Rivaroxaban

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.

DOSAGE AND ADMINISTRATION Nonvalvular Atrial Fibrillation : 15 or 20 mg, once daily with food ( 2.1 ) Treatment 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 ) Reduction 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 6 months of standard anticoagulant treatment ( 2.1 ) Prophylaxis of DVT Following Hip or Knee Replacement Surgery : 10 mg orally once daily with or without food ( 2.1 ) Prophylaxis 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 a total recommended duration of 31 to 39 days ( 2.1 ) CAD or PAD : 2.5 mg orally twice daily with or without food, in combination with aspirin (75–100 mg) once daily ( 2.1 ) Pediatric Patients: See dosing recommendations in the Full Prescribing Information ( 2.2 ) 2.1 Recommended Dosage in Adults Table 1: Recommended Dosage in Adults Indication Renal Considerations Calculate CrCl based on actual weight [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6) ] . Dosage Food/Timing [See Clinical Pharmacology (12.3) ] . Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation CrCl >50 mL/min 20 mg once daily Take with evening meal CrCl ≤50 mL/min Patients 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 daily Take with evening meal Treatment of DVT and/or PE CrCl ≥15 mL/min 15 mg twice daily ▼ after 21 days, transition to ▼ 20 mg once daily Take with food, at the same time each day CrCl <15 mL/min Avoid Use Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE CrCl ≥15 mL/min 10 mg once daily, after at least 6 months of standard anticoagulant treatment Take with or without food CrCl <15 mL/min Avoid Use Prophylaxis of DVT Following: - Hip Replacement Surgery CrCl ≥15 mL/min 10 mg once daily for 35 days, 6–10 hours after surgery once hemostasis has been established Take with or without food CrCl <15 mL/min Avoid Use - Knee Replacement Surgery [See Dosage and Administration (2.4) ] . CrCl ≥15 mL/min 10 mg once daily for 12 days, 6–10 hours after surgery once hemostasis has been established Take with or without food CrCl <15 mL/min Avoid Use Prophylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding CrCl ≥15 mL/min 10 mg once daily, in hospital and after hospital discharge, for a total recommended duration of 31 to 39 days Take with or without food CrCl <15 mL/min Avoid Use Reduction of Risk of Major Cardiovascular Events (CV Death, MI, and Stroke) in CAD No dose adjustment needed based on CrCl 2.5 mg twice daily , plus aspirin (75–100 mg) once daily Take with or without food Reduction of Risk of Major Thrombotic Vascular Events in PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PAD No dose adjustment needed based on CrCl 2.5 mg twice daily , plus aspirin (75–100 mg) once daily. When starting therapy after a successful lower extremity revascularization procedure, initiate once hemostasis has been established. Take with or without food 2.2 Recommended Dosage in Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients Table 2: Recommended Dosage in Pediatric Patients Birth to Less than 18 Years for Treatment of and Reduction in Risk of Recurrent VTE Initiate XARELTO treatment following at least 5 days of initial parenteral anticoagulation therapy. , Patients <6 months of age should meet the following criteria: at birth were at least 37 weeks of gestation, have had at least 10 days of oral feeding, and weigh ≥2.6 kg at the time of dosing. Dosage Form Body Weight 1 mg XARELTO = 1 mL Suspension Dosage Total Daily Dose All doses should be taken with feeding or with food since exposures match that of 20 mg daily dose in adults. Once a Day Once a day: approximately 24 hours apart; 2 times a day: approximately 12 hours apart; 3 times a day: approximately 8 hours apart 2 Times a Day 3 Times a Day Oral Suspension Only 2.6 kg to 2.9 kg 0.8 mg 2.4 mg 3 kg to 3.9 kg 0.9 mg 2.7 mg 4 kg to 4.9 kg 1.4 mg 4.2 mg 5 kg to 6.9 kg 1.6 mg 4.8 mg 7 kg to 7.9 kg 1.8 mg 5.4 mg 8 kg to 8.9 kg 2.4 mg 7.2 mg 9 kg to 9.9 kg 2.8 mg 8.4 mg 10 kg to 11.9 kg 3 mg 9 mg 12 kg to 29.9 kg 5 mg 10 mg Oral Suspension or Tablets 30 kg to 49.9 kg 15 mg 15 mg ≥50 kg 20 mg 20 mg Dosing of XARELTO was not studied and therefore dosing cannot be reliably determined in the following patient populations. Its use is therefore not recommended in children less than 6 months of age with any of the following: Less than 37 weeks of gestation at birth Less than 10 days of oral feeding Body weight of less than 2.6 kg. To increase absorption, all doses should be taken with feeding or with food. Monitor the child's weight and review the dose regularly, especially for children below 12 kg. This is to ensure a therapeutic dose is maintained. All pediatric patients (except <2 years old with catheter-related thrombosis): Therapy with XARELTO should be continued for at least 3 months in children with thrombosis. Treatment can be extended up to 12 months when clinically necessary. The benefit of continued therapy beyond 3 months should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential risk of bleeding. Pediatric patients <2 years old with catheter-related thrombosis: Therapy with XARELTO should be continued for at least 1 month in children less than 2 years old with catheter-related thrombosis. Treatment can be extended up to 3 months when clinically necessary. The benefit of continued therapy beyond 1 month should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential risk of bleeding. Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure Table 3: Recommended Dosage for Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease Dosage Form Body Weight 1 mg XARELTO = 1 mL Suspension Dosage Total Daily Dose All doses can be taken with or without food since exposures match that of 10 mg daily dose in adults. Once a Day Once a day: approximately 24 hours apart; 2 times a day: approximately 12 hours apart. 2 Times a Day Oral Suspension Only 7 kg to 7.9 kg 1.1 mg 2.2 mg 8 kg to 9.9 kg 1.6 mg 3.2 mg 10 kg to 11.9 kg 1.7 mg 3.4 mg 12 kg to 19.9 kg 2 mg 4 mg 20 kg to 29.9 kg 2.5 mg 5 mg 30 kg to 49.9 kg 7.5 mg 7.5 mg Oral Suspension or Tablets ≥50 kg 10 mg 10 mg Administration in Pediatric Patients Food Effect: For the treatment of VTE in children, the dose should be taken with food to increase absorption. For thromboprophylaxis after Fontan procedure, the dose can be taken with or without food. Vomit or Spit up: If the patient vomits or spits up the dose within 30 minutes after receiving the dose, a new dose should be given. However, if the patient vomits more than 30 minutes after the dose is taken, the dose should not be re-administered and the next dose should be taken as scheduled. If the patient vomits or spits up the dose repeatedly, the caregiver should contact the child's doctor right away. Tablets: XARELTO tablet must not be split in an attempt to provide a fraction of a tablet dose. For children unable to swallow 10, 15, or 20 mg whole tablets, XARELTO oral suspension should be used. XARELTO 2.5 mg tablets are not recommended for use in pediatric patients [see Use in Specific Populations (8.4) ] . Use i

