FREQUENTLY ASKED QUESTIONS ABOUT XARELTO^®

REDUCING STROKE RISK IN NVAF

How was NVAF defined in ROCKET AF?

In ROCKET AF, NVAF was defined as atrial fibrillation in the absence of hemodynamically significant mitral valve stenosis or a prosthetic heart valve. However, patients with mitral valve repair, such as annuloplasty with or without prosthetic ring, commissurotomy, and/or valvuloplasty, were permitted.¹

How was the ITT population defined in ROCKET AF?

In ROCKET AF, the ITT population included all patients who underwent randomization and were followed for events during treatment or after premature discontinuation. The randomized population included 14,264 patients (7131 in the XARELTO^® group and 7133 in the warfarin group). However, the ITT population that was analyzed for efficacy included a total of 14,171 patients (7081 in the XARELTO^® group and 7090 in the warfarin group) because patients from 1 site were excluded from the efficacy analysis (50 from the XARELTO^® group and 43 in the warfarin group) due to violation of good clinical practice.²

How was the per-protocol population defined in ROCKET AF?

The per-protocol population included every patient who underwent randomization in the trial and who received at least 1 dose of XARELTO^®, did not have a major protocol violation, and was followed for events while receiving XARELTO^® or within 2 days after discontinuation (on-treatment).²

In ROCKET AF, the per-protocol population included 13,962 patients (6958 patients in the XARELTO^® group and 7004 patients in the warfarin group).²

How was the safety, as-treated population defined in ROCKET AF?

The safety, as-treated, or safety, on-treatment, population included patients who received at least 1 dose of XARELTO^® and were followed for events, regardless of adherence to the protocol, while they were receiving XARELTO^® or within 2 days after discontinuation.²

In ROCKET AF, the safety, as-treated population included 14,143 patients (7061 patients in the XARELTO^® group and 7082 patients in the warfarin group). The randomized ITT population included 14,264 patients, but because of violations of good clinical practice at 1 site, 93 patients (50 in the XARELTO^® group and 43 in the warfarin group) were excluded from all efficacy analyses before unblinding and 28 patients (20 in the XARELTO^® group and 8 in the warfarin group) were excluded because they did not receive the first dose of the study drug.^1,2

What is the rationale for once-daily dosing of XARELTO^®?

Phase 1 data showed that once-daily XARELTO^® demonstrated FXa inhibition through 24 hours.³ This was the basis for the once-daily dosing schedule in ROCKET AF, which demonstrated the efficacy and safety of XARELTO^® in reducing the risk of stroke in more than 14,000 patients. XARELTO^® should be taken once daily with the evening meal for patients with NVAF. For other indications, see the prescribing information.⁴

The clinical significance of pharmacokinetics and pharmacodynamics has not been established.

Who was in the study population in the ROCKET AF clinical trial?

ROCKET AF was a large, double-blind, double-dummy study evaluating XARELTO^® versus dose-adjusted warfarin in more than 14,000 patients.² The study population had prior stroke or multiple comorbidities, including CHF, hypertension, aged ≥75 years, diabetes, and prior stroke or TIA, reflecting an increased risk for stroke. With a 3.5 mean CHADS₂ score, ROCKET AF patients were at moderate to high risk for stroke and candidates for anticoagulation prophylaxis.

What were the clinical results for patients with moderate renal impairment receiving a 15-mg dose of XARELTO^®?

In ROCKET AF, 21% (n=2950) of the study population had moderate renal impairment (CrCl 30 to 49 mL/min) at the time of enrollment.⁴ The dose of XARELTO^® in these patients was 15 mg once daily, taken with the evening meal. The findings in these patients were consistent with those who had better renal function (CrCl ≥50 mL/min) and with the overall ROCKET AF trial results. These patients had a median age of 79 years; a mean CHADS₂ score of 3.7, reflecting an increased risk for stroke; and a higher prevalence of heart failure, peripheral vascular disease, and prior MI than those with better renal function.⁴

Efficacy and safety results in patients with moderate renal impairment (CrCl 30 to 49 mL/min) receiving XARELTO^® 15 mg once daily were generally consistent with those with better renal function (CrCl ≥50 mL/min) given XARELTO^® 20 mg once daily, and consistent with the overall trial.⁴

In NVAF, can XARELTO^® be temporarily interrupted?

