Usual Adult Dose for Atrial Fibrillation

20 mg orally once a day with evening meal

Comments:

• Limited data are available on the relative efficacy of this drug and warfarin in reducing risk of stroke and systemic embolism when warfarin therapy is well-controlled.

Use: To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation

Usual Adult Dose for Deep Vein Thrombosis

15 mg orally twice a day

• After 21 days: Should transition to 20 mg orally once a day

Comments:

• This dosage should be taken with food, at the same time each day.

Uses:

• For the treatment of deep vein thrombosis (DVT)
• For the treatment of pulmonary embolism (PE)

Usual Adult Dose for Pulmonary Embolism

15 mg orally twice a day

• After 21 days: Should transition to 20 mg orally once a day

Comments:

• This dosage should be taken with food, at the same time each day.

Uses:

• For the treatment of deep vein thrombosis (DVT)
• For the treatment of pulmonary embolism (PE)

Usual Adult Dose for Deep Vein Thrombosis - Recurrent Event

10 mg orally once a day

Comments:

• This dosage should be started after at least 6 months of standard anticoagulant therapy.
• This dosage may be taken with or without food.

Use: For the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months

Usual Adult Dose for Pulmonary Embolism - Recurrent Event

10 mg orally once a day

Comments:

• This dosage should be started after at least 6 months of standard anticoagulant therapy.
• This dosage may be taken with or without food.

Use: For the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months

Usual Adult Dose for Deep Vein Thrombosis Prophylaxis after Hip Replacement Surgery

10 mg orally once a day

Duration of Therapy:

• Hip replacement surgery: 35 days
• Knee replacement surgery: 12 days

Comments:

• This dosage should be started 6 to 10 hours after surgery once hemostasis has been established.
• This dosage may be taken with or without food.

Use: For the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery

Usual Adult Dose for Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery

10 mg orally once a day

Duration of Therapy:

• Hip replacement surgery: 35 days
• Knee replacement surgery: 12 days

Comments:

• This dosage should be started 6 to 10 hours after surgery once hemostasis has been established.
• This dosage may be taken with or without food.

Use: For the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery

Usual Adult Dose for Venous Thromboembolism

10 mg orally once a day
Total duration of therapy: 31 to 39 days

Comments:

• This dosage is recommended in hospital and after hospital discharge.
• This dosage may be taken with or without food.
• This drug is not for use for primary venous thromboembolism (VTE) prophylaxis in hospitalized, acutely ill medical patients with the following conditions (at high risk of bleeding): history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage; active cancer (i.e., undergoing acute, in-hospital cancer treatment); active gastroduodenal ulcer in the 3 months before therapy; history of bleeding in the 3 months before therapy; or dual antiplatelet therapy.

Use: For the prophylaxis of VTE and VTE related death during hospitalization and post hospital discharge in patients admitted for an acute medical illness who are at risk of thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding

Usual Adult Dose for Coronary Artery Disease

2.5 mg orally twice a day

Comments:

• This regimen should include aspirin (75 to 100 mg) once a day.
• When starting therapy after a successful lower extremity revascularization procedure, this dosage should be started once hemostasis has been established.
• This dosage may be taken with or without food.

Uses:

• In combination with aspirin, to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, stroke) in patients with coronary artery disease (CAD)
• In combination with aspirin, to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, major amputation of a vascular etiology) in patients with peripheral artery disease (PAD), including patients who recently underwent a lower extremity revascularization procedure due to symptomatic PAD

Usual Adult Dose for Peripheral Arterial Disease

2.5 mg orally twice a day

Comments:

• This regimen should include aspirin (75 to 100 mg) once a day.
• When starting therapy after a successful lower extremity revascularization procedure, this dosage should be started once hemostasis has been established.
• This dosage may be taken with or without food.

Uses:

• In combination with aspirin, to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, stroke) in patients with coronary artery disease (CAD)
• In combination with aspirin, to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, major amputation of a vascular etiology) in patients with peripheral artery disease (PAD), including patients who recently underwent a lower extremity revascularization procedure due to symptomatic PAD

Usual Adult Dose for Cardiovascular Risk Reduction

2.5 mg orally twice a day

Comments:

• This regimen should include aspirin (75 to 100 mg) once a day.
• When starting therapy after a successful lower extremity revascularization procedure, this dosage should be started once hemostasis has been established.
• This dosage may be taken with or without food.

