RIVAROXABAN

Rivaroxaban USP a factor Xa (FXa) inhibitor, is the active ingredient in rivaroxaban tablets USP 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 435.88. 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. Each rivaroxaban tablets USP contains 2.5 mg, 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of rivaroxaban tablets USP are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for rivaroxaban tablets USP 2.5 mg is Opadry Ò Yellow, containing HPMC 2910/hypermellose 15 mpass, titanium dioxide, macrogol 4000/PEG 3350, iron oxide yellow and for rivaroxaban 10 mg tablets are Opadry Ò Pink , for rivaroxaban 15 mg tablets are Opadry Ò Red, and rivaroxaban 20 mg tablets are Opadry Ò Red, containing HPMC 2910/hypermellose 15 mpass, titanium dioxide, macrogol 4000/PEG 3350, and iron oxide red.

INDICATIONS & USAGE Rivaroxaban tablet is a factor Xa inhibitor indicated: to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation ( 1.1 ) for treatment of deep vein thrombosis (DVT) ( 1.2 ) for treatment of pulmonary embolism (PE) ( 1.3 ) for reduction in the risk of recurrence of DVT or PE ( 1.4 ) for 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 Rivaroxaban tablet 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 rivaroxaban tablets and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [ see Clinical Studies ( 14.1 )]. 1.2 Treatment of Deep Vein Thrombosis Rivaroxaban tablet is indicated for the treatment of deep vein thrombosis (DVT). 1.3 Treatment of Pulmonary Embolism Rivaroxaban tablet 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 Rivaroxaban tablet 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 Rivaroxaban tablet 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 III Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding Rivaroxaban tablet 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) Rivaroxaban tablets, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease. 1.8 Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD Rivaroxaban tablets, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with PAD, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD. 1.9 Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients Rivaroxaban 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. 1.10 Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure Rivaroxaban tablet is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

DOSAGE & ADMINISTRATION • Nonvalvular Atrial Fibrillation : 15 or 20 mg, once daily with food ( 2.1 ) • Treatment of DVT and/or PE : 15 mg orally twice daily with food for the first 21 days followed by 20 mg orally once daily with food for the remaining treatment ( 2.1 ) • Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE : 10 mg once daily with or without food, after at least 6 months of standard anticoagulant treatment ( 2.1 ) • Prophylaxis of DVT Following Hip or Knee Replacement Surgery : 10 mg orally once daily with or without food ( 2.1 ) • Prophylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding : 10 mg once daily, with or without food, in hospital and after hospital discharge for a total recommended duration of 31 to 39 days ( 2.1 ) • CAD or PAD : 2.5 mg orally twice daily with or without food, in combination with aspirin (75-100 mg) once daily ( 2.1 ) • Pediatric Patients : See dosing recommendations in the Full Prescribing Information ( 2.2 ) 2.1 Recommended Dosage in Adults Table 1: Recommended Dosage in Adults Indication Renal Considerations* Dosage Food/Timing† Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation CrCl >50 mL/min 20 mg once daily Take with evening meal CrCl ≤50 mL/min‡ 15 mg once daily Take with evening meal Treatment of DVT and/or PE CrCl ≥15 mL/min‡ 15 mg twice daily ▼ after 21 days, transition to ▼ 20 mg once daily Take with food, at the same time each day CrCl <15 mL/min Avoid Use Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE CrCl ≥15 mL/min‡ 10 mg once daily, after at least 6 months of standard anticoagulant treatment Take with or without food CrCl <15 mL/min Avoid Use Prophylaxis of DVT Following: -Hip Replacement Surgery§ CrCl ≥15 mL/min‡ 10 mg once daily for 35 days, 6-10 hours after surgery once hemostasis has been established Take with or without food CrCl < 15 mL/min Avoid Use Knee Replacement Surgery§ 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 III Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding CrCl ≥15 mL/min‡ 10 mg once daily, in hospital and after hospital discharge, for a total recommended duration of 31 to 39 days Take with or without food CrCl < 15 mL/min Avoid Use Reduction of Risk of Major Cardiovascular Events (CV Death, MI, and Stroke) in CAD No dose adjustment needed based on CrCl 2.5 mg twice daily, plus aspirin (75-100 mg) once daily Take with or without food Reduction of Risk of Major Thrombotic Vascular Events in PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PAD No dose adjustment needed based on CrCl 2.5 mg twice daily, plus aspirin (75-100 mg) once daily. When starting therapy after a successful lower extremity revascularization procedure, initiate once hemostasis has been established. Take with or without food * Calculate CrCl based on actual weight. [See Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.6 )] † See Clinical Pharmacology ( 12.3 ) ‡ Patients with CrCl <30 mL/min were not studied, but administration of Rivaroxaban is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Use in Specific Populations ( 8.6 )] § See Dosage and Administration ( 2.4 ) 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*,† Dosage Form Body Weight Dosage Total Daily Dose ‡ Once a Day § Tablets 30 kg to 49.9 kg 15 mg 15 mg ≥50 kg 20 mg 20 mg * Initiate rivaroxaban treatments 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. ‡ 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 Dosing of rivaroxaban tablets 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 rivaroxaban tablets 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 tablets 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 