RIVAROXABAN_- rivaroxaban_tablet, film coated

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. Rivaroxaban produces dose-dependent inhibition of FXa activity. Clotting tests, such as prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTestregistered, 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. Specific Populations Renal Impairment [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 Creatinine Clearance (mL/min) 50-79 30-49 15-29 ESRD (on ESRD 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. Hepatic Impairment Absorption [see Dosage and Administration ( 2. 1 14 14 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. Race Elderly [see Use in Specific Populations ( 8. 5 Pediatric Patients Renal Impairment [see Use in Specific Populations ( 8. 6 Hemodialysis in ESRD subjects: Pediatric Patients: 2 th [see Dosage and Administration ( 2. 6 Hepatic Impairment [see Use in Specific Populations ( 8. 7 No clinical data are available in pediatric patients with hepatic impairment Drug Interactions In vitro In vitro [see Drug Interactions ( 7 Figure 3 Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban in Adults Anticoagulants NSAIDs/Aspirin Clopidogrel Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems fig-02 fig-03 In a thorough QT study in healthy men and women aged 50 years and older, no QTc prolonging effects were observed for Rivaroxaban tablets (15 mg and 45 mg, single-dose).

Rivaroxaban tablets are a factor Xa inhibitor indicated: 1. 10 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 Rivaroxaban tablets are indicated for the treatment of deep vein thrombosis (DVT). Rivaroxaban tablets are indicated for the treatment of pulmonary embolism (PE). Rivaroxaban tablets 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. Rivaroxaban tablets are indicated for the prophylaxis of DVT, which may lead to PE in adult patients undergoing knee or hip replacement surgery. Rivaroxaban tablets 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 Clinical Studies ( 14. 5 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. 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. Rivaroxaban tablet 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. Rivaroxaban tablet is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

Nonvalvular Atrial Fibrillation 2. 1 Treatment of DVT and/or PE 2. 1 Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE 2. 1 Prophylaxis of DVT Following Hip or Knee Replacement Surgery 2. 1 Prophylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding 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. 2 Table 1: Recommended Dosage in Adults Indication Renal Considerations* Dosage Food/Timingdagger Prophylaxis of DVT Following: 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 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 2. 5 mg twice daily Take with or without food * Calculate CrCl based on actual weight. See Warnings and Precautions ( 5. 4 ) and Use in Specific Populations ( 8. 4 ) Dosing of rivaroxaban 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 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 rivaroxaban 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 rivaroxaban 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. Food Effect: 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: rivaroxaban tablet must not be split in an attempt to provide a fraction of a tablet dose. Use in Renal Impairment in Pediatric Patients 2 2 If SCr is measured with routine methods that have not been recalibrated to be traceable to IDMS (e. , the traditional Jaffé reaction), the eGFR should be obtained from the original Schwartz formula: eGFR (mL/min/1. 73 m 2 k = 0. 55 in children 1 year to 13 years Patients Less than 1 Year of Age th Table 4: Reference Values of Serum Creatinine in Pediatric Patients <1 Year of Age Age 97. 5 th Percentile of Creatinine (mumol/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 Switching from Warfarin to Rivaroxaban tablets Switching from Rivaroxaban tablets to Warfarin en dash Pediatric Patients: Switching from Rivaroxaban tablets to Anticoagulants other than Warfarin en dash [see Drug Interactions ( 7. 4 Switching from Anticoagulants other than Warfarin to If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, Rivaroxaban tablets should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see Warnings and Precautions ( 5. 1 Adults For patients receiving 15 mg twice daily: The patient should take Rivaroxaban tablets immediately to ensure intake of 30 mg Rivaroxaban tablets per day. Two 15 mg tablets may be taken at once. Pediatric Patients For adult patients who are unable to swallow whole tablets, Rivaroxaban tablets tablets (all strengths) may be crushed and mixed with applesauce immediately prior to use and administered orally. After the administration of a crushed rivaroxaban tablets, 15 mg or 20 mg tablet, the dose should be immediately followed by food. Administration with food is not required for the 2. 5 mg or 10 mg tablets [ see Clinical Pharmacology ( 12. 3 rivaroxaban tablets see Clinical Pharmacology ( 12. 3 Administration of rivaroxaban tablets suspension via NG tube or gastric feeding tube: rivaroxaban tablets oral suspension may be given through NG or gastric feeding tube. After the administration, flush the feeding tube with water. An in vitro compatibility study indicated that rivaroxaban tablets suspension can be used with PVC, polyurethane or silicone NG tubing.

