Dosage & Administration
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Xarelto Prescribing Information
A. Premature discontinuation of XARELTO increases the risk of thrombotic events
Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.4), Warnings and Precautions (5.1), and Clinical Studies (14.1)] .
B. Spinal/epidural hematoma
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. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
- use of indwelling epidural catheters
- concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
- a history of traumatic or repeated epidural or spinal punctures
- a history of spinal deformity or spinal surgery
- optimal timing between the administration of XARELTO and neuraxial procedures is not known
[see Warnings and Precautions (5.2, 5.3)and Adverse Reactions (6.2)].
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.3)] .
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.3)] .
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
XARELTO is indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation.
There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies (14.1)].
Treatment of Deep Vein Thrombosis
XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
Treatment of Pulmonary Embolism
XARELTO is indicated for the treatment of pulmonary embolism (PE).
Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism
XARELTO is indicated for the reduction in 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 at least 6 months.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in adult patients undergoing knee or hip replacement surgery.
Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding
XARELTO is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE related death during hospitalization and post hospital discharge in adult patients 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 [see Warnings and Precautions (5.2)and Clinical Studies (14.5)] .
Reduction of Risk of Major Cardiovascular Events in Patients with Coronary Artery Disease (CAD)
XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease.
Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD
XARELTO, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with PAD, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD.
Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients
XARELTO is indicated for the treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment.
Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure
XARELTO is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.
Recommended Dosage in Adults
| Indication | Renal Considerations * | Dosage | Food/Timing † |
|---|---|---|---|
| |||
| Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation | CrCl >50 mL/min | 20 mg once daily | Take with evening meal |
| CrCl ≤50 mL/min ‡ | 15 mg once daily | Take with evening meal | |
| Treatment of DVT and/or PE | CrCl ≥15 mL/min ‡ | 15 mg twice daily ▼ after 21 days, 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: | |||
| CrCl ≥15 mL/min ‡ | 10 mg once daily for 35 days, 6–10 hours after surgery once hemostasis has been established | Take with or without food |
| CrCl <15 mL/min | Avoid Use | ||
| CrCl ≥15 mL/min ‡ | 10 mg once daily for 12 days, 6–10 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 (75–100 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 (75–100 mg) once daily. When starting therapy after a successful lower extremity revascularization procedure, initiate once hemostasis has been established. | Take with or without food |
Recommended Dosage in Pediatric Patients
Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients
| Dosage Form | Body Weight | 1 mg XARELTO = 1 mL Suspension | |||
|---|---|---|---|---|---|
| Dosage | Total Daily Dose ‡ | ||||
| Once a Day § | 2 Times a Day § | 3 Times a Day § | |||
| |||||
| Oral Suspension Only | 2.6 kg to 2.9 kg | 0.8 mg | 2.4 mg | ||
| 3 kg to 3.9 kg | 0.9 mg | 2.7 mg | |||
| 4 kg to 4.9 kg | 1.4 mg | 4.2 mg | |||
| 5 kg to 6.9 kg | 1.6 mg | 4.8 mg | |||
| 7 kg to 7.9 kg | 1.8 mg | 5.4 mg | |||
| 8 kg to 8.9 kg | 2.4 mg | 7.2 mg | |||
| 9 kg to 9.9 kg | 2.8 mg | 8.4 mg | |||
| 10 kg to 11.9 kg | 3 mg | 9 mg | |||
| 12 kg to 29.9 kg | 5 mg | 10 mg | |||
| Oral Suspension or Tablets | 30 kg to 49.9 kg | 15 mg | 15 mg | ||
| ≥50 kg | 20 mg | 20 mg | |||
Dosing of XARELTO was not studied and therefore dosing cannot be reliably determined in the following patient populations. Its use is therefore not recommended in children less than 6 months of age with any of the following:
- Less than 37 weeks of gestation at birth
- Less than 10 days of oral feeding
- Body weight of less than 2.6 kg.
To increase absorption, all doses should be taken with feeding or with food.
Monitor the child's weight and review the dose regularly, especially for children below 12 kg. This is to ensure a therapeutic dose is maintained.
