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Rivaroxaban, a factor Xa (FXa) inhibitor, is the active ingredient in XARELTO ® Tablets and XARELTO ® for oral suspension with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.

The molecular formula of rivaroxaban is

C 19 H 18 ClN 3 O 5 S and the molecular weight is 435.89.

The structural formula is

Rivaroxaban is a pure ( S )-enantiomer.

It is an odorless, non-hygroscopic, white to yellowish powder.

Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.

XARELTO tablet contains 2.5 mg, 10 mg, 15 mg, or 20 mg of rivaroxaban.

The inactive ingredients of

XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.

Additionally, the proprietary film coating mixture used for XARELTO 2.5 mg is Opadry ® Light Yellow, containing ferric oxide yellow, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 10 mg tablets is Opadry ® Pink and for XARELTO 15 mg tablets is Opadry ® Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is Opadry ® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

XARELTO for oral suspension is supplied as granules in bottles containing 155 mg of rivaroxaban (1 mg of rivaroxaban per mL after reconstitution).

The inactive ingredients are: anhydrous citric acid, hypromellose, mannitol, microcrystalline cellulose and carboxymethylcellulose sodium, sodium benzoate, sucralose, sweet and creamy flavor and xanthan gum.

is a factor Xa inhibitor indicated: to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation for treatment of deep vein thrombosis (DVT) for treatment of pulmonary embolism (PE) for reduction in the risk of recurrence of DVT or PE for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery for prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients to reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD) 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 for treatment of VTE and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure 1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation XARELTO is 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 XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled. 1.2 Treatment of Deep Vein Thrombosis XARELTO is indicated for the treatment of deep vein thrombosis (DVT). 1.3 Treatment of Pulmonary Embolism XARELTO is indicated for the treatment of pulmonary embolism (PE). 1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in 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 XARELTO is 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 XARELTO is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding. 1.7 Reduction of Risk of Major Cardiovascular Events in Patients with Coronary Artery Disease (CAD) XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in 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 XARELTO, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of 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 XARELTO is 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 XARELTO is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

Mechanism of Action XARELTO 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.

The relationship between systemic exposure and pharmacodynamic activity of rivaroxaban was altered in adult subjects with renal impairment relative to healthy control subjects.

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) Separate stand-alone study.

ESRD (post-dialysis) PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the plasma concentration-time curve; AUEC = Area under the effect-time curve Exposure AUC 44 52 64 47 56 FXa Inhibition AUEC 50 86 100 49 33 PT Prolongation AUEC 33 116 144 112 158 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.

Cardiac Electrophysiology In a thorough

QT study in healthy men and women aged 50 years and older, no QTc prolonging effects were observed for XARELTO (15 mg and 45 mg, single dose). 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.

XARELTO 2.5 mg and 10 mg tablets can be taken with or without food.

XARELTO 20 mg administered in the fasted state has an absolute bioavailability of approximately 66%.

Coadministration of

XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and C max increasing by 39% and 76% respectively with food).

XARELTO 15 mg and 20 mg tablets should be taken with food.

The maximum concentrations (C max ) of rivaroxaban appear to 4 hours after tablet intake.

The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH.

XARELTO (30 mg single dose) with the H 2 -receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or XARELTO (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban.

Absorption of rivaroxaban is dependent on the site of drug release in the GI tract.

A 29% and 56% decrease in AUC and C max 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.

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 [ 14 C]-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 [ 14 C]-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 known as 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 to 9 hours in healthy subjects aged to 45 years.

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 Gender Gender did not influence the pharmacokinetics or pharmacodynamics of XARELTO.

Japanese subjects were found to have 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.

The terminal elimination half-life is to 13 hours in the elderly subjects aged to 76 years.

The rate and extent of absorption were similar between the tablet and suspension.

After repeated administration of rivaroxaban for the treatment of VTE, the C max of rivaroxaban in plasma was observed at median times of 1.5 to 2.2 hours in subjects who ranged from birth to less than 18 years of age.

In children who were 6 months to 9 years of age, in vitro plasma protein binding of rivaroxaban is approximately 90%.

The half-life of rivaroxaban in plasma of pediatric patients treated for VTE decreased with decreasing age.