The following clinically significant adverse reactions are also discussed in other sections of the labeling: [see Boxed Warning and Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 7 [see Boxed Warning and Warnings and Precautions ( 5. 3 The most common adverse reaction (>5%) in adult patients was bleeding. 1 To report SUSPECTED ADVERSE REACTIONS, contact contact Macleods Pharma USA, Inc. , at 1-888-943-3210 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. [see Warnings and Precautions ( 5. 2 Table 5: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days Parameter Rivaroxaban tablets N=7111 n (%/year) Warfarin N=7125 n (%/year) Rivaroxaban tablets vs. Warfarin HR (95% CI) Major Bleeding dagger 395 (3. 20) Intracranial double dagger 55 (0. 93) Hemorrhagic section 36 (0. 96) Other ICH 19 (0. 34) Gastrointestinal (GI) paragraph 221 (2. 99) Fatal Bleeding # 27 (0. 79) ICH 24 (0. 96) Non-intracranial 3 (0. 82) Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. section paragraph # Figure 1 shows the risk of major bleeding events across major subgroups Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF en dash On Treatment Plus 2 Days Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) Table 6 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. Table 6: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Parameter Rivaroxaban tablets dagger N=4130 n (%) Enoxaparin/ VKAdagger N=4116 n (%) Major bleeding event 40 (1. 7) Fatal bleeding 3 (<0. 2) Intracranial 2 (<0. 1) Non-fatal critical organ bleeding 10 (0. 7) Intracranialdouble dagger 3 (<0. 2) Retroperitonealdouble dagger 1 (<0. 2) Intraoculardouble dagger 3 (<0. 1) Intra-articulardouble dagger 0 4 (<0. 1) Non-fatal non-critical organ bleedingsection 27 (0. 9) Decrease in Hb >= 2 g/dL 28 (0. 0) Transfusion of >=2 units of whole blood or packed red blood cells 18 (0. 6) Clinically relevant non-major bleeding 357 (8. 7) Any bleeding 1169 (28. 3) 1153 (28. 0) * 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. section Reduction in the Risk of Recurrence of DVT and/or PE Table 7: Bleeding Events* in EINSTEIN CHOICE Parameter Rivaroxaban tablets 10 mg N=1127 n (%) Acetylsalicylic Acid (aspirin) 100 mg N=1131 n (%) Major bleeding event 5 (0. 3) Fatal bleeding 0 1 (<0. 1) Non-fatal critical organ bleeding 2 (0. 1) Non-fatal non-critical organ bleedingsection 3 (0. 1) Clinically relevant non-major (CRNM) bleedingparagraph 22 (2. 8) Any bleeding 151 (13. 2) * Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. section paragraph In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the Rivaroxaban tablets 20 mg group compared to the Rivaroxaban tablets 10 mg or aspirin 100 mg groups. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Table 8: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3) Rivaroxaban tablets 10 mg Enoxaparindagger Total treated patients N=4487 n (%) N=4524 n (%) Major bleeding event 14 (0. 2) Fatal bleeding 1 (<0. 1) 0 Bleeding into a critical organ 2 (<0. 1) Bleeding that required re-operation 7 (0. 1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 4 (0. 1) Any bleeding eventdouble dagger 261 (5. 6) Hip Surgery Studies N=3281 n (%) N=3298 n (%) Major bleeding event 7 (0. 1) Fatal bleeding 1 (<0. 1) 0 Bleeding into a critical organ 1 (<0. 1) Bleeding that required re-operation 2 (0. 1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 3 (0. 1) Any bleeding eventdouble dagger 201 (6. 8) Knee Surgery Study N=1206 n (%) N=1226 n (%) Major bleeding event 7 (0. 5) Fatal bleeding 0 0 Bleeding into a critical organ 1 (0. 2) Bleeding that required re-operation 5 (0. 3) Extra-surgical site bleeding 1 (0. 1) 0 Any bleeding eventdouble dagger 60 (5. 9) * Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event. Following Rivaroxaban tablets treatment, the majority of major bleeding complications (>=60%) occurred during the first week after surgery. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Table 9: Bleeding Events in MAGELLAN* Studyen dashSafety Analysis Set - On Treatment Plus 2 Days MAGELLAN Study Rivaroxaban tablets 10 mg N=3218 n (%) Enoxaparin 40 mg /placebo N=3229 n (%) Major bleedingdouble daggerdagger 22 (0. 5) Critical site bleeding 7 (0. 1) Fatal bleedingsection 3 (<0. 1) Clinically relevant non-major bleeding events (CRNM) 93 (2. 1) * Patients at high risk of bleeding (i. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal Reduction of Risk of Major Cardiovascular Events in Patients with CAD Table 10 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial. Table 10: Major Bleeding Events* in COMPASS - On Treatment Plus 2 Days* Parameter rivaroxaban N=9134 n (%/year) Placebo N=9107 n (%/year) rivaroxaban vs. Placebo HR (95 % CI) Modified ISTH Major Bleedingdouble dagger 263 (1. 3) - Fatal bleeding event 12 (<0. 7) -Symptomatic bleeding in critical organ (non-fatal) - Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) 7 (<0. 5) - Bleeding leading to hospitalization (non-fatal, not in critical organ, not 188 (1. 7) Major GI bleeding 117 (0. 4) Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment in the safety analysis set in COMPASS patients. CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD The incidence of premature permanent discontinuation due to bleeding events for rivaroxaban 2. 5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4. 6% and in COMPASS PAD was 2. 3%, respectively. Table 11 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal. Table 11: Major Bleeding Events* in VOYAGER-On Treatment Plus 2 Days Rivaroxaban dagger N=3256 Placebodagger N=3248 Rivaroxaban vs. Placebo HR (95 % CI) Parameter n (%) Event rate %/year n (%) Event rate %/year TIMI Major Bleeding 62 (1. 1) Fatal bleeding 6 (0. 2) Intracranial bleeding 13 (0. 6) Clinically overt signs of 46 (1. 2) * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. dagger Other Adverse Reactions Table 12: Other Adverse Reactions* Reported by >=1% of Rivaroxaban Tablets -Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies Body System EINSTEIN DVT Study Rivaroxaban tablets 20 mg N=1718 n (%) Enoxaparin/VKA N=1711 n (%) Gastrointestinal disorders Abdominal pain 46 (2. 5) General disorders and administration site conditions Fatigue 24 (1. 9) Musculoskeletal and connective tissue disorders Back pain 50 (2. 8) Muscle spasm 23 (1. 8) Nervous system disorders Dizziness 38 (2. 3) Psychiatric disorders Anxiety 24 (1. 6) Depression 20 (1. 6) Insomnia 28 (1. 1) EINSTEIN PE Study Rivaroxaban tablets 20 mg N=2412 n (%) Enoxaparin/VKA N=2405 n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2. 1) * Adverse reaction with Relative Risk >1. 5 for Rivaroxaban tablets versus comparator Non-hemorrhagic adverse reactions reported in >=1% of Rivaroxaban tablets -treated patients in RECORD 1-3 studies are shown in Table 13: Other Adverse Drug Reactions* Reported by >=1% of Rivaroxaban Tablets -Treated Patients in RECORD 1-3 Studies Body System Rivaroxaban tablets 10 mg N=4487 n (%) Enoxaparindagger N=4524 n (%) Injury, poisoning and procedural complications Wound secretion 125 (2. 0) Musculoskeleta and connective tissue disorders Pain in extremity 74 (1. 2) Muscle spasm 52 (1. 7) Nervous system disorders Syncope 55 (1. 7) Skin and subcutaneous tissue disorders Pruritus 96 (2. 8) Blister 63 (1. 9) * Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients Table 14 shows the number of patients experiencing bleeding events in the EINSTEIN Junior study. In female patients who had experienced menarche, ages 12 to <18 years of age, menorrhagia occurred in 23 (27%) female patients in the rivaroxaban group and 5 (10%) female patients in the comparator group. Table 14: Bleeding Events in EINSTEIN Junior Study en dash Safety Analysis Set -Main Treatment Period* Parameter rivaroxaban N=329 n (%) Comparator Group N=162 n (%) Major bleedingsection 0 2 (1. 2) Clinically relevant non-major bleedingparagraph 10 (3. 6) Trivial bleeding 113 (34. 2) Any bleeding 119 (36. 8) * These events occurred after randomization until 3 months of treatment (1 month for patients <2 years with central venous catheter-related VTE (CVC-VTE). Non-bleeding adverse reactions reported in >=5% of rivaroxaban -treated patients are shown in Table 15. Table 15: Other Adverse Reactions* Reported in rivaroxaban tablets -Treated Patients by >=5% in EINSTEIN Junior Study Adverse Reaction rivaroxaban N=329 n (%) Comparator Group N=162 n (%) Pain in extremity 23 (7) 7 (4. 3) Fatiguedagger 23 (7) 7 (4. 3) *Adverse reaction with Relative Risk >1. 5 for rivaroxaban versus comparator. A clinically relevant adverse reaction in rivaroxaban -treated patients was vomiting (10. 6% in the rivaroxaban group vs 8% in the comparator group). Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease (CHD) after the Fontan Procedure Table 16 shows the number of patients experiencing bleeding events in the UNIVERSE study. Table 16: Bleeding Events in UNIVERSE Study -Safety Analysis Set -On Treatment Plus 2 Days Parameter Rivaroxaban * N=64 n (%) Aspirin N=34 n (%) Major Bleedingdagger 1 (1. 6) 0 Epistaxis leading to transfusion 1 (1. 6) 0 Clinically relevant non-major (CRNM) bleedingsection 4 (6. 8) Trivial bleeding 21 (32. 3) Any bleeding 23 (35. 2) * Treatment schedule: body weight-adjusted doses of rivaroxaban or aspirin (approximately 5 mg/kg); randomized 2:1 (rivaroxaban : Aspirin). Non-bleeding adverse reactions reported in >=5% of rivaroxaban treated patients are shown in Table 17. Table 17: Other Adverse Reactions* Reported by >=5% of rivaroxaban tablets -Treated Patients in UNIVERSE Study (Part B) Adverse Reaction (rivaroxaban N=64 n (%) Aspirin N=34 n (%) Cough 10 (15. 8) Vomiting 9 (14. 8) Gastroenteritisdagger 8 (12. 9) Rashdagger 6 (9. 9) * Adverse reaction with Relative Risk >1. 5 for rivaroxaban versus aspirin. rivaroxaban-fig-01 The following adverse reactions have been identified during post-approval use of Rivaroxaban tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Gastrointestinal disorders: Hepatobiliary disorders: Immune system disorders: Nervous system disorders: Renal disorders: Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders:.

