rivaroxaban granule

WARNING: (A) PREMATURE DISCONTINUATION OF RIVAROXABAN FOR ORAL SUSPENSION INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA A. Premature discontinuation of rivaroxaban for oral suspension increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including rivaroxaban for oral suspension, increases the risk of thrombotic events. If anticoagulation with rivaroxaban for oral suspension is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration ( 2.3 , 2.4 ) and Warnings and Precautions ( 5.1 ). B. Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with rivaroxaban for oral suspension who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as non- steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants a history of traumatic or repeated epidural or spinal punctures a history of spinal deformity or spinal surgery optimal timing between the administration of rivaroxaban for oral suspension and neuraxial procedures is not known [see Warnings and Precautions ( 5.2 , 5.3 ) and Adverse Reactions ( 6.2 )]. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions ( 5.3 )] . Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions ( 5.3 )] . WARNING: (A) PREMATURE DISCONTINUATION OF RIVAROXABAN FOR ORAL SUSPENSION INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning. (A) Premature discontinuation of rivaroxaban for oral suspension increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including rivaroxaban for oral suspension, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if rivaroxaban for oral suspension is discontinued for a reason other than pathological bleeding or completion of a course of therapy. ( 2.2 , 2.3 , 5.1 ). (B) Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with rivaroxaban for oral suspension who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. ( 5.2 , 5.3 , 6.2 ) Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently. Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated. ( 5.3 )

