XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. There is no specific antidote for XARELTO®.
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 prothrombin complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin complex concentrate (aPCC) or recombinant factor VIIa (rFVIIa) has not been evaluated.
This is not intended to replace clinical judgment or determine individual patient care.
XARELTO® is a selective inhibitor of Factor Xa (FXa). It does not require a cofactor (such as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.
The Janssen CarePath Support Program for XARELTO® can help eligible patients find payment assistance programs for their XARELTO® prescriptions.
If a patient does not have coverage for XARELTO®, a comprehensive list of additional programs is available at Janssen Prescription Assistance.
Discontinue warfarin and start XARELTO® as soon as the international normalized ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.
Discontinue low-molecular-weight heparin (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.
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
XARELTO® is contraindicated in patients with active major bleeding or patients with hypersensitivity to rivaroxaban. 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.
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis [see Boxed Warning].
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
An 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.
Pregnancy Category C: XARELTO® should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO® dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
CrCl = creatinine clearance.
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.
Concurrent use of XARELTO® with other anticoagulants should be avoided because of the increased bleeding risk. Promptly evaluate any signs or symptoms of blood loss.
Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO®. Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban.
Phase 1 data showed that once-daily XARELTO® demonstrated Factor Xa inhibition through 24 hours.*9 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 nonvalvular AF. For other indications, see the dosing information.
*The clinical significance of pharmacokinetics and pharmacodynamics has not been established.
ROCKET AF was a large, double-blind, double-dummy study evaluating XARELTO® versus dose-adjusted warfarin in more than 14,000 patients. The study population had prior stroke or multiple comorbidities, including CHF, hypertension, age ≥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, according to guidelines, at moderate to high risk for stroke and candidates for anticoagulation prophylaxis.10
CHADS2 = CHF, hypertension, age ≥75 years, diabetes mellitus, prior stroke or TIA; CHF = congestive heart failure; TIA = transient ischemic attack.
In ROCKET AF, 21% (n=2950/14,264) of the study population had moderate renal impairment (CrCl 30 to 49 mL/min) at the time of enrollment. 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 normal renal function.11 10% (n=1474/14,264) of patients in ROCKET AF received the lower dose of XARELTO® (15 mg once daily).
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.11
CHADS2 = CHF, hypertension, age ≥75 years, diabetes mellitus, prior stroke or TIA; CHF = congestive heart failure; CrCI = creatinine clearance; MI = myocardial infarction; TIA = transient ischemic attack.
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.
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.12-16
In these clinical trials, the efficacy outcomes of XARELTO® in the elderly (≥65 years) were similar to that 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