`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`XARELTO® safely and effectively. See full prescribing information for
`
`
`
`
`
`XARELTO.
`
`XARELTO (rivaroxaban) tablets, for oral use
`
`XARELTO (rivaroxaban) for oral suspension
`
`
`Initial U.S. Approval: 2011
`
`
`
`WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO
`
`
`
`
`
`
`
`
`
`INCREASES THE RISK OF THROMBOTIC EVENTS,
`
`(B) SPINAL/EPIDURAL HEMATOMA
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`(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. To reduce this risk,
`
`
`
`
`consider coverage with another anticoagulant if XARELTO is
`
`
`
`
`
`discontinued for a reason other than pathological bleeding or completion
`
`
`
`
`
`of a course of therapy. (2.2, 2.3, 5.1, 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. (5.2, 5.3, 6.2)
`
`
`
`
`Monitor patients frequently for signs and symptoms of neurological
`
`impairment and if observed, treat urgently. Consider the benefits and
`
`
`risks before neuraxial intervention in patients who are or who need to be
`
`
`
`anticoagulated. (5.3)
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`
`
`Indications and Usage (1.7, 1.8)
`08/2021
`
`
`
`Indications and Usage (1.9, 1.10)
`12/2021
`
`
`Dosage and Administration (2.1)
`08/2021
`
`
`
`Dosage and Administration (2.2, 2.3, 2.5, 2.6, 2.7)
`12/2021
`
`
`
`
`
`Warnings and Precautions (5.4, 5.5)
`12/2021
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`
`XARELTO is a factor Xa inhibitor indicated:
`
`
`
`
`to reduce risk of stroke and systemic embolism in nonvalvular atrial
`
`
`
`
`
`
`•
`fibrillation (1.1)
`
`
`for treatment of deep vein thrombosis (DVT) (1.2)
`
`
`
`for treatment of pulmonary embolism (PE) (1.3)
`
`
`
`for reduction in the risk of recurrence of DVT or PE (1.4)
`
`
`
`for the prophylaxis of DVT, which may lead to PE in patients
`
`
`
`
`
`undergoing knee or hip replacement surgery (1.5)
`
`
`
`
`
`for prophylaxis of venous thromboembolism (VTE) in acutely ill
`
`
`
`
`medical patients (1.6)
`
`
`
`to reduce the risk of major cardiovascular events in patients with
`
`
`
`
`coronary artery disease (CAD) (1.7)
`
`
`to reduce the risk of major thrombotic vascular events in patients with
`
`
`
`
`
`peripheral artery disease (PAD), including patients after recent lower
`
`
`extremity revascularization due to symptomatic PAD (1.8)
`
`for treatment of VTE and reduction in the risk of recurrent VTE in
`
`
`
`
`
`pediatric patients from birth to less than 18 years (1.9)
`
`
`
`
`
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`for thromboprophylaxis in pediatric patients 2 years and older with
`
`
`
`
`congenital heart disease after the Fontan procedure (1.10)
`
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`•
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`•
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`•
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`•
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`•
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`•
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`•
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`•
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`
`•
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`WARNING: (A) PREMATURE DISCONTINUATION OF
`
`
`XARELTO INCREASES THE RISK OF THROMBOTIC
`
`
`EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`1.1 Reduction of Risk of Stroke and Systemic
`
`
`
`Embolism in Nonvalvular Atrial Fibrillation
`
`
`1.2
`Treatment of Deep Vein Thrombosis
`
`
`1.3
`Treatment of Pulmonary Embolism
`
`
`
`1.4 Reduction in the Risk of Recurrence of Deep
`
`
`Vein Thrombosis and/or Pulmonary Embolism
`
`Reference ID: 4945528
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`Nonvalvular Atrial Fibrillation: 15 or 20 mg, once daily with food (2.1)
