Xarelto

— THERAPEUTIC CATEGORIES —
  • Thromboembolic disorders
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Xarelto Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Rivaroxaban 2.5mg, 10mg, 15mg, 20mg; tabs.

    Pharmacological Class

    Factor Xa inhibitor.

    See Also

    How Supplied

    Tabs 2.5mg—60, 180, 100 (10×10 blister cards); 10mg, 15mg—30, 90, 100 (10×10 blister cards); 20mg—30, 90, 1000, 100 (10×10 blister cards); Starter Pack (for DVT/PE)—1 (51 tabs); Susp—150mL (w. oral dosing syringes)

    How Supplied

    Xarelto Tablets are available in the following strengths and packages:

    • 2.5 mg tablets – 60, 180 bottles; Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

    • 10 mg tablets – 30, 90 bottles; Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

    • 15 mg tablets – 30, 90 bottles; Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

    • 20 mg tablets – 30, 90 bottles; Bulk bottle containing 1000 tablets; Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

    • Starter Pack for DVT and PE – 30-day starter blister pack containing 51 tablets (42 tablets of 15 mg and 9 tablets of 20 mg)

    Xarelto for Oral Suspension is supplied as white to off-white granules in an amber glass bottle containing 155 mg rivaroxaban packaged with 2 oral dosing syringes. After reconstitution with 150 mL of purified water, 1 mL of the suspension contains 1 mg rivaroxaban.

    Storage

    For tablets, granules and reconstituted oral suspension:

    • Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

    Manufacturer

    Janssen Pharmaceuticals, Inc.

    Generic Availability

    NO

    Mechanism of Action

    Rivaroxaban is an orally bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor for activity. Activiation of factor X to factor Xa via the intrinsic and extrinsic pathways plays a central role in the cascade of blood coagulation.

    Xarelto Indications

    Indications

    To reduce the risk of stroke and systemic embolism in adults with nonvalvular atrial fibrillation. Treatment of deep vein thrombosis (DVT), pulmonary embolism (PE). To reduce the risk of recurrence of DVT and/or PE in adult patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting ≥6 months. Prophylaxis of DVT, which may lead to PE in adult patients undergoing knee or hip replacement surgery. Prophylaxis of venous thromboembolism (VTE) and VTE related death during hospitalization and post hospital discharge in adults admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding. In combination with aspirin, to reduce the risk of major cardiovascular (CV) events in adults with coronary artery disease (CAD). In combination with aspirin, to reduce the risk of major thrombotic vascular events in adults with peripheral artery disease (PAD), including those who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD. Treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to <18yrs after at least 5 days of initial parenteral anticoagulant treatment. Thromboprophylaxis in pediatric patients aged ≥2yrs with congenital heart disease after undergoing the Fontan procedure.

    Xarelto Dosage and Administration

    Adult

    15mg and 20mg tabs: take with food. If unable to swallow whole tabs: may crush tabs and mix with applesauce immediately prior to use, or give via NG or gastric tube (see full labeling). Nonvalvular atrial fibrillation (CrCl >50mL/min): 20mg once daily with the evening meal; (CrCl ≤50mL/min): 15mg once daily with the evening meal. Treatment of DVT, PE (CrCl ≥15mL/min): 15mg twice daily for first 21 days, then 20mg once daily. Reduction in risk of recurrence of DVT, PE at continued risk (CrCl ≥15mL/min): 10mg once daily, after ≥6 months of standard anticoagulant therapy. Prophylaxis of DVT (CrCl ≥15mL/min): 10mg once daily (take 6–10hrs after surgery once hemostasis established) for 35 days (hip) or 12 days (knee). Prophylaxis of VTE (CrCl ≥15mL/min): 10mg once daily (in hospital and after hospital discharge) for 31–39 days. CrCl <15mL/min: avoid use for DVT/VTE prophylaxis, DVT/PE risk reduction or treatment. CAD or PAD: 2.5mg twice daily (w. aspirin); for PAD after lower extremity revascularization procedure: initiate once hemostasis has been established. Switching to or from warfarin, or other anticoagulants: see full labeling.

    Adult

    Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation

    • CrCl >50 mL/min – 20 mg once daily with evening meal.

    • CrCl ≤50 mL/min – 15 mg once daily with evening meal.

    Treatment of DVT and/or PE 

    • CrCl ≥15 mL/min – 15 mg twice daily for 21 days, then transition to 20 mg once daily. Take with food, at the same time each day.

    • CrCl <15 mL/min – Avoid use.

    Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE

    • CrCl ≥15 mL/min – 10 mg once daily, after at least 6 months of standard anticoagulant treatment. Take with or without food.

    • CrCl <15 mL/min – Avoid use.

    Prophylaxis of DVT Following Hip Replacement Surgery

    • CrCl ≥15 mL/min – 10 mg once daily for 35 days; 6 to 10 hours after surgery once hemostasis has been established. Take with or without food.

    • CrCl <15 mL/min – Avoid use.

    Prophylaxis of DVT Following Knee Replacement Surgery

    • CrCl ≥15 mL/min – 10 mg once daily for 12 days; 6 to 10 hours after surgery once hemostasis has been established. Take with or without food.

    • CrCl <15 mL/min – Avoid use.

    Prophylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding

    • CrCl ≥15 mL/min – 10 mg once daily, in hospital and after hospital discharge, for a total recommended duration of 31 to 39 days. Take with or without food.

    • CrCl <15 mL/min – Avoid use.

    Reduction of Risk of Major Cardiovascular Events (CV Death, MI, and Stroke) in CAD

    • No dose adjustment needed based on CrCl – 2.5 mg twice daily, plus aspirin (75 mg to 100 mg) once daily. Take with or without food.

