RIVAROXABAN

WARNING: (A) PREMATURE DISCONTINUATION OF RIVAROXABAN TABLETS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA WARNING: (A) PREMATURE DISCONTINUATION OF RIVAROXABAN TABLETS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA A. Premature discontinuation of rivaroxaban tablets increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including rivaroxaban tablets, increases the risk of thrombotic events. If anticoagulation with rivaroxaban tablets are 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), Warnings and Precautions (5.1)] . B. Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with rivaroxaban tablets 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 tablets 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 TABLETS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning. (A) Premature discontinuation of rivaroxaban tablets increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including rivaroxaban tablets, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if rivaroxaban tablets are discontinued for a reason other than pathological bleeding or completion of a course of therapy. (2.3, 5.1) (B) Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with rivaroxaban tablets 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 tablets can cause serious and fatal bleeding. An agent to reverse the activity of rivaroxaban is available. (5.2) Pregnancy-related hemorrhage: Use rivaroxaban tablets with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. (5.7, 8.1) Prosthetic heart valves: Rivaroxaban tablets use not recommended. (5.8) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: Rivaroxaban tablets use not recommended. (5.10) 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including rivaroxaban tablet, 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 tablet to warfarin in clinical trials in atrial fibrillation patients. If rivaroxaban tablet are 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 tablet increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe rivaroxaban tablet 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 tablet 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)] . Reversal of Anticoagulant Effect An agent to reverse the anti-factor Xa activity of rivaroxaban is 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 tablet and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban tablet [see Clinical Pharmacology (12.3)] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban tablet are 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 tablet [see Clinical Pharmacology (12.3)] . The next rivaroxaban tablet dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of rivaroxaban tablet 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 Discontinue rivaroxaban tablet in patients who develop acute renal failure while on treatment [see 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 tablet 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)] . 5.6 Use with P-gp and Strong CYP3A Inhibitors or Inducers Avoid concomitant use of rivaroxaban tablet with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions (7.2)] . Avoid concomitant use of rivaroxaban tablet 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 tablet should be used only if the potential benefit justifies the potential risk to the mother and fetus. Rivaroxaban tablet dosing in pregnancy has not been studied. The anticoagulant effect of rivaroxaban 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 tablet are not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to rivaroxaban tablet experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of rivaroxaban tablet have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of rivaroxaban tablet are 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 tablet are 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 tablet, 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 reaction (>5%) in adult patients was bleeding. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Camber Pharmaceuticals, Inc., at 1-866-495-8330 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. Hemorrhage The most common adverse reactions with rivaroxaban tablet were bleeding complications [see Warnings and Precautions (5.2)] . 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. CI:confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis Parameter Rivaroxaban Tablets † N=9134 n (%/year) Placebo † N=9107 n (%/year) Rivaroxaban Tablets plus 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.(0.5, 8) 1.2 (0.4, 4) - 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) 1.1 (0.6, 2) 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) 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 Tablets † N=3256 Placebo † N=3248 Rivaroxaban Tablets 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, 2.1) Fatal bleeding 6 (0.2) 0.09 6 (0.2) 0.09 1 (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 Adverse reaction with Relative Risk >1.5 for rivaroxaban tablets versus comparator Reported by ≥1 % of Rivaroxaban-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies 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 to 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 to 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) 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) 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 tablets versus aspirin. † The following terms were combined: Gastroenteritis: gastroenteritis, gastroenteritis viral Rash: rash, rash maculo-papular, viral rash Adverse Reaction Rivaroxaban Tablets 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 tablet. 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)

