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 a randomized study of 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 (<15mL/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

DVT AND PE TREATMENT AND REDUCTION IN THE RISK 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.6,7

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.8 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.9-13

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.14

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.15,16

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.7 In the PE study, approximately 57% and 37% of all patients were allocated to 6 months and 12 months of treatment, respectively.8

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.17

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.17

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).17

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.18-20

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?

Janssen CarePath can help eligible patients find financial assistance options to help them pay for their XARELTO® prescriptions.

Your patients can call 877-CarePath (877-227-3728) between 8:00 AM–8:00 PM ET, Monday to Friday, to talk with a Care Coordinator who will explain available options to them. Multilingual phone support is available.

If a patient does not have coverage for XARELTO®, a comprehensive list of additional programs is available at JanssenPrescriptionAssistance.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.2,3,6,7,18-21 The INR is not recommended because it is only calibrated and validated for VKAs.21

Is there anyone who should not use XARELTO®?

XARELTO® is contraindicated in patients with active major bleeding or patients with hypersensitivity to XARELTO®. 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.

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 Factor Xa 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 15 to 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®.

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.

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.

AF = atrial fibrillation; aPCC = activated prothrombin complex concentrate; CHF = congestive heart failure; CrCl = creatinine clearance; DVT = deep vein thrombosis; ESRD = end-stage renal disease; FXa = Factor Xa; INR = international normalized ratio; ITT = intent-to-treat; LMWH = low-molecular-weight heparin; MI = myocardial infarction; NSAID = nonsteroidal anti-inflammatory drug; NVAF = nonvalvular atrial fibrillation; PCC = prothrombin complex concentrate; PD = pharmacodynamics; PE = pulmonary embolism; PK = pharmacokinetics; rFVIIa = recombinant factor VIIa; TIA = transient ischemic attack; VKA = vitamin K antagonist; VTE = venous thromboembolism.