Uses:

• In combination with aspirin, to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, stroke) in patients with coronary artery disease (CAD)
• In combination with aspirin, to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, major amputation of a vascular etiology) in patients with peripheral artery disease (PAD), including patients who recently underwent a lower extremity revascularization procedure due to symptomatic PAD

Usual Pediatric Dose for Venous Thromboembolism

Birth to Less than 18 Years:
Oral suspension:

• Weight 2.6 to 2.9 kg: 0.8 mg orally 3 times a day
• Weight 3 to 3.9 kg: 0.9 mg orally 3 times a day
• Weight 4 to 4.9 kg: 1.4 mg orally 3 times a day
• Weight 5 to 6.9 kg: 1.6 mg orally 3 times a day
• Weight 7 to 7.9 kg: 1.8 mg orally 3 times a day
• Weight 8 to 8.9 kg: 2.4 mg orally 3 times a day
• Weight 9 to 9.9 kg: 2.8 mg orally 3 times a day
• Weight 10 to 11.9 kg: 3 mg orally 3 times a day
• Weight 12 to 29.9 kg: 5 mg orally twice a day
• Weight 30 to 49.9 kg: 15 mg orally once a day
• Weight at least 50 kg: 20 mg orally once a day

Tablets:

• Weight 30 to 49.9 kg: 15 mg orally once a day
• Weight at least 50 kg: 20 mg orally once a day

Comments:

• This drug should be started after at least 5 days of initial parenteral anticoagulation therapy.
• Dosing of this drug was not studied and therefore cannot be reliably determined in the following patient populations; this drug should not be used in children younger than 6 months with any of the following: less than 37 weeks of gestation at birth, less than 10 days of oral feeding, or body weight of less than 2.6 kg.
• To increase absorption, all doses should be administered with feedings or with food (exposures match that of 20 mg daily dose in adults).
• Once a day: Doses should be administered about 24 hours apart; twice a day: Doses should be administered about 12 hours apart; 3 times a day: Doses should be administered about 8 hours apart.
• The child's weight should be monitored and the dose should be reviewed regularly, especially for children weighing less than 12 kg; this is to ensure a therapeutic dose is maintained.
• All pediatric patients (except younger than 2 years with catheter-related thrombosis): This drug should be continued for at least 3 months in children with thrombosis.
• Therapy can be extended up to 12 months when clinically necessary; the benefit of continued therapy beyond 3 months should be assessed on an individual basis considering the risk for recurrent thrombosis versus the potential risk of bleeding.
• Pediatric patients younger than 2 years with catheter-related thrombosis: This drug should be continued for at least 1 month in such patients.
• Therapy can be extended for up to 3 months when clinically necessary; the benefit of continued therapy beyond 1 month should be assessed on an individual basis considering the risk for recurrent thrombosis versus the potential risk of bleeding.

Use: For the treatment of VTE and the reduction in the risk of recurrent VTE in patients after at least 5 days of initial parenteral anticoagulant therapy

Usual Pediatric Dose for Congenital Heart Disease

2 Years or Older:
Oral suspension:

• Weight 7 to 7.9 kg: 1.1 mg orally twice a day
• Weight 8 to 9.9 kg: 1.6 mg orally twice a day
• Weight 10 to 11.9 kg: 1.7 mg orally twice a day
• Weight 12 to 19.9 kg: 2 mg orally twice a day
• Weight 20 to 29.9 kg: 2.5 mg orally twice a day
• Weight 30 to 49.9 kg: 7.5 mg orally once a day
• Weight at least 50 kg: 10 mg orally once a day

Tablets:

• Weight at least 50 kg: 10 mg orally once a day

Comments:

• All doses can be administered with or without food (exposures match that of 10 mg daily dose in adults).
• Once a day: Doses should be administered about 24 hours apart; twice a day: Doses should be administered about 12 hours apart.

Use: For thromboprophylaxis in patients with congenital heart disease who have undergone the Fontan procedure

Renal Dose Adjustments

ADULT PATIENTS:
Reduction in risk of stroke in nonvalvular atrial fibrillation:

• CrCl greater than 50 mL/min: No adjustment recommended
• CrCl up to 50 mL/min: 15 mg orally once a day with evening meal
• If acute renal failure develops during therapy: Dose adjustment or discontinuation of this drug should be considered.