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 patients with AF. If XARELTO^® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

The label provides guidance if therapy with XARELTO^® must be interrupted or temporarily stopped for surgery or other interventions (see section 2.7 of the Prescribing Information). If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO^® should be stopped at least 24 hours before the procedure to reduce the risk of bleeding. In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO^®, the increased risk of bleeding should be weighed against the urgency of intervention. XARELTO^® should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short. If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.

Is there any information on the use of XARELTO^® in patients with ESRD?

ESRD⁵ (<15 mL/min)

Clinical efficacy and safety studies with XARELTO^® did not enroll patients with ESRD on dialysis
In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO^® 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study
It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF

PAD/CAD

Why was aspirin chosen as the comparator in the COMPASS trial?

The ACC/AHA issued guidelines for the secondary prevention of cardiovascular events in both CAD and chronic PAD patients. Both guidelines recommend aspirin as the antiplatelet therapy for secondary prevention of major cardiovascular events based on outcomes from long-term studies.^6,7

For patients with CAD, the ACC/AHA guideline recommends an aspirin dose between 75 mg and 162 mg daily.*⁶

For patients with PAD, the ACC/AHA guideline recommends an aspirin dose between 75 mg and 325 mg daily.⁷

*Treatment with aspirin 75 mg to 162 mg daily should be continued indefinitely in the absence of contraindications in patients with stable ischemic heart disease.⁶

Why didn’t the COMPASS trial study the XARELTO^® vascular dose* versus dual antiplatelet therapy (DAPT)?

The COMPASS trial studied patients with stable CAD and PAD.⁸

Aspirin was chosen as the comparator for the COMPASS trial since it is the only Level 1A-recommended antithrombotic in the ACC/AHA guideline for both CAD and PAD.^6,7

DAPT (clopidogrel with aspirin, 75 mg to 100 mg) referenced in the ACC/AHA guideline is only recommended as a reasonable alternative (2b level of evidence) to aspirin in certain conditions or patient types with limited data.^7,9

The average time since an acute cardiovascular event in the COMPASS trial was 7 years.⁸ Given this and current guideline-based recommendations, patients on DAPT were excluded from the COMPASS trial.^8,10

*XARELTO^® 2.5 mg twice daily plus aspirin (100 mg in clinical trial; 75 mg to 100 mg in practice) once daily.

Why is the indication for CAD/PAD dosed 2.5 mg twice daily?

The COMPASS trial evaluated 27,395 patients with stable CAD and/or PAD on 3 different study arms including XARELTO^® 2.5 mg twice daily in combination with aspirin 100 mg once daily.⁸ XARELTO^® is also indicated for other conditions requiring different dosage strengths and dosing regimens (once daily or twice daily) based on the specific trial designs for VTE and stroke risk reduction in NVAF.

Rationale for the XARELTO^® 2.5 mg vascular dose was supported by ATLAS TIMI-51, a phase 3 trial that evaluated the twice-daily 2.5 mg dose in addition to either aspirin alone or dual antiplatelet therapy in patients with acute coronary syndrome (ACS).¹¹ While this indication was not FDA approved, outcomes prompted continuing the clinical evaluation of rivaroxaban 2.5 mg twice daily in combination with aspirin that led to the COMPASS trial rationale and study design.¹⁰

XARELTO^® provides condition-specific dosing across a broad range of thrombotic risk.

What were the procedural characteristics of the patients enrolled in the VOYAGER trial?

Participants in the VOYAGER trial were either endovascular or surgical LER patients.²⁹ A majority (about two thirds [65%]) had been treated with an endovascular procedure, and a little more than one third (35%) had been treated surgically.²⁸ Among endovascular procedures, the most common procedures were balloon angioplasty, bare-metal stent, and drug-coated balloon.²⁹

Both patient types were studied using the XARELTO^® vascular dose* with relative risk reduction proven among both populations.^†29

*XARELTO^® 2.5 mg twice daily plus aspirin (100 mg in clinical trial; 75 mg to 100 mg in practice) once daily.