    Reduction of Risk of Major Thrombotic Vascular Events in PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PAD

    • No dose adjustment needed based on CrCl – 2.5 mg twice daily, plus aspirin (75 mg to 100 mg) once daily. Take with or without food. When starting therapy after a successful lower extremity revascularization procedure, initiate once hemostasis has been established.

    Switching to and from Xarelto

    • Switching from Warfarin to Xarelto: When switching, discontinue warfarin and start Xarelto as soon as the INR is below 3.0 in adults and below 2.5 in pediatric patients to avoid periods of inadequate anticoagulation.

    • Switching from Xarelto to Warfarin

      • Adults – No clinical trial data are available. One approach is to discontinue Xarelto and begin both a parenteral anticoagulant and warfarin at the time the next dose of Xarelto would have been taken.

    • Switching from Xarelto to Anticoagulants other than Warfarin: For patients currently taking Xarelto and transitioning to an anticoagulant with rapid onset, discontinue Xarelto and give the first dose of the other anticoagulant (oral or parenteral) at the time of the next scheduled Xarelto dose would have been taken.

    • Switching from Anticoagulants other than Warfarin to Xarelto: For patient currently taking an anticoagulant other than warfarin, initiate Xarelto 0 to 2 hours prior to the next schedule administration of the drug and do not administer the other anticoagulant. For unfractionated heparin administered by continuous infusion, discontinue the infusion and start Xarelto at the same time.

    Discontinuation for Surgery and other Interventions

    • Discontinue Xarelto at least 24 hours prior to the procedure to reduce the risk of bleeding if anticoagulation must be stopped with surgical or other procedures.

    • Restart Xarelto after the surgical or other procedures as soon as adequate hemostasis has been established. Consider administering a parenteral anticoagulant if an oral medication cannot be taken during or after surgical intervention.

    Missed Dose

    • For patients receiving 2.5 mg twice daily: if a dose is missed, the patient should take a single 2.5 mg dose as recommended at the next scheduled time. 

    • For patients receiving 15 mg twice daily: The patient should take Xarelto immediately to ensure intake of 30 mg Xarelto per day. Two 15 mg tablets may be taken at once. 

    • For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed Xarelto dose immediately. The dose should not be doubled within the same day to make up for a missed dose. 

    Administration Options

    • For adults who are unable to swallow whole tablets, Xarelto tablets may be crushed and mixed with applesauce immediately prior to use. After crushing Xarelto 15 mg or 20 mg tablets, the dose should be immediately followed by food.

    • Administration of Xarelto tablets via nasogastric (NG) tube or gastric feeding tube:

      • May crush Xarelto tablets and suspend in 50 mL of water, then administer via NG tube or gastric feeding tube. Avoid administering Xarelto distal to the stomach. After administering Xarelto 15 mg or 20 mg tablets, the dose should be immediately followed by enteral feeding.

      • Crushed Xarelto tablets are stable in water and in applesauce for up to 4 hours.

    • Administration of Xarelto suspension via NG tube or gastric feeding tube:

      • May administer oral suspension via NG or gastric feeding tube.

      • For treatment or reduction in risk of recurrent VTE in pediatric patients, administer enteral feeding immediately after the dose is given.

    Children

    VTE: <6mos (<37 weeks of gestation at birth); (<10 days of oral feeding); or (<2.6kg): not recommended. Take with feeding or food. May be given via NG or gastric tube. (2.6–2.9kg): 0.8mg oral susp 3 times daily; (3–3.9kg): 0.9mg oral susp 3 times daily; (4–4.9kg): 1.4mg oral susp 3 times daily; (5–6.9kg): 1.6mg oral susp 3 times daily; (7–7.9kg): 1.8mg oral susp 3 times daily; (8–8.9kg): 2.4mg oral susp 3 times daily; (9–9.9kg): 2.8mg oral susp 3 times daily; (10–11.9kg): 3mg oral susp 3 times daily; (12–29.9kg): 5mg oral susp 2 times daily; (30–49.9kg): 15mg oral susp or tab once daily; (≥50kg): 20mg oral susp or tab once daily. Pediatric patients with or without catheter-related thrombosis: see full labeling. Thromboprophylaxis: <2yrs: not established. Take with or without food. ≥2yrs (7–7.9kg): 1.1mg oral susp 2 times daily; (8–9.9kg): 1.6mg oral susp 2 times daily; (10–11.9kg): 1.7mg oral susp 2 times daily; (12–19.9kg): 2mg oral susp 2 times daily; (20–29.9kg): 2.5mg oral susp 2 times daily; (30–49.9kg): 7.5mg oral susp once daily; (≥50kg): 10mg oral susp or tab once daily. Use of 2.5mg tabs are not recommended. If unable to swallow 10, 15, or 20mg whole tabs; may give oral susp. Renal impairment, switching to or from warfarin, or other anticoagulants: see full labeling.