5 WARNINGS AND PRECAUTIONS Risk of Bleeding : Rivaroxaban for oral suspension can cause serious and fatal bleeding. ( 5.2 ) Pregnancy-Related Hemorrhage : Use rivaroxaban for oral suspension with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. ( 5.7 , 8.1 ) Prosthetic Heart Valves : Rivaroxaban for oral suspension use not recommended. ( 5.8 ) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome : Rivaroxaban for oral suspension use not recommended. ( 5.10 ) 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including rivaroxaban for oral suspension, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from rivaroxaban tablets to warfarin in clinical trials in another indication in patients. If rivaroxaban for oral suspension is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration ( 2.3 , 2.4 )] . 5.2 Risk of Bleeding Rivaroxaban for oral suspension increases the risk of bleeding, including in any organ, and can cause serious or fatal bleeding. In deciding whether to prescribe rivaroxaban for oral suspension to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue rivaroxaban for oral suspension in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y 12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions ( 7.4 )] , selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions ( 7.2 )] . Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of rivaroxaban for oral suspension for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e., undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy. rivaroxaban for oral suspension is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding. Reversal of Anticoagulant Effect A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology ( 12.3 )] . Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended. Reversal of Anticoagulant Effect A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology ( 12.3 )] . Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended. 5.3 Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning] . To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban for oral suspension and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban for oral suspension [see Clinical Pharmacology ( 12.3 )] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban for oral suspension is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of rivaroxaban for oral suspension [ see Clinical Pharmacology ( 12.3 ) ]. The next rivaroxaban for oral suspension dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of rivaroxaban for oral suspension for 24 hours. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae. 5.4 Use in Patients with Renal Impairment Pediatric Patients There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m 2 ); therefore, avoid the use of rivaroxaban for oral suspension in these patients. There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5 th percentile; therefore, avoid the use of rivaroxaban for oral suspension in these patients [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . 5.5 Use in Patients with Hepatic Impairment No clinical data are available for adult patients with severe hepatic impairment. Avoid use of rivaroxaban for oral suspension in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations ( 8.7 )] . No clinical data are available in pediatric patients with hepatic impairment. 5.6 Use with P-gp and Strong CYP3A Inhibitors or Inducers Avoid concomitant use of rivaroxaban for oral suspension with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions ( 7.2 )] . Avoid concomitant use of rivaroxaban for oral suspension with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions ( 7.3 )] . 5.7 Risk of Pregnancy-Related Hemorrhage In pregnant women, rivaroxaban for oral suspension should be used only if the potential benefit justifies the potential risk to the mother and fetus. Rivaroxaban for oral suspension dosing in pregnancy has not been studied. The anticoagulant effect of rivaroxaban for oral suspension cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.1 )] . 5.8 Patients with Prosthetic Heart Valves On the basis of the GALILEO study, use of rivaroxaban tablets is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to rivaroxaban tablets experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of rivaroxaban for oral suspension have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of rivaroxaban for oral suspension is not recommended in patients with prosthetic heart valves. 5.9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy Initiation of rivaroxaban for oral suspension is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy. 5.10 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including rivaroxaban for oral suspension, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed in other sections of the labeling: Increased Risk of Stroke After Discontinuation in Another Indication [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 reactions (>10 %) in pediatric patients were bleeding, cough, vomiting, and gastroenteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561, 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. 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 for oral suspension 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 for oral suspension 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 for oral suspension 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 for oral suspension; randomized 2:1 (rivaroxaban for oral suspension: 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 for Oral Suspension † N=329 n (%) Comparator Group ‡ N=162 n (%) Major bleeding § 0 2 (1.2) Clinically relevant non-major bleeding ¶ 10 (3) 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 for oral suspension -treated patients are shown in Table 15. Table 15: Other Adverse Reactions * Reported in Rivaroxaban for Oral Suspension-Treated Patients by ≥5 % in EINSTEIN Junior Study * Adverse reaction with Relative Risk >1.5 for rivaroxaban for oral suspension versus comparator. † The following terms were combined: fatigue, asthenia. Adverse Reaction Rivaroxaban for Oral Suspension 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 for oral suspension -treated patients was vomiting (10.6 % in the rivaroxaban for oral suspension 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 oral suspension 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 for oral suspension or aspirin (approximately 5 mg/kg). Discontinuation due to bleeding events occurred in 1 (1.6 %) patient in the rivaroxaban for oral suspension 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 Parameter Rivaroxaban for Oral Suspension Treatment schedule: body weight-adjusted doses of rivaroxaban for oral suspension or aspirin (approximately 5 mg/kg); randomized 2:1 (Rivaroxaban for Oral Suspension:Aspirin). N=64 n (%) Aspirin N=34 n (%) Major Bleeding 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. 1 (1.6) 0 Epistaxis leading to transfusion 1 (1.6) 0 Clinically relevant non-major (CRNM) bleeding 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. 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 for oral suspension-treated patients are shown in Table 17. Table 17: Other Adverse Reactions * Reported by ≥5 % of Rivaroxaban for Oral Suspension-Treated Patients in UNIVERSE Study (Part B) * Adverse reaction with Relative Risk >1.5 for rivaroxaban for oral suspension versus aspirin. † The following terms were combined: Gastroenteritis: gastroenteritis, gastroenteritis viral Rash: rash, rash maculo-papular, viral rash Adverse Reaction Rivaroxaban for Oral Suspension 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 for oral suspension. 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