^†Treatment schedule: XARELTO^® 2.5 mg twice daily versus placebo; all patients received aspirin 100 mg once daily as background therapy.

What were the notable baseline characteristics of patients enrolled in the VOYAGER trial?

The median age of PAD patients was 67 years and 26% of the patient population were women.²⁹

Primary comorbidities included²⁹:

40% of patients had diabetes mellitus
20% had an eGFR less than 60 mL per minute per 1.73 m² of body-surface area
35% were active smokers at randomization
31% had known coronary disease
11% had previous myocardial infarction

Common medications at baseline included²⁹:

79% were taking statin therapy
63% were taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs)
51% of patients were taking clopidogrel

Values are approximate.

What were the differences between the primary and secondary endpoints in the VOYAGER trial?

Primary Efficacy Outcome^29,30:

Composite of:

acute limb ischemia
major amputation of vascular etiology
MI
ischemic stroke
CV death

Secondary Efficacy Outcomes^29,30:

ALI, major amputation of a vascular etiology, MI, ischemic stroke, or CHD death
unplanned index limb revascularizations for recurrent limb ischemia
vascular hospitalizations for a peripheral or coronary event of a thrombotic nature
ALI, major amputation of a vascular etiology, MI, ischemic stroke, or all-cause mortality
ALI, major amputation of a vascular etiology, MI, all stroke, or CV death
death from any cause
VTE

Principal Safety Outcome^29,30:

TIMI major bleeding*

Secondary Safety Outcomes²⁹:

ISTH major bleeding^†
BARC major bleeding^‡

*TIMI major bleeding is defined as fatal bleeding, intracranial hemorrhage, a decrease in hemoglobin level of ≥5 g/dL, or a decrease in hematocrit of ≥15%.
^†ISTH major bleeding is defined as fatal bleeding, bleeding into a critical site, a decrease in hemoglobin level of ≥2 g/dL, or transfusion of at least 2 units of packed red cells or whole blood.
^‡BARC major bleeding is defined as grade 3b or higher.

In the VOYAGER trial, when was the XARELTO^® vascular dose* initiated post LER?

After a successful LER procedure, treatment was initiated once homeostasis had been established.²⁸ Patients in the VOYAGER trial received treatment with the XARELTO^® vascular dose* within an average of 5 days post LER, with some receiving treatment as early as 2 days after successful LER.²⁹

*XARELTO^® 2.5 mg twice daily plus aspirin (100 mg in clinical trial; 75 mg to 100 mg in practice) once daily.

What was the average length of time that patients in the VOYAGER trial were followed on the XARELTO^® vascular dose* treatment post LER?

The median follow-up period in the VOYAGER trial was 28 months (interquartile range, 22 to 34 months).²⁹

*XARELTO^® 2.5 mg twice daily plus aspirin (100 mg in clinical trial; 75 mg to 100 mg in practice) once daily.

For treatment of PAD post LER, how long should patients stay on the XARELTO^® vascular dose*?

Patients should stay on the XARELTO^® vascular dose* for the duration of treatment per the physician’s discretion. Patients in the VOYAGER trial were studied up to 36 months post treatment.^†29

*XARELTO^® 2.5 mg twice daily plus aspirin (100 mg in clinical trial; 75 mg to 100 mg in practice) once daily.

^†48 months was the longest any patient was in the VOYAGER trial.

What was the average length of time patients in the VOYAGER trial stayed on clopidogrel? What was the maximum time allowed?