`
`
`
`
`
`•
`Treatment of DVT and/or PE: 15 mg orally twice daily with food for the
`
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`
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`
`
`•
`first 21 days followed by 20 mg orally once daily with food for the
`
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`
`
`
`
`
`
`remaining treatment (2.1)
`
`
`Reduction in the Risk of Recurrence of DVT and/or PE in patients at
`
`
`
`
`continued risk for DVT and/or PE: 10 mg once daily with or without
`
`
`
`food, after at least 6 months of standard anticoagulant treatment (2.1)
`
`
`
`
`
`
`
`Prophylaxis of DVT Following Hip or Knee Replacement Surgery:
`
`
`
`
`
`10 mg orally once daily with or without food (2.1)
`
`
`
`
`
`
`
`Prophylaxis of VTE in Acutely Ill Medical Patients at Risk for
`
`
`Thromboembolic Complications Not at High Risk of Bleeding: 10 mg
`
`
`
`
`once daily, with or without food, in hospital and after hospital discharge
`
`
`
`
`
`for a total recommended duration of 31 to 39 days (2.1)
`
`
`
`
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`CAD or PAD: 2.5 mg orally twice daily with or without food, in
`
`
`
`
`
`
`combination with aspirin (75-100 mg) once daily (2.1)
`
`
`
`Pediatric Patients: See dosing recommendations in the Full Prescribing
`
`
`
`
`Information (2.2)
`
`--------------------DOSAGE FORMS AND STRENGTHS---------------------­
`Tablets: 2.5 mg, 10 mg, 15 mg, and 20 mg (3)
`
`
`
`
`
`
`•
`For oral suspension: 1 mg/mL once reconstituted (3)
`
`
`
`•
`-------------------------------CONTRAINDICATIONS-----------------------------­
`Active pathological bleeding (4)
`
`
`
`•
`Severe hypersensitivity reaction to XARELTO (4)
`
`
`
`
`•
`---------------------------WARNINGS AND PRECAUTIONS------------------­
`Risk of bleeding: XARELTO can cause serious and fatal bleeding. An
`
`
`
`
`
`•
`agent to reverse the activity of rivaroxaban is available. (5.2)
`
`
`
`
`
`
`Pregnancy-related hemorrhage: Use XARELTO with caution in
`
`
`
`pregnant women due to the potential for obstetric hemorrhage and/or
`
`
`
`
`emergent delivery. (5.7, 8.1)
`
`
`Prosthetic heart valves: XARELTO use not recommended. (5.8)
`
`
`
`
`
`Increased Risk of Thrombosis in Patients with Triple Positive
`
`
`
`Antiphospholipid Syndrome: XARELTO use not recommended. (5.10)
`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS-----------------------------­
`
`The most common adverse reaction (>5%) in adult patients was
`
`
`
`
`
`•
`bleeding. (6.1)
`
`
`The most common adverse reactions (>10%) in pediatric patients were
`
`
`
`
`bleeding, cough, vomiting, and gastroenteritis. (6.1)
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or
`
`
`
`
`www.fda.gov/medwatch.
`---------------------------------DRUG INTERACTIONS---------------------------­
`
`
`Avoid combined P-gp and strong CYP3A inhibitors and inducers (7.2,
`
`
`
`
`
`•
`7.3)
`
`Anticoagulants: Avoid concomitant use (7.4)
`
`
`
`
`•
`-----------------------USE IN SPECIFIC POPULATIONS----------------------­
`
`
`Renal impairment: Avoid or adjust dose (8.6)
`
`
`
`
`
`•
`Hepatic impairment: Avoid use in Child-Pugh B and C hepatic
`
`
`
`
`
`
`•
`impairment or hepatic disease associated with coagulopathy (8.7)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide.
`
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`
`Revised: 01/2022
`
`
`
`
`
`
`1.5 Prophylaxis of Deep Vein Thrombosis Following
`
`
`
`Hip or Knee Replacement Surgery
`
`
`1.6 Prophylaxis of Venous Thromboembolism in
`
`Acutely Ill Medical Patients at Risk for
`
`
`Thromboembolic Complications Not at High Risk
`
`
`of Bleeding
`
`1.7 Reduction of Risk of Major Cardiovascular Events
`
`
`in Patients with Coronary Artery Disease (CAD)
`
`
`1.8 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
`
`
`
`
` 1
`
`