Treatment of DVT and/or PE, reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE, prophylaxis of DVT after hip or knee replacement surgery, prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding:

• CrCl at least 15 mL/min: No adjustment recommended
• CrCl less than 15 mL/min: Not recommended
• If acute renal failure develops during therapy: This drug should be discontinued.

PEDIATRIC PATIENTS:
Younger Than 1 Year:

• Serum creatinine results above 97.5th percentile: Not recommended

Reference values of serum creatinine in patients younger than 1 year (Age: 97.5th Percentile of Creatinine):

• Week 2: 0.52 mg/dL (45 mcmol/L)
• Week 3: 0.46 mg/dL (41 mcmol/L)
• Week 4: 0.42 mg/dL (37 mcmol/L)
• Month 2: 0.37 mg/dL (33 mcmol/L)
• Month 3 to 9: 0.34 mg/dL (30 mcmol/L)
• Month 10 to 12: 0.36 mg/dL (32 mcmol/L)

1 Year or Older:

• Mild renal dysfunction (estimated GFR 50 to 80 mL/min/1.73 m2): No adjustment recommended
• Moderate or severe renal dysfunction (estimated GFR less than 50 mL/min/1.73 m2): Not recommended

Comments:
ADULT PATIENTS:

• CrCl should be calculated based on actual weight.
• Nonvalvular atrial fibrillation:
• Renal function should be periodically assessed as clinically indicated (i.e., more often in situations in which renal function may decline) and therapy should be adjusted accordingly.
• Patients with CrCl less than 30 mL/min were not studied, but use of this drug is expected to result in serum drug levels similar to those in patients with moderate renal dysfunction (CrCl 30 to less than 50 mL/min).
• Treatment of DVT, PE, and reduction in the risk of recurrence of DVT and PE; prophylaxis of DVT after hip or knee replacement surgery; prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding:
• Patients with CrCl less than 30 mL/min were not studied, but use of this drug is expected to result in serum drug levels similar to those in patients with moderate renal dysfunction (CrCl 30 to less than 50 mL/min); drug exposure and pharmacodynamic effects are increased in patients with CrCl less than 30 mL/min compared to patients with normal renal function.
• Limited clinical data are available in patients with CrCl 15 to less than 30 mL/min; close observation and prompt evaluation of any signs/symptoms of blood loss are recommended for these patients.
• There are no clinical data in patients with CrCl less than 15 mL/min.
• Reduction of risk of major cardiovascular events (cardiovascular death, myocardial infarction, stroke) in CAD: No dose adjustment is needed based on CrCl.
• Reduction of risk of major thrombotic vascular events in PAD, including patients after lower extremity revascularization due to symptomatic PAD: No dose adjustment is needed based on CrCl.

PEDIATRIC PATIENTS:

• Younger than 1 year: Renal function should be determined using serum creatinine; there are no clinical data for patients with serum creatinine results above 97.5th percentile.
• At least 1 year of age: Limited clinical data are available for patients with estimated GFR less than 50 mL/min/1.73 m2.
• Estimated GFR can be done using the updated Schwartz formula if serum creatinine is measured by an enzymatic creatinine method that has been calibrated to be traceable to isotope dilution mass spectrometry (IDMS).
• If serum creatinine is measured with routine methods that have not been recalibrated to be traceable to IDMS (e.g., the traditional Jaffe reaction), the estimated GFR should be obtained from the original Schwartz formula.

Liver Dose Adjustments

Adult patients:

• Moderate and severe liver dysfunction (Child-Pugh B and C) or any liver disease associated with coagulopathy: Not recommended (drug exposure and bleeding risk may be increased)

Pediatric patients:

• Liver dysfunction: Data not available

Comments:

• No clinical data are available for pediatric patients with liver dysfunction or adult patients with severe liver dysfunction.

