` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`215859Orig1s000
`
`
`LABELING
`
`
`
`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)
`for thromboprophylaxis in pediatric patients 2 years and older with
`congenital heart disease after the Fontan procedure (1.10)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: (A) PREMATURE DISCONTINUATION OF
`XARELTO INCREASES THE RISK OF THROMBOTIC
`EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
`1
`INDICATIONS AND USAGE
`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: 4909093
`
`
`
`
`
`
`
`
`
`
`
`-----------------------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
`first 21 days followed by 20 mg orally once daily with food for the
`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)
`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.
`
`
`
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`
`
`
`
`
`
`Revised: 12/2021
`
`
`
`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
`5.1
`Increased Risk of Thrombotic Events after
`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
`5.10
`Increased Risk of Thrombosis in Patients with
`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 F brillation
`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: 4909093
`
`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)].
`
` 1
`
`INDICATIONS AND USAGE
`
`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: 4909093
`
`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: 4909093
`
`4
`
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`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: 4909093
`
`5
`
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`
`
`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
`
`Reduction in Risk of Stroke
`in Nonvalvular Atrial
`Fibrillation
`Treatment of DVT and/or
`PE
`
`CrCl ≥15 mL/min‡
`
`15 mg twice daily
`▼ after 21 days, transition to ▼
`20 mg once daily
`
`Food/Timing†
`
`Take with evening meal
`Take with evening meal
`
`Take with food,
`at the same time each day
`
`Avoid Use
`10 mg once daily, after at least 6
`Take with or without food
`months of standard anticoagulant
`treatment
`
`Avoid Use
`
`Take with or without food
`
`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
`
`Avoid Use
`
`2.5 mg twice daily, plus aspirin
`(75-100 mg) once daily
`
`Take with or without food
`
`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)
`
`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§
`
`CrCl <15 mL/min
`CrCl ≥15 mL/min‡
`
`CrCl <15 mL/min
`CrCl ≥15 mL/min‡
`
`CrCl <15 mL/min
`
`No dose
`adjustment needed
`based on CrCl
`
`No dose
`adjustment needed
`based on CrCl
`
`
`- Knee Replacement
`Surgery§
`
`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
`
`†
`‡
`
`§
`
`
`Reference ID: 4909093
`
`6
`
`
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`
`
`2.2 Recommended Dosage in Pediatric Patients
`Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous
`Thromboembolism in Pediatric Patients
`Table 2:
`Recommended Dosage in Pediatric Patients Birth to Less than 18 Years for Treatment of and
`Reduction in Risk of Recurrent VTE*,†
`
`Dosage Form
`
`Body Weight
`
`Oral Suspension Only
`
`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
`
`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
`20 mg
`
`
`20 mg
`
`
`Oral Suspension or
`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:
`
` 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: 4909093
`
`7
`
`
`
`
`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
`Table 3:
`Recommended Dosage for Thromboprophylaxis in Pediatric Patients with Congenital Heart
`Disease
`Dosage Form
`
`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.
`
`Body Weight
`
`Oral Suspension Only
`
`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
`
`1 mg XARELTO = 1 mL Suspension
`Total Daily Dose*
`Dosage
`2 Times a Day†
`
`1.1 mg
`2.2 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
`
`Once a Day†
`
`
`
`
`
`7.5 mg
`10 mg
`
`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: 4909093
`
`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
`97.5th Percentile of Creatinine
`Age
`(mg/dL)
`(µmol/L)
`0.52
`46
`0.46
`41
`0.42
`37
`0.37
`33
`0.34
`30
`0.34
`30
`0.34
`30
`0.36
`32
`
`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.
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`Reference ID: 4909093
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`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.
`
`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.
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`Reference ID: 4909093
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`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 the usual time without
`compensating for the missed dose.
`On the following day, the patient should continue with their regular regimen.
`
`
`
`
`
`2.6 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)].
`
`Administration of 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
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`Reference ID: 4909093
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`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 vitro compatibility 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 vitro compatibility study indicated that XARELTO suspension can be used with PVC,
`polyurethane or silicone NG tubing.
`
`2.7 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 20C to 25C (68F to 77F);
`excursions permitted between 15C to 30C (59F to 86F). 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.
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`Reference ID: 4909093
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`3 DOSAGE FORMS AND STRENGTHS
` 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