`

`
`
`
`1.9
`
`Treatment of Venous Thromboembolism and
`Reduction in Risk of Recurrent Venous
`
`
`
`Thromboembolism in Pediatric Patients
`
`
`1.10 Thromboprophylaxis in Pediatric Patients with
`
`Congenital Heart Disease after the Fontan
`
`Procedure
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dosage in Adults
`
`
`2.2 Recommended Dosage in Pediatric Patients
`
`
`
`2.3 Switching to and from XARELTO
`
`
`2.4 Discontinuation for Surgery and other
`
`
`
`Interventions
`
`
`2.5 Missed Dose
`
`
`
`2.6 Administration Options
`
`2.7 Preparation Instructions for Pharmacy of
`
`
`
`XARELTO for Oral Suspension
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Increased Risk of Thrombotic Events after
`5.1
`
`
`
`
`Premature Discontinuation
`
`
`5.2 Risk of Bleeding
`
`
`5.3 Spinal/Epidural Anesthesia or Puncture
`
`
`
`5.4 Use in Patients with Renal Impairment
`
`
`
`5.5 Use in Patients with Hepatic Impairment
`
`
`5.6 Use with P-gp and Strong CYP3A Inhibitors or
`
`
`
`
`Inducers
`
`
`5.7 Risk of Pregnancy-Related Hemorrhage
`
`
`5.8 Patients with Prosthetic Heart Valves
`
`
`5.9 Acute PE in Hemodynamically Unstable Patients
`
`
`or Patients Who Require Thrombolysis or
`
`
`Pulmonary Embolectomy
`
`Increased Risk of Thrombosis in Patients with
`5.10
`
`
`
`
`Triple Positive Antiphospholipid Syndrome
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 General Inhibition and Induction Properties
`
`
` 7.2 Drugs that Inhibit Cytochrome P450 3A Enzymes
`
`
`
` and Drug Transport Systems
`
`
`7.3 Drugs that Induce Cytochrome P450 3A
`
`Enzymes and Drug Transport Systems
`
`
`7.4 Anticoagulants and NSAIDs/Aspirin
`
`
`
`
`
`
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`8.1 Pregnancy
`
`
`
`8.2
`Lactation
`
`
`
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`12.6 QT/QTc Prolongation
`
`
`13 NON-CLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`
`
`Fertility
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Stroke Prevention in Nonvalvular Atrial Fibrillation
`
`
`
`
`14.2 Treatment of Deep Vein Thrombosis (DVT)
`
`
`
`and/or Pulmonary Embolism (PE)
`
`
`
`14.3 Reduction in the Risk of Recurrence of DVT
`
`
`
`and/or PE
`
`14.4 Prophylaxis of Deep Vein Thrombosis Following
`
`Hip or Knee Replacement Surgery
`
`
`
`14.5 Prophylaxis of Venous Thromboembolism in
`
`
`Acutely Ill Medical Patients at Risk for
`
`
`
`
`Thromboembolic Complications Not at High Risk
`
`
`of Bleeding
`
`
`14.6 Reduction of Risk of Major Cardiovascular Events
`
`
`
`
`in Patients with CAD
`
`
`14.7 Reduction of Risk of Major Thrombotic Vascular
`
`Events in Patients with PAD, Including Patients
`
`after Lower Extremity Revascularization due to
`
`
`
`
`Symptomatic PAD
`
`
`14.8 Treatment of Venous Thromboembolism and
`
`
`Reduction in Risk of Recurrent Venous
`
`
`
`Thromboembolism in Pediatric Patients
`
`
` 14.9 Thromboprophylaxis in Pediatric Patients with
`
`Congenital Heart Disease after the Fontan
`
`
`Procedure
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`
`
`Reference ID: 4945528
`
`
`
` 2
`
`

`

`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
` WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE
`
` RISK OF THROMBOTIC EVENTS,
`
` (B) SPINAL/EPIDURAL HEMATOMA
`
`
`
`
`
`
`
` 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)].
`
`
`
` INDICATIONS AND USAGE
` 1
`
`
`
`
` 1.1 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4945528
`
`
`
` 3
`
`

`

`
`
`
`
`
` 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)].
`
`
`
` 1.2 Treatment of Deep Vein Thrombosis
`
`
`
`
` XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
`
`
`
` 1.3 Treatment of Pulmonary Embolism
`
`
`
` XARELTO is indicated for the treatment of pulmonary embolism (PE).
`
`
`
`
`
` 1.4 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1.5 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.
`
`
`
`
`
`
`
`
`
`
`
`
` 1.6 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1.7 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.
`
`
`
`
`
`
`
`Reference ID: 4945528
`
`
`
` 4
`
`

`

`
`
`
`
` 1.8 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.
`
`
`
`
`
`
`
`
`
` 1.9 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.
`
`
`
`
`
`
`
`
`
`
`
`1.10 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.
`
`
`
`Reference ID: 4945528
`
`
`
` 5
`
`