Dosage Total Daily Dose * Once a Day † Tablets ≥50 kg 10 mg 10 mg *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. Administration in Pediatric Patients Food Effect: For the treatment of VTE in children, the dose should be taken with food to increase absorption. For thromboprophylaxis after Fontan procedure, the dose can be taken with or without food. Vomit or Spit up: If the patient vomits or spits up the dose within 30 minutes after receiving the dose, a new dose should be given. However, if the patient vomits more than 30 minutes after the dose is taken, the dose should not be re-administered and the next dose should be taken as scheduled. If the patient vomits or spits up the dose repeatedly, the caregiver should contact the child’s doctor right away. Tablets: Rivaroxaban tablets must not be split in an attempt to provide a fraction of a tablet dose. Rivaroxaban tablets 2.5 mg tablets are not recommended for use in pediatric patients [see Use in Specific Populations ( 8.4 )] . 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 x 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 m2) = 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 rivaroxaban tablets in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile, as no clinical data are available. Table 4: Reference Values of Serum Creatinine in Pediatric Patients <1 Year of Age Age 97.5th Percentile of Creatinine (mg/dL) 97.5th 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 rivaroxaban tablets Switching from Warfarin to rivaroxaban tablets - When switching patients from warfarin to rivaroxaban tablets, discontinue warfarin and start rivaroxaban tablets 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 Rivaroxaban tablets to Warfarin – Adults: No clinical trial data are available to guide converting patients from rivaroxaban tablets to warfarin. Rivaroxaban tablets 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 rivaroxaban tablets and begin both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban tablets would have been taken. Pediatric Patients: To ensure adequate anticoagulation during the transition from rivaroxaban tablets to warfarin, continue rivaroxaban tablets 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 rivaroxaban tablets. Co-administration of rivaroxaban tablets and warfarin is advised to continue until the INR is ≥ 2.0. Once rivaroxaban tablet is discontinued, INR testing may be done reliably 24 hours after the last dose. Switching from rivaroxaban tablets to Anticoagulants other than Warfarin - For adult and pediatric patients currently taking rivaroxaban tablets and transitioning to an anticoagulant with rapid onset, discontinue rivaroxaban tablets and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next rivaroxaban tablets dose would have been taken [see Drug Interactions (7.4)]. Switching from Anticoagulants other than Warfarin to rivaroxaban tablets - For adult and pediatric patients currently receiving an anticoagulant other than warfarin, start rivaroxaban tablets 0 to 2 hours prior to the next scheduled administration of the drug (e.g., low molecular weight heparin or nonwarfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start rivaroxaban tablets 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 rivaroxaban tablets should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see Warnings and Precautions ( 5.2 )]. In deciding whether a procedure should be delayed until 24 hours after the last dose of rivaroxaban tablets, the increased risk of bleeding should be weighed against the urgency of intervention. Rivaroxaban tablets should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short [see Warnings and Precautions ( 5.1 )]. If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant. 2.5 Missed Dose Adults For patients receiving 2.5 mg twice daily: if a dose is missed, the patient should take a single 2.5 mg rivaroxaban tablets dose as recommended at the next scheduled time. 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. For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed rivaroxaban tablets dose immediately. The dose should not be doubled within the same day to make up for a missed dose. Pediatric Patients If rivaroxaban tablet is taken once a day, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed. The patient should not take two doses to make up for a missed dose. If rivaroxaban tablet is taken two times a day, the patient should take the missed morning dose as soon as possible once it is noticed. A missed morning dose may be taken together with the evening dose. A missed evening dose can only be taken in the same evening. If rivaroxaban tablet is taken three times a day, if a dose is missed, the patient should skip the missed dose and go back to the regular dosing schedule at the usual time without compensating for the missed dose. On the following day, the patient should continue with their regular regimen. 2.6 Administration Options For adult patients who are unable to swallow whole tablets, Rivaroxaban tablets (all strengths) may be crushed and mixed with applesauce immediately prior to use and administered orally. After the administration of a crushed rivaroxaban 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 )] . Administration of rivaroxaban tablets via nasogastric (NG) tube or gastric feeding tube : After confirming gastric placement of the tube, rivaroxaban tablets (all strengths) may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube. Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of rivaroxaban tablets distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. After the administration of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding. Enteral feeding is not required following administration of the 2.5 mg or 10 mg tablets [see Clinical Pharmacology ( 12.3 )] . Crushed rivaroxaban tablets (all strengths) are stable in water and in applesauce for up to 4 hours. An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed rivaroxaban tablets to PVC or silicone nasogastric (NG) tubing.