Rivaroxaban tablets is contraindicated in patients with: [see Warnings and Precautions ( 5. 2 [see Adverse Reactions ( 6. 2 Active pathological bleeding ( 4 4.

Renal impairment: Avoid or adjust dose ( 8. 7 Risk Summary [see Warnings and Precautions ( 5. 7 Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Fetal/Neonatal Adverse Reactions Labor or Delivery [see Warnings and Precautions ( 5. 7 Data Human Data in vitro Animal Data Risk Summary (see Data). Data Animal Data 14 Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The safety and effectiveness of rivaroxaban tablets 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 rivaroxaban tablets is supported in these age groups by evidence from adequate and well-controlled studies of rivaroxaban tablets 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. rivaroxaban tablets 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. 8 [see Dosage and Administration ( 2. 9 Of the total number of patients in the RECORD 1-3 clinical studies evaluating Rivaroxaban tablets, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were>75 years. In the MAGELLAN study, approximately 67% were 65 years and over and about 37% were >75 years. In clinical trials the efficacy of Rivaroxaban tablets 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, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology ( 12. 3 14 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 Nonvalvular Atrial Fibrillation Patients with Chronic Kidney Disease not on Dialysis [see Clinical Pharmacology ( 12. 3 Patients with End-Stage Renal Disease on Dialysis [see Clinical Pharmacology ( 12. 3 Treatment of DVT and/or PE and Reduction in the Risk of Recurrence of DVT and/or PE [see Clinical Pharmacology ( 12. 3 Prophylaxis of DVT Following Hip or Knee Replacement Surgery [see Clinical Pharmacology ( 12. 3 Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding [see Clinical Pharmacology ( 12. 3 Reduction of Risk of Major Cardiovascular Events in Patients with CAD and Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients After Recent Lower Extremity Revascularization due to Symptomatic PAD Patients with Chronic Kidney Disease not on Dialysis [see Clinical Pharmacology ( 12. 3 Pediatric Use 2 2 th [see Dosage and Administration ( 2. 2 In a pharmacokinetic study, compared to healthy adult subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B). [see Clinical Pharmacology ( 12. 3 No clinical data are available in pediatric patients with hepatic impairment.

Combined P-gp and strong CYP3A inhibitors and inducers: ( 7. 4 Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. 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. Interaction with Combined P-gp and Strong CYP3A Inhibitors [see Warnings and Precautions ( 5. 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 [see Warnings and Precautions ( 5. 3 Avoid concomitant use of Rivaroxaban tablets with drugs that are combined P-gp and strong CYP3A inducers (e. , carbamazepine, phenytoin, rifampin, St. John’s wort) [see Warnings and Precautions ( 5. 3 Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology ( 12. 3 [see Warnings and Precautions ( 5.

OVERDOSAGE
Overdose of Rivaroxaban tablets may lead to hemorrhage. Discontinue Rivaroxaban tablets 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 Rivaroxaban tablets overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see Warnings and Precautions ( 5.2 12.3
NONCLINICAL TOXICOLOGY
Rivaroxaban was not carcinogenic when administered by oral gavage to mice or rats for up to 2 years. The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/day) were 1- and 2-times, respectively, the human exposure of unbound drug at the human dose of 20 mg/day. Systemic exposures of unbound drug in male and female rats at the highest dose tested (60 mg/kg/day) were 2- and 4-times, respectively, the human exposure. in vitro in vivo
CLINICAL STUDIES
The evidence for the efficacy and safety of Rivaroxaban was derived from Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonist for the prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) [NCT00403767], a multi-national, double-blind study comparing Rivaroxaban (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to 50 mL/min) to warfarin (titrated to INR 2. 0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more of the following additional risk factors for stroke: Table 19 Primary Composite Endpoint Results in ROCKET AF Study (Intent-to-Treat Population) Rivaroxaban Warfarin Rivaroxaban vs. Warfarin Event N=7081 n (%) Event Rate (per 100 Pt- yrs) N=7090 n (%) Event Rate (per 100 Pt- yrs) Hazard Ratio (95% CI) Primary Composite Endpoint* 269 (3. 03) Stroke 253 (3. 2 Hemorrhagic Strokedagger 33 (0. 4 Ischemic Stroke 206 (2. 6 Unknown Stroke Type 19 (0. 1 Non-CNS Systemic Embolism 20 (0. 