Over 50% of the randomized patients (3313/6564) received clopidogrel for a median duration of 29.0 days. Although there is no recommended length of use for clopidogrel, it was to be administered for up to 6 months after revascularization at the discretion of the VOYAGER investigators.*³¹

The XARELTO^® vascular dose^† reduced the relative risk reduction of adverse cardiovascular and limb events^‡ with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of the XARELTO^® vascular dose^† was similar with or without the use of clopidogrel, but there was a trend for more ISTH major bleeding when clopidogrel was used for 30 days or more. The evidence shows a reduction of risk when XARELTO^® is added to aspirin after LER regardless of concomitant clopidogrel; the evidence also shows that a shorter course of clopidogrel (<30 days) may result in less bleeding.³¹

*Clopidogrel use was not a randomized therapy and was associated with a different patient profile of CV risk, bleeding risk, and burden of concomitant CVD between the groups; direct comparisons of the efficacy and safety of clopidogrel in this setting are confounded, particularly without adjustment.

^†XARELTO^® 2.5 mg twice daily plus aspirin (100 mg in clinical trial; 75 mg to 100 mg in practice) once daily.

^‡A composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or CV death.

What were the outcomes of patients in the VOYAGER trial who were prescribed clopidogrel?

More than 50% of the randomized patients (3313/6564) received clopidogrel for a median duration of 29.0 days.³¹

Efficacy:

Over 3 years, the hazard ratio (HR) for the primary outcome (composite of acute limb ischemia, major amputation of vascular etiology, MI, ischemic stroke, or CV death) of the XARELTO^® vascular dose* versus placebo^† was HR = 0.85 (95% CI: 0.71-1.01) with clopidogrel and HR = 0.86 (95% CI: 0.73-1.01) without clopidogrel (P=0.92). The XARELTO^® vascular dose* resulted in an early apparent clinical difference in acute limb ischemia within 30 days (HR = 0.45 [95% CI: 0.14-1.46] with clopidogrel; HR = 0.48 [95% CI: 0.22-1.01] without clopidogrel [P=0.93]).³¹

Safety:

Compared with aspirin, the XARELTO^® vascular dose* had similar TIMI major bleeding regardless of clopidogrel use (P=0.71). With clopidogrel use >30 days, the XARELTO^® vascular dose* was associated with more ISTH major bleeding within 365 days (HR = 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel.³¹

*XARELTO^® 2.5 mg twice daily plus aspirin (100 mg in clinical trial; 75 mg to 100 mg in practice) once daily.

^†Patients on placebo received aspirin 100 mg once daily.

What is the difference between absolute risk reduction (ARR) and relative risk reduction (RRR)?

What are the differences between TIMI, ISTH, and BARC bleeding criteria?

*A bleeding event that directly leads to death within 7 days.
^†Bleeding that’s visible to the eye or detectable on an imaging study.
BARC 4 bleeding was not examined because coronary artery bypass surgeries were rare during trial follow-up.

In the VOYAGER trial, what were the results for death from any cause or death due to cardiovascular events?

In the VOYAGER clinical trial, death from any cause or from cardiovascular reasons was a secondary outcome that was tested in a hierarchical fashion. However, these mortality endpoints did not meet a statistically significant difference between experimental and control arms.²⁹

DVT AND PE TREATMENT AND REDUCTION OF RECURRENCE

Do I need to bridge patients with heparin or LMWH to XARELTO^®?

There is no need to bridge with heparin or LMWH for the DVT and PE treatment indications. XARELTO^® can be used as a single, oral agent at the time of diagnosis; it can also be used following initial treatment with heparin or LMWH.^12,13

Initiation of XARELTO^® is not recommended acutely as an alternative to unfractionated heparin in patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

Why is XARELTO^® dosed 15 mg twice daily for the first 21 days, then 20 mg once daily?

Recurrent VTE is more likely to occur in the first 3 weeks following an initial event.¹⁴ A dose of 15 mg twice daily is given at the beginning of treatment to ensure adequate anticoagulation during the highest risk period for recurrence. After 21 days, the risk of recurrence is lower, so the dosage of XARELTO^® is reduced to 20 mg once daily. Dose selections were based on two phase 2 studies plus analysis of historical data with other anticoagulants.^15-19

Why were the EINSTEIN–DVT and –PE bleeding/safety data pooled in the Prescribing Information?