<table ID="ID82" width="0" styleCode="Noautorules"><caption> Table 14: Bleeding Events in EINSTEIN Junior Study&#x2013;Safety Analysis Set - Main Treatment Period^*</caption><col width="261"/><col width="197"/><col width="164"/><tfoot><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^* These events occurred after randomization until 3 months of treatment (1 month for patients &lt;2 years with central venous catheter-related VTE (CVC-VTE). Patients may have more than one event.</paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^&#x2020; Treatment schedule: body weight-adjusted doses of rivaroxaban for oral suspension; randomized 2:1 (rivaroxaban for oral suspension: Comparator).</paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^&#x2021; Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA.</paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^&#xA7; Defined as clinically overt bleeding associated with a decrease in hemoglobin of &#x2265;2 g/dL, a transfusion of &#x2265;2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.</paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^&#xB6; 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.</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Parameter</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Rivaroxaban for Oral Suspension</content>^&#x2020;<content styleCode="bold"> N=329 </content><content styleCode="bold"> n (%)</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Comparator</content><content styleCode="bold"> Group</content>^&#x2021; <content styleCode="bold"> N=162 </content><content styleCode="bold"> n (%)</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Major bleeding^&#xA7; </td><td styleCode=" Botrule Rrule" align="center"> 0 </td><td styleCode=" Botrule Rrule" align="center"> 2 (1.2) </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Clinically relevant non-major bleeding^&#xB6; </td><td styleCode=" Botrule Rrule" align="center"> 10 (3) </td><td styleCode=" Botrule Rrule" align="center"> 1 (0.6) </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Trivial bleeding </td><td styleCode=" Botrule Rrule" align="center"> 113 (34.3) </td><td styleCode=" Botrule Rrule" align="center"> 44 (27.2) </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Any bleeding </td><td styleCode=" Botrule Rrule" align="center"> 119 (36.2) </td><td styleCode=" Botrule Rrule" align="center"> 45 (27.8) </td></tr></tbody></table>

<table ID="ID84" width="508" styleCode="Noautorules"><col width="136"/><col width="168"/><col width="204"/><tfoot><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^* Adverse reaction with Relative Risk &gt;1.5 for rivaroxaban for oral suspension versus comparator.</paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^&#x2020; The following terms were combined: fatigue, asthenia.</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Adverse Reaction</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Rivaroxaban for Oral Suspension</content> <content styleCode="bold"> N=329</content> <content styleCode="bold"> n (%)</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Comparator</content><content styleCode="bold"> Group</content> <content styleCode="bold"> N=162</content> <content styleCode="bold"> n (%)</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Pain in extremity </td><td styleCode=" Botrule Rrule" align="center"> 23 (7) </td><td styleCode=" Botrule Rrule" align="center"> 7 (4.3) </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Fatigue^&#x2020; </td><td styleCode=" Botrule Rrule" align="center"> 23 (7) </td><td styleCode=" Botrule Rrule" align="center"> 7 (4.3) </td></tr></tbody></table>

<table ID="ID86" width="621" styleCode="Noautorules"><caption> Table 16: Bleeding Events in UNIVERSE Study - Safety Analysis Set - On Treatment Plus 2 Days </caption><col width="261"/><col width="180"/><col width="180"/><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Parameter</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Rivaroxaban for Oral Suspension</content><footnote ID="ID86_0"> Treatment schedule: body weight-adjusted doses of rivaroxaban for oral suspension or aspirin (approximately 5 mg/kg); randomized 2:1 (Rivaroxaban for Oral Suspension:Aspirin).</footnote> <content styleCode="bold"> N=64</content> <content styleCode="bold"> n (%)</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Aspirin</content><footnoteRef IDREF="ID86_0"/><content styleCode="bold"> N=34</content> <content styleCode="bold"> n (%)</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Major Bleeding<footnote ID="ID86_1"> Defined as clinically overt bleeding associated with a decrease in hemoglobin of &#x2265;2 g/dL, a transfusion of the equivalent of &#x2265;2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.</footnote> </td><td styleCode=" Botrule Rrule" align="center"> 1 (1.6) </td><td styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Epistaxis leading to transfusion </td><td styleCode=" Botrule Rrule" align="center"> 1 (1.6) </td><td styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Clinically relevant non-major (CRNM) bleeding<footnote ID="ID86_2"> 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.</footnote> </td><td styleCode=" Botrule Rrule" align="center"> 4 (6.3) </td><td styleCode=" Botrule Rrule" align="center"> 3 (8.8) </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Trivial bleeding </td><td styleCode=" Botrule Rrule" align="center"> 21 (32.8) </td><td styleCode=" Botrule Rrule" align="center"> 12 (35.3) </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Any bleeding </td><td styleCode=" Botrule Rrule" align="center"> 23 (35.9) </td><td styleCode=" Botrule Rrule" align="center"> 14 (41.2) </td></tr></tbody></table>