Rivaroxaban

XARELTO 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 the 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 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 [see Clinical Studies (14.1) ].

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 [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) 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.

2.5 mg tablets: 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 10 mg tablets: Round, light red, biconvex and film-coated with a triangle pointing down above a "10" marked on one side and "Xa" on the other side 15 mg tablets: Round, red, biconvex, and film-coated with a triangle pointing down above a "15" marked on one side and "Xa" on the other side 20 mg tablets: Triangle-shaped, dark red, and film-coated with a triangle pointing down above a "20" marked on one side and "Xa" on the other side For oral suspension: white to off-white granules; once reconstituted, provide flavored white to off-white opaque liquid with a concentration of 1 mg/mL. Tablets: 2.5 mg, 10 mg, 15 mg, and 20 mg ( 3 ) For oral suspension: 1 mg/mL once reconstituted ( 3 )

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

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. […]

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. […]

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 XARELTO 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 XARELTO 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 XARELTO 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 XARELTO 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 XARELTO 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) ] .

Renal impairment: Avoid or adjust dose ( 8.6 ) Hepatic impairment: Avoid use in Child-Pugh B and C hepatic impairment or hepatic disease associated with coagulopathy ( 8.7 )

8.1 Pregnancy Risk Summary The limited available data on XARELTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use 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 [see Warnings and Precautions (5.2 , 5.7) ] . 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. Clinical Considerations Disease-Associated 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. Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see Warnings and Precautions (5.7) ]. 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. Animal Data 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).

8.2 Lactation Risk Summary Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition (see Data ) . Data Animal Data Following a single oral administration of 3 mg/kg of radioactive [ 14 C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.

8.3 Females and Males of Reproductive Potential Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including XARELTO should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

8.4 Pediatric Use 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 [see Dosage and Administration (2.2) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.8) ] . The safety and effectiveness of XARELTO have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure. Use of 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 [see Dosage and Administration (2.2) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.9) ] . 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.

8.5 Geriatric Use 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 [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] .

8.6 Renal Impairment In pharmacokinetic studies, compared to healthy adult subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in adult subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3) ] . […]

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.