    Children

    Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients (birth to less than 18 years old) 

    • Oral Suspension Only

      • 2.6 kg to 2.9 kg – 0.8 mg three times daily (total daily dose of 2.4 mg)

      • 3 kg to 3.9 kg – 0.9 mg three times daily (total daily dose of 2.7 mg)

      • 4 kg to 4.9 kg – 1.4 mg three times daily (total daily dose of 4.2 mg)

      • 5 kg to 6.9 kg – 1.6 mg three times daily (total daily dose of 4.8 mg)

      • 7 kg to 7.9 kg – 1.8 mg three times daily (total daily dose of 5.4 mg)

      • 8 kg to 8.9 kg – 2.4 mg three times daily (total daily dose of 7.2 mg)

      • 9 kg to 9.9 kg – 2.8 mg three times daily (total daily dose of 8.4 mg)

      • 10 kg to 11.9 kg – 3 mg three times daily (total daily dose of 9 mg)

      • 12 kg to 29.9 kg – 5 mg two times daily (total daily dose of 10 mg)

    • Oral Suspension or Tablets

      • 30 kg to 49.9 kg – 15 mg once a day (total daily dose of 15 mg)

      • ≥50 kg – 20 mg once a day (total daily dose of 20 mg)

    • Initiate Xarelto treatment after at least 5 days of initial parenteral anticoagulation therapy. Patients <6 months of age should meet the following criteria:

      • At birth were at least 37 weeks of gestation

      • Have had at least 10 days of oral feeding

      • Weigh ≥2.6 kg at the time of dosing

    • All doses may be taken with feeding or with food to increase absorption. Monitor child’s weight and review the dose regularly especially for children <12 kg.

    • All pediatric patients (except <2 years old with catheter-related thrombosis):

      • Continue treatment for at least 3 months in children with thrombosis. May extend treatment up to 12 months when clinically necessary. Assess the benefit of continued therapy beyond 3 months on an individual basis.

    • Pediatric patients <2 years old with catheter-related thrombosis:

      • Continue treatment for at least 1 month in children <2 years old with catheter-related thrombosis. May extend treatment up to 3 months when clinically necessary. Assess the benefit of continued therapy beyond 1 month on an individual basis.

    Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure

    • Oral Suspension Only

      • 7 kg to 7.9 kg – 1.1 mg two times daily (total daily dose of 2.2 mg)

      • 8 kg to 9.9 kg – 1.6 mg two times daily (total daily dose of 3.2 mg)

      • 10 kg to 11.9 kg – 1.7 mg two times daily (total daily dose of 3.4 mg)

      • 12 kg to 19.9 kg – 2 mg two times daily (total daily dose of 4 mg)

      • 20 kg to 29.9 kg – 2.5 mg two times daily (total daily dose of 5 mg)

      • 30 kg to 49.9 kg – 7.5 mg once a day (total daily dose of 7.5 mg)

    • Oral Suspension or Tablets

      • ≥50 kg – 10 mg once a day (total daily dose of 10 mg)

    Administration in Pediatric Patients 

    • Food Effect

      • For VTE treatment in children, the dose should be taken with food to increase absorption.

      • For thromboprophylaxis after Fontan procedure, the dose can be taken with or without food.

    • Vomit or Spit up

      • If the dose is vomited or spit up within 30 minutes after taking, a new dose should be given. Do not administer if the dose is vomited or spit up more than 30 minutes after taking.

    • Tablets

      • Do not split tablets to provide a fraction of a tablet dose. Use oral suspension for children. Do not use Xarelto 2.5 mg tablets in pediatric patients.

    Use in Renal Impairment in Pediatric Patients 1 Year of Age or Older

    • Mild renal impairment (eGFR 50 to ≤ 80 mL/min/1.73 m2): No dose adjustment is required.

    • Moderate or severe renal impairment (eGFR <50 mL/min/1.73m2): Avoid use as limited clinical data are available.

    Use in Renal Impairment in Pediatric Patients Less than 1 Year of Age 

    • Determine renal function using serum creatinine.

    • Avoid use in patients <1 year of age with serum creatinine results above 97.5th percentile, as no clinical date are available.

    • See full labeling for reference values of serum creatinine.

    Switching to and from Xarelto

    • Switching from Warfarin to Xarelto: When switching, discontinue warfarin and start Xarelto as soon as the INR is below 3.0 in adults and below 2.5 in pediatric patients to avoid periods of inadequate anticoagulation.

    • Switching from Xarelto to Warfarin

      • Pediatric patients: To ensure adequate anticoagulation, continue Xarelto for at least 2 days after the first dose of warfarin. Obtain an INR after 2 days of co-administration prior to the next dose of Xarelto. Co-administer Xarelto and warfarin until INR is ≥ 2.0. Once Xarelto is discontinued, may test INR 24 hours after the last dose.

    • Switching from Xarelto to Anticoagulants other than Warfarin: For patients currently taking Xarelto and transitioning to an anticoagulant with rapid onset, discontinue Xarelto and give the first dose of the other anticoagulant (oral or parenteral) at the time of the next scheduled Xarelto dose would have been taken.

    • Switching from Anticoagulants other than Warfarin to Xarelto: For patient currently taking an anticoagulant other than warfarin, initiate Xarelto 0 to 2 hours prior to the next schedule administration of the drug and do not administer the other anticoagulant. For unfractionated heparin administered by continuous infusion, discontinue the infusion and start Xarelto at the same time.

    Discontinuation for Surgery and other Interventions

    • Discontinue Xarelto at least 24 hours prior to the procedure to reduce the risk of bleeding if anticoagulation must be stopped with surgical or other procedures.

    • Restart Xarelto after the surgical or other procedures as soon as adequate hemostasis has been established. Consider administering a parenteral anticoagulant if an oral medication cannot be taken during or after surgical intervention.

    Missed Dose

    • If Xarelto is taken once a day, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed. The patient should not take two doses to make up for a missed dose. 

    • If Xarelto is taken two times a day, the patient should take the missed morning dose as soon as possible once it is noticed. A missed morning dose may be taken together with the evening dose. A missed evening dose can only be taken in the same evening. 

    • If Xarelto is taken three times a day, if a dose is missed, the patient should skip the missed dose and go back to the regular dosing schedule at the usual time without compensating for the missed dose. On the following day, the patient should continue with their regular regimen. 