Mean half-life values were 4.2 hours in adolescents, 3 hours in children to 12 years of age, 1.9 hours in children 0.5 to <2 years of age, and 1.6 hours in children <0.5 years of age.

An exploratory analysis in pediatric patients treated for VTE did not reveal relevant differences in rivaroxaban exposure based on gender or race.

Renal Impairment The safety and pharmacokinetics of single-dose XARELTO (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.

Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment.

Increases in pharmacodynamic effects were also observed.

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.

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 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 to 50 mL/min taking XARELTO 15 mg. Hemodialysis had no significant impact on rivaroxaban exposure.

Protein binding was similar (86% to 89%) in healthy controls and ESRD subjects in this study.

Limited clinical data are available in children 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m 2 ) or in children younger than 1 year with serum creatinine results above 97.5th percentile.

Hepatic Impairment The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy adult subjects (n=16) and adult subjects with varying degrees of hepatic impairment.

No patients with severe hepatic impairment (Child-Pugh C) were studied.

Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B) .

No clinical data are available in pediatric patients with hepatic impairment.

In vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A nor induces CYP1A2, 2B6, 2C19, or 3A.

In vitro data also indicates a low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters, the latter also known as BCRP.

The effects of coadministered drugs on the pharmacokinetics of rivaroxaban exposure are summarized in Figure 3.

Figure 3: Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban in Adults Anticoagulants In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity.

In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT.

Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban.

NSAIDs/Aspirin In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding.

NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO.

Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban.

In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively.

The change in bleeding time was approximately twice the maximum increase seen with either drug alone.

There was no change in the pharmacokinetics of either drug.

Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems In a pharmacokinetic trial, XARELTO was administered as a single dose in subjects with mild (CrCl = 50 to 79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A inhibitor).

Compared to

XARELTO administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported a 76% and 99% increase in AUC inf and a 56% and 64% increase in C max, respectively.

Similar trends in pharmacodynamic effects were a.

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 Bleeding Risk Spinal/Epidural Hematoma The most common adverse reaction (>5%) in adult patients was bleeding The most common adverse reactions (>10%) in pediatric patients were bleeding, cough, vomiting, and gastroenteritis To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc.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.

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.

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. 395 386 1.04 Intracranial Hemorrhage (ICH) Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. 55 84 0.67 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 58 0.63 Other ICH 19 26 0.74 Gastrointestinal (GI) Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. 221 140 1.61 Fatal Bleeding Fatal bleeding is adjudicated death with the primary cause of death from bleeding. 27 55 0.50 ICH 24 42 0.58 Non-intracranial 3 13 0.23 Figure 1 shows the risk of major bleeding events across major subgroups.

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 72 Fatal bleeding 3 (<0.1) 8 Intracranial 2 (<0.1) 4 (<0.1) Non-fatal critical organ bleeding 10 29 Intracranial Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group 3 (<0.1) 10 Retroperitoneal 1 (<0.1) 8 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 37 Decrease in Hb ≥ 2 g/dL 28 42 Transfusion of ≥2 units of whole blood or packed red blood cells 18 25 Clinically relevant non-major bleeding 357 357 Any bleeding 1169 1153 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 3 Fatal bleeding 0 1 (<0.1) Non-fatal critical organ bleeding 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 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 20 Any bleeding 151 138 In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO.

The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 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) XARELTO 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 9 Fatal bleeding 1 (<0.1) 0 Bleeding into a critical organ 2 (<0.1) 3 Bleeding that required re-operation 7 5 Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 4 1 (<0.1) Any bleeding event Includes major bleeding events 261 251 Hip Surgery Studies N=3281 n (%) N=3298 n (%) Major bleeding event 7 3 Fatal bleeding 1 (<0.1) 0 Bleeding into a critical organ 1 (<0.1) 1 (<0.1) Bleeding that required re-operation 2 1 (<0.1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 3 1 (<0.1) Any bleeding event 201 191 Knee Surgery Study N=1206 n (%) N=1226 n (%) Major bleeding event 7 6 Fatal bleeding 0 0 Bleeding into a critical organ 1 2 Bleeding that required re-operation 5 4 Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 1 0 Any bleeding event 60 60 Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of 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 XARELTO 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 XARELTO 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.

• On Treatment Plus 2 Days MAGELLAN Study Patients received either XARELTO or placebo once daily for 35 ±4 days starting in hospital and continuing post hospital discharge or received enoxaparin or placebo once daily for 10 ±4 days in the hospital.