`

`
`
`Reduction in Risk of Stroke
`
` in Nonvalvular Atrial
`Fibrillation
`
` Treatment of DVT and/or
`PE
`
`
`
`
`
`
`
`
` CrCl ≥15 mL/min‡
`
`
`
`
`
`
`
`
` CrCl <15 mL/min
`
`
` CrCl ≥15 mL/min‡
`
`
`
`
`
`
`
`
`
` 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
` Prophylaxis of DVT Following:
`
`
`
` - Hip Replacement
`
` CrCl ≥15 mL/min‡
`
`Surgery§
`
`
`
`
`
`
`
`
`
`
` - Knee Replacement
`
`Surgery§
`
`
`
`
`
`
`
`
`
` CrCl <15 mL/min
`
`
` CrCl ≥15 mL/min‡
`
`
`
`
`
`
` CrCl <15 mL/min
`
`
` CrCl ≥15 mL/min‡
`
`
`
`
`
` CrCl <15 mL/min
`
`
`
`
`
`
`
` Food/Timing†
`
`
`
`
` Take with evening meal
`
`
` Take with evening meal
`
` Take with food,
`
` at the same time each day
`
`
`
`
`
`
`
`
`
`
`
`
` 15 mg twice daily
`
` ▼ after 21 days, transition to ▼
`
`
` 20 mg once daily
`
`
`
`
`
`
`
`
`
` Avoid Use
`
` 10 mg once daily, after at least 6
`
`
`
` Take with or without food
`
` months of standard anticoagulant
`
` treatment
`
`
`
` Avoid Use
`
` 10 mg once daily for 35 days, 6­
`
`
`10 hours after surgery once
` hemostasis has been established
`
` Avoid Use
`
` 10 mg once daily for 12 days, 6­
` Take with or without food
`
`
`
`
`10 hours after surgery once
`
`
` hemostasis has been established
`
` Avoid Use
`
`
` 10 mg once daily, in hospital and
` Take with or without food
`
`
`
`after hospital discharge, for a total
`
`recommended duration of 31 to
`
`
` 39 days
`
`
`
` Take with or without food
`
`
`
`
`
`
`
` Avoid Use
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`
`
` 2.1 Recommended Dosage in Adults
` Table 1:
`
` Recommended Dosage in Adults
`
`
`
`
` Indication
`
` Renal
` Considerations*
`
`
`
`
` CrCl >50 mL/min
`
` CrCl ≤50 mL/min‡
`
`
`
`
`
`
` Dosage
`
`
`
`
` 20 mg once daily
`
`
` 15 mg once daily
`
`
`
` Prophylaxis of VTE in
`
`
` Acutely Ill Medical Patients
` at Risk for
`
` Thromboembolic
`
`
` Complications Not at High
` Risk of Bleeding
`
`
`
` Reduction of Risk of Major
`
` Cardiovascular Events (CV
`
` Death, MI, and Stroke) in
`
`
`
`
` CAD
` 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
`
`
`
`
`
` Take with or without food
`
`
`
` No dose
`
` adjustment needed
`
` based on CrCl
`
`
`
`
`
`
` Take with or without food
`
`
`
` 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.
` * Calculate CrCl based on actual weight. [See Warnings and Precautions (5.4) and Use in Specific Populations
`
` (8.6)]
`
`See Clinical Pharmacology (12.3)
`
`
`
`
` Patients with CrCl <30 mL/min were not studied, 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 Use in Specific Populations (8.6)]
`
`
`
`
`
`
`
` See Dosage and Administration (2.4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`†
`
`
` ‡
`
`§
`
`
`
`
`
`
`
`Reference ID: 4945528
`
`
`
` 6
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.2 Recommended Dosage in Pediatric Patients
` Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous
`
`
`
`Thromboembolism in Pediatric Patients
`
`
`
` Recommended Dosage in Pediatric Patients Birth to Less than 18 Years for Treatment of and
`
`
` Table 2:
`
`Reduction in Risk of Recurrent VTE*,†
`
`
`
`
` 1 mg XARELTO = 1 mL Suspension
`
` Total Daily
`
`
` Dosage
`
` Dose‡
` Once a Day§ 2 Times a Day§ 3 Times a Day§
`
`
`
`
`
`
`
`
` 0.8 mg
`
`
` 2.4 mg
`
`
`
`
` 0.9 mg
`
`
` 2.7 mg
`
`
`
`
` 1.4 mg
`
` 4.2 mg
`
`
`
`
`
` 1.6 mg
`
` 4.8 mg
`
`
`
`
`
` 1.8 mg
`
` 5.4 mg
`
`
`
`
`
` 2.4 mg
`
` 7.2 mg
`
`
`
`
`
` 2.8 mg
`
` 8.4 mg
`
`
`
`
`
` 3 mg
`
` 9 mg
`
`
`
`
` 5 mg
`
` 10 mg
`
`
`
`
`
` 15 mg
`
`
` 15 mg
`
` Oral Suspension or
`
`
`
`
` 20 mg
`
`
` 20 mg
`
` Tablets
`
`
`*
` Initiate XARELTO treatment following 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, and weigh ≥2.6 kg at the time of dosing.
`‡ All doses should be taken with feeding or with food since exposures match that of 20 mg daily dose in adults.
`
`
`
`
`
`
`
`
`
`
`
`
`§ Once a day: approximately 24 hours apart; 2 times a day: approximately 12 hours apart; 3 times a day: approximately 8 hours apart
`
`
`
`
`
`
`
`
`
`
`
`
` 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:
`
`
`
`
`
`
`
` Dosage Form
`
`
`
` Oral Suspension Only
`
`
`
`
`
`
`
` Body Weight
`
`
`
`
`
`
`
`
` 2.6 kg to 2.9 kg
`
`
`
`
`
` 3 kg to 3.9 kg
`
` 4 kg to 4.9 kg
`
`
`
`
`
`
` 5 kg to 6.9 kg
`
`
`
`
` 7 kg to 7.9 kg
`
`
`
`
`
` 8 kg to 8.9 kg
`
`
`
`
`
` 9 kg to 9.9 kg
`
`
`
`
`
` 10 kg to 11.9 kg
`
`
`
`
`
` 12 kg to 29.9 kg
`
`
`
`
`
` 30 kg to 49.9 kg
`
`
`
`
`
` ≥50 kg
`
`
`
`
`
`
`
`
`
`
` • 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.
`
`
`Reference ID: 4945528
`
`
`
` 7
`
`