All pediatric patients (except <2 years old with catheter-related thrombosis):Therapy with XARELTO should be continued for at least 3 months in children with thrombosis. Treatment 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 taking into account the risk for recurrent thrombosis versus the potential risk of bleeding.
Pediatric patients <2 years old with catheter-related thrombosis:Therapy with XARELTO should be continued for at least 1 month in children less than 2 years old with catheter-related thrombosis. Treatment can be extended up to 3 months when clinically necessary. The benefit of continued therapy beyond 1 month should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential risk of bleeding.
Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure
| Dosage Form | Body Weight | 1 mg XARELTO = 1 mL Suspension | ||
|---|---|---|---|---|
| Dosage | Total Daily Dose * | |||
| Once a Day † | 2 Times a Day † | |||
| ||||
| Oral Suspension Only | 7 kg to 7.9 kg | 1.1 mg | 2.2 mg | |
| 8 kg to 9.9 kg | 1.6 mg | 3.2 mg | ||
| 10 kg to 11.9 kg | 1.7 mg | 3.4 mg | ||
| 12 kg to 19.9 kg | 2 mg | 4 mg | ||
| 20 kg to 29.9 kg | 2.5 mg | 5 mg | ||
| 30 kg to 49.9 kg | 7.5 mg | 7.5 mg | ||
| Oral Suspension or Tablets | ≥50 kg | 10 mg | 10 mg | |
Administration in Pediatric Patients
Food Effect:
For the treatment of VTE 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 patient vomits or spits up the dose within 30 minutes after receiving the dose, a new dose should be given. However, if the patient 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 the patient vomits or spits up the dose repeatedly, the caregiver should contact the child's doctor right away.
Tablets:XARELTO tablet must not be split in an attempt to provide a fraction of a tablet dose.
For children unable to swallow 10, 15, or 20 mg whole tablets, XARELTO oral suspension should be used. XARELTO 2.5 mg tablets are not recommended for use in pediatric patients [see Use in Specific Populations (8.4)] .
Use in Renal Impairment in Pediatric Patients
Patients 1 Year of Age or Older
- Mild renal impairment (eGFR: 50 to ≤ 80 mL/min/1.73 m 2): No dose adjustment is required.
- Moderate or severe renal impairment (eGFR: <50 mL/min/1.73 m 2): avoid use, as limited clinical data are available.
Estimated glomerular filtration rate (eGFR) can be done using the updated Schwartz formula, eGFR (Schwartz) = (0.413 × height in cm)/serum creatinine in mg/dL, if serum creatinine (SCr) is measured by an enzymatic creatinine method that has been calibrated to be traceable to isotope dilution mass spectrometry (IDMS).
If SCr is measured with routine methods that have not been recalibrated to be traceable to IDMS (e.g., the traditional Jaffé reaction), the eGFR should be obtained from the original Schwartz formula: eGFR (mL/min/1.73 m 2) = k * height (cm)/SCr (mg/dL), where k is proportionality constant:
- k = 0.55 in children 1 year to 13 years
- k = 0.55 in girls > 13 and < 18 years
- k = 0.70 in boys > 13 and < 18 years
Patients Less than 1 Year of Age
Determine renal function using serum creatinine. Avoid use of XARELTO in pediatric patients younger than 1 year with serum creatinine results above 97.5 thpercentile, as no clinical data are available.
| Age | 97.5 thPercentile of Creatinine (mg/dL) | 97.5 thPercentile of Creatinine (µmol/L) |
|---|---|---|
| Week 2 | 0.52 | 46 |
| Week 3 | 0.46 | 41 |
| Week 4 | 0.42 | 37 |
| Month 2 | 0.37 | 33 |
| Month 3 | 0.34 | 30 |
| Month 4–6 | 0.34 | 30 |
| Month 7–9 | 0.34 | 30 |
| Month 10–12 | 0.36 | 32 |
Switching to and from XARELTO
Switching from Warfarin to XARELTO- When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (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 to guide converting patients from XARELTO to warfarin. XARELTO affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. 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.