    Administration Options

    • For adults who are unable to swallow whole tablets, Xarelto tablets may be crushed and mixed with applesauce immediately prior to use. After crushing Xarelto 15 mg or 20 mg tablets, the dose should be immediately followed by food.

    • Administration of Xarelto tablets via nasogastric (NG) tube or gastric feeding tube:

      • May crush Xarelto tablets and suspend in 50 mL of water, then administer via NG tube or gastric feeding tube. Avoid administering Xarelto distal to the stomach. After administering Xarelto 15 mg or 20 mg tablets, the dose should be immediately followed by enteral feeding.

      • Crushed Xarelto tablets are stable in water and in applesauce for up to 4 hours.

    • Administration of Xarelto suspension via NG tube or gastric feeding tube:

      • May administer oral suspension via NG or gastric feeding tube.

      • For treatment or reduction in risk of recurrent VTE in pediatric patients, administer enteral feeding immediately after the dose is given.

    Renal Impairment

    • Nonvalvular Atrial Fibrillation

      • Monitor renal function periodically as clinically indicated and adjust therapy accordingly.

      • Consider dose adjustment or discontinuation of Xarelto in patients who develop acute renal failure.

    • Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE 

      • For patients with CrCl 15–<30mL/min: monitor closely and promptly evaluate any signs or symptoms of blood loss.

      • For patients with CrCl <15 mL/min including dialysis patients: avoid use of Xarelto.

      • Discontinue Xarelto if acute renal failure develops.

    • Prophylaxis of DVT Following Hip or Knee Replacement Surgery 

      • For patients with CrCl 15–<30mL/min: monitor closely and promptly evaluate any signs or symptoms of blood loss.

      • For patients with CrCl <15 mL/min including dialysis patients: avoid use of Xarelto.

      • Discontinue Xarelto if acute renal failure develops.

    • Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding 

      • For patients with CrCl 15–<30mL/min: monitor closely and promptly evaluate any signs or symptoms of blood loss.

      • For patients with CrCl <15 mL/min including dialysis patients: avoid use of Xarelto.

      • Discontinue Xarelto if acute renal failure develops.

    • Pediatric Patients 

      • For pediatric patients 1 year of age and older with moderate to severe renal impairment (eGFR <50 mL/min/1.73m2): avoid use of Xarelto.

      • For pediatric patients less than 1 year with serum creatinine results above 97.5th percentile: avoid use of Xarelto.

    Hepatic Impairment

    • Avoid use of Xarelto in patients with moderate and severe hepatic impairment or patients with any hepatic disease associated with coagulopathy.

    Other Modifications

    Females and Males of Reproductive Potential

    • Assess the risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, with the use of Xarelto in females of reproductive potential and those with abnormal uterine bleeding.

    Administration

    15mg and 20mg tabs: take with food. If unable to swallow whole tabs: may crush tabs and mix with applesauce immediately prior to use, or give by NG or gastric tube (see full labeling). Missed dose: Patients taking 2.5mg twice daily: take a single 2.5mg dose as recommended at the scheduled time. Patients taking 15mg twice daily: take dose immediately to ensure 30mg intake per day; two 15mg tablets may be taken at once. Patients taking 20, 15, or 10mg daily: take dose immediately. Do not remove epidural catheter <18hrs after rivaroxaban dose; do not give next dose <6hrs after catheter removal. Delay dose for 24hrs if traumatic puncture occurs.

    Nursing Considerations

    15mg and 20mg tabs: take with food. If unable to swallow whole tabs: may crush tabs and mix with applesauce immediately prior to use, or give by NG or gastric tube (see full labeling). Missed dose: Patients taking 2.5mg twice daily: take a single 2.5mg dose as recommended at the scheduled time. Patients taking 15mg twice daily: take dose immediately to ensure 30mg intake per day; two 15mg tablets may be taken at once. Patients taking 20, 15, or 10mg daily: take dose immediately. Do not remove epidural or intrathecal catheter <18hrs after rivaroxaban dose; do not give next dose <6hrs after catheter removal. Delay dose for 24hrs if traumatic puncture occurs.

    Xarelto Contraindications

    Contraindications

    Active pathological bleeding.

    Xarelto Boxed Warnings

    Boxed Warning

    Premature discontinuation increases risk of thrombotic events. Spinal/epidural hematoma.

    Xarelto Warnings/Precautions

    Warnings/Precautions

    Premature discontinuation increases risk of thrombotic events; if discontinued for reason other than bleeding or therapy completion, consider coverage with another anticoagulant. Increased risk of spinal/epidural hematoma in anticoagulated patients receiving neuraxial anesthesia or undergoing spinal puncture (see full labeling); monitor for signs/symptoms of neurological impairment. Increased risk of bleeding; monitor for signs/symptoms of blood loss; discontinue if active pathological hemorrhage occurs. Do not use for primary VTE prophylaxis in hospitalized, acutely ill medical patients at high risk of bleeding (see full labeling). Patients with prosthetic heart valves, triple-positive antiphospholipid syndrome, pulmonary embolism (presenting hemodynamic instability), or those requiring thrombolysis or pulmonary embolectomy: not recommended. Moderate or severe hepatic impairment, hepatic disease associated with coagulopathy: avoid. Assess renal function periodically; consider dose adjustment or discontinue if acute renal failure develops. Renal impairment: see full labeling. Discontinue ≥24hrs before surgery. Elderly. Labor & delivery. Pregnancy: risk of pregnancy-related hemorrhage. Nursing mothers.