WARNINGS AND PRECAUTIONS Risk of bleeding: XARELTO can cause serious and fatal bleeding ( 5.2 ) Pregnancy-related hemorrhage: Use XARELTO with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery ( 5.7 , 8.1 ) Prosthetic heart valves: XARELTO use not recommended ( 5.8 ) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: XARELTO use not recommended ( 5.10 ) 5.1 Increased 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 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 XARELTO increases the risk of bleeding, including in any organ, 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 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 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 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 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 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 XARELTO [see Clinical Pharmacology (12.3) ] . The next XARELTO dose should not be administered earlier than 6 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. 5.4 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 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 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 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 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 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 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 XARELTO in these patients. Discontinue XARELTO i

CONTRAINDICATIONS Rivaroxaban tablets is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions ( 5.2 )] • severe hypersensitivity reaction to rivaroxaban tablets (e.g., anaphylactic reactions) [see Adverse Reactions ( 6.2 )] • Active pathological bleeding ( 4 ) • Severe hypersensitivity reaction to rivaroxaban tablets ( 4 )

DRUG INTERACTIONS Avoid combined P-gp and strong CYP3A inhibitors and inducers. ( 7.2 , 7.3 ) Anticoagulants : Avoid concomitant use ( 7.4 ) 7.1 General Inhibition and Induction Properties Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters, the latter also known as breast cancer resistance protein (BCRP). 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. 7.2 Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems Interaction with Combined P-gp and Strong CYP3A Inhibitors Avoid concomitant administration of rivaroxaban tablets 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 a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with rivaroxaban tablets 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 Impairment Rivaroxaban tablets 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 )]. 7.3 Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems Avoid concomitant use of rivaroxaban tablets with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) [see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 )] . 7.4 Anticoagulants 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 rivaroxaban tablets 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 )] .