- Pediatric Patients:
To ensure adequate anticoagulation during the transition from XARELTO to warfarin, continue XARELTO for at least 2 days after the first dose of warfarin. After 2 days of co-administration, an INR should be obtained prior to the next scheduled dose of XARELTO. Co-administration of XARELTO and warfarin is advised to continue until the INR is ≥ 2.0.
Once XARELTO is discontinued, INR testing may be done reliably 24 hours after the last dose.
Switching from XARELTO to Anticoagulants other than Warfarin- For adult and pediatric 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 that the next XARELTO dose would have been taken [see Drug Interactions (7.4)] .
Switching from Anticoagulants other than Warfarin to XARELTO -For adult and pediatric patients currently receiving an anticoagulant other than warfarin, start XARELTO 0 to 2 hours prior to the next scheduled administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO at the same time.
Discontinuation for Surgery and other Interventions
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 [see Warnings and Precautions (5.2)] . 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 [see Warnings and Precautions (5.1)] . If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.
Missed Dose
Adults
- For patients receiving 2.5 mg twice daily: if a dose is missed, the patient should take a single 2.5 mg XARELTO 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.
Pediatric Patients
- 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 adult patients who are unable to swallow whole tablets, XARELTO tablets (all strengths) may be crushed and mixed with applesauce immediately prior to use and administered orally. After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should be immediately followed by food. Administration with food is not required for the 2.5 mg or 10 mg tablets [see Clinical Pharmacology (12.3)] .
Administrationof XARELTO tablets via nasogastric (NG) tube or gastric feeding tube:After confirming gastric placement of the tube, XARELTO tablets (all strengths) may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube. Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of XARELTO distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding. Enteral feeding is not required following administration of the 2.5 mg or 10 mg tablets [see Clinical Pharmacology (12.3)] .
Crushed XARELTO tablets (all strengths) are stable in water and in applesauce for up to 4 hours. An in vitrocompatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed XARELTO tablet to PVC or silicone nasogastric (NG) tubing.
Administration of XARELTO suspension via NG tube or gastric feeding tube: XARELTO oral suspension may be given through NG or gastric feeding tube. After the administration, flush the feeding tube with water.
For the treatment or reduction in risk of recurrent VTE in pediatric patients, the dose should then be immediately followed by enteral feeding to increase absorption. For the thromboprophylaxis in pediatric patients with congenital heart disease who have undergone the Fontan procedure, the dose does not require to be followed by enteral feeding.
An in vitrocompatibility study indicated that XARELTO suspension can be used with PVC, polyurethane or silicone NG tubing.
Preparation Instructions for Pharmacy of XARELTO for Oral Suspension
Do not add flavor as product is already flavored (sweet and creamy).
Reconstitute before dispensing:
- Tap the bottle until all granules flow freely.
- Add 150 mL of purified water for reconstitution.
- Shake for 60 seconds. Check that all granules are wetted and the suspension is uniform.
- Push the adaptor into bottleneck and recap bottle.
- The suspension must be used within 60 days.
- Write the "Discard after" date on the bottle and carton.
Dispensing Instructions:
- Dispense in the original bottle.
- Dispense the bottle upright with the syringes provided in the original carton.
Store reconstituted suspension 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). Do not freeze.
It is recommended the pharmacist counsel the caregiver on proper use. Alert the patient or caregiver to read the Medication Guide and Instructions for Use.
- 2.5 mg tablets: Round, light yellow, and film-coated with a triangle pointing down above a "2.5" marked on one side and "Xa" on the other side
- 10 mg tablets: Round, light red, biconvex and film-coated with a triangle pointing down above a "10" marked on one side and "Xa" on the other side
- 15 mg tablets: Round, red, biconvex, and film-coated with a triangle pointing down above a "15" marked on one side and "Xa" on the other side
- 20 mg tablets: Triangle-shaped, dark red, and film-coated with a triangle pointing down above a "20" marked on one side and "Xa" on the other side
- For oral suspension: white to off-white granules; once reconstituted, provide flavored white to off-white opaque liquid with a concentration of 1 mg/mL.