    Warnings/Precautions

    Increased Risk of Thrombotic Events after Premature Discontinuation 

    • Increased risk of thrombotic events if Xarelto is prematurely discontinued in the absence of adequate alternative anticoagulation.

    • In clinical trials, an Increased rate of stroke was observed during transition from Xarelto to warfarin among atrial fibrillation patients.

    • Consider coverage with another anticoagulant if Xarelto is discontinued for a reason other than pathological bleeding or completion of a course of therapy.

    Risk of Bleeding

    • Increased risk of bleeding, which can be serious or fatal.

    • Weigh the risk of thrombotic events against the risk of bleeding when deciding to initiate Xarelto therapy in patients at increased risk of bleeding.

    • During Xarelto treatment, promptly evaluate for signs/symptoms of blood loss; consider the need for blood replacement.

    • Discontinue Xarelto in patients with active pathological hemorrhage.

    • Increased risk of bleeding with concomitant use of other drugs that impair hemostasis (eg, aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, NSAIDs, SSRIs, and SNRIs). Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors may increase bleeding risk.

    • Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding

      • Increased risk of bleeding in acutely ill medical patients with the following conditions with the use of Xarelto for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e., undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the 3 months prior to treatment, or dual antiplatelet therapy.

      • Do not use Xarelto in these hospitalized, acutely ill medical patients at high risk of bleeding.

    • Reversal of Anticoagulant Effect

      • Do not monitor anticoagulation effect of rivaroxaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa activity.

      • May consider using procoagulant reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate or recombinant factor VIIa) to reverse the anti-factor Xa activity of rivaroxaban - but this has not been evaluated for clinical efficacy and safety.

    Spinal/Epidural Anesthesia or Puncture

    • Increased risk of spinal/epidural hematoma in anticoagulated patients receiving neuraxial anesthesia or undergoing spinal puncture.

    • To reduce the risk of bleeding, consider the pharmacokinetic profile of Xarelto. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of Xarelto is low. This exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

    • Do not remove an indwelling epidural or intrathecal catheter before at least 2 half-lives have elapsed after the last administration of Xarelto (eg, 18 hours for patients aged 20–45 years; and 26 hours for elderly patients aged 60–76 years). 

    • Do not administer the next Xarelto dose earlier than 6 hours after the removal of the catheter. Delay administering Xarelto for 24 hours if traumatic puncture occurs.

    • If a physician decides to give anticoagulation while receiving epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently for signs/symptoms of neurological impairment. 

    • Initiate urgent diagnosis and treatment if signs or symptoms of spinal hematoma are suspected.

    Use in Patients with Renal Impairment 

    • Nonvalvular Atrial Fibrillation

      • Monitor renal function periodically as clinically indicated and adjust therapy accordingly.

      • Consider dose adjustment or discontinuation of Xarelto in patients who develop acute renal failure.

    • Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE 

      • For patients with CrCl 15–<30mL/min: monitor closely and promptly evaluate any signs or symptoms of blood loss.

      • For patients with CrCl <15 mL/min including dialysis patients: avoid use of Xarelto.

      • Discontinue Xarelto if acute renal failure develops.

    • Prophylaxis of DVT Following Hip or Knee Replacement Surgery 

      • For patients with CrCl 15–<30mL/min: monitor closely and promptly evaluate any signs or symptoms of blood loss.

      • For patients with CrCl <15 mL/min including dialysis patients: avoid use of Xarelto.

      • Discontinue Xarelto if acute renal failure develops.

    • Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding 

      • For patients with CrCl 15–<30mL/min: monitor closely and promptly evaluate any signs or symptoms of blood loss.

      • For patients with CrCl <15 mL/min including dialysis patients: avoid use of Xarelto.

      • Discontinue Xarelto if acute renal failure develops.

    • Pediatric Patients 

      • For pediatric patients 1 year of age and older with moderate to severe renal impairment (eGFR <50 mL/min/1.73m2): avoid use of Xarelto.

      • For pediatric patients less than 1 year with serum creatinine results above 97.5th percentile: avoid use of Xarelto.

    Use in Patients with Hepatic Impairment

    • Avoid use of Xarelto in patients with moderate and severe hepatic impairment or patients with any hepatic disease associated with coagulopathy.

    Use with P-gp and Strong CYP3A Inhibitors or Inducers 

    • Avoid use with known combined P-gp and strong CYP3A inhibitors or combined P-gp and strong CYP3A inducers.

    Risk of Pregnancy-Related Hemorrhage 

    • Only use during pregnancy if the potential benefit justified the potential risk.

    • Monitor promptly for any signs or symptoms suggesting blood loss.

    Patients with Prosthetic Heart Valves

    • The use of Xarelto is not recommended in patients who have had transcatheter aortic valve replacement (TAVR).

    • The use of Xarelto is not recommended in patients with prosthetic heart valves.

    Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy

    • Initiation of Xarelto is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy. 

    Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome  

    • Not recommended for use in patients with triple-positive antiphospholipid syndrome.

    Pregnancy Considerations

    Risk Summary

    • Insufficient data to inform a drug-associated risk of adverse developmental outcomes. Exercise caution in pregnant patients due to the potential for pregnancy related hemorrhage and/or emergent delivery. Consider the benefits and risks of Xarelto for the other and possible risks to the fetus.

    Clinical Considerations

    • Disease-Associated Maternal and/or Embryo/Fetal Risk: Increased risk for venous thromboembolism especially in women with inherited or acquired thrombophilias. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss. 

    • Fetal/Neonatal Adverse Reactions: Risk of bleeding at any site in the fetus and/or neonate.

    • Labor or Delivery: Increased risk for bleeding. Balance the risk of bleeding with the risk of thrombotic events when considering the use of Xarelto in this setting.

