XARELTO® DOSING AND TRANSITION MANAGEMENT

XARELTO® DOSING Renal dosing considerations Patients with Nonvalvular AF: Periodically assess renal function as clinically mg indicated (ie, more frequently in situations in which renal function CrCl >50 mL/min: ONCE DAILY may decline) and adjust therapy accordingly. Consider dose with the evening meal Reduce adjustment or discontinuation of XARELTO® in patients who stroe ris in  OR ‚ develop acute renal failure while on XARELTO®. NONALLAR AF Patients with All Other Indications: Avoid using XARELTO® in patients with mg CrCl 15 to 50 mL/min: CrCl <30 mL/min. ONCE DAILY with the evening meal Please see full Prescribing Information for additional dosing considerations.

® mg with food for first 2 days SWITCHING PATIENTS TO AND FROM XARELTO TWICE DAILY SWITCHING TO XARELTO® Treatment ‚ ON DAY TRANSITION TO ‚ of DT and E ® with food at approximately From Stop warfarin and start XARELTO when INR is <3.0 mg the same time each day for ONCE DAILY remaining treatment From Stop the infusion and start XARELTO® at the same time unfractionated Reduction in the ris of recurrence with or without food after From Start XARELTO® 0 to 2 hours prior to the next scheduled of DT andor E in mg at least 6 months of standard other evening administration of the other ONCE DAILY patients at continued anticoagulant treatment ® ris for DT andor E SWITCHING FROM XARELTO One approach is to stop XARELTO® and start parenteral KNEE: 12 days rophylaxis of To warfarin* anticoagulant and warfarin at time of next scheduled HIP: 35 days XARELTO® dose DT which may mg The initial dose should be taen lead to E after Stop XARELTO® and start other anticoagulant when the ONCE DAILY 6 to 0 hours after surgery To other anticoagulants† NEE or I next dose of XARELTO® would have been given provided that has replacement surgery been established *No data are available to guide converting patients from XARELTO® to warfarin. ® Tablets shown not actual size. XARELTO affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. †Oral or parenteral rapid-onset anticoagulants. No routine monitoring is required1–7 CrCl = creatinine clearance; INR = international normalized ratio.

6 Indications approved by the FDA For the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial To reduce the risk of and systemic in patients with treatment lasting at least 6 months nonvalvular (AF). There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke For the prophylaxis of DVT, which may lead to PE in patients undergoing and systemic embolism when warfarin therapy is well controlled surgery For the treatment of deep vein (DVT) For the prophylaxis of DVT, which may lead to PE in patients undergoing surgery For the treatment of (PE) IMPORTANT SAFETY INFORMATION WARNING: (A) PREMATURE DISCONTINUATION OF for spinal procedures. Factors that can increase the risk of developing XARELTO® INCREASES THE RISK OF THROMBOTIC EVENTS, epidural or spinal hematomas in these patients include: (B) SPINAL/EPIDURAL HEMATOMA Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as ® A. Premature discontinuation of XARELTO increases the non-steroidal anti-inflammatory drugs (NSAIDs), inhibitors, risk of thrombotic events other anticoagulants, see Drug Interactions Premature discontinuation of any oral anticoagulant, including A history of traumatic or repeated epidural or spinal punctures XARELTO®, increases the risk of thrombotic events. If anticoagulation A history of spinal deformity or spinal surgery ® with XARELTO is discontinued for a reason other than pathological Optimal timing between the administration of XARELTO® and or completion of a course of therapy, consider coverage neuraxial procedures is not known with another anticoagulant. Monitor patients frequently for signs and symptoms of neurological B. Spinal/epidural hematoma impairment. If neurological compromise is noted, urgent treatment Epidural or spinal hematomas have occurred in patients treated with is necessary. XARELTO® who are receiving neuraxial anesthesia or undergoing Consider the benefits and risks before neuraxial intervention in spinal puncture. These hematomas may result in long-term or patients anticoagulated or to be anticoagulated permanent paralysis. Consider these risks when scheduling patients for thromboprophylaxis.