Dose Adjustments

Switching To and From This Drug:

• From Warfarin: When switching patients from warfarin to this drug, warfarin should be discontinued and this drug should be started as soon as the INR is below 3 in adult patients and below 2.5 in pediatric patients to avoid periods of inadequate anticoagulation.
• To Warfarin:
• Adult patients: No clinical trial data are available to guide conversion from this drug to warfarin. This drug affects INR so INR measurements made during coadministration with warfarin may not be useful to determine the appropriate dose of warfarin; 1 approach is to discontinue this drug and start a parenteral anticoagulant plus warfarin at the time the next dose of this drug would have been administered.
• Pediatric patients: To ensure adequate anticoagulation during the switch from this drug to warfarin, this drug should be continued for at least 2 days after the first dose of warfarin; after 2 days of coadministration, an INR should be obtained before the next scheduled dose of this drug, and coadministration of this drug and warfarin should continue until the INR is at least 2.
• Once this drug is discontinued, INR testing may be done reliably 24 hours after the last dose.
• From Other Anticoagulants Other Than Warfarin: For adult and pediatric patients currently administered an anticoagulant other than warfarin, this drug should be started 0 to 2 hours before the next scheduled administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and administration of the other anticoagulant should be omitted; for unfractionated heparin administered by continuous infusion, the infusion should be stopped and this drug should be started at the same time.
• To Other Anticoagulants Other Than Warfarin: For adult and pediatric patients currently taking this drug and switching to an anticoagulant with rapid onset, this drug should be discontinued and the first dose of the other anticoagulant (oral or parenteral) should be administered at the time that the next dose of this drug would have been taken.

Discontinuation for Surgery and Other Interventions:

• If anticoagulation must be stopped to reduce the risk of bleeding with surgical or other procedures, this drug should be discontinued at least 24 hours before the procedure to reduce the risk of bleeding.
• When deciding if a procedure should be delayed until 24 hours after the last dose of this drug, the increased risk of bleeding should be weighed against the urgency of intervention.
• This drug should be started after the surgical or other procedures as soon as adequate hemostasis has been established, noting the time to onset of therapeutic effect is short.
• If oral therapy cannot be taken during or after surgical intervention, administration of a parenteral anticoagulant should be considered.

Precautions

US BOXED WARNINGS:

• PREMATURE TREATMENT DISCONTINUATION INCREASES RISK OF THROMBOTIC EVENTS: Premature discontinuation of any oral anticoagulant (including this drug) increases the risk of thrombotic events; coverage with another anticoagulant should be considered if anticoagulation with this drug is discontinued for a reason other than pathological bleeding or completion of therapy.
• SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas have occurred in patients treated with this drug who were receiving neuraxial anesthesia or undergoing spinal puncture; such hematomas may cause long-term or permanent paralysis. These risks should be considered when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural/spinal hematomas in such patients include: use of indwelling epidural catheters, coadministration with other drugs that affect hemostasis (e.g., NSAIDs, platelet inhibitors, other anticoagulants), history of traumatic or repeated epidural/spinal punctures, history of spinal deformity or spinal surgery, optimal timing between use of this drug and neuraxial procedures is not known. Patients should be monitored frequently for signs/symptoms of neurological impairment; urgent treatment is required if neurological compromise is noted. Benefits and risks should be considered prior to neuraxial intervention in anticoagulated patients or patients to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS:

• Active pathological bleeding
• Severe hypersensitivity reaction to the active component (e.g., anaphylactic reactions)

Safety and efficacy of the 2.5 mg tablets have not been established in patients younger than 18 years; this formulation is not recommended for use in these patients.

Consult WARNINGS section for additional precautions.

Dialysis

Adult Patients:
Nonvalvular atrial fibrillation:

• ESRD on intermittent hemodialysis: 15 mg orally once a day

Treatment of DVT, PE, and reduction in the risk of recurrence of DVT and PE; prophylaxis of DVT after hip or knee replacement surgery; prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding:

• CrCl less than 15 mL/min (including patients on dialysis): Not recommended

Reduction of risk of major cardiovascular event in patients with CAD and reduction of risk of major thrombotic vascular events in patients with PAD, including patients after recent lower extremity revascularization due to symptomatic PAD:

• ESRD on intermittent hemodialysis: No adjustment recommended

Comments:

• Treatment of DVT, PE, and reduction in the risk of recurrence of DVT and PE; prophylaxis of DVT after hip or knee replacement surgery; prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding: There are no clinical data in patients with CrCl less than 15 mL/min (including patients on dialysis).
• Due to high plasma protein binding, this drug is not dialyzable.