    Nursing Mother Considerations

    Risk Summary

    • Rivaroxaban has been detected in human milk.

    • Consider the developmental and health benefits of breastfeeding, along with the mother’s clinical need for Xarelto and any potential adverse effects on the breastfed infant.

    Pediatric Considerations

    • The safety and effectiveness of Xarelto have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure. 

    • The safety and effectiveness of Xarelto have been established in pediatric patients from birth to less than 18 years for the treatment of VTE and the reduction in risk of recurrent VTE.

    • Xarelto 2.5 mg tablets are not recommended for use in pediatric patients.

    Geriatric Considerations

    • The efficacy of Xarelto was similar in elderly patients to that seen in patients younger than 65 years.

    • Older patients had higher rates of thrombotic and bleeding events.

    Renal Impairment Considerations

    • Nonvalvular Atrial Fibrillation

      • Monitor renal function periodically as clinically indicated and adjust therapy accordingly.

      • Consider dose adjustment or discontinuation of Xarelto in patients who develop acute renal failure.

    • Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE 

      • For patients with CrCl 15–<30mL/min: monitor closely and promptly evaluate any signs or symptoms of blood loss.

      • For patients with CrCl <15 mL/min including dialysis patients: avoid use of Xarelto.

      • Discontinue Xarelto if acute renal failure develops.

    • Prophylaxis of DVT Following Hip or Knee Replacement Surgery 

      • For patients with CrCl 15–<30mL/min: monitor closely and promptly evaluate any signs or symptoms of blood loss.

      • For patients with CrCl <15 mL/min including dialysis patients: avoid use of Xarelto.

      • Discontinue Xarelto if acute renal failure develops.

    • Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding 

      • For patients with CrCl 15–<30mL/min: monitor closely and promptly evaluate any signs or symptoms of blood loss.

      • For patients with CrCl <15 mL/min including dialysis patients: avoid use of Xarelto.

      • Discontinue Xarelto if acute renal failure develops.

    • Pediatric Patients 

      • For pediatric patients 1 year of age and older with moderate to severe renal impairment (eGFR <50 mL/min/1.73m2): avoid use of Xarelto.

      • For pediatric patients less than 1 year with serum creatinine results above 97.5th percentile: avoid use of Xarelto.

    Hepatic Impairment Considerations

    • Avoid use of Xarelto in patients with moderate and severe hepatic impairment or patients with any hepatic disease associated with coagulopathy.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Assess the risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, with the use of Xarelto in females of reproductive potential and those with abnormal uterine bleeding.

    Xarelto Pharmacokinetics

    Absorption

    • Absolute bioavailability for the 2.5 mg and 10 mg dose: ~80 to 100% and is not affected by food.

    • Absolute bioavailability for the 20 mg in the fasted state: ~66% and is increased when taken with food.

    • Xarelto 15 mg and 20 mg should be taken with food.

    • Maximum concentrations of rivaroxaban: ~2 to 4 hours after intake.

    • Avoid administering rivaroxaban distal to the stomach because it can results in reduced absorption.

    Distribution

    • Protein binding: ~92 to 95% with albumin being the main binding component.

    • Steady-state volume of distribution: ~50 L.

    Metabolism

    Hepatic (CYP3A4/5, 2J2).

    Elimination

    • Renal (30%), fecal (21%). 

    • Terminal half-life: ~5–9 hours (20–45 years of age); 11–13 hours (60–76 years of age).

    Xarelto Interactions

    Interactions

    Increased risk of bleeding with concomitant aspirin, clopidogrel, enoxaparin, warfarin, chronic NSAIDs. Avoid concomitant aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, NSAIDs, SSRIs, SNRIs, combined P-gp and strong CYP3A inhibitors (eg, ketoconazole, ritonavir). Increased thrombotic events with combined P-gp and strong CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort); avoid. Renal impairment (CrCl 15–<80mL/min): do not use Xarelto if receiving concomitant combined P-gp and moderate CYP3A inhibitors (eg, erythromycin), unless benefit justifies the risk.

    Xarelto Adverse Reactions

    Adverse Reactions

    Bleeding events (may be serious or fatal), back pain, wound secretion, pruritus, pain in extremity, abdominal pain, blister.

    Xarelto Clinical Trials

    Clinical Trials

    Stroke Prevention in Nonvalvular Atrial Fibrillation 

    • The efficacy and safety of Xarelto was compared to warfarin in the ROCKET AF trial (NCT00403767) to reduce the risk of stroke and non-CNS systemic embolism in 14,264 patients with nonvalvular atrial fibrillation (AF). Eligible patients had 1 or more of the following additional risk factors for stroke:

      • A prior stroke, transient ischemic attack, or non-CNS systemic embolism, or 2 or more of the following risk factors: age ≥75 years, hypertension, HF or LVEF ≤35%, or diabetes mellitus.

    • Patients were randomly assigned to receive either:

      • Xarelto (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30–50 mL/min) or warfarin (titrated to INR 2.0 to 3.0).

    • Xarelto achieved noninferiority to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism (HR, 0.88 [95% CI, 0.74-1.03]). Xarelto did not demonstrate superiority to warfarin.

    • The utility of Xarelto for preventing post-cardioversion stroke and systemic embolism is unknown.

    Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE)

    • The efficacy of Xarelto was evaluated in 8281 patients for the treatment of DVT and/or PE in the EINSTEIN DVT (NCT00440193) and EINSTEIN PE (NCT00439777) studies. Patients were excluded from the studies if they required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with CrCl <30 mL/min, significant liver disease, or active bleeding.