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

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 Indoco Remedies Limited at +1-833-856-0880 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 rivaroxaban tablets. Hemorrhage The most common adverse reactions with rivaroxaban tablets 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 rivaroxaban tablets 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*-On Treatment Plus 2 Days Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. * 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. † 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. ‡ Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. § Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. ¶ Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. # Fatal bleeding is adjudicated death with the primary cause of death from bleeding. Parameter Rivaroxaban Tablets N=7111 n (%/year) Warfarin N=7125 n (%/year) Rivaroxaban Tablets vs. Warfarin HR (95% CI) Major Bleeding † 395 (3.6) 386 (3.5) 1.04 (0.90, 1.20) Intracranial Hemorrhage (ICH) ‡ 55 (0.5) 84 (0.7) 0.67 (0.47, 0.93) Hemorrhagic Stroke§ 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)¶ 221 (2.0) 140 (1.2) 1.61 (1.30, 1.99) Fatal 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. Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – 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) 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 rivaroxaban tablets vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for rivaroxaban tablets-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* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies * 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. † Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: rivaroxaban tablets 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)] ‡ Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group § 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 Parameter Rivaroxaban Tablets† 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‡ 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§ 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 rivaroxaban tablets 10 mg, 2% for rivaroxaban tablets 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for rivaroxaban tablets 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* in EINSTEIN CHOICE * 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. † Treatment schedule: rivaroxaban tablets 10 mg once daily or aspirin 100 mg once daily. ‡ 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. § 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. Parameter Rivaroxaban Tablets † 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‡ 3 (0.3) 1 (<0.1) Clinically relevant non-major (CRNM) bleeding§ 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 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 In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with rivaroxaban tablets. 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* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3) * 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. † Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) ‡ Includes major bleeding events Rivaroxaban Tablets 10 mg Enoxaparin† Total treated patients N=4487 n (%) N=4524 n (%) Major bleeding event 14 (0.3) 9 (0.2) Fatal bleeding 1 (<0.1) 0 Bleeding into a critical organ 2 (<0.1) 3 (0.1) Bleeding that required re-operation 7 (0.2) 5 (0.1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 4 (0.1) 1 (<0.1) Any bleeding event‡ 261 (5.8) 251 (5.6) Hip Surgery Studies N=3281 n (%) N=3298 n (%) Major bleeding event 7 (0.2) 3 (0.1) Fatal bleeding 1 (<0.1) 0 Bleeding into a critical organ 1 (<0.1) 1 (<0.1) Bleeding that required re-operation 2 (0.1) 1 (<0.1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 3 (0.1) 1 (<0.1) Any bleeding event‡ 201 (6.1) 191 (5.8) Knee Surgery Study N=1206 n (%) N=1226 n (%) Major bleeding event 7 (0.6) 6 (0.5) Fatal bleeding 0 0 Bleeding into a critical organ 1 (0.1) 2 (0.2) Bleeding that required re-operation 5 (0.4) 4 (0.3) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 1 (0.1) 0 Any bleeding event‡ 60 (5.0) 60 (4.9) 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 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 rivaroxaban tablets 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 Rivaroxaban 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 * Study–Safety Analysis Set -On Treatment Plus 2 Days * 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. † 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. ‡ 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. § Fatal bleeding is adjudicated death with the primary cause of death from bleeding. ¶ Patients received either Rivaroxaban 