The EINSTEIN–DVT and –PE trials had nearly identical designs, inclusion and exclusion criteria, and outcome measures. This allowed the safety data to be pooled and evaluated across a much larger population of more than 8200 patients.²⁰

How was the duration of treatment (3, 6, or 12 months) determined in the EINSTEIN–DVT and EINSTEIN–PE studies?

In EINSTEIN-DVT and EINSTEIN-PE, the enrolling physician determined treatment duration at the time of randomization based on the patient’s profile and local treatment preferences.^21,22

For the DVT study, approximately 63% of all patients were allocated to 6 months of treatment, while 25% were allocated to 12 months of treatment.¹³ In the PE study, approximately 57% and 37% of all patients were allocated to 6 months and 12 months of treatment, respectively.¹⁴

How were DVT and PE confirmed in the EINSTEIN studies?

The criteria for a diagnosis of DVT were the presence of (1) a new noncompressible venous segment, (2) a substantial increase (≥4 mm) in the diameter of the thrombus during full compression in a previously abnormal segment on ultrasonography, or (3) a new intraluminal filling defect on venography.²³

The criteria for a diagnosis of PE were (1) a new intraluminal filling defect on spiral computed tomography or pulmonary angiography, (2) a cutoff of a vessel of >2.5 mm in diameter on pulmonary angiography, (3) a new perfusion defect of at least 75% of a segment with corresponding normal ventilation (high probability), or (4) a new non–high-probability perfusion defect associated with DVT, as documented by ultrasonography or venography.²³

Fatal PE was diagnosed based on objective diagnostic testing, autopsy, or death, which could not be attributed to a documented cause and for which PE could not be ruled out (unexplained death).²³

DVT PROPHYLAXIS FOLLOWING HIP OR KNEE REPLACEMENT SURGERY

Is the once-daily dosing of XARELTO^® sufficient to protect patients for a full 24 hours for DVT prophylaxis?

The efficacy and safety profiles of XARELTO^® taken once daily were demonstrated in large, randomized, multicenter clinical trials for DVT prophylaxis in patients following knee or hip replacement surgery.^24-27

Is XARELTO^® safe for use in my older hip and knee replacement patients?

Of the total number of patients in the RECORD1, RECORD2, and RECORD3 clinical trials, about 54% were ≥65 years, while about 15% were >75 years.

In these clinical trials, the efficacy outcomes of XARELTO^® in the elderly (≥65 years) were similar to those seen in patients <65 years
Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups

Can you tell me about the study population in the RECORD clinical trial program?

XARELTO^® was studied in 3 randomized, controlled clinical trials—RECORD1, RECORD2, and RECORD3—that included more than 9000 patients undergoing elective knee or hip replacement surgery.

GENERAL

Does the dose of XARELTO^® need to be adjusted for patients’ body weight?

Extremes in body weight (≤50 kg or ≥120 kg) did not influence XARELTO^® exposure. Therefore, XARELTO^® dosing does not need to be adjusted.

How do I manage a bleed with XARELTO^®? Is there a reversal agent for XARELTO^®?

XARELTO^® increases the risk of bleeding and can cause serious or fatal bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO^® in patients with active pathological hemorrhage. XARELTO^® has a half-life of approximately 5 to 9 hours in healthy subjects aged 20 to 45 years and 11 to 13 hours in the elderly.

Partial reversal of prothrombin time prolongation has been seen after administration of PCCs in healthy volunteers. The use of procoagulant reversal agents like aPCC or rFVIIa has not been evaluated.

This is not intended to replace clinical judgment or determine individual patient care.

How does XARELTO^® work?

XARELTO^® is a selective inhibitor of FXa. It does not require a cofactor (such as anti-thrombin III) for activity. XARELTO^® inhibits free FXa and prothrombinase activity. XARELTO^® has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, XARELTO^® decreases thrombin generation.

My patient can’t afford XARELTO^®. Do you offer any resources to help him/her?

Once a decision has been made to prescribe XARELTO^® (rivaroxaban)...

XARELTO withMe-the personalized experience that connects your patients to educational support and cost support options.