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 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 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 XARELTO. Hemorrhage The most common adverse reactions with XARELTO 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 XARELTO 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 XARELTO N=7111 n (%/year) Warfarin N=7125 n (%/year) XARELTO 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 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 XARELTO vs. enoxaparin/Vitamin K 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 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 XARELTO Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 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 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 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 XARELTO Treatment schedule: XARELTO 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 XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rivaroxaban is a selective inhibitor of FXa. It does not require a 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 Rivaroxaban produces dose-dependent inhibition of FXa activity. Clotting tests, such as prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest ® , are also prolonged dose-dependently. In children treated with rivaroxaban, the correlation between anti-factor Xa to plasma concentrations is linear with a slope close to 1. Monitoring for anticoagulation effect of rivaroxaban using anti-FXa activity or a clotting test is not recommended. Specific Populations Renal Impairment The relationship between systemic exposure and pharmacodynamic activity of rivaroxaban was altered in adult subjects with renal impairment relative to healthy control subjects [see Use in Specific Populations ( 8.6 )]. Table 18: Percentage Increase in Rivaroxaban PK and PD Measures in Adult Subjects with Renal Impairment Relative to Healthy Subjects from Clinical Pharmacology Studies Measure Parameter Creatinine Clearance (mL/min) 50-79 30-49 15-29 ESRD (on dialysis)* ESRD (post-dialysis)* Exposure AUC 44 52 64 47 56 FXa Inhibition AUEC 50 86 100 49 33 PT Prolongation AUEC 33 116 144 112 158 *Separate stand-alone study. PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the plasma concentration-time curve; AUEC = Area under the effect-time curve Hepatic Impairment Anti-Factor Xa activity was similar in adult subjects with normal hepatic function and in mild hepatic impairment (Child-Pugh A 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 Absorption The 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. Rivaroxaban 2.5 mg tablets and 10 mg tablets can be taken with or without food. Rivaroxaban Tablets 20 mg administered in the fasted state has an absolute bioavailability of approximately 66%. Coadministration of Rivaroxaban Tablets with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). Rivaroxaban 15 mg tablets and 20 mg tablets should be taken with food [see Dosage and Administration ( 2.1 )]. The maximum concentrations (C max ) of rivaroxaban appear 2 hours to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of Rivaroxaban Tablets (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or Rivaroxaban Tablets (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. A 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 a study with 44 healthy subjects, both mean AUC and C max values for 20 mg rivaroxaban administered orally as a 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 a liquid meal, only mean AUC was comparable to that after the whole tablet, and C max was 18% lower. Distribution 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. Metabolism Approximately 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. Excretion In a Phase 1 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 a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated BCRP). Rivaroxaban’s affinity for influx transporter proteins is unknown. Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5 hours to 9 hours in healthy subjects aged 20 years to 45 years. Specific Populations The 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 Adult Populations on the Pharmacokinetics of Rivaroxaban [see Dosage and Administration ( 2.1 )] Gender Gender did not influence the pharmacokinetics or pharmacodynamics of Rivaroxaban Tablets. Race Healthy 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. Elderly The terminal elimination half-life is 11 hours to 13 hours in the elderly subjects aged 60 years to 76 years [see Use in Specific Populations ( 8.5 )]. Renal Impairment The safety and pharmacokinetics of single-dose Rivaroxaban Tablets (10 mg) were evaluated in a 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 a single 15 mg dose in ESRD subjects dosed 3 hours after the completion of a 4-hour hemodialysis session (post-dialysis) is 56% higher when compared to subjects with normal renal function (see Table 18). The systemic exposure to rivaroxaban administered 2 hours prior to a 4-hour hemodialysis session with a dialysate flow rate of 600 mL/min and a blood flow rate in the range of 320 mL/min 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 mL/min to 50 mL/ min taking Rivaroxaban Tablets 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 Impairment The safety and pharmacokinetics of single-dose Rivaroxaban Tablets (10 mg) were evaluated in a study in healthy adult subjects (n=16) and adult 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 im