2 * The primary endpoint was the time to first occurrence of stroke (any type) or non-CNS systemic embolism. Data are shown for all randomized patients followed to site notification that the study would end. Figure 4: Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group (Intent-to-Treat Population) Figure 5: Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AF* (Intent-to-Treat Population) fig-04 fig-05 EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism Studies Table 20 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies. Table 20: Primary Composite Endpoint Results* in EINSTEIN DVT and EINSTEIN PE Studies en dash Intent-to-Treat Population Event Rivaroxaban 20 mgdagger Enoxaparin/VKAdagger Rivaroxaban vs. Enoxaparin/VKA Hazard Ratio (95% CI) EINSTEIN DVT Study N=1731 n (%) N=1718 n (%) Primary Composite Endpoint 36 (2. 04) Death (PE) 1 (<0. 1) 0 Death (PE cannot be excluded) 3 (0. 3) Symptomatic PE and DVT 1 (<0. 1) 0 Symptomatic recurrent PE only 20 (1. 0) Symptomatic recurrent DVT only 14 (0. 6) EINSTEIN PE Study N=2419 n (%) N=2413 n (%) Primary Composite Endpoint 50 (2. 68) Death (PE) 3 (0. 1) Death (PE cannot be excluded) 8 (0. 2) Symptomatic PE and DVT 0 2 (<0. 1) Symptomatic recurrent PE only 23 (1. 8) Symptomatic recurrent DVT only 18 (0. 7) * For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (3, 6 or 12 months) irrespective of the actual treatment duration. If the same patient had several events, the patient may have been counted for several components. Figure 6: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) en dash EINSTEIN DVT Study Figure 7: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) en dash EINSTEIN PE Study fig-06 fig-07 EINSTEIN CHOICE Study Table 21: Primary Composite Endpoint and its Components Results* in EINSTEIN CHOICE Study en dash Full Analysis Set Event Rivaroxaban 10 mg N=1,127 n (%) Acetylsalicylic Acid (Aspirin) 100 mg N=1,131 n (%) Rivaroxaban 10 mg vs. Aspirin 100 mg Hazard Ratio (95% CI) Primary Composite Endpoint 13 (1. 26 Symptomatic recurrent DVT 8 (0. 6) Symptomatic recurrent PE 5 (0. 7) Death (PE) 0 1 (<0. 1) Death (PE cannot be excluded) 0 1 (<0. 1) * For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (12 months) irrespective of the actual treatment duration. The individual component of the primary endpoint represents the first occurrence of the event. Figure 8: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Full Analysis Set) en dash EINSTEIN CHOICE Study fig-08 Rivaroxaban was studied in 9011 patients (4487 Rivaroxaban -treated, 4524 enoxaparin-treated patients) in the RE C OR D Table 22: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery - Modified Intent-to-Treat Population RECORD 1 RECORD 2 Treatment Dosage and Duration Rivaroxaban 10 mg once daily Enoxaparin 40 mg once daily RRR*, p-value Rivaroxaban 10 mg once daily Enoxaparindagger 40 mg once daily RRR*, p-value Number of Patients N=1513 N=1473 N=834 N=835 Total VTE 17 (1. 9%) 71% 17 (2. 4%) 76% Components of Total VTE Proximal DVT 1 (0. 8%) Distal DVT 12 (0. 2%) Non-fatal PE 3 (0. 5%) Death (any cause) 4 (0. 5%) Number of Patients N=1600 N=1587 N=928 N=929 Major VTE double dagger 3 (0. 1%) 91% (95% 6 (0. 8%) 87% (95% Number of Patients N=2103 N=2119 N=1178 N=1179 Symptomatic VTE 5 (0. 3%) * Relative Risk Reduction; CI = confidence interval Table 23: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Knee Replacement Surgery - Modified Intent-to-Treat Population RECORD 3 Treatment Dosage and Duration Rivaroxaban 10 mg once daily Enoxaparin 40 mg once daily RRR*, p-value Number of Patients N=813 N=871 Total VTE 79 (9. 7%) 164 (18. 8%) 48% Components of events contributing to Total VTE Proximal DVT 9 (1. 2%) Distal DVT 74 (9. 1%) 154 (17. 7%) Non-fatal PE 0 4 (0. 5%) Death (any cause) 0 2 (0. 2%) Number of Patients N=895 N=917 Major VTE 9 (1. 5%) 60% (95% CI: Number of Patients N=1206 N=1226 Symptomatic VTE 8 (0. 0%) * Relative Risk Reduction; CI = confidence interval The efficacy and safety of rivaroxaban for prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding was evaluated in the MAGELLAN study (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically iLL patients comparing rivaroxabaN with enoxaparin [NCT00571649]). MAGELLAN was a multicenter, randomized, double-blind, parallel-group efficacy and safety study comparing rivaroxaban to enoxaparin, in the prevention of VTE in hospitalized acutely ill medical patients during the in-hospital and post-hospital discharge period. Eligible patients included adults who were at least 40 years of age, hospitalized for an acute medical illness, at risk of VTE due to moderate or severe immobility, and had additional risk factors for VTE. The population at risk of VTE was required to have one or more of the following VTE risk factors, i. prolonged immobilization, age >=75 years, history of cancer, history of VTE, history of heart failure,thrombophilia, acute infectious disease contributing to the hospitalization and BMI >=35 kg/m2). The causes for hospitalization included heart failure, active cancer, acute ischemic stroke, acute infectious and inflammatory disease and acute respiratory insufficiency. Patients were randomized to receive either rivaroxaban 10 mg once daily for 35 +/-4 days starting in hospital and continuing post hospital discharge (n=4050) or enoxaparin 40 mg once daily for 10 +/-4 days starting in hospital followed by placebo post-discharge (n=4051). Table 24: Efficacy Results at Day 35 (modified Intent-to-Treat) and at Day 10 (per protocol) in the MAGELLAN Study Events from Day 1 to Day 35, mITT analysis set Rivaroxaban 10 mg N=2967 n (%) Enoxaparin 40 mg/ placebo N=3057 n (%) RR (95% CI) Primary Composite Endpoint at Day 35 131 (4. 