XARELTO 10 mg N=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 15 (0.

Overdose of

XARELTO may lead to hemorrhage.

XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.

The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered.

Due to the high plasma protein binding, rivaroxaban is not dialyzable.

Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products.

A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available.

is contraindicated in patients with: active pathological bleeding severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) Active pathological bleeding Severe hypersensitivity reaction to XARELTO.

15 or 20 mg, once daily with food 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 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 Prophylaxis of DVT Following Hip or Knee Replacement Surgery: 10 mg orally once daily with or without food 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 to 39 days CAD or PAD: 2.5 mg orally twice daily with or without food, in combination with aspirin (75–100 mg) once daily Pediatric Patients: See dosing recommendations in the Full Prescribing Information 2.1 Recommended Dosage in Adults Table 1: Recommended Dosage in Adults Indication Renal Considerations Calculate CrCl based on actual weight.

• 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.

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 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.

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: 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: approximately 24 hours apart; 2 times a day: approximately 12 hours apart.

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.

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.

Use in Renal Impairment in Pediatric Patients Patients 1 Year of Age or Older Mild renal impairment (eGFR: 50 to ≤ 80 mL/min/1.73 m 2 ): No dose adjustment is required.

Moderate or severe renal impairment (eGFR: <50 mL/min/1.73 m 2 ): avoid use, as limited clinical data are available.

Estimated glomerular filtration rate (eGFR) can be done using the updated Schwartz formula, eGFR (Schwartz) = (0.413 × height in cm)/serum creatinine in mg/dL, if serum creatinine (SCr) is measured by an enzymatic creatinine method that has been calibrated to be traceable to isotope dilution mass spectrometry (IDMS).

If SCr is measured with routine methods that have not been recalibrated to be traceable to IDMS (e.g., the traditional Jaffé reaction), the eGFR should be obtained from the original Schwartz formula: eGFR (mL/min/1.73 m 2 ) = k * height (cm)/SCr (mg/dL), where k is proportionality constant: k = 0.55 in children 1 year to 13 years k = 0.55 in girls > 13 and < 18 years k = 0.70 in boys > 13 and < 18 years Patients Less than 1 Year of Age Determine renal function using serum creatinine.

Avoid use of

XARELTO in pediatric patients younger than 1 year with serum creatinine results above 97.5 th percentile, as no clinical data are available.

Table 4: Reference Values of Serum Creatinine in Pediatric Patients <1 Year of Age Age 97.5 th Percentile of Creatinine (mg/dL) 97.5 th Percentile of Creatinine (µmol/L) Week 2 0.52 46 Week 3 0.46 41 Week 4 0.42 37 Month 2 0.37 33 Month 3 0.34 30 Month 4–6 0.34 30 Month 7–9 0.34 30 Month 10–12 0.36 32 2.3 Switching to and from XARELTO Switching from Warfarin to XARELTO.

• When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is below 3.0 in adults and below 2.5 in pediatric patients to avoid periods of inadequate anticoagulation.

Switching from XARELTO to

Warfarin – Adults: No clinical trial data are available to guide converting patients from XARELTO to warfarin.

XARELTO affects

INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin.

One approach is to discontinue

XARELTO and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO would have been taken.

To ensure adequate anticoagulation during the transition from XARELTO to warfarin, continue XARELTO for at least 2 days after the first dose of warfarin.

After 2 days of co-administration, an INR should be obtained prior to the next scheduled dose of XARELTO.

Co-administration of

XARELTO and warfarin is advised to continue until the INR is ≥ 2.0.

XARELTO is discontinued, INR testing may be done reliably 24 hours after the last dose.

Switching from XARELTO to Anticoagulants other than Warfarin.

• For adult and pediatric patients currently taking XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO dose would have been taken.

Switching from Anticoagulants other than Warfarin to XARELTO.

• For adult and pediatric patients currently receiving an anticoagulant other than warfarin, start XARELTO to 2 hours prior to the next scheduled administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant.

For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO at the same time. 2.4 Discontinuation for Surgery and other Interventions If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO should be stopped at least 24 hours before the procedure to reduce the risk of bleeding.

In deciding whether a procedure should be delayed until 24 hours after the last dos.