Important Safety Information continued on next page. Please see accompanying full Prescribing Information, including Boxed WARNINGS, or visit https://www.xareltohcp.com/PI XARELTO® DOSING AND TRANSITION MANAGEMENT

Temporary discontinuation for surgery and other procedures Other administration options If XARELTO® must be discontinued for a procedure, follow these For patients who are unable to swallow whole tablets: guidelines: Crush and mix a 10-mg, 15-mg, or 20-mg XARELTO® tablet with Before procedure: applesauce immediately prior to use and administer orally Stop XARELTO® at least 24 hours before the procedure Immediately follow the 15-mg or 20-mg dose with food In deciding whether a procedure should be delayed until 24 hours after For administration via nasogastric (NG) tube or gastric feeding tube: the last dose of XARELTO®, the increased risk of bleeding should be Confirm gastric placement of the tube, then crush a 10-mg, 15-mg, or weighed against the urgency of intervention 20-mg XARELTO® tablet, suspend in 50 mL of water, and administer After procedure: via an NG tube or gastric feeding tube ® Restart XARELTO® as soon as adequate hemostasis is established Avoid administering XARELTO distal to the stomach, which can result in reduced absorption and, thereby, reduced drug exposure If oral cannot be taken during or after surgical procedures, consider a parenteral anticoagulant Immediately follow the 15-mg or 20-mg dose with enteral feeding Note that the half-life of XARELTO® is 5 to 9 hours in healthy subjects aged 20 to 45 years and 11 to 13 hours in the elderly.

IMPORTANT SAFETY INFORMATION (cont’d) CONTRAINDICATIONS and 26 hours in elderly patients aged 60 to 76 years), after the last ® ® Active pathological bleeding administration of XARELTO . The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter. If ® Severe hypersensitivity reaction to XARELTO traumatic puncture occurs, delay the administration of XARELTO® for (eg, anaphylactic reactions) 24 hours. Should the physician decide to administer anticoagulation WARNINGS AND PRECAUTIONS in the context of epidural or spinal anesthesia/analgesia or , monitor frequently to detect any signs or symptoms of Increased Risk of Thrombotic Events After Premature Discontinuation: neurological impairment, such as midline back pain, sensory and Premature discontinuation of any oral anticoagulant, including motor deficits (numbness, tingling, or weakness in lower limbs), or XARELTO®, in the absence of adequate alternative anticoagulation bowel and/or bladder dysfunction. Instruct patients to immediately increases the risk of thrombotic events. An increased rate of stroke report if they experience any of the above signs or symptoms. If was observed during the transition from XARELTO® to warfarin in signs or symptoms of spinal hematoma are suspected, initiate urgent clinical trials in atrial fibrillation patients. If XARELTO® is discontinued diagnosis and treatment including consideration for for a reason other than pathological bleeding or completion of a decompression even though such treatment may not prevent or course of therapy, consider coverage with another anticoagulant. reverse neurological sequelae. Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause Use in Patients With Renal Impairment: serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue • Nonvalvular Atrial Fibrillation: Periodically assess renal function as XARELTO® in patients with active pathological hemorrhage. clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider • A specific for is not available. Because dose adjustment or discontinuation of XARELTO® in patients who of high , rivaroxaban is not expected develop acute renal failure while on XARELTO®. to be dialyzable. • Treatment of (DVT), Pulmonary Embolism • Concomitant use of other drugs that impair hemostasis increases (PE), and Reduction in the Risk of Recurrence of DVT and of PE: the risk of bleeding. These include , P2Y platelet inhibitors, 12 Avoid the use of XARELTO® in patients with CrCl <30 mL/min other antithrombotic agents, fibrinolytic therapy, NSAIDs, selective due to an expected increase in rivaroxaban exposure and serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine pharmacodynamic effects in this patient population. reuptake inhibitors (SNRIs). • Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia Replacement Surgery: Avoid the use of XARELTO® in patients with (spinal/epidural anesthesia) or spinal puncture is employed, patients CrCl <30 mL/min due to an expected increase in rivaroxaban exposure treated with anticoagulant agents for prevention of thromboembolic and pharmacodynamic effects in this patient population. Observe complications are at risk of developing an epidural or spinal closely and promptly evaluate any signs or symptoms of blood loss in hematoma, which can result in long-term or permanent paralysis. To patients with CrCl 30 to 50 mL/min. Patients who develop acute renal reduce the potential risk of bleeding associated with the concurrent failure while on XARELTO® should discontinue the treatment. use of XARELTO® and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO®. Use in Patients With Hepatic Impairment: No clinical data are available Placement or removal of an epidural catheter or lumbar puncture is for patients with severe hepatic impairment. Avoid use of XARELTO® in best performed when the anticoagulant effect of XARELTO® is low; patients with moderate (Child-Pugh B) and severe (Child-Pugh C) however, the exact timing to reach a sufficiently low anticoagulant hepatic impairment or with any hepatic disease associated with effect in each patient is not known. An indwelling epidural or , since drug exposure and bleeding risk may be increased. intrathecal catheter should not be removed before at least 2 half- lives have elapsed (ie, 18 hours in young patients aged 20 to 45 years