    • Patients were randomly assigned to receive either:

      • Xarelto (at an initial dose of 15 mg twice daily with food for the first 3 weeks, followed by Xarelto 20 mg once daily with food) or enoxaparin 1 mg/kg twice daily for at least 5 days with vitamin K antagonist (VKA) and then continued with VKA only after the target INR (2.0–3.0) was reached.

    • In both studies, Xarelto achieved noninferiority to enoxaparin/VKA for the primary composite of time to first occurrence of recurrent DVT or non-fatal or fatal PE (EINSTEIN DVT: HR, 0.68 [95% CI, 0.44-1.04]; EINSTEIN PE: HR, 1.12 [95% CI, 0.75-1.68]).

    Reduction in the Risk of Recurrence of DVT and/or PE

    • The efficacy of Xarelto was evaluated in 2275 patients to reduce the risk of recurrence of DVT and of PE in the EINSTEIN CHOICE study (NCT02064439).

    • Patients were randomly assigned to receive either:

      • Xarelto (10 or 20 mg once daily with food) or 100 mg acetylsalicyclic acid (aspirin) once daily in patients who had completed 6 to 12 months of anticoagulant treatment for DVT and/or PE following the acute event.

    • Xarelto achieved superiority to aspirin 100mg for the primary composite endpoint of time to first occurrence of recurrent DVT or nonfatal or fatal PE (HR, 0.26 [95% CI, 0.14-0.47]; P <.0001).

    Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

    • The efficacy of Xarelto was evaluated in a total of 9011 patients in the RECORD 1, 2, and 3 studies (NCT00329628, NCT00332020, NCT00361894).

    • RECORD 1 and 2:

      • These randomized, double-blind, clinical studies included 6727 patients undergoing elective total hip replacement surgery. Patients were randomly assigned to receive either Xarelto 10 mg once daily starting at least 6 to 8 hours after wound closure or enoxaparin 40 mg once daily started 12 hours preoperatively.

      • In RECORD 1, Xarelto met the primary composite endpoint with a relative risk reduction of 71% in total VTE vs enoxaparin (95% CI, 50-83; P <.001). Xarelto also had a relative risk reduction of 91% in major VTE vs enoxaparin (95% CI, 71-97; P <.001).

      • In RECORD 2, Xarelto met the primary composite endpoint with a relative risk reduction of 76% in total VTE vs enoxaparin (95% CI, 59-86; P <.001). Xarelto also had a relative risk reduction of 87% in major VTE vs enoxaparin (95% CI, 69-94; P <.001).

    • RECORD 3:

      • This clinical studiy included 6727 patients undergoing elective total knee replacement surgery. Patients were randomly assigned to receive either Xarelto 10 mg once daily starting at least 6 to 8 hours after wound closure or enoxaparin 40 mg once daily starting 12 hours preoperatively.

      • In RECORD 3, Xarelto met the primary composite endpoint with a relative risk reduction of 48% in total VTE vs enoxaparin (95% CI, 34-60; P <.001). Xarelto also had a relative risk reduction of 60% in major VTE vs enoxaparin (95% CI, 14-81; P <.024).

    Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding

    • The efficacy and safety of Xarelto for prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding was evaluated in the MAGELLAN study (NCT00571649).

    • Eligible patients included adults aged ≥40 years who were hospitalized for an acute medical illness, at risk for VTE due to moderate or severe immobility, and had additional risk factors for VTE. The causes for hospitalization included HF, active cancer, acute ischemic stroke, acute infectious and inflammatory disease and acutre respiratory insufficiency.

    • Patients were randomly assigned to receive either: 

      • Xarelto 10mg once daily for 35 ±4 days starting in hospital and continuing post hospital discharge (n=4050) or enoxaparin 40 mg once daily for 10 ±4 days starting in hospital followed by placebo post-discharge (n=4051). 

    • The major efficacy outcome was a composite endpoint that included asymptomatic proximal deep venous thrombosis (DVT) in lower extremity, symptomatic proximal or distal DVT in the lower extremity, symptomatic non-fatal pulmonary embolism (PE), and death related to venous thromboembolism (VTE).

    • Xarelto was found to be noninferior to enoxaparin in short-term use (10±4 days) and superior in long-term use (35±4 days) vs short-term use of enoxaparin followed by placebo. However, major clinically relevant bleeding was found to be higher in the Xarelto group. 

    Reduction of Risk of Major Cardiovascular Events in Patients with CAD 

    • The efficacy and safety of Xarelto was evaluated in the phase 3 COMPASS trial (N=27,395) for the reduction in the risk of stroke, MI, or CV death in patients with coronary artery disease (CAD) or peripheral artery disease (PAD).

    • Patients were randomly assigned to receive rivaroxaban 2.5 mg orally twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg orally twice daily alone, or aspirin 100 mg once daily alone.

    • Xarelto 2.5mg twice daily + aspirin 100mg once daily showed a 24% reduction in the risk of major CV events in patients with chronic CAD and/or PAD compared with aspirin alone (HR, 0.76 [95% CI, 0.66-0.86]; P =.00004). Specifically, the data showed a 44% reduction in stroke, 25% reduction in CV death, and 14% reduction in MI. 

    Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PAD

    • The approval was based on data from the double-blind, placebo-controlled phase 3 VOYAGER PAD study (NCT02504216) and the COMPASS PAD study.

    • VOYAGER PAD:

      • The efficacy and safety of rivaroxaban in 6564 patients aged 50 years and older with symptomatic PAD after lower extremity revascularization procedures. Patients were randomly assigned 1:1 to receive Xarelto 2.5 mg twice daily plus aspirin or placebo plus aspirin.