Other Comments

Administration advice:

• Consult the manufacturer product information regarding missed doses.
• For adult patients unable to swallow whole tablets, tablets (all strengths) may be crushed and mixed with applesauce immediately before use and administered orally.
• After administration of a crushed 15 or 20 mg tablet, immediately follow the dose with food.
• Administration with food is not required for the 2.5 or 10 mg tablets.
• Pediatric patients: If the patient vomits or spits up the dose within 30 minutes after receiving the dose, administer a new dose; if the patient vomits more than 30 minutes after dosing, do not readminister the dose and administer the next dose as scheduled. If the patient vomits or spits up the dose repeatedly, the caregiver should contact the physician at once.
• Do not split tablets in an attempt to provide a fraction of a tablet dose for pediatric patients.
• For children unable to swallow 10, 15, or 20 mg whole tablets, use the oral suspension; do not use the 2.5 mg tablets in pediatric patients.
• Oral suspension: Use within 60 days.
• Administration of the oral suspension via nasogastric (NG) tube or gastric feeding tube: The oral suspension may be administered through NG or gastric feeding tube; after administration, flush the feeding tube with water.
• For the treatment or reduction in risk of recurrent VTE in pediatric patients, immediately follow the dose with enteral feeding (to increase absorption).
• For the thromboprophylaxis in pediatric patients with congenital heart disease who have undergone the Fontan procedure, enteral feeding is not required after the dose.
• Administration of tablets via NG tube or gastric feeding tube: After confirming gastric placement of the tube, tablets (all strengths) may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube; since absorption of this drug depends on the site of drug release, do not administer this drug distal to the stomach (which can result in reduced absorption and thus, reduced drug exposure).
• After administration of a crushed 15 or 20 mg tablet, immediately follow the dose with enteral feeding.
• Enteral feeding is not required after administration of the 2.5 or 10 mg tablets.

Storage requirements:

• Granules, reconstituted oral suspension, tablets: Store at room temperature between 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F).
• Granules, reconstituted oral suspension: Do not freeze.
• Crushed tablets (all strengths) are stable in water and in applesauce for up to 4 hours

Reconstitution/preparation techniques (oral suspension):

• Flavor should not be added as this product is already flavored (sweet and creamy).
• This product should be reconstituted before dispensing.
• The manufacturer product information should be consulted.

General:

• The oral suspension should be dispensed in the original bottle, upright with the syringes provided in the original carton.
• An in vitro compatibility study indicated no adsorption of this drug from a water suspension of a crushed tablet to polyvinyl chloride (PVC) or silicone NG tubing; an in vitro compatibility study indicated the oral suspension can be used with PVC, polyurethane, or silicone NG tubing.

Monitoring:

• General: Child's weight, especially if less than 12 kg (regularly)
• Hematologic: For signs/symptoms of blood loss
• Nervous System: For signs/symptoms of neurological impairment (frequently with spinal/epidural anesthesia or spinal puncture)
• Renal: Renal function (as clinically indicated)

Patient advice:

• For the oral suspension, read the US FDA-approved patient labeling (Medication Guide and Instructions for Use); for the tablets, read the US FDA-approved patient labeling (Medication Guide).
• Take this drug only as directed.
• Do not stop this drug without first consulting health care professional.
• Pediatric patients: The adult caregiver should administer the dose; use the syringes provided in the original carton.
• Report any unusual bleeding/bruising to physician.
• If you have had neuraxial anesthesia or spinal puncture (especially if you are taking NSAIDs or platelet inhibitors), watch for signs/symptoms of spinal or epidural hematoma (e.g., back pain, tingling, numbness [especially in the lower limbs], muscle weakness, stool/urine incontinence); if any of these symptoms occur, contact physician immediately.
• Inform health care professional that you are taking this drug before scheduling any invasive procedure (including dental procedures).
• Inform physicians and dentists if you are taking, or plan to take, any prescription or nonprescription medications or herbal products.
• Inform physician immediately if you become pregnant or intend to become pregnant during therapy.
• Pregnant patients: Immediately report to physician any bleeding or symptoms of blood loss.
• If you are nursing or intend to nurse during anticoagulant therapy, discuss with physician the benefits and risks of this drug for you and for the child.
• Patients of childbearing potential: Discuss pregnancy planning with physician.

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