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. MAGELLAN Study¶ Rivaroxaban Tablets 10 mg N=3218 n (%) Enoxaparin 40 mg /placebo N=3229 n (%) Major bleeding‡† 22 (0.7) 15 (0.5) Critical site bleeding 7 (0.2) 4 (0.1) Fatal bleeding§ 3 (<0.1) 1 (<0.1) Clinically relevant non-major bleeding events (CRNM) 93 (2.9) 34 (1.1) Reduction of Risk of Major Cardiovascular Events in Patients with CAD In the COMPASS trial overall, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for rivaroxaban tablets 2.5 mg twice daily vs. 1.2% for placebo on background therapy for all patients with aspirin 100 mg once daily. The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar. Table 10 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial. Table 10: Major Bleeding Events in COMPASS -On Treatment Plus 2 Days * * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment in the safety analysis set in COMPASS patients. † Treatment schedule: Rivaroxaban tablets, 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily. ‡ Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization. Parameter Rivaroxaban Tablets † N=9134 n (%/year) Placebo† N=9107 n (%/year) Rivaroxaban Tablets vs. Placebo HR (95 % CI) Modified ISTH Major Bleeding‡ 263 (1.6) 144 (0.9) 1.8 (1.5, 2.3) -Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial 12 (<0.1) 6 (<0.1) 6 (<0.1) 8 (<0.1) 3 (<0.1) 5 (<0.1) 1.5 (0.6, 3.7) 2.0 (0.5, 8.0) 1.2 (0.4, 4.0) -Symptomatic bleeding in critical organ (non-fatal) -ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH 58 (0.3) 23 (0.1) 18 (0.1) 6 (<0.1) 43 (0.3) 21 (0.1) 13 (<0.1) 9 (<0.1) 1.4 (0.9, 2.0) 1.1 (0.6, 2.0) 1.4 (0.7, 2.8) 0.7 (0.2, 1.9) -Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) 7 (<0.1) 6 (<0.1) 1.2 (0.4, 3.5) -Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation) 188 (1.1) 91 (0.5) 2.1 (1.6, 2.7) Major GI bleeding 117 (0.7) 49 (0.3) 2.4 (1.7, 3.4) 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 tablets, 2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% vs. 1.6% and in COMPASS PAD was 2.7% vs. 1.3%, respectively. Table 11 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal. Table 11: Major Bleeding Events* in VOYAGER-On Treatment Plus 2 Days *Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. † Treatment schedule: Rivaroxaban tablets 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily. CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria Rivaroxaban † N=3256 Placebo† N=3248 Rivaroxaban vs. Placebo HR (95 % CI) Parameter n (%) Event rate %/year n (%) Event rate %/year TIMI Major Bleeding (CABG/non-CABG) 62 (1.9) 0.96 44 (1.4) 0.67 1.4 (1.0, 2.1) Fatal bleeding 6 (0.2) 0.09 6 (0.2) 0.09 1.0 (0.3, 3.2) Intracranial bleeding 13 (0.4) 0.20 17 (0.5) 0.26 0.8 (0.4, 1.6) Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL or drop in hematocrit of ≥15% 46 (1.4) 0.71 24 (0.7) 0.36 1.9 (1.2, 3.2) Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of Rivaroxaban-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 12. Table 12: Other Adverse Reactions* Reported by ≥1% of Rivaroxaban-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies *Adverse reaction with Relative Risk >1.5 for rivaroxaban versus comparator. Body System Adverse Reaction EINSTEIN DVT Study Rivaroxaban tablets 20 mg N=1718 n (%) Enoxaparin/VKA N=1711 n (%) Gastrointestinal disorders Abdominal pain 46 (2.7) 25 (1.5) General disorders and administration site conditions Fatigue 24 (1.4) 15 (0.9) Musculoskeletal and connective tissue disorders Back pain 50 (2.9) 31 (1.8) Muscle spasm 23 (1.3) 13 (0.8) Nervous system disorders Dizziness 38 (2.2) 22 (1.3) Psychiatric disorders Anxiety 24 (1.4) 11 (0.6) Depression 20 (1.2) 10 (0.6) Insomnia 28 (1.6) 18 (1.1) EINSTEIN PE Study Rivaroxaban tablets 20 mg N=2412 n (%) Enoxaparin/VKA N=2405 n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1) Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban-treated patients in RECORD 1-3 studies are shown in Table 13. Table 13: Other Adverse Drug Reactions* Reported by ≥1% of Rivaroxaban-Treated Patients in RECORD 1-3 Studies *Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication † Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) Body System Adverse Reaction Rivaroxaban tablets 10 mg N=4487 n (%) Enoxaparin† N=4524 n (%) Injury, poisoning and procedural complications Wound secretion 125 (2.8) 89 (2.0) Musculoskeletal and connective tissue disorders Pain in extremity 74 (1.7) 55 (1.2) Muscle spasm 52 (1.2) 32 (0.7) Nervous system disorders Syncope 55 (1.2) 32 (0.7) Skin and subcutaneous tissue disorders Pruritus 96 (2.1) 79 (1.8) Blister 63 (1.4) 40 (0.9) Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients The safety assessment is based on data from the EINSTEIN Junior Phase 3 study in 491 patients from birth to less than 18 years of age. Patients were randomized 2:1 to receive body weight-adjusted doses of Rivaroxaban or comparator (unfractionated heparin, low molecular weight heparin, fondaparinux or VKA). Discontinuation due to bleeding events occurred in 6 (1.8%) patients in the rivaroxaban group and 3 (1.9%) patients in the comparator group. 