      • The primary efficacy endpoint of the study was the time to first occurrence of major thrombotic vascular events: myocardial infarction, ischemic stroke, acute limb ischemia, major amputation, or death from cardiovascular (CV) causes; the primary safety endpoint was the time to first occurrence of major bleeding events according to the Thrombolysis in Myocardial Infarction (TIMI) classification.

      • Xarelto plus aspirin significantly reduced the risk of major thrombotic vascular events with an event rate per year of 6.8% vs 8.0% for placebo plus aspirin(hazard ratio 0.85; 95% CI, 0.76-0.96; P =.0085). The incidence of TIMI major bleeding did not differ significantly between Xarelto and placebo.

    • COMPASS PAD:

      • The efficacy and safety of Xarelto 2.5 mg twice daily vs placebo on a background of aspirin 100 mg once daily in patients with PAD.

      • Xarelto plus aspirin significantly reduced the risk of major thrombotic vascular events with an event rate per year of 3.4% vs 4.8% for placebo (hazard ratio 0.71; 95% CI, 0.57-0.87). 

    Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients

    • The efficacy and safety of Xarelto was evaluated in the phase 3 EINSTEIN-Jr trial (NCT02234843) in 500 children from birth to 17 years with acute VTE who had received initial parenteral anticoagulant therapy. 

    • Patients were randomly assigned 2:1 to receive either a body weight-adjusted dose of Xarelto (tablets or oral suspension) or standard of care (eg, unfractionated heparin, low molecular weight heparin, subcutaneous fondaparinux, and/or oral vitamin K antagonist). 

    • There was a similar low risk of symptomatic recurrent VTE with Xarelto vs standard of care (1.2% vs 3.0%, respectively; hazard ratio [HR] 0.40; 95% CI, 0.11-1.41). Symptomatic recurrent VTE or major bleeding events occurred in 1.2% (n=4/335) of the Xarelto arm vs 4.2% (n=7/165) of the comparator arm. Complete resolution of thrombus on repeat imaging without recurrent VTE occurred in 128 of 335 children in the Xarelto group and 43 of 165 children in the comparator group.

    Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure

    • The UNIVERSE study compared the efficacy and safety of Xarelto with aspirin for thromboprophylaxis in children 2 to 8 years of age with congenital heart disease who had the Fontan procedure. In Part A of the study, patients received Xarelto for 1 year, while in Part B, patients were randomly assigned to receive Xarelto or aspirin for 1 year.

    • Results showed that 8.3% of patients (n=1/12) in Part A experienced a thrombotic event. In Part B of the study, 1.6% of patients (n=1/64) treated with Xarelto experienced a thrombotic event vs 8.8% of patients (n=3/34) treated with aspirin.

    Xarelto Note

    Not Applicable

    Xarelto Patient Counseling

    Patient Counseling

    Instructions for Patient Use 

    • Remind patients to not discontinue Xarelto without first talking to their healthcare professional. 

    Adults 

    • Advise patients with atrial fibrillation to take Xarelto once daily with the evening meal. 

    • Advise patients for initial treatment of DVT and/or PE to take Xarelto 15 mg or 20 mg tablets with food at approximately the same time every day. 

    • Advise patients who are at a continued risk of recurrent DVT and/or PE after at least 6 months of initial treatment, to take Xarelto 10 mg once daily with or without food. 

    • Advise patients who cannot swallow the tablet whole to crush Xarelto and combine with a small amount of applesauce followed by food. 

    • For patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush the Xarelto tablet and mix it with a small amount of water before administering via the tube. 

    • If a dose is missed, advise the patient according to the instructions in the Full Prescribing Information based on their dosing schedule.

    Pediatric Patients 

    • The adult caregiver should administer the dose. Advise caregivers to use the syringes provided in the original carton. 

    • Advise the caregiver whether the dose needs to be taken with food or not. 

    • Advise the caregiver the tablet must not be split in an attempt to provide a fraction of a tablet dose. 

    • If a child vomits or spits up the dose within 30 minutes after receiving the dose, a new dose should be given. However, if the child vomits more than 30 minutes after the dose is taken, the dose should not be re-administered and the next dose should be taken as scheduled. If a child vomits or spits up the dose repeatedly, the caregiver should contact the child’s doctor right away. 

    • For children who are unable to swallow whole tablets, Xarelto oral suspension may be used. 

    • If a dose is missed, advise the patient according to the instructions in the Full Prescribing Information based on their dosing schedule.

    Bleeding Risks 

    • Advise patients to report any unusual bleeding or bruising to their physician. Inform patients that it might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily when they are treated with Xarelto. 

    • If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to contact his or her physician immediately.

    Invasive or Surgical Procedures 

    • Instruct patients to inform their healthcare professional that they are taking Xarelto before any invasive procedure (including dental procedures) is scheduled. 

    Concomitant Medication and Herbals 

    • Advise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential interactions. 

    Pregnancy and Pregnancy-Related Hemorrhage 

    • Advise patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with Xarelto. 

    • Advise pregnant women receiving Xarelto to immediately report to their physician any bleeding or symptoms of blood loss. 

    Lactation 

    • Advise patients to discuss with their physician the benefits and risks of Xarelto for the mother and for the child if they are nursing or intend to nurse during anticoagulant treatment. 

    Females and Males of Reproductive Potential 

    • Advise patients who can become pregnant to discuss pregnancy planning with their physician. 

    Cost Savings Program

    Xarelto Savings and Support

    Images

    • Latest News Your top articles for Monday

    • Haymarket Medical NetworkTop Picks

    • Loading...

      Continuing Medical Education (CME/CE) Courses

      Show More