96) Symptomatic non-fatal PE 10 (0. 5) Symptomatic DVT in lower extremity 13 (0. 5) Asymptomatic proximal DVT in lower extremity 103 (3. 4) VTE related death 19 (0. 0) Events from Day 1 to Day 10, PP analysis set Rivaroxaban 10 mg N=2938 n (%) Enoxaparin 40 mg N=2993 n (%) RR (95% CI) Primary Composite Endpoint at Day 10 78 (2. 31) Symptomatic non-fatal PE 6 (0. 1) Symptomatic DVT in lower extremity 7 (0. 2) Asymptomatic proximal DVT in lower extremity 71 (2. 4) VTE related death 3 (0. 2) mITT analysis set plus all-cause mortality N=3096 n (%) N=3169 n (%) RR (95% CI) Other Composite Endpoint at Day 35 266 (8. 09) Symptomatic non-fatal PE 10 (0. 4) Symptomatic DVT in lower extremity 13 (0. 2) All-cause mortality 159 (5. 8) m Table 25: Efficacy Results at Day 35 (modified Intent-to-Treat) and at Day 10 (per protocol) in patients not at a high risk of bleeding in the MAGELLAN Study* Events from Day 1 to Day 35, mITT analysis set Rivaroxaban 10 mg N=2419 n (%) Enoxaparin 40 mg/ placebo N=2506 n (%) RR (95% CI) Primary Composite Endpoint at Day 35 94 (3. 88) Symptomatic non-fatal PE 7 (0. 4) Symptomatic DVT in lower extremity 9 (0. 4) Asymptomatic proximal DVT in lower extremity 73 (3. 4) VTE related death 15 (0. 0) Events from Day 1 to Day 10, PP analysis set Rivaroxaban 10 mg N=2385 n (%) Enoxaparin 40 mg N=2433 n (%) RR (95% CI) Primary Composite Endpoint at Day 10 58 (2. 15) Symptomatic non-fatal PE 5 (0. 1) Symptomatic DVT in lower extremity 6 (0. 2) Asymptomatic proximal DVT in lower extremity 52 (2. 5) VTE related death 2 (<0. 2) mITT analysis set plus all-cause mortality N=2504 n (%) N=2583 n (%) RR (95% CI) Other Composite Endpoint at Day 35 184 (7. 02) Symptomatic non-fatal PE 7 (0. 4) Asymptomatic proximal DVT in lower extremity 73 (2. 3) All-cause mortality 107 (4. 3) * Patients at high risk of bleeding (i. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded. The evidence for the efficacy and safety of rivaroxaban for the reduction in the risk of stroke, myocardial infarction, or cardiovascular death in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) was derived from the double-blind, placebo-controlled Cardiovascular OutcoMes for People using Anticoagulation StrategieS trial (COMPASS) [NCT10776424]. A total of 27,395 patients were evenly randomized to rivaroxaban 2. 5 mg orally twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg orally twice daily alone, or aspirin 100 mg once daily alone. Because the 5 mg dose alone was not superior to aspirin alone, only the data concerning the 2. 5 mg dose plus aspirin are discussed below. Patients with established CAD or PAD were eligible. Patients with CAD who were younger than 65 years of age The mean age was 68 years and 21% of the subject population were >=75 years. Of the included patients, 91% had CAD (and will be referred to as the COMPASS CAD population), 27% had PAD (and will be referred to as the COMPASS PAD population), and 18% had both CAD and PAD. Of the patients with CAD, 69% had prior MI, 60% had prior percutaneous transluminal coronary angioplasty (PTCA)/atherectomy/ percutaneous coronary intervention (PCI), and 26% had history of coronary artery bypass grafting (CABG) prior to study. Of the patients with PAD, 49% had intermittent claudication, 27% had peripheral artery bypass surgery or peripheral percutaneous transluminal angioplasty, 26% had asymptomatic carotid artery stenosis > 50%, and 4% had limb or foot amputation for arterial vascular disease. The mean duration of follow-up was 23 months. Relative to placebo, rivaroxaban reduced the rate of the primary composite outcome of stroke, myocardial infarction or cardiovascular death: HR 0. 76 (95% CI: 0. In the COMPASS CAD population, the benefit was observed early with a constant treatment effect over the entire treatment period (see Table 26 and Figure 10). A benefit-risk analysis of the data from COMPASS was performed by comparing the number of CV events (CV deaths, myocardial infarctions and non-hemorrhagic strokes) prevented to the number of fatal or life-threatening bleeding events (fatal bleeds + symptomatic non-fatal bleeds into a critical organ) in the rivaroxaban group versus the placebo group. Compared to placebo during 10,000 patient-years of treatment, rivaroxaban would be expected to result in 70 fewer CV events and 12 additional life-threatening bleeds, indicating a favorable balance of benefits and risks. The results in the COMPASS CAD population were consistent across major subgroups (see Figure 9). Figure 9: Risk of Primary Efficacy Outcome by Baseline Characteristics in the COMPASS CAD Population (Intent-to-Treat Population) *All patients received aspirin 100 mg once daily as background therapy. Table 26: Efficacy results from COMPASS CAD Population * Event Rivaroxaban N=8313 Placebo N=8261 Hazard Ratio (95% CI) n (%) Event Rate (%/year) n (%) Event Rate (%/year) Stroke, MI or CV death 347 (4. 