Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information XARELTO® (rivaroxaban) tablets 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) in full Prescribing Information]. 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. 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] 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]. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid th e use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular effects in this patient population. Observe closely and promptly evaluate Atrial Fibrillation: XARELTO is indicated to reduce the risk of stroke and 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 systemic embolism in patients with nonvalvular atrial fibrillation. There are limited data on the relative effectiveness of XARELTO and discontinue the treatment [see Use in Specific Populations]. warfarin in reducing the risk of stroke and systemic embolism when Use in Patients with Hepatic Impairment: No clinical data are available warfarin therapy is well-controlled [see Clinical Studies (14.1) in full for patients with severe hepatic impairment. Prescribing Information]. Avoid use of XARELTO in patients with moderate (Child-Pugh B) and Treatment of Deep Vein Thrombosis: XARELTO is indicated for the severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk treatment of deep vein thrombosis (DVT). Treatment of Pulmonary Embolism: XARELTO is indicated for the may be increased [see Use in Specific Populations]. Use with P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid treatment of pulmonary embolism (PE). Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of concomitant use of XARELTO with combined P-gp and strong CYP3A4 Pulmonary Embolism: XARELTO is indicated for the reduction in the risk inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, of recurrence of deep vein thrombosis and of pulmonary embolism indinavir, and conivaptan) [see Drug Interactions]. Avoid concomitant use of XARELTO with drugs that are combined P-gp following initial 6 months treatment for DVT and/or PE. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, Replacement Surgery: XARELTO is indicated for the prophylaxis of DVT, St. John’s wort) [see Drug Interactions]. which may lead to PE in patients undergoing knee or hip replacement Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to surgery. the mother and fetus. XARELTO dosing in pregnancy has not been CONTRAINDICATIONS studied. The anticoagulant effect of XARELTO cannot be monitored with XARELTO is contraindicated in patients with: standard laboratory testing nor readily reversed. Promptly evaluate • active pathological bleeding [see Warnings and Precautions] any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin • severe hypersensitivity reaction to XARELTO (e.g., anaphylactic and/or hematocrit, hypotension, or fetal distress). reactions) [see Adverse Reactions] Patients with Prosthetic Heart Valves: The safety and efficacy of WARNINGS AND PRECAUTIONS XARELTO have not been studied in patients with prosthetic heart valves. Increased Risk of Thrombotic Events after Premature Discontinuation: Therefore, use of XARELTO is not recommended in these patients. Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the Acute PE in Hemodynamically Unstable Patients or Patients Who risk of thrombotic events. An increased rate of stroke was observed Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO during the transition from XARELTO to warfarin in clinical trials in atrial is not recommended acutely as an alternative to unfractionated heparin fibrillation patients. If XARELTO is discontinued for a reason other than in patients with pulmonary embolism who present with hemodynamic pathological bleeding or completion of a course of therapy, consider instability or who may receive thrombolysis or pulmonary embolectomy. coverage with another anticoagulant [see Dosage and Administration ADVERSE REACTIONS (2.2, 2.6) and Clinical Studies (14.1) in full Prescribing Information]. The following adverse reactions are also discussed in other sections of Risk of Bleeding: XARELTO increases the risk of bleeding and can cause the labeling: serious or fatal bleeding. In deciding whether to prescribe XARELTO to • Increased risk of stroke after discontinuation in nonvalvular atrial fibrillation [see Boxed Warning and Warnings and Precautions] patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. • Bleeding risk [see Warnings and Precautions] Promptly evaluate any signs or symptoms of blood loss and consider the • Spinal/epidural hematoma [see Boxed Warning and Warnings and Precautions] need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of Clinical Trials Experience: Because clinical trials are conducted under rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years. widely varying conditions, adverse reaction rates observed in the Concomitant