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 – Safety Analysis Set -Main Treatment Period* * These events occurred after randomization until 3 months of treatment (1 month for patients <2 years with central venous catheter-related VTE (CVC-VTE). Patients may have more than one event. † Treatment schedule: body weight-adjusted doses of rivaroxaban; randomized 2:1 (Rivaroxaban: Comparator). ‡ Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA. § 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. ¶ Defined as clinically overt bleeding, which 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. Parameter Rivaroxaban† N=329 n (%) Comparator Group‡ N=162 n (%) Major bleeding§ 0 2 (1.2) Clinically relevant non-major bleeding¶ 10 (3.0) 1 (0.6) Trivial bleeding 113 (34.3) 44 (27.2) Any bleeding 119 (36.2) 45 (27.8) Non-bleeding adverse reactions reported in ≥5% of rivaroxaban-treated patients are shown in Table 15. Table 15: Other Adverse Reactions* Reported in rivaroxaban-Treated Patients by ≥5% in EINSTEIN Junior Study * Adverse reaction with Relative Risk >1.5 for rivaroxaban versus comparator. † The following terms were combined: fatigue, asthenia. Adverse Reaction Rivaroxaban N=329 n (%) Comparator Group N=162 n (%) Pain in extremity 23 (7) 7 (4.3) Fatigue† 23 (7) 7 (4.3) 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 The data below are based on Part B of the UNIVERSE study which was designed to evaluate the safety and efficacy of Rivaroxaban for thromboprophylaxis in 98 children with CHD after the Fontan procedure who took at least one dose of study drug. Patients in Part B were randomized 2:1 to receive either body weight-adjusted doses of Rivaroxaban or aspirin (approximately 5 mg/kg). Discontinuation due to bleeding events occurred in 1 (1.6%) patient in the rivaroxaban group and no patients in the aspirin group. 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 * Treatment schedule: body weight-adjusted doses of rivaroxaban or aspirin (approximately 5 mg/kg); randomized 2:1 (Rivaroxaban: Aspirin). † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. § Defined as clinically overt bleeding, which 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. Parameter Rivaroxaban* N=64 n (%) Aspirin* N=34 n (%) Major Bleeding† 1 (1.6) 0 Epistaxis leading to transfusion 1 (1.6) 0 Clinically relevant non-major (CRNM) bleeding§ 4 (6.3) 3 (8.8) Trivial bleeding 21 (32.8) 12 (35.3) Any bleeding 23 (35.9) 14 (41.2) 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-Treated Patients in UNIVERSE Study (Part B) *Adverse reaction with Relative Risk >1.5 for rivaroxaban versus aspirin. † The following terms were combined: Gastroenteritis: gastroenteritis, gastroenteritis viral Rash: rash, rash maculo-papular, viral rash Adverse Reaction Rivaroxaban N=64 n (%) Aspirin N=34 n (%) Cough 10 (15.6) 3 (8.8) Vomiting 9 (14.1) 3 (8.8) Gastroenteritis† 8 (12.5) 1 (2.9) Rash† 6 (9.4) 2 (5.9) 6.2 Postmarketing Experience 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: agranulocytosis, thrombocytopenia Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury) Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: hemiparesis Renal disorders: Anticoagulant-related nephropathy Respiratory, thoracic and mediastinal disorders: Eosinophilic pneumonia Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) Injury, poisoning and procedural complications: Atraumatic splenic rupture

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. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events. 7.2 Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems Interaction with Combined P-gp and Strong CYP3A Inhibitors Avoid concomitant administration of rivaroxaban tablets with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with rivaroxaban tablets as the change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology (12.3)]. Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment Rivaroxaban tablets should not be used in patients with CrCl 15 to < 80mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. 7.3 Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems Avoid concomitant use of rivaroxaban tablets with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 )]. 7.4 Anticoagulants and NSAIDs/Aspirin Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology ( 12.3 )]. Avoid concurrent use of rivaroxaban tablets with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions ( 5.2 )].