<table ID="ID739" width="590"><caption> Table 10: Major Bleeding Events in COMPASS -On Treatment Plus 2 Days^*</caption><colgroup><col width="217"/><col width="126"/><col width="97"/><col width="150"/></colgroup><tfoot><tr><td colspan="4" align="left"><paragraph styleCode="First Footnote">^*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.</paragraph></td></tr><tr><td colspan="4" align="left"><paragraph styleCode="First Footnote">^&#x2020;Treatment schedule: rivaroxaban tablets 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily</paragraph></td></tr><tr><td colspan="4" align="left"><paragraph styleCode="First Footnote">^&#x2021;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.</paragraph></td></tr><tr><td colspan="4" align="left"><paragraph styleCode="First Footnote">CI:confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center"><content styleCode="bold"> Parameter</content></td><td styleCode="Botrule Rrule Toprule" align="center" valign="top"><content styleCode="bold"> Rivaroxaban Tablets</content>^&#x2020;<content styleCode="bold"> N=9134</content> <content styleCode="bold"> n (%/year)</content></td><td styleCode="Botrule Rrule Toprule" align="center" valign="top"><content styleCode="bold"> Placebo</content>^&#x2020;<content styleCode="bold"> N=9107</content> <content styleCode="bold"> n (%/year)</content></td><td styleCode="Botrule Rrule Toprule" align="center" valign="top"><content styleCode="bold"> Rivaroxaban Tablets </content><content styleCode="bold"> plus Placebo</content> <content styleCode="bold"> HR (95 % CI)</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Modified ISTH Major Bleeding^&#x2021;</td><td styleCode="Botrule Rrule" align="center">263 (1.6)</td><td styleCode="Botrule Rrule" align="center">144 (0.9)</td><td styleCode="Botrule Rrule" align="center">1.8 (1.5, 2.3)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">- Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial</td><td styleCode="Botrule Rrule" align="center" valign="top">12 (&lt;0.1) 6 (&lt;0.1) 6 (&lt;0.1)</td><td styleCode="Botrule Rrule" align="center" valign="top">8 (&lt;0.1) 3 (&lt;0.1) 5 (&lt;0.1)</td><td styleCode="Botrule Rrule" align="center" valign="top">1.5 (0.6, 3.7) 2.(0.5, 8) 1.2 (0.4, 4)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">- Symptomatic bleeding in critical organ (non-fatal) - ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH</td><td styleCode="Botrule Rrule" align="center" valign="bottom">58 (0.3) 23 (0.1) 18 (0.1) 6 (&lt;0.1)</td><td styleCode="Botrule Rrule" align="center" valign="bottom">43 (0.3) 21 (0.1) 13 (&lt;0.1) 9 (&lt;0.1)</td><td styleCode="Botrule Rrule" align="center" valign="bottom">1.4 (0.9, 2) 1.1 (0.6, 2) 1.4 (0.7, 2.8) 0.7 (0.2, 1.9)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">- Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ)</td><td styleCode="Botrule Rrule" align="center" valign="top">7 (&lt;0.1)</td><td styleCode="Botrule Rrule" align="center" valign="top">6 (&lt;0.1)</td><td styleCode="Botrule Rrule" align="center" valign="top">1.2 (0.4, 3.5)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">- Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation)</td><td styleCode="Botrule Rrule" align="center" valign="top">188 (1.1)</td><td styleCode="Botrule Rrule" align="center" valign="top">91 (0.5)</td><td styleCode="Botrule Rrule" align="center" valign="top">2.1 (1.6, 2.7)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Major GI bleeding</td><td styleCode="Botrule Rrule" align="center">117 (0.7)</td><td styleCode="Botrule Rrule" align="center">49 (0.3)</td><td styleCode="Botrule Rrule" align="center">2.4 (1.7, 3.4)</td></tr></tbody></table>

<table ID="ID800" width="594"><caption> Table 11: Major Bleeding Events^* in VOYAGER-On Treatment Plus 2 Days </caption><colgroup><col width="174"/><col width="72"/><col width="69"/><col width="79"/><col width="80"/><col width="120"/></colgroup><tfoot><tr><td colspan="6" align="left"><paragraph styleCode="First Footnote">^* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories.</paragraph></td></tr><tr><td colspan="6" align="left"><paragraph styleCode="First Footnote">^&#x2020; Treatment schedule: rivaroxaban tablets 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily.</paragraph></td></tr><tr><td colspan="6" align="left"><paragraph styleCode="First Footnote">CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center"/><td styleCode="Botrule Rrule Toprule" colspan="2" align="center"><content styleCode="bold"> Rivaroxaban Tablets</content>^&#x2020;<content styleCode="bold"> N=3256</content></td><td styleCode="Botrule Rrule Toprule" colspan="2" align="center"><content styleCode="bold"> Placebo</content>^&#x2020; <content styleCode="bold"> N=3248</content></td><td styleCode="Botrule Rrule Toprule" rowspan="2" align="center" valign="top"><content styleCode="bold"> Rivaroxaban Tablets</content><content styleCode="bold"> vs. Placebo</content> <content styleCode="bold"> HR (95 % CI)</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center" valign="top"><content styleCode="bold"> Parameter</content></td><td styleCode="Botrule Rrule" align="center"><content styleCode="bold"> n (%)</content></td><td styleCode="Botrule Rrule" align="center"><content styleCode="bold"> Event rate %/year</content></td><td styleCode="Botrule Rrule" align="center"><content styleCode="bold"> n (%)</content></td><td styleCode="Botrule Rrule" align="center"><content styleCode="bold"> Event rate %/year</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">TIMI Major Bleeding (CABG/non-CABG)</td><td styleCode="Botrule Rrule" align="center">62 (1.9)</td><td styleCode="Botrule Rrule" align="center">0.96</td><td styleCode="Botrule Rrule" align="center">44 (1.4)</td><td styleCode="Botrule Rrule" align="center">0.67</td><td styleCode="Botrule Rrule" align="center">1.4 (1, 2.1)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Fatal bleeding</td><td styleCode="Botrule Rrule" align="center">6 (0.2)</td><td styleCode="Botrule