Important Safety Information continued on next page. Please see accompanying full Prescribing Information, including Boxed WARNINGS, or visit https://www.xareltohcp.com/PI XARELTO® DOSING AND TRANSITION MANAGEMENT

developmental outcomes. Use XARELTO® with caution in pregnant IMPORTANT SAFETY INFORMATION (cont’d) patients because of the potential for -related hemorrhage WARNINGS AND PRECAUTIONS (cont’d) and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO® cannot be reliably Use With P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid monitored with standard laboratory testing. Consider the benefits concomitant use of XARELTO® with known combined P-gp and strong and risks of XARELTO® for the mother and possible risks to the fetus CYP3A4 inhibitors. Avoid concomitant use of XARELTO® with drugs when prescribing XARELTO® to a pregnant woman. that are known combined P-gp and strong CYP3A4 inducers. • Fetal/Neonatal adverse reactions: Based on the pharmacologic Risk of Pregnancy-Related Hemorrhage: In pregnant women, activity of Factor Xa inhibitors and the potential to cross the XARELTO® should be used only if the potential benefit justifies the , bleeding may occur at any site in the fetus and/or neonate. ® potential risk to the mother and fetus. XARELTO dosing in pregnancy • Labor or delivery: The risk of bleeding should be balanced with the ® has not been studied. The anticoagulant effect of XARELTO cannot risk of thrombotic events when considering the use of XARELTO® in be monitored with standard laboratory testing nor readily reversed. this setting. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a ® drop in hemoglobin and/or hematocrit, hypotension, or fetal distress). • There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been Patients With Prosthetic Valves: The safety and efficacy established. Post-marketing experience is currently insufficient to ® of XARELTO have not been studied in patients with prosthetic determine a rivaroxaban-associated risk for major birth defects or ® heart valves. Therefore, use of XARELTO is not recommended . in these patients. : Rivaroxaban has been detected in human milk. There Acute PE in Hemodynamically Unstable Patients/Patients Who are insufficient data to determine the effects of rivaroxaban on Require or Pulmonary Embolectomy: Initiation the breastfed child or on milk production. The developmental ® of XARELTO is not recommended acutely as an alternative to and health benefits of should be considered along unfractionated heparin in patients with pulmonary embolism with the mother’s clinical need for XARELTO® and any potential who present with hemodynamic instability or who may receive adverse effects on the breastfed infant from XARELTO® or from the thrombolysis or pulmonary embolectomy. underlying maternal condition. DRUG INTERACTIONS Females and Males of Reproductive Potential: Females of Combined P-gp and strong CYP3A4 inhibitors increase exposure to reproductive potential requiring anticoagulation should discuss rivaroxaban and may increase the risk of bleeding. pregnancy planning with their physician. Combined P-gp and strong CYP3A4 inducers decrease exposure to Pediatric Use: Safety and effectiveness in pediatric patients have not rivaroxaban and may increase the risk of thromboembolic events. been established. XARELTO ® should not be used in patients with CrCl 15 to <80 mL/min OVERDOSAGE who are receiving concomitant combined P-gp and moderate CYP3A4 Discontinue XARELTO® and initiate appropriate therapy if bleeding inhibitors (eg, ) unless the potential benefit justifies the complications associated with overdosage occur. A specific antidote for potential risk. rivaroxaban is not available. The use of activated charcoal to reduce Coadministration of enoxaparin, warfarin, aspirin, , and absorption in case of XARELTO® overdose may be considered. Due to chronic NSAID use may increase the risk of bleeding. the high plasma protein binding, rivaroxaban is not dialyzable.

® Avoid concurrent use of XARELTO with other anticoagulants due to ADVERSE REACTIONS IN CLINICAL STUDIES increased bleeding risk, unless benefit outweighs risk. Promptly evaluate The most common adverse reactions with XARELTO® were any signs or symptoms of blood loss if patients are treated concomitantly bleeding complications. with aspirin, other platelet aggregation inhibitors, or NSAIDs. 083074-171026 USE IN SPECIFIC POPULATIONS Please see accompanying full Prescribing Information, including Boxed WARNINGS, or visit https://www.xareltohcp.com/PI Pregnancy: The limited available data on XARELTO® in pregnant women are insufficient to inform a drug-associated risk of adverse

References: 1. The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. 2. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. 3. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the Rocket AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. 4. Lassen MR, Ageno W, Borris LC, et al; for the RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786. 5. Kakkar AK, Brenner B, Dahl OE, et al; for the RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39. 6. Eriksson BI, Borris LC, Friedman RJ, et al; for the RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775. 7. Mueck W, Eriksson BI, Bauer KA, et al. Population and pharmacodynamics of rivaroxaban – an oral, direct Factor Xa inhibitor – in patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008;47(3):203-216.

XARELTO® is licensed from HealthCare AG, 51368 Leverkusen, Germany. © , Inc. 2017 November 2017 010032-170828

Janssen Pharmaceuticals, Inc.