`

` Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the
`
` Fontan Procedure
` Recommended Dosage for Thromboprophylaxis in Pediatric Patients with Congenital Heart
`
`
` Table 3:
`
` Disease
`
` Dosage Form
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1 mg XARELTO = 1 mL Suspension
`
`Total Daily Dose*
`
`
`
`
` Dosage
` 2 Times a Day†
`
`
`
`
`
` 2.2 mg
`
`
` 1.1 mg
`
`
` 1.6 mg
`
`
` 3.2 mg
`
` 1.7 mg
`
`
` 3.4 mg
`
` 2 mg
` 4 mg
`
`
`
`
` 2.5 mg
`
` 5 mg
`
`
`
`
` 7.5 mg
`
`
`
`
` 10 mg
`
`
`
` Body Weight
`
`
`
`
`
`
`
` 7 kg to 7.9 kg
`
`
`
`
` 8 kg to 9.9 kg
` 10 kg to 11.9 kg
`
`
`
`
`
`
` 12 kg to 19.9 kg
`
`
`
`
`
` 20 kg to 29.9 kg
`
`
`
`
`
` 30 kg to 49.9 kg
`
`
`
`
`
` ≥50 kg
`
`
`
`
` Oral Suspension Only
`
`
`
`
`
`
`
`
`
` Once a Day†
`
`
`
`
`
`
`
` 7.5 mg
`
`
` 10 mg
`
`
`
`
`
` Oral Suspension or
`
` Tablets
`
`
` * All doses can be taken with or without food since exposures match that of 10 mg daily dose in adults.
`
`
`
`
`
`
`
`
`
`† Once a day: approximately 24 hours apart; 2 times a day: approximately 12 hours apart.
`
`
`
`
`
`
`
`
`
`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)].
`
`
`Reference ID: 4945528
`
`
`
` 8
`
`

`

`
` 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 m2): No dose adjustment is
`
`
`
` required.
`
` • Moderate or severe renal impairment (eGFR: <50 mL/min/1.73 m2): 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 x 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 m2) = 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 97.5th percentile, as no clinical data are
`
`
`
`available.
`
`
`
`
` Table 4:
`
`
`
`
`
` Reference Values of Serum Creatinine in Pediatric Patients <1 Year of Age
`
`
` 97.5th Percentile of Creatinine
`
`
`
`
` Age
` 97.5th Percentile of Creatinine
` (µmol/L)
`
`
` (mg/dL)
`
` 46
`
` 0.52
`
` 41
`
` 0.46
`
` 37
`
` 0.42
`
` 33
`
` 0.37
`
` 30
`
` 0.34
`
` 30
`
` 0.34
`
` 30
`
` 0.34
`
` 32
`
` 0.36
`
`
`
`
`
` Week 2
`
` Week 3
`
` Week 4
`
` Month 2
`
` Month 3
`
` Month 4-6
`
` Month 7-9
` Month 10-12
`
` 2.3 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.
`
`Reference ID: 4945528
`
`
`
` 9
`
`

`

`
` 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
`
` the other anticoagulant. For
`
`
`
` warfarin oral anticoagulant) and omit administration of
`
` unfractionated heparin being administered by continuous infusion, stop the infusion and start
`
` XARELTO at the same time.
`
`
` 2.4 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.
`
`Reference ID: 4945528
`
`
`
` 10
`
`

`

`
`
`
`
` 2.5 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 t