1 INDICATIONS AND USAGE Rivaroxaban tablets are a factor Xa inhibitor indicated: 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 ) 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.

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 Another Indication [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 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 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.

Hemorrhage The most common adverse reactions with rivaroxaban were bleeding complications [see Warnings and Precautions (5.2 )].

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 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 † N=9,134 n (%/year) Placebo † N=9,107 n (%/year) Rivaroxaban vs.

Placebo HR (95% CI) Modified ISTH Major Bleeding ‡ 263 (1.6) 144 (0.9) 1.8 (1.5, 2.3) - Fatal bleeding event 12 (<0.1) 8 (<0.1) 1.5 (0.6, 3.7) Intracranial hemorrhage (ICH) 6 (<0.1) 3 (<0.1) 2 (0.5, 8) Non-intracranial 6 (<0.1) 5 (<0.1) 1.2 (0.4, 4) - Symptomatic bleeding in critical organ (non-fatal) 58 (0.3) 43 (0.3) 1.4 (0.9, 2) - ICH (fatal and non-fatal) 23 (0.1) 21 (0.1) 1.1 (0.6, 2) Hemorrhagic Stroke 18 (0.1) 13 (<0.1) 1.4 (0.7, 2.8) Other ICH 6 (<0.1) 9 (<0.1) 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 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 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 N=3,256 Placebo N=3,248 Rivaroxaban 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) 0.20 17 (0.5) 0.26 0.8 (0.4, 1.6) Clinically overt signs of hemorrhage associated with a drop in hemoglobin 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 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 -treated patients in the EINSTEIN 1 (Study) and EINSTEIN 2 (Study) studies are shown in Table 12.

Table 12: Other Adverse Reactions* Reported by ≥1% of Rivaroxaban-Treated Patients in EINSTEIN 1 (Study) and EINSTEIN 2 (Study) Body System Adverse Reaction EINSTEIN 1 (Study) Rivaroxaban 20 mg N=1,718 n (%) Enoxaparin/VKA N=1,711 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 2 (Study) Rivaroxaban 20 mg N=2,412 n (%) Enoxaparin/VKA N=2,405 n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1) * Adverse reaction with Relative Risk >1.5 for rivaroxaban versus comparator Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban -treated patients in RECORD 1 to 3 studies are shown in Table 13.

Table 13: Other Adverse Drug Reactions* Reported by ≥1% of Rivaroxaban-Treated Patients in RECORD 1 to 3 Studies Body System Adverse Reaction Rivaroxaban 10 mg N = 4,487 n (%) Enoxaparin † N = 4,524 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) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of rivaroxaban.

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