FDA label 6e27158f-b0f7-f9f4-e053-2a91aa0a5091

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA A. PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO 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 (2.2 , 2.6 ), Warnings and Precautions (5.1) , and Clinical Studies (14.1) ] . B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO 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 XARELTO 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 XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy ( 2.2 , 2.6 , 5.1 , 14.1 ). (B) SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO 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: XARELTO can cause serious and fatal bleeding. Promptly evaluate signs and symptoms of blood loss. ( 5.2 ) Pregnancy-related hemorrhage: Use XARELTO with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. Promptly evaluate signs and symptoms of blood loss. ( 5.7 ) Prosthetic heart valves: XARELTO use not recommended ( 5.8 ) 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO 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 (2.2 , 2.6 ) and Clinical Studies (14.1) ] . 5.2 Risk of Bleeding XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO 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 XARELTO 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, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3) ]. Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions (7.1) ] . Reversal of Anticoagulant Effect A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) ] . Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated. 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 and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban [see Clinical Pharmacology (12.3) ] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed 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 Nonvalvular Atrial Fibrillation Avoid the use of XARELTO in patients with CrCl <15 mL/min since drug exposure is increased. Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly . Discontinue XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations (8.7) ]. Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population [see Use in Specific Populations (8.7) ] . Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use in Specific Populations (8.7) ]. 5.5 Use in Patients with Hepatic Impairment No clinical data are available for patients with severe hepatic impairment. Avoid use of XARELTO 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 (8.8) ] . 5.6 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers Avoid concomitant use of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, and conivaptan) [see Drug Interactions (7.1) ] . Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) [see Drug Interactions (7.2) ] . 5.7 Risk of Pregnancy-Related Hemorrhage In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress). 5.8 Patients with Prosthetic Heart Valves The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO is not recommended in these patients. 5.9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy Initiation of XARELTO 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.

6 ADVERSE REACTIONS The following 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%) was bleeding. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 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, 16326 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 4728 patients who received either XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily (EINSTEIN DVT, EINSTEIN PE) or 20 mg orally once daily (EINSTEIN Extension) to treat DVT, PE, and to reduce the risk of recurrence of DVT and of PE; and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1–3). Hemorrhage The most common adverse reactions with XARELTO 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 XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups. Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial. Table 1: Bleeding Events in ROCKET AF 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. - On Treatment Plus 2 Days Parameter XARELTO N = 7111 n (%/year) Warfarin N = 7125 n (%/year) XARELTO vs. Warfarin HR (95% CI) Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. Major Bleeding 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. 395 (3.6) 386 (3.5) 1.04 (0.90, 1.20) Intracranial Hemorrhage (ICH) Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. 55 (0.5) 84 (0.7) 0.67 (0.47, 0.93) Hemorrhagic Stroke Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. 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) Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. 221 (2.0) 140 (1.2) 1.61 (1.30, 1.99) Fatal Bleeding Fatal bleeding is adjudicated death with the primary cause of death from 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. Figure 1 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and to Reduce the Risk of Recurrence of DVT and of 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 XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients. Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. Table 2: Bleeding Events 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. in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Parameter XARELTO Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 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)] 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 Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group 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 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 27 (0.7) 37 (0.9) Decrease in Hb ≥ 2g/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) EINSTEIN Extension Study In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for XARELTO vs. 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both XARELTO and placebo treatment groups. Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN Extension study. Table 3: Bleeding Events 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. in EINSTEIN Extension Study Parameter XARELTO Treatment schedule: XARELTO 20 mg once daily; matched placebo once daily 20 mg N = 598 n (%) Placebo N = 590 n (%) Major bleeding event There were no fatal or critical organ bleeding events. 4 (0.7) 0 Decrease in Hb ≥2 g/dL 4 (0.7) 0 Transfusion of ≥2 units of whole blood or packed red blood cells 2 (0.3) 0 Gastrointestinal 3 (0.5) 0 Menorrhagia 1 (0.2) 0 Clinically relevant non-major bleeding 32 (5.4) 7 (1.2) Any bleeding 104 (17.4) 63 (10.7) 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 XARELTO. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4. Table 4: Bleeding Events 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. in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1–3) XARELTO 10 mg Enoxaparin Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3) 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 Includes major bleeding events 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 XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery. Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN Extension study are shown in Table 5. Table 5: Other Adverse Reactions Adverse reaction (with Relative Risk >1.5 for XARELTO versus placebo) occurred after the first dose and up to 2 days after the last dose of study drug. Incidences are based on the number of patients, not the number of events. Although a patient may have had 2 or more clinical adverse reactions, the patient is counted only once in a category. The same patient may appear in different categories. Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN Extension Study System Organ Class Preferred Term XARELTO N = 598 n (%) Placebo N = 590 n (%) Gastrointestinal disorders Abdominal pain upper 10 (1.7) 1 (0.2) Dyspepsia 8 (1.3) 4 (0.7) Toothache 6 (1.0) 0 General disorders and administration site conditions Fatigue 6 (1.0) 3 (0.5) Infections and infestations Sinusitis 7 (1.2) 3 (0.5) Urinary tract infection 7 (1.2) 3 (0.5) Musculoskeletal and connective tissue disorders Back pain 22 (3.7) 7 (1.2) Osteoarthritis 10 (1.7) 5 (0.8) Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 6 (1.0) 2 (0.3) Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1–3 studies are shown in Table 6. Table 6: Other Adverse Drug Reactions 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 Reported by ≥1% of XARELTO-Treated Patients in RECORD 1–3 Studies System/Organ Class Adverse Reaction XARELTO 10 mg Enoxaparin Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3) N = 4487 n (%) 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) Other clinical trial experience: In an investigational study of acute medically ill patients being treated with XARELTO 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of rivaroxaban. 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 Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury) Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