® (rivaroxaban) Tablets are available in the strengths and packages listed below: 2.5 mg tablets are round, light yellow, and film-coated with a triangle pointing down above a "2.5" marked on one side and "Xa" on the other side.

The tablets are supplied in the packages listed: NDC 50458-577-60 Bottle containing 60 tablets NDC 50458-577-18 Bottle containing 180 tablets NDC 50458-577-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 10 mg tablets are round, light red, biconvex film-coated tablets marked with a triangle pointing down above a "10" on one side, and "Xa" on the other side.

The tablets are supplied in the packages listed: NDC 50458-580-30 Bottle containing 30 tablets NDC 50458-580-90 Bottle containing 90 tablets NDC 50458-580-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 15 mg tablets are round, red, biconvex film-coated tablets with a triangle pointing down above a "15" marked on one side and "Xa" on the other side.

The tablets are supplied in the packages listed: NDC 50458-578-30 Bottle containing 30 tablets NDC 50458-578-90 Bottle containing 90 tablets NDC 50458-578-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 20 mg tablets are triangle-shaped, dark red film-coated tablets with a triangle pointing down above a "20" marked on one side and "Xa" on the other side.

The tablets are supplied in the packages listed: NDC 50458-579-30 Bottle containing 30 tablets NDC 50458-579-90 Bottle containing 90 tablets NDC 50458-579-89 Bulk bottle containing 1000 tablets NDC 50458-579-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) Starter Pack for treatment of deep vein thrombosis and treatment of pulmonary embolism: NDC 50458-584-51 30-day starter blister pack containing 51 tablets: 42 tablets of 15 mg and 9 tablets of 20 mg XARELTO ® (rivaroxaban) for oral suspension is available in the strength and package listed below: NDC 50458-575-01 Supplied as white to off-white granules in an amber glass bottle containing 155 mg rivaroxaban packaged with two oral dosing syringes.

After reconstitution with 150 mL of purified water, 1 mL of the suspension contains 1 mg rivaroxaban.

Discard reconstituted suspension after "Discard after" date written on the bottle.

Storage of tablets, granules and reconstituted suspension: Store at room temperature between 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) .

Do not freeze the granules or reconstituted suspension.

Keep out of the reach of children.

Storage of tablets, granules and reconstituted suspension: Store at room temperature between 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) .

Do not freeze the granules or reconstituted suspension.

Keep out of the reach of children.

Risk Summary The limited available data on XARELTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.

XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery.

The anticoagulant effect of

XARELTO cannot be reliably monitored with standard laboratory testing.

Consider the benefits and risks of

XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Maternal and/or Embryo/Fetal Risk Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias.

Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia.

Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.

Fetal/Neonatal Adverse Reactions Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery.

The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.

Data Human Data There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established.

Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage.

In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.

Rivaroxaban crosses the placenta in animals.

Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis.

This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis.

This dose corresponds to about 14 times the human exposure of unbound drug.

In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

The safety and effectiveness of

XARELTO have been established in pediatric patients from birth to less than 18 years for the treatment of VTE and the reduction in risk of recurrent VTE.

Use of

XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO in adults with additional pharmacokinetic, safety and efficacy data from a multicenter, prospective, open-label, active-controlled randomized study in 500 pediatric patients from birth to less than 18 years of age.

XARELTO was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth; had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg.

XARELTO have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO in adults with additional data from a multicenter, prospective, open-label, active controlled study in 112 pediatric patients to evaluate the single.

• and multiple-dose pharmacokinetic properties of XARELTO and the safety and efficacy of XARELTO when used for thromboprophylaxis for 12 months in children with single ventricle physiology who had the Fontan procedure.

Clinical studies that evaluated safety, efficacy, pharmacokinetic and pharmacodynamic data support the use of XARELTO 10 mg, 15 mg, and 20 mg tablets in pediatric patients.

For the

XARELTO 2.5 mg tablets, there are no safety, efficacy, pharmacokinetic and pharmacodynamic data to support the use in pediatric patients.

Therefore, XARELTO 2.5 mg tablets are not recommended for use in pediatric patients.

Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.

Of the total number of adult patients in clinical trials for the approved indications of XARELTO (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over.

In clinical trials the efficacy of

XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years.

Both thrombotic and bleeding event rates were higher in these older patients.