate %/year TIMI Major Bleeding (CABG/non-CABG) 62 (1.9) 0.96 44 (1.4) 0.67 1.4 (1, 2.1) Fatal bleeding 6 (0.2) 0.09 6 (0.2) 0.09 1 (0.3, 3.2) Intracranial bleeding 13 (0.4) 0.2 17 (0.5) 0.26 0.8 (0.4, 1.6) Clinically overt signs of hemorrhage associated with a drop in haemoglobin of ≥5 g/dL or drop in hematocrit of ≥15% 46 (1.4) 0.71 24 (0.7) 0.36 1.9 (1.2, 3.2) * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories.

† Treatment schedule: Rivaroxaban tablets 2.5 mg twice daily or placebo.

All patients received background therapy with aspirin 100 mg once daily.

CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria 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 * 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 20 mg N=2412 n (%) Enoxaparin/ VKA N=2405 n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1) * Adverse reaction with Relative Risk >1.5 for rivaroxaban tablets versus comparator Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban tablets-treated patients in RECORD 1 to 3 studies are shown in Table 13.

Table 13: Other Adverse Drug Reactions * Reported by ≥1% of Rivaroxaban Tablets-Treated Patients in RECORD 1 to 3 Studies Body System Adverse Reaction Rivaroxaban Tablets 10 mg N = 4487 n (%) Enoxaparin † N = 4524 n (%) Injury, poisoning and procedural complications Wound secretion 125 (2.8) 89 (2) Musculoskeletal and connective tissue disorders Pain in extremity 74 (1.7) 55 (1.2) Muscle spasm 52 (1.2) 32 (0.7) Nervous system disorders Syncope 55 (1.2) 32 (0.7) Skin and subcutaneous tissue disorders Pruritus 96 (2.1) 79 (1.8) Blister 63 (1.4) 40 (0.9) * Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication † Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1 to 3) 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 tablets 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 tablets 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 tablets group and 5 (10%) female patients in the comparator group.

Table 14: Bleeding Events in EINSTEIN Junior Study – Safety Analysis Set - Main Treatment Period* Parameter Rivaroxaban Tablets † N=329 n (%) Comparator Group ‡ N=162 n (%) Major bleeding § 0 2 (1.2) Clinically relevant non-major bleeding ¶ 10 (3) 1 (0.6) Trivial bleeding 113 (34.3) 44 (27.2) Any bleeding 119 (36.2) 45 (27.8) * 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.

† Treatment schedule: body weight-adjusted doses of rivaroxaban tablets; randomized 2:1 (Rivaroxaban tablets: Comparator).

‡ Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA.

§ 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.

¶ 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.

Non-bleeding adverse reactions reported in ≥5% of rivaroxaban-treated patients are shown in Table 15.

Table 15: Other Adverse Reactions* Reported in Rivaroxaban Tablets-Treated Patients by ≥5% in EINSTEIN Junior Study Adverse Reaction Rivaroxaban Tablets N=329 n (%) Comparator Group N=162 n (%) Pain in extremity 23 (7) 7 (4.3) Fatigue † 23 (7) 7 (4.3) * Adverse reaction with Relative Risk >1.5 for rivaroxaban tablets versus comparator.

† The following terms were combined: fatigue, asthenia.

A clinically relevant adverse reaction in rivaroxaban tablets-treated patients was vomiting (10.6% in the rivaroxaban tablets 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 tablets 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 tablets or aspirin (approximately 5 mg/kg).

Discontinuation due to bleeding events occurred in 1 (1.6%) patient in the rivaroxaban tablets 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 Tablets * N=64 n (%) Aspirin * N=34 n (%) Major Bleeding † 1 (1.6) 0 Epistaxis leading to transfusion 1 (1.6) 0 Clinically relevant non-major (CRNM) bleeding § 4 (6.3) 3 (8.8) Trivial bleeding 21 (32.8) 12 (35.3) Any bleeding 23 (35.9) 14 (41.2) * Treatment schedule: body weight-adjusted doses of rivaroxaban tablets or aspirin (approximately 5 mg/kg); randomized 2:1 (Rivaroxaban tablets: Aspirin).

† 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.

§ 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.

Non-bleeding adverse reactions reported in ≥5% of rivaroxaban tablets-treated patients are shown in Table 17.

Table 17: Other Adverse Reactions* Reported by ≥ 5% of Rivaroxaban Tablets-Treated Patients in UNIVERSE Study (Part B) Adverse Reaction Rivaroxaban Tablets N=64 n (%) Aspirin N=34 n (%) Cough 10 (15.6) 3 (8.8) Vomiting 9 (14.1) 3 (8.8) Gastroenteritis † 8 (12.5) 1 (2.9) Rash † 6 (9.4) 2 (5.9) * Adverse reaction with Relative Risk >1.5 for rivaroxaban tablets versus aspirin.

† The following terms were combined: Gastroenteritis: gastroenteritis, gastroenteritis viral Rash: rash, rash maculo-papular, viral rash rivaroxaban-fig-1 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