XARELTO withMe is designed to help patients throughout their treatment journey:

Access helpful tips and educational content about their condition and treatment
Find options for both commercially and government-insured patients that may help lower out-of-pocket costs for XARELTO^®
Stay on track with refill notifications

Only patients can sign up at XARELTOwithMe.com or by calling 888-XARELTO (888-927-3586), Monday–Friday, 8:00 _AM–8:00 _PM ET.

If you have any questions or need support, call 888-XARELTO (888-927-3586), Monday–Friday, 8:00 _AM–8:00 _PM ET.

Visit JanssenCarePath.com.

How do I switch patients from warfarin to XARELTO^®?

Discontinue warfarin and start XARELTO^® as soon as the INR is below 3.0 to avoid periods of inadequate anticoagulation.

How do I switch patients from anticoagulants other than warfarin to XARELTO^®?

Discontinue LMWH or any non-warfarin oral anticoagulant treatment and start XARELTO^® 0 to 2 hours prior to the next scheduled evening administration of the drug. For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO^® at the same time.

What should I tell a patient if he or she misses a dose?

If a dose of XARELTO^® is not taken at the scheduled time, administer the dose as soon as possible on the same day.

For patients receiving 15 mg twice daily: The patient should take XARELTO^® immediately to ensure intake of 30-mg XARELTO^® per day. In this particular instance, two 15-mg tablets may be taken at once. The patient should continue with the regular 15-mg twice-daily intake as recommended on the following day
For patients receiving 20 mg, 15 mg, or 10 mg once daily: The patient should take the missed XARELTO^® dose immediately

Do patients taking XARELTO^® need to have their coagulation levels monitored?

XARELTO^® requires no routine coagulation monitoring with treatment due to predictable PK/PD.^{2,3,12,13,24-27} The INR is not recommended because it is only calibrated and validated for VKAs.²⁷

Is there anyone who should not use XARELTO^®?

XARELTO^® is contraindicated in patients with active major bleeding or patients with hypersensitivity to XARELTO^®. Use of XARELTO^® is not recommended in patients who have had transcatheter aortic valve replacement (TAVR), based on the results of the GALILEO study, which reported higher rates of death and bleeding in patients randomized to XARELTO^® compared to those randomized to an antiplatelet regimen. The safety and efficacy of XARELTO^® have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO^® is not recommended in patients with prosthetic heart valves.

Are there any considerations for using XARELTO^® in patients who received 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 XARELTO^® and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO^® [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO^® 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 (ie, 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 XARELTO^®. The next XARELTO^® dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO^® 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.

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. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

Can XARELTO^® be used in pregnant women?

Pregnancy: The limited available data on XARELTO^® in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO^® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO^® cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO^® for the mother and possible risks to the fetus when prescribing XARELTO^® to a pregnant woman.

Fetal/Neonatal adverse reactions: Based on the pharmacologic activity of FXa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

Labor or delivery: The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO^® in this setting.

There are no adequate or well-controlled studies of XARELTO^® in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage.

Can I use XARELTO^® in patients with renal impairment?

Reducing stroke risk in NVAF

For patients with CrCl ≤50 mL/min, the dose of XARELTO^® should be reduced to 15 mg once daily with the evening meal.

Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation of XARELTO^® in patients who develop acute renal failure while taking XARELTO^®.

VTE prophylaxis in acutely ill medical patients

Avoid using XARELTO^® in patients with CrCl <15 mL/min

Treatment of DVT and PE and reducing risk of recurrence

Avoid the use of XARELTO^® in patients with CrCl <30 mL/min due to an expected increase in XARELTO^® exposure and pharmacodynamic effects in this patient population.

DVT prophylaxis after knee or hip replacement surgery

Avoid the use of XARELTO^® in patients with CrCl <30 mL/min due to an expected increase in XARELTO^® 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 taking XARELTO^® should discontinue the treatment.

Reducing risk of major cardiovascular events in CAD

For patients with CrCl <15 mL/min, no data are available, and limited data are available for patients with a CrCl of 15 to 30 mL/min. Clinical efficacy and safety studies with XARELTO^® did not enroll patients with end-stage renal disease (ESRD) on dialysis.