Pregnancy
Risk Summary
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 [see Warnings and Precautions (5.2, 5.7)] .
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.
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
All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see Warnings and Precautions (5.7)]. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.
Data
Human Data
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. In an in vitroplacenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.
Animal Data
Rivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).
Lactation
Risk Summary
Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition (see Data) .
Data
Animal Data
Following a single oral administration of 3 mg/kg of radioactive [ 14C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.
Females and Males of Reproductive Potential
Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.
The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including XARELTO should be assessed in females of reproductive potential and those with abnormal uterine bleeding.
Pediatric Use
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. Use of XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO in adults with additional pharmacokinetic, safety and efficacy data from a multicenter, prospective, open-label, active-controlled randomized study in 500 pediatric patients from birth to less than 18 years of age. XARELTO was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth; had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3)and Clinical Studies (14.8)] .
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. Use of XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO in adults with additional data from a multicenter, prospective, open-label, active controlled study in 112 pediatric patients to evaluate the single- and multiple-dose pharmacokinetic properties of XARELTO and the safety and efficacy of XARELTO when used for thromboprophylaxis for 12 months in children with single ventricle physiology who had the Fontan procedure [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3)and Clinical Studies (14.9)] .
Clinical studies that evaluated safety, efficacy, pharmacokinetic and pharmacodynamic data support the use of XARELTO 10 mg, 15 mg, and 20 mg tablets in pediatric patients. For the XARELTO 2.5 mg tablets, there are no safety, efficacy, pharmacokinetic and pharmacodynamic data to support the use in pediatric patients. Therefore, XARELTO 2.5 mg tablets are not recommended for use in pediatric patients.
Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.
Geriatric Use
Of the total number of adult patients in clinical trials for the approved indications of XARELTO (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients [see Clinical Pharmacology (12.3)and Clinical Studies (14)] .
Renal Impairment
In pharmacokinetic studies, compared to healthy adult subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in adult subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3)] .
Nonvalvular Atrial Fibrillation
Patients with Chronic Kidney Disease not on Dialysis
In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl <30 mL/min were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment [see Clinical Pharmacology (12.3)] .
Patients with End-Stage Renal Disease on Dialysis
Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (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 [see Clinical Pharmacology (12.2, 12.3)] . 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.
Treatment of DVT and/or PE and Reduction in the Risk of Recurrence of DVT and/or PE
In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.
Prophylaxis of DVT Following Hip or Knee Replacement Surgery
The combined analysis of the RECORD 1–3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. In the RECORD 1–3 trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.
Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding
Patients with CrCl values <30 mL/min at screening were excluded from the MAGELLAN study. In patients with CrCl <30 mL/min a dose of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)] . Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid use of XARELTO in patients with CrCl <15 mL/min.
Reduction of Risk of Major Cardiovascular Events 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
Patients with Chronic Kidney Disease not on Dialysis
Patients with a CrCl <15 mL/min at screening were excluded from COMPASS and VOYAGER, and limited data are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3)] , whose efficacy and safety outcomes were similar to those with preserved renal function.
Patients with End-Stage Renal Disease on Dialysis
No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS or VOYAGER. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study [see Clinical Pharmacology (12.2, 12.3)] . It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS.
Pediatric Use
No dosage adjustment is required in patients 1 year of age or older with mild renal impairment (eGFR 50 to ≤ 80 mL/min/1.73 m 2). There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m 2); therefore, avoid the use of XARELTO in these patients.
There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5 thpercentile; therefore, avoid the use of XARELTO in these patients [see Dosage and Administration (2.2)] .
Hepatic Impairment
In a pharmacokinetic study, compared to healthy adult subjects with normal liver function, AUC increases of 127% were observed in adult subjects with moderate hepatic impairment (Child-Pugh B).
The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3)] .
Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.
No clinical data are available in pediatric patients with hepatic impairment.
XARELTO is contraindicated in patients with:
- active pathological bleeding [see Warnings and Precautions (5.2)]
- severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see Adverse Reactions (6.2)]