Rivaroxaban

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 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), Warnings and Precautions ( 5.1 )] . B. Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with rivaroxaban 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 R IVAROXABAN 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 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 ( 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 tablets, 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 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)]. 5.2 Risk of Bleeding Rivaroxaban tablets increase the risk of bleeding, including in any organ, and can cause serious or fatal bleeding. In deciding whether to prescribe rivaroxaban tablets 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 tablets 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 tablets for second another indication: 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 tablets are not for use for second another indication in these hospitalized, acutely ill medical patients at high risk of bleeding. Reversal of Anticoagulant Effect A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology ( 12.3 )]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended. 5.3 Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning] . To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban tablets and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban tablets [see Clinical Pharmacology ( 12.3 )] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban tablets 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 tablets [see Clinical Pharmacology ( 12.3 )] . The next rivaroxaban tablets dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of rivaroxaban tablets 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 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 tablets in these patients [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 tablets 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 tablets with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions ( 7.2 )]. Avoid concomitant use of rivaroxaban tablets 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 tablets should be used only if the potential benefit justifies the potential risk to the mother and fetus. Rivaroxaban tablets dosing in pregnancy has not been studied. The anticoagulant effect of rivaroxaban tablets 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 experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of rivaroxaban tablets have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of rivaroxaban tablets 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 tablets 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 tablets, 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 Apotex Corp. at 1-800-706-5575 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 tablets 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 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 * Parameter Rivaroxaban † N=9,134 n (%/year) Placebo † N=9,107 n (%/year) Rivaroxaban 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) * 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 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 Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD The incidence of premature permanent discontinuation due to bleeding events for rivaroxaban 2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% 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 Rivaroxaban † N=3,256 Placebo † N=3,248 Rivaroxaban vs. Placebo Parameter n (%) Event rate %/year n (%) Event rate %/year HR (95 % CI) 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) * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. † Treatment schedule: Rivaroxaban 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 Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban-treated patients in the EINSTEIN 1 (Study) and EINSTEIN 2 (Study) are shown in Table 12. Table 12: Other Adverse Reactions* Reported by ≥1% of Rivaroxaban-Treated Patients in EINSTEIN 1 (Study) and EINSTEIN 2 (Study) Body System Adverse Reaction EINSTEIN 1 (Study) Rivaroxaban 20 mg N=1,718 n (%) Enoxaparin/VKA N=1,711 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 2 (Study) Rivaroxaban 20 mg N=2,412 n (%) Enoxaparin/VKA N=2,405 n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1) * Adverse reaction with Relative Risk >1.5 for rivaroxaban versus comparator Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban-treated patients in RECORD 1 to 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 Body System Adverse Reaction Rivaroxaban 10 mg N=4,487 n (%) Enoxaparin † N=4,524 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) * 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) 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

<table frame="box" rules="all"><tbody><tr><td><content styleCode="bold"> </content><content styleCode="bold"> </content><content styleCode="bold">Parameter</content><content styleCode="bold"/></td><td align="center"><content styleCode="bold">Rivaroxaban</content>^&#x2020;<content styleCode="bold"> N=9,134 </content><content styleCode="bold"/><content styleCode="bold">n (%/year)</content></td><td><content styleCode="bold">Placebo</content>^&#x2020; <content styleCode="bold"> N=9,107</content><content styleCode="bold"/> <content styleCode="bold">n (%/year)</content></td><td><content styleCode="bold">Rivaroxaban vs.</content> <content styleCode="bold">Placebo </content><content styleCode="bold">HR (95 % CI)</content></td></tr><tr><td> Modified ISTH Major Bleeding^&#x2021;</td><td> 263 (1.6) </td><td> 144 (0.9) </td><td> 1.8 (1.5, 2.3) </td></tr><tr><td> - Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial </td><td> 12 (&lt;0.1) 6 (&lt;0.1) 6 (&lt;0.1) </td><td align="center"> 8 (&lt;0.1) 3 (&lt;0.1) 5 (&lt;0.1) </td><td> 1.5 (0.6, 3.7) 2.0 (0.5, 8.0) 1.2 (0.4, 4.0) </td></tr><tr><td>- Symptomatic bleeding in critical organ (non-fatal) - ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH </td><td> 58 (0.3) 23 (0.1) 18 (0.1) 6 (&lt;0.1) </td><td align="center"><content styleCode="bold"> </content> 43 (0.3) 21 (0.1) 13 (&lt;0.1) 9 (&lt;0.1) </td><td> 1.4 (0.9, 2.0) 1.1 (0.6, 2.0) 1.4 (0.7, 2.8) 0.7 (0.2, 1.9) </td></tr><tr><td> - Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) </td><td> 7 (&lt;0.1) </td><td> 6 (&lt;0.1) </td><td> 1.2 (0.4, 3.5) </td></tr><tr><td> - Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation) </td><td> 188 (1.1) </td><td> 91 (0.5) </td><td> 2.1 (1.6, 2.7) </td></tr><tr><td> Major GI bleeding </td><td> 117 (0.7) </td><td> 49 (0.3) </td><td> 2.4 (1.7, 3.4) </td></tr></tbody></table>