No dose adjustment needed based on CrCl

Reducing risk of major thrombotic vascular events in PAD

No dose adjustment needed based on CrCl

Can I use XARELTO^® in patients with hepatic impairment?

No clinical data are available for patients with severe hepatic impairment. You should avoid use of XARELTO^® in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

Can XARELTO^® be used concurrently with other anticoagulants?

Avoid concurrent use of XARELTO^® with other anticoagulants because of increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

Can XARELTO^® be used concurrently with aspirin or other NSAIDs?

In a single-dose drug interaction study, there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with XARELTO^®. However, aspirin and other NSAIDs are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with XARELTO^®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

How is XARELTO^® eliminated?

Approximately 1/3 (36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces.

The clinical significance of pharmacokinetics and pharmacodynamics has not been established.

The patient support and resources provided by XARELTO withMe are not intended to provide medical advice, replace a treatment plan from the patient's doctor or nurse, provide case management services or serve as a reason to prescribe XARELTO^®.

ACC = American College of Cardiology; AF = atrial fibrillation; AHA = American Heart Association; ALI = acute limb ischemia; aPCC = activated prothrombin complex concentrate; ARR = absolute risk reduction; BARC = Bleeding Academic Research Consortium; CAD = coronary artery disease; CHD = coronary heart disease; CHF = congestive heart failure; CrCl = creatinine clearance; CV = cardiovascular; CVD = cardiovascular disease; DOAC = direct oral anticoagulant; DVT = deep vein thrombosis; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; FXa = Factor Xa; INR = international normalized ratio; IQR = interquartile range; ISTH = International Society on Thrombosis and Haemostasis; ITT = intent-to-treat; LE = lower extremity; LER = lower extremity revascularization; LMWH = low-molecular-weight heparin; MI = myocardial infarction; NSAID = nonsteroidal anti-inflammatory drug; NVAF = nonvalvular atrial fibrillation; PAD = peripheral artery disease; PCC = prothrombin complex concentrate; PD = pharmacodynamics; PE = pulmonary embolism; PK = pharmacokinetics; rFVIIa = recombinant factor VIIa; RR = relative risk; RRR = relative risk reduction; TIA = transient ischemic attack; TIMI = Thrombolysis in Myocardial Infarction; U = unit; VKA = vitamin K antagonist; VTE = venous thromboembolism.