86) - Stroke 74 (0. 75) - MI 169 (2. 05) - CV death 139 (1. 93) Coronary heart disease death, MI, ischemic stroke, acute limb ischemia 299 (3. 83) - Coronary heart disease deathsection 80 (1. 99) - Ischemic stroke 56 (0. 67) - Acute limb ischemia# 13 (0. 93) CV deathparagraph, MI, ischemic stroke, acute limb ischemia 349 (4. 84) All-cause mortality 262 (3. 90) * intention to treat analysis set, primary analyses. dagger double dagger rivaroxaban vs. placebo section paragraph # Figure 10: Time to first occurrence of primary efficacy outcome (stroke, myocardial infarction, cardiovascular death) in COMPASS CAD Population* *All patients received aspirin 100 mg once daily as background therapy. CI: confidence interval fig-9 figure-10 The efficacy and safety of rivaroxaban 2. 5 mg orally twice daily versus placebo on a background of aspirin 100 mg once daily in patients with PAD were evaluated in the COMPASS study (n=4996) and will be referred to as the COMPASS PAD population [see Clinical Studies (14. Eligible patients included adults who were at least 50 years of age with documented moderate to severe symptomatic lower extremity atherosclerotic PAD who had a successful peripheral surgical procedure and/or endovascular procedure with or without clopidogrel (up to a maximum of 6 months was allowed; median duration of therapy was 31 days). Patients had either a prior history of limb revascularization with ankle brachial index <=0. 85 or no prior history of limb Figure 11: Time to First Occurrence of Primary Efficacy Outcome (Myocardial Infarction, Ischemic Stroke, Cardiovascular Death, Acute Limb Ischemia, Major Amputation due to Vascular Origins) in VOYAGER* *All patients received aspirin 100 mg once daily as background therapy. Figure 12 shows the risk of primary efficacy outcome across major subgroups. Subgroup analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. The primary efficacy endpoint generally shows homogeneous results across subgroups. Figure 12: Risk of Primary Efficacy Outcome by Baseline Characteristics in VOYAGER (Intent-to-Treat Population)* *All patients received aspirin 100 mg once daily as background therapy. Table 27 provides the efficacy event rates for the prespecified endpoints in VOYAGER and similar endpoints in the COMPASS PAD population. Table 27: Efficacy Results in VOYAGER (Intent-to-Treat Population) and COMPASS PAD VOYAGER COMPASS PAD Rivaroxaban N=3286 Placebo N=3278 Hazard Ratio (95% CI)* p-valuedagger Rivaroxaban N=2492 Placebo N=2504 Hazard Ratio (95% CI)* Outcome Components Event Rate (%/year) Event Rate (%/year) 5- Component double dagger 6. 09) Ischemic Stroke section 0. 93) CV death paragraph 2. 99) Major amputation # 1. 79) VOYAGER Secondary Efficacy OutcomesÞ MI, ischemic stroke, CHD death ß 5. 83) Unplanned index limb à 8. 79, N/A N/A N/A Hospitalization for a coronary or peripheral cause of a thrombotic # 3. 77) MI, ischemic stroke, all-cause mortality, ALI, and major 8. 96) MI, all-cause stroke, CV death, ALI, and 6. 86) All-cause mortality 4. 16) VTE events è 0. 49) Efficacy endpoints in COMPASS PAD were analysed according to the pre-specified endpoints in VOYAGER when applicable. * dagger double dagger section paragraphCV death includes Coronary Heart Disease death, or death due to other CV causes or sudden cardiac arrest and unknown death. # Þ ß à è fig-11 fig-12 Rivaroxaban for the treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE was evaluated in the EINSTEIN Junior Phase 3 study [NCT02234843], a multicenter, open-label, active-controlled, randomized study in 500 pediatric patients from birth to less than 18 years with confirmed VTE. There were 276 children aged 12 to <18 years, 101 children aged 6 to <12 years, 69 children aged 2 to <6 years, and 54 children aged <2 years. Patients <6 months of age were excluded from enrollment if they were <37 weeks of gestation at birth, or had <10 days of oral feeding, or had a body weight of <2. Table 28: Efficacy Results in EINSTEIN Junior Study en dash Full Analysis Set Event Rivaroxaban * N=335 n (%) (95% CI) Comparator Group N=165 n (%) (95% CI) Rivaroxaban O vs. Comparator Group Risk Difference (95% CI) Rivaroxaban vs. Comparator Group Hazard Ratio (95% CI) Primary efficacy 4 (1. 40 Secondary efficacy outcome: Symptomatic 5 (1. 