<table width="100%" ID="t1"> <caption>Table 1: Bleeding Events in ROCKET AF <footnote ID="K1792">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.</footnote>- On Treatment Plus 2 Days </caption> <col width="30%" align="left" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <thead> <tr> <th align="center" styleCode="Lrule">Parameter</th> <th>XARELTO N = 7111 n (%/year) </th> <th>Warfarin N = 7125 n (%/year) </th> <th styleCode="Rrule">XARELTO vs. Warfarin HR (95% CI) </th> </tr> </thead> <tfoot> <tr> <td colspan="4" align="left">Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major.</td> </tr> </tfoot> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule">Major Bleeding <footnote ID="K1848">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.</footnote> </td> <td>395 (3.6)</td> <td>386 (3.5)</td> <td styleCode="Rrule">1.04 (0.90, 1.20)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Intracranial Hemorrhage (ICH) <footnote ID="K1862">Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma.</footnote> </td> <td>55 (0.5)</td> <td>84 (0.7)</td> <td styleCode="Rrule">0.67 (0.47, 0.93)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Hemorrhagic Stroke <footnote ID="K1876">Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days.</footnote> </td> <td>36 (0.3)</td> <td>58 (0.5)</td> <td styleCode="Rrule">0.63 (0.42, 0.96)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Other ICH</td> <td>19 (0.2)</td> <td>26 (0.2)</td> <td styleCode="Rrule">0.74 (0.41, 1.34)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Gastrointestinal (GI) <footnote ID="K1902">Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding.</footnote> </td> <td>221 (2.0)</td> <td>140 (1.2)</td> <td styleCode="Rrule">1.61 (1.30, 1.99)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Fatal Bleeding <footnote ID="K1916">Fatal bleeding is adjudicated death with the primary cause of death from bleeding.</footnote> </td> <td>27 (0.2)</td> <td>55 (0.5)</td> <td styleCode="Rrule">0.50 (0.31, 0.79)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> ICH</td> <td>24 (0.2)</td> <td>42 (0.4)</td> <td styleCode="Rrule">0.58 (0.35, 0.96)</td> </tr> <tr> <td styleCode="Lrule"> Non-intracranial</td> <td>3 (0.0)</td> <td>13 (0.1)</td> <td styleCode="Rrule">0.23 (0.07, 0.82)</td> </tr> </tbody> </table>