use of other drugs that impair hemostasis increases the clinical trials of a drug cannot be directly compared to rates in the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other clinical trials of another drug and may not reflect the rates observed in antithrombotic agents, fibrinolytic therapy, and non-steroidal anti- clinical practice. inflammatory drugs (NSAIDs) [see Drug Interactions]. During clinical development for the approved indications, 16326 patients Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors were exposed to XARELTO. These included 7111 patients who received (e.g., ketoconazole and ritonavir) increases rivaroxaban exposure and XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 may increase bleeding risk [see Drug Interactions]. for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 4728 Reversal of Anticoagulant Effect: A specific antidote for rivaroxaban is not available. Because of high patients who received either XARELTO 15 mg orally twice daily for three plasma protein binding, rivaroxaban is not expected to be dialyzable [see weeks followed by 20 mg orally once daily (EINSTEIN DVT, EINSTEIN PE) Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine or 20 mg orally once daily (EINSTEIN Extension) to treat DVT, PE, and to sulfate and vitamin K are not expected to affect the anticoagulant reduce the risk of recurrence of DVT and of PE; and 4487 patients who activity of rivaroxaban. Partial reversal of prothrombin time prolongation received XARELTO 10 mg orally once daily for prophylaxis of DVT has been seen after administration of prothrombin complex concentrates following hip or knee replacement surgery (RECORD 1-3). (PCCs) in healthy volunteers. The use of other procoagulant reversal Hemorrhage: The most common adverse reactions with XARELTO were agents like activated prothrombin complex concentrate (APCC) or bleeding complications [see Warnings and Precautions]. recombinant factor VIIa (rFVIIa) has not been evaluated. Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia adverse reactions associated with permanent drug discontinuation were (spinal/epidural anesthesia) or spinal puncture is employed, patients bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for treated with anticoagulant agents for prevention of thromboembolic warfarin. The incidence of discontinuations for non-bleeding adverse complications are at risk of developing an epidural or spinal hematoma events was similar in both treatment groups. which can result in long-term or permanent paralysis [see Boxed Table 1 shows the number of patients experiencing various types of Warning]. bleeding events in the ROCKET AF trial. 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) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information]. 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 and Adverse Reactions]. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions]. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions]. XARELTO® (rivaroxaban) tablets Table 1: Bleeding Events in ROCKET AF* Parameter XARELTO Event N = 7111 Rate n (%) (per 100 Pt-yrs) 395 (5.6) 3.6 91 (1.3) 0.8 Warfarin N = 7125 n (%) Event Rate (per 100 Pt-yrs) 3.5 1.2 386 (5.4) Major bleeding† 133 (1.9) Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal. 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* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Parameter XARELTO† N = 4130 n (%) Major bleeding event Fatal bleeding Intracranial Non-fatal critical organ bl eeding Intracranial‡ Retroperitoneal‡ Intraocular‡ Intra-articular‡ Non-fatal non-critical organ bleeding§ Decrease in Hb ≥ 2g/dL Transfusion of ≥2 units of whole blood or packed red blood cells Clinically relevant non-major bleeding Any bleeding 40 (1.0) 3 (<0.1) 2 (<0.1) 10 (0.2) 3 (<0.1) 1 (<0.1) 3 (<0.1) 0 27 (0.7) 28 (0.7) 18 (0.4) Enoxaparin/ VKA† N = 4116 n (%) 72 (1.7) 8 (0.2) 4 (<0.1) 29 (0.7) 10 (0.2) 8 (0.2) 2 (<0.1) 4 (<0.1) 37 (0.9) 42 (1.0) 25 (0.6) 357 (8.6) 1169 (28.3) 357 (8.7) 1153 (28.0) * Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. † Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: 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)] ‡ Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells 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* in EINSTEIN Extension Study Parameter Major bleeding event‡ Decrease in Hb ≥2 g/dL Transfusion of ≥2 units of whole blood or packed red blood cells Gastrointestinal Menorrhagia Clinically relevant non-major bleeding Any bleeding XARELTO† 20 mg N = 598 n (%) 4 (0.7) 4 (0.7) 2 (0.3) Placebo† 3 (0.5) 1 (0.2) 32 (5.4) 104 (17.4) 0 0 7 (1.2) 63 (10.7) N = 590 n (%) 0 0 0 * Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. † Treatment schedule: XARELTO 20 mg once daily; matched placebo once daily ‡ There were no fatal or critical organ bleeding events. 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.