1% * dagger double dagger section Complete resolution of thrombus on repeat imaging without recurrent VTE occurred in 128 of 335 children (38. 2%, 95% CI 33. 5%) in the rivaroxaban group and 43 of 165 children (26. 1%, 95% CI 19. 0%) in the comparator group. Symptomatic recurrent VTE or major bleeding events occurred in 4 of 335 children (1. 2%, 95% CI 0. 0%) in the rivaroxaban group and 7 of 165 children (4. 2%, 95% CI 2. 4%) in the comparator group. The efficacy and safety of rivaroxaban for thromboprophylaxis in pediatric patients with congenital heart disease who have undergone the Fontan procedure was evaluated in the UNIVERSE Phase 3 study [NCT02846532]. UNIVERSE was a prospective, open-label, active controlled, multicenter, 2-part study, designed to evaluate the single-and multiple-dose pharmacokinetic properties of rivaroxaban (Part A), and to evaluate the safety and efficacy of rivaroxaban when used for thromboprophylaxis for 12 months compared with aspirin (Part B) in children 2 to 8 years of age with single ventricle physiology who had the Fontan procedure. Patients in Part B were randomized 2:1 to receive either body weight-adjusted doses of rivaroxaban (exposures to match that of 10 mg daily dose in adults) or aspirin (approximately 5 mg/kg). Patients with eGFR <30 ml/min/1. 73 m2 were excluded. Table 29: Efficacy Results in UNIVERSE Study en dash Full Analysis Set Part A* Part B Event Rivaroxaban N=12 n (%) (95% CI)double dagger Rivaroxaban section N=64 n (%) (95% CI)double dagger sectionAspirin N=34 n (%) (95% CI) double dagger Rivaroxaban vs. Aspirin Risk Difference (95% CI)paragraph Primary efficacy outcome: any thrombotic event 1 (8. 1%) Ischemic stroke 0 (0. 9%) Pulmonary embolism 0 (0. 4%) Venous thrombosis 1 (8. 1%) * Part A: single arm; not randomized dagger double dagger section Treatment schedule: body weight-adjusted doses of rivaroxaban (exposures to match that of 10 mg daily dose in adults) or aspirin (approximately 5 mg/kg) paragraph.
SPL MEDGUIDE SECTION
MEDICATION GUIDE Dispense with Medication Guide available at: www.macleodspharma.com/usa Increased risk of blood clots if you stop taking rivaroxaban tablets. Do not stop taking rivaroxaban tablets without talking to the doctor who prescribes it for you. Stopping rivaroxaban tablets increases your risk of having a stroke. Increased risk of bleeding You may have a higher risk of bleeding if you take rivaroxaban tablets and take other medicines that increase your risk of bleeding, including: Tell your doctor Call your doctor or get medical help right away if you or your child develop any of these signs or symptoms of bleeding: Spinal or epidural blood clots (hematoma). Tell your doctor What is Rivaroxaban tablets? Do not take rivaroxaban tablets if you or your child: Before taking rivaroxaban tablets, tell your doctor about all of your medical conditions, including if you or your child: Tell your doctor tell your doctor “What is the most important information I should know about rivaroxaban tablets?” for signs and symptoms of bleeding. Tell all of your doctors and dentists Tell your doctor about all the medicines you or your child take “What is the most important information I should know about rivaroxaban tablets?” Especially tell your doctor if you or your child take: How should I take rivaroxaban tablets? Do not change your dose or stop taking rivaroxaban tablets unless your doctor tells you to. If you take rivaroxaban tablets for: Atrial fibrillation that is not caused by a heart valve problem: 1 time a day with your evening meal. Blood clots in the veins of your legs or lungs: 1 or 2 times a day 10 mg dose with or without food. 15 mg and 20 mg doses with food at the same time each day. If you take the 15 mg dose of Rivaroxaban tablets 2 times a day (a total of 30 mg of Rivaroxaban tablets in 1 day): If you take rivaroxaban tablets 1 time a day: Hip or knee replacement surgery: Blood clots in people hospitalized for an acute illness: Reducing the risk of serious heart problems, heart attack and stroke in coronary artery disease: Reducing the risk of a sudden decrease in blood flow to the legs, major amputation, serious heart problems or stroke in people with peripheral artery disease including those who have recently had a procedure to improve blood flow to the legs: For children who take rivaroxaban tablets: What are the possible side effects of rivaroxaban tablets? What is the most important information I should know about rivaroxaban tablets?” The most common side effect of rivaroxaban tablets in adult was bleeding. The most common side effects of rivaroxaban tablets in children include: How should I store Rivaroxaban tablets? Keep rivaroxaban tablets and all medicines out of the reach of children. General information about the safe and effective use of rivaroxaban tablets. What are the ingredients in rivaroxaban tablets? Active ingredient: Inactive ingredients tablets: Revised: 05/2025

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