<table width="100%"> <caption>Table 2: Bleeding Events <footnote ID="K2004">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.</footnote> in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies </caption> <col width="60%" align="left" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <thead> <tr> <th align="center" styleCode="Lrule">Parameter</th> <th styleCode="Lrule">XARELTO <footnote ID="t2f1">Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 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&#x2013;3.0)]</footnote> N = 4130 n (%) </th> <th styleCode="Lrule Rrule">Enoxaparin/ VKA <footnoteRef IDREF="t2f1"/> N = 4116 n (%) </th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule Botrule">Major bleeding event</td> <td styleCode="Rrule Botrule">40 (1.0)</td> <td styleCode="Rrule Botrule">72 (1.7)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule"> Fatal bleeding</td> <td styleCode="Rrule Botrule">3 (&lt;0.1)</td> <td styleCode="Rrule Botrule">8 (0.2)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule"> Intracranial</td> <td styleCode="Rrule Botrule">2 (&lt;0.1)</td> <td styleCode="Rrule Botrule">4 (&lt;0.1)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule"> Non-fatal critical organ bleeding</td> <td styleCode="Rrule Botrule">10 (0.2)</td> <td styleCode="Rrule Botrule">29 (0.7)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule"> Intracranial <footnote ID="t2f2">Treatment-emergent major bleeding events with at least &gt;2 subjects in any pooled treatment group</footnote> </td> <td styleCode="Rrule Botrule">3 (&lt;0.1)</td> <td styleCode="Rrule Botrule">10 (0.2)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule"> Retroperitoneal <footnoteRef IDREF="t2f2"/> </td> <td styleCode="Rrule Botrule">1 (&lt;0.1)</td> <td styleCode="Rrule Botrule">8 (0.2)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule"> Intraocular <footnoteRef IDREF="t2f2"/> </td> <td styleCode="Rrule Botrule">3 (&lt;0.1)</td> <td styleCode="Rrule Botrule">2 (&lt;0.1)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule"> Intra-articular <footnoteRef IDREF="t2f2"/> </td> <td styleCode="Rrule Botrule">0</td> <td styleCode="Rrule Botrule">4 (&lt;0.1)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule"> Non-fatal non-critical organ bleeding <footnote ID="K2140">Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb &#x2265; 2 g/dL and/or transfusion of &#x2265;2 units of whole blood or packed red blood cells</footnote> </td> <td styleCode="Rrule Botrule">27 (0.7)</td> <td styleCode="Rrule Botrule">37 (0.9)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule"> Decrease in Hb &#x2265; 2g/dL</td> <td styleCode="Rrule Botrule">28 (0.7)</td> <td styleCode="Rrule Botrule">42 (1.0)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule"> Transfusion of &#x2265;2 units of whole blood or packed red blood cells</td> <td styleCode="Rrule Botrule">18 (0.4)</td> <td styleCode="Rrule Botrule">25 (0.6)</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule">Clinically relevant non-major bleeding</td> <td styleCode="Rrule Botrule">357 (8.6)</td> <td styleCode="Rrule Botrule">357 (8.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Any bleeding</td> <td styleCode="Rrule">1169 (28.3)</td> <td styleCode="Rrule">1153 (28.0)</td> </tr> </tbody> </table>

<table width="100%"> <caption>Table 3: Bleeding Events <footnote ID="K2210">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.</footnote> in EINSTEIN Extension Study </caption> <col width="60%" align="left" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th align="center" styleCode="Lrule">Parameter</th> <th styleCode="Lrule">XARELTO <footnote ID="t3f1">Treatment schedule: XARELTO 20 mg once daily; matched placebo once daily</footnote> 20 mg N = 598 n (%) </th> <th styleCode="Lrule Rrule">Placebo <footnoteRef IDREF="t3f1"/> N = 590 n (%) </th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Major bleeding event <footnote ID="K2259">There were no fatal or critical organ bleeding events.</footnote> </td> <td styleCode="Rrule">4 (0.7)</td> <td styleCode="Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Decrease in Hb &#x2265;2 g/dL</td> <td styleCode="Rrule">4 (0.7)</td> <td styleCode="Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Transfusion of &#x2265;2 units of whole blood or packed red blood cells</td> <td styleCode="Rrule">2 (0.3)</td> <td styleCode="Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Gastrointestinal</td> <td styleCode="Rrule">3 (0.5)</td> <td styleCode="Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Menorrhagia</td> <td styleCode="Rrule">1 (0.2)</td> <td styleCode="Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Clinically relevant non-major bleeding</td> <td styleCode="Rrule">32 (5.4)</td> <td styleCode="Rrule">7 (1.2)</td> </tr> <tr> <td styleCode="Lrule Rrule">Any bleeding</td> <td styleCode="Rrule">104 (17.4)</td> <td styleCode="Rrule">63 (10.7)</td> </tr> </tbody> </table>