<table frame="box" rules="all"><tbody><tr align="center"><td> </td><td colspan="2"><content styleCode="bold">Rivaroxaban</content>&#x2020; <content styleCode="bold"> N=3,256</content><content styleCode="bold"/></td><td colspan="2"><content styleCode="bold">Placebo</content>&#x2020; <content styleCode="bold"> N=3,248</content><content styleCode="bold"/></td><td><content styleCode="bold">Rivaroxaban vs.</content> <content styleCode="bold">Placebo</content><content styleCode="bold"/></td></tr><tr><td><content styleCode="bold">Parameter</content><content styleCode="bold"/></td><td><content styleCode="bold">n (%)</content></td><td><content styleCode="bold">Event rate </content><content styleCode="bold">%/year</content><content styleCode="bold"/></td><td><content styleCode="bold">n (%)</content></td><td><content styleCode="bold">Event rate </content><content styleCode="bold">%/year</content><content styleCode="bold"/></td><td><content styleCode="bold">HR (95 % CI)</content></td></tr><tr><td> TIMI Major Bleeding (CABG/non-CABG) </td><td> 62 (1.9) </td><td> 0.96 </td><td> 44 (1.4) </td><td> 0.67 </td><td> 1.4 (1.0, 2.1) </td></tr><tr><td align="right"> Fatal bleeding </td><td> 6 (0.2) </td><td> 0.09 </td><td> 6 (0.2) </td><td> 0.09 </td><td> 1.0 (0.3, 3.2) </td></tr><tr><td align="right"> Intracranial bleeding </td><td> 13 (0.4) </td><td> 0.20 </td><td> 17 (0.5) </td><td> 0.26 </td><td> 0.8 (0.4, 1.6) </td></tr><tr><td align="right"> 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> 46 (1.4) </td><td> 0.71 </td><td> 24 (0.7) </td><td> 0.36 </td><td> 1.9 (1.2, 3.2) </td></tr></tbody></table>

<table frame="box" rules="all"><tbody><tr><td align="center" valign="middle"><content styleCode="bold">Body System</content> Adverse Reaction </td><td> </td><td> </td></tr><tr><td><content styleCode="bold"> </content><content styleCode="bold"> EINSTEIN 1 (Study) </content></td><td align="center"><content styleCode="bold">Rivaroxaban 20 mg</content><content styleCode="bold"/><content styleCode="bold"> N=1,718</content><content styleCode="bold"/><content styleCode="bold"> n (%)</content><content styleCode="bold"/></td><td align="center"><content styleCode="bold">Enoxaparin/VKA N=1,711</content><content styleCode="bold"/><content styleCode="bold"> n (%)</content><content styleCode="bold"/></td></tr><tr><td><content styleCode="bold">Gastrointestinal</content><content styleCode="bold"> </content><content styleCode="bold">disorders</content><content styleCode="bold"/></td><td> </td><td> </td></tr><tr><td> Abdominal pain </td><td> 46 (2.7) </td><td> 25 (1.5) </td></tr><tr><td><content styleCode="bold">General disorders and administration site conditions</content></td><td> </td><td> </td></tr><tr><td> Fatigue </td><td> 24 (1.4) </td><td> 15 (0.9) </td></tr><tr><td><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td> </td><td> </td></tr><tr><td> Back pain </td><td> 50 (2.9) </td><td> 31 (1.8) </td></tr><tr><td> Muscle spasm </td><td> 23 (1.3) </td><td> 13 (0.8) </td></tr><tr><td><content styleCode="bold">Nervous system disorders</content></td><td> </td><td> </td></tr><tr><td> Dizziness </td><td> 38 (2.2) </td><td> 22 (1.3) </td></tr><tr><td><content styleCode="bold">Psychiatric disorders</content></td><td> </td><td> </td></tr><tr><td> Anxiety </td><td> 24 (1.4) </td><td> 11 (0.6) </td></tr><tr><td> Depression </td><td> 20 (1.2) </td><td> 10 (0.6) </td></tr><tr><td> Insomnia </td><td> 28 (1.6) </td><td> 18 (1.1) </td></tr><tr><td><content styleCode="bold"> </content><content styleCode="bold"> EINSTEIN 2 (Study) </content></td><td><content styleCode="bold">Rivaroxaban 20 mg</content><content styleCode="bold"/><content styleCode="bold"> N=2,412</content><content styleCode="bold"/><content styleCode="bold"> n (%)</content><content styleCode="bold"/></td><td><content styleCode="bold">Enoxaparin/VKA N=2,405</content><content styleCode="bold"/><content styleCode="bold"> n (%)</content><content styleCode="bold"/></td></tr><tr><td><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td><td> </td><td> </td></tr><tr><td> Pruritus </td><td> 53 (2.2) </td><td> 27 (1.1) </td></tr></tbody></table>