References: 1. Online supplement to: 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. Accessed January 1st, 2022. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1009638/suppl_file/nejmoa1009638_appendix.pdf 2. 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. 3. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412-421. 4. Fox KAA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32(19):2387-2394. 5. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis. Am J Nephrol. 2016;43(4):229-236. 6. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACC/AHA/ACP/AATS/PCNA/SCAl/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):2564-2603. 7. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017;135:e726-e779. 8. Eikelboom JW, Connolly SJ, Bosch J, et al; for the COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330. 9. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. Circulation. 2016;134(10):e123-e155. 10. Bosch J, Eikelboom JW, Connolly SJ, et al. Rationale, design and baseline characteristics of participants in the Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) trial. Can J Cardiol. 2017;33(8):1027-1035. 11. Mega JL, Braunwald E, Wiviott SD, et al; for the ATLAS ACS 2-TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9-19. 12. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. 13. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. 14. Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med. 2000;160(22):3431-3436. 15. Limone BL, Hernandez AV, Michalak D, Bookhart BK, Coleman CI. Timing of recurrent venous thromboembolism early after the index event: a meta-analysis of randomized controlled trials. Thromb Res. 2013;132(4):420-426. 16. Buller HR, Lensing AWA, Prins MH, et al; on behalf of the EINSTEIN-DVT Dose-Ranging Study Investigators. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the EINSTEIN-DVT Dose-Ranging Study. Blood. 2008;112(6):2242-2247. 17. Agnelli G, Gallus A, Goldhaber SZ, et al; ODIXa-DVT Study Investigators. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation. 2007;116(2):180-187. 18. The van Gogh Investigators. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med. 2007;357(11):1094-1104. 19. Fiessinger J-N, Huisman MV, Davidson BL, et al; THRIVE Treatment Study Investigators. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA. 2005;293(6):681-689. 20. Prins MH, Lensing AWA, Bauersachs R, et al; on behalf of the EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11(1):21. 21. Online supplement to: The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. Supplementary Protocol. N Engl J Med. 2010;363(26):2499-2510. 2010:1-107. Accessed January 1st, 2022. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1007903/suppl_file/nejmoa1007903_protocol.pdf 22. Online supplement to: The EINSTEIN—PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. Supplementary Protocol. N Engl J Med. 2012;366:1287-1297. 2010:1-114. Accessed January 1st, 2022. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1113572/suppl_file/nejmoa1113572_protocol.pdf 23. Online supplement to: The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):1-16. Accessed January 1st, 2022. https://www.nejm.org/doi/suppl/10.1056/NEJMoa1007903/suppl_file/nejmoa1007903_appendix.pdf 24. Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786. 25. Kakkar AK, Brenner B, Dahl OE, et al; 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. 26. Eriksson BI, Borris LC, Dahl OE, et al; ODIXa-HIP Study Investigators. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation. 2006;114(22):2374-2381. 27. Mueck W, Eriksson BI, Bauer KA. Population pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor—in patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008;47(3):203-216. 28. XARELTO^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 29. Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization [article and supplementary appendix]. N Engl J Med. 2020;382(21):1994-2004. 30. Capell WH, Bonaca MP, Nehler MR, et al. Rationale and design for the vascular outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD). Am Heart J. 2018;199:83-91. 31. Hiatt WR, Bonaca MP, Patel MR, et al. Rivaroxaban and aspirin in peripheral artery disease lower extremity revascularization: impact of concomitant clopidogrel on efficacy and safety. Circulation. 2020;142(23):2219-2230. 32. Schechtman E. Odds ratio, relative risk, absolute risk reduction, and the number needed to treat—which of these should we use? Value Health. 2002;5(5):431-436. 33. Bergmark BA, Kamphuisen PW, Wiviott SD, et al. Comparison of events across bleeding scales in the ENGAGE AF-TIMI 48 trial. Circulation. 2019;140:1792-1801.

Use in Patients With Renal Impairment: Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation of XARELTO^® in patients who develop any renal failure while on XARELTO^®.²

Patients With End-Stage Renal Disease on Dialysis: Clinical efficacy and safety studies with XARELTO^® did not enroll patients with CrCl <30 mL/min or ESRD on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO^® 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis, as was seen in ROCKET AF.²

*XARELTO^® is indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation. The use of XARELTO^® is not recommended in patients with prosthetic heart valves. While no longer using the "valvular" and "nonvalvular classifications of AF and concluding that those terms are obsolete, the 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation notes that DOACs are currently recommended as first-line therapy over warfarin in patients with AF (except moderate to severe mitral stenosis or mechanical heart valve recipients).

ACC = American College of Cardiology; ACCP = American College of Clinical Pharmacy; AF = atrial fibrillation; AHA = American Heart Association; CrCl = creatinine clearance; DOAC = direct oral anticoagulant; ESRD = end-stage renal disease; HRS = Heart Rhythm Society; NVAF = nonvalvular atrial fibrillation.

References: 1. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83(1):109-279. 2. XARELTO^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.

*XARELTO^® is indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation. The use of XARELTO^® is not recommended in patients with prosthetic heart valves. While no longer using the "valvular" and "nonvalvular" classifications of AF and concluding that those terms are obsolete, the 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation notes that DOACs are currently recommended as first-line therapy over warfarin in patients with AF (except moderate to severe mitral stenosis or mechanical heart valve recipients).

ACC = American College of Cardiology; ACCP = American College of Clinical Pharmacy; AF = atrial fibrillation; AHA = American Heart Association; DOAC = direct oral anticoagulant; HRS = Heart Rhythm Society; NVAF = nonvalvular atrial fibrillation.

Reference: 1. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83(1):109-279.

FREQUENTLY ASKED QUESTIONS ABOUT XARELTO®

FREQUENTLY ASKED QUESTIONS ABOUT XARELTO^®