Rrule" align="center">0.09</td><td styleCode="Botrule Rrule" align="center">6 (0.2)</td><td styleCode="Botrule Rrule" align="center">0.09</td><td styleCode="Botrule Rrule" align="center">1 (0.3, 3.2)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Intracranial bleeding</td><td styleCode="Botrule Rrule" align="center">13 (0.4)</td><td styleCode="Botrule Rrule" align="center">0.20</td><td styleCode="Botrule Rrule" align="center">17 (0.5)</td><td styleCode="Botrule Rrule" align="center">0.26</td><td styleCode="Botrule Rrule" align="center">0.8 (0.4, 1.6)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Clinically overt signs of hemorrhage associated with a drop in hemoglobin of &#x2265;5 g/dL or drop in hematocrit of &#x2265;15 %</td><td styleCode="Botrule Rrule" align="center">46 (1.4)</td><td styleCode="Botrule Rrule" align="center">0.71</td><td styleCode="Botrule Rrule" align="center">24 (0.7)</td><td styleCode="Botrule Rrule" align="center">0.36</td><td styleCode="Botrule Rrule" align="center">1.9 (1.2, 3.2)</td></tr></tbody></table>

<table ID="ID588" width="621"><caption> Table 12: Other Adverse Reactions<footnote ID="ID588_0"> Adverse reaction with Relative Risk &gt;1.5 for rivaroxaban tablets versus comparator</footnote> Reported by &#x2265;1 % of Rivaroxaban-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies</caption><colgroup><col width="319"/><col width="180"/><col width="122"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="bold"> Body System </content> Adverse Reaction</td><td styleCode="Botrule Rrule Toprule" valign="top"/><td styleCode="Botrule Rrule Toprule" align="center" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> EINSTEIN DVT Study </content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Rivaroxaban Tablets </content><content styleCode="bold"> 20 mg </content> <content styleCode="bold"> N=1718 </content> <content styleCode="bold"> n (%) </content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Enoxaparin/VKA </content> <content styleCode="bold"> N=1711 </content> <content styleCode="bold"> n (%) </content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom"><content styleCode="bold"> Gastrointestinal disorders </content></td><td styleCode="Botrule Rrule" align="center" valign="top"/><td styleCode="Botrule Rrule" align="center" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom">Abdominal pain</td><td styleCode="Botrule Rrule" align="center" valign="top">46 (2.7)</td><td styleCode="Botrule Rrule" align="center" valign="top">25 (1.5)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom"><content styleCode="bold"> General disorders and administration site conditions </content></td><td styleCode="Botrule Rrule" align="center" valign="top"/><td styleCode="Botrule Rrule" align="center" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom">Fatigue</td><td styleCode="Botrule Rrule" align="center" valign="top">24 (1.4)</td><td styleCode="Botrule Rrule" align="center" valign="top">15 (0.9)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom"><content styleCode="bold"> Musculoskeletal and connective tissue disorders </content></td><td styleCode="Botrule Rrule" align="center" valign="top"/><td styleCode="Botrule Rrule" align="center" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom">Back pain</td><td styleCode="Botrule Rrule" align="center" valign="top">50 (2.9)</td><td styleCode="Botrule Rrule" align="center" valign="top">31 (1.8)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom">Muscle spasm</td><td styleCode="Botrule Rrule" align="center" valign="top">23 (1.3)</td><td styleCode="Botrule Rrule" align="center" valign="top">13 (0.8)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom"><content styleCode="bold"> Nervous system disorders </content></td><td styleCode="Botrule Rrule" align="center" valign="top"/><td styleCode="Botrule Rrule" align="center" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Dizziness</td><td styleCode="Botrule Rrule" align="center" valign="top">38 (2.2)</td><td styleCode="Botrule Rrule" align="center" valign="top">22 (1.3)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom"><content styleCode="bold"> Psychiatric disorders </content></td><td styleCode="Botrule Rrule" align="center" valign="top"/><td styleCode="Botrule Rrule" align="center" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Anxiety</td><td styleCode="Botrule Rrule" align="center" valign="top">24 (1.4)</td><td styleCode="Botrule Rrule" align="center" valign="top">11 (0.6)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Depression</td><td styleCode="Botrule Rrule" align="center" valign="top">20 (1.2)</td><td styleCode="Botrule Rrule" align="center" valign="top">10 (0.6)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Insomnia</td><td styleCode="Botrule Rrule" align="center" valign="top">28 (1.6)</td><td styleCode="Botrule Rrule" align="center" valign="top">18 (1.1)</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left"><content styleCode="bold"> EINSTEIN PE Study </content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Rivaroxaban</content><content styleCode="bold"> Tablets 20 mg </content> <content styleCode="bold"> N=2412 </content> <content styleCode="bold"> n (%) </content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Enoxaparin/VKA </content> <content styleCode="bold"> N=2405 </content> <content styleCode="bold"> n (%)</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom"><content styleCode="bold"> Skin and subcutaneous tissue disorders </content></td><td styleCode="Botrule Rrule" align="center" valign="top"/><td styleCode="Botrule Rrule" align="center" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom">Pruritus</td><td styleCode="Botrule Rrule" align="center" valign="top">53 (2.2)</td><td styleCode="Botrule Rrule" align="center" valign="top">27 (1.1)</td></tr></tbody></table>