`(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
`
`
`Dosage and Administration (2.1)
`08/2021
`
`
`----------------------------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)
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`-----------------------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)
`
`
`--------------------DOSAGE FORMS AND STRENGTHS---------------------­
`Tablets: 2.5 mg, 10 mg, 15 mg, and 20 mg (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%) was bleeding. (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: 08/2021
`
`
`
`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
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`2.2 Switching to and from XARELTO
`
`2.3 Discontinuation for Surgery and other
`
`
`
`Interventions
`
`
`
`2.4 Missed Dose
`
`
`2.5 Administration Options
`
`
`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
`
`
`
` 1
`
` 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
`
`
`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.
`
`
`
`
`
`
`
`
`•
`
`•
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`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
`
`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)
`
`
`Reference ID: 4845827
`
`

`

`
`
`
`
`
` 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
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`
`
`
`
`
`Reference ID: 4845827
`
`
`
` 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 (2.2, 2.3), 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 patients with
`
`
` nonvalvular atrial fibrillation.
`
`
`
`
`
`Reference ID: 4845827
`
`
`
` 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 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 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 patients with coronary artery
`
`
`
` disease.
`
`
`
`
`Reference ID: 4845827
`
`
`
` 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 patients with PAD, including patients who have recently
`
`
`
` undergone a lower extremity revascularization procedure due to symptomatic PAD.
`
`
`Reference ID: 4845827
`
`
`
` 5
`
`

`

`
`
` 2 DOSAGE AND ADMINISTRATION
` 2.1 Recommended Dosage
`
`
` Table 1:
`
`
`
`
` Recommended Dosage
` Indication
` Renal
`
`
` Considerations*
`
`
`
`
` CrCl >50 mL/min
`
` CrCl ≤50 mL/min‡
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
` Dosage
`
`
`
`
` 20 mg once daily
`
`
`
` 15 mg once daily
`
`
`
` Food/Timing†
`
`
`
` Take with evening meal
`
`
` Take with evening meal
`
`
`
`
`
` 15 mg twice daily
`
`
` ▼ after 21 days, transition to ▼
`
`
`
`
` 20 mg once daily
`
`
`
`
`
`
`
`
`
`
`
` 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
`
` Take with or without food
`
`
`
`
`
`
`
`
`
` No dose
`
`
`
` adjustment needed
` based on CrCl
`
`
`
`
`
`
`
`
` 2.5 mg twice daily, plus aspirin
`
`
` (75-100 mg) once daily
`
`
` 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 (2.3)
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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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` ‡
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`
`§
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`
`Reference ID: 4845827
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`
`
` 6
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`

`

`
` 2.2 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 to avoid periods of inadequate anticoagulation.
`
`
`
`Switching from XARELTO to Warfarin - 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.
`
`
`
`Switching from XARELTO to Anticoagulants other than Warfarin - For patients currently taking
`
`
`
`XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and
`
`
`
`
`give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO
`
`
`dose would have been taken [see Drug Interactions (7.4)].
`
`
`
`Switching from Anticoagulants other than Warfarin to XARELTO - For patients currently receiving
`
`
`
`
`
`an anticoagulant other than warfarin, start XARELTO 0 to 2 hours prior to the next scheduled
`
`
`evening 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.
`
`
`
`
`2.3 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.
`
`
`
`2.4 Missed Dose
`
`
`
`
`
`• 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.
`
`Reference ID: 4845827
`
`
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` 7
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`

`

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`
`
`
`
`
`
` • 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.
`
`
` 2.5 Administration Options
`
`
`
` For 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 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)].
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`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
` 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
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`
`
` • 10 mg tablets: Round, light red, biconvex and film-coated with a triangle pointing down above
`
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` a “10” marked on one side and “Xa” on the other side
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` • 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
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`
`
` • 20 mg tablets: Triangle-shaped, dark red, and film-coated with a triangle pointing down above
`
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` a “20” marked on one side and “Xa” on the other side
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`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
`
`
` 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)]
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`
`
`
`
`
` 8
`
`Reference ID: 4845827
`
`

`

`
`
`
` 5 WARNINGS AND PRECAUTIONS
` Increased Risk of Thrombotic Events after Premature Discontinuation
`
`
` 5.1
`
`
`
`
`
` Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of
`
` adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of
`
` stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial
`
`
`
`
`
`
` fibrillation patients. If 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 (2.2, 2.3) and Clinical Studies (14.1)].
`
`
`
` 5.2 Risk of Bleeding
`
`
`
`
`
`
` XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding
`
` whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic
`
`
`
`
`
`
` events should be weighed against the risk of bleeding.
`
`
`
`
`
` Promptly evaluate any signs or symptoms of blood loss and consider the need for blood
`
` replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The
`
`
` terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
`
`
`
`
`
`
`
`
` Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include
`
` aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic
`
`
`
`
`
`therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.4)], selective
`
`
`serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.
`
`
`Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases
`
`
`rivaroxaban exposure and may increase bleeding risk [see Drug Interactions (7.2)].
`
`
`Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding
`
`
`
`Acutely ill medical patients with the following conditions are at increased risk of bleeding with
`
`
`the use of XARELTO for primary VTE prophylaxis: history of bronchiectasis, pulmonary
`cavitation, or pulmonary hemorrhage, active cancer (i.e. undergoing acute, in-hospital cancer
`treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding
`
`
`
`
`in the three months prior to treatment, or dual antiplatelet therapy. XARELTO is not for use for
`
`
`
`primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.
`
`
`Reversal of Anticoagulant Effect
`
`
`
`An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma
`
`
`
`protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology (12.3)]. Protamine
`
`
`
`sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of
`
`
`
`procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated
`
`
`
`
`prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been
`
`
`
` 9
`
`Reference ID: 4845827
`
`

`

`
` evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of
`
`
`
`
`
`
`
` rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not
`
` recommended.
`
` 5.3 Spinal/Epidural Anesthesia or Puncture
`
`
`
` When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients
` treated with anticoagulant agents for prevention of thromboembolic complications are at risk of
`
`
`
`
` developing an epidural or spinal hematoma which can result in long-term or permanent paralysis
`
` [see Boxed Warning].
`
` To reduce the potential risk of bleeding associated with the concurrent use of XARELTO and
`
`
`
` epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
` XARELTO [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or
`
`
`
`
`
`
` lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however,
` the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
`
`
`
`
`
`
`
`
`
`
`
`
`
` An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives
`
` have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients
` aged 60 to 76 years), after the last administration of XARELTO [see Clinical Pharmacology
`
`
`
` (12.3)]. The next XARELTO dose should not be administered earlier than 6 hours after the
`
`
`
`
`
`
` removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for
`
`
`
`
`
`
` 24 hours.
`
`
`
`
`
` Should the physician decide to administer anticoagulation in the context of epidural or spinal
`
` anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of
`
` neurological impairment, such as midline back pain, sensory and motor deficits (numbness,
`
`
` tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to
`
`
`
`
` immediately report if they experience any of the above signs or symptoms. If signs or symptoms
`
` of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration
`
` for spinal cord decompression even though such treatment may not prevent or reverse neurological
`
`
`
` sequelae.
`
`
`
`
`
` 5.4 Use in Patients with Renal Impairment
` Nonvalvular Atrial Fibrillation
`
`Periodically assess renal function as clinically indicated (i.e., more frequently in situations in
`
`
`
`which renal function may decline) and adjust therapy accordingly [see Dosage and Administration
`
`
`
`
`
`(2.1)]. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute
`
`
`
`
`renal failure while on XARELTO [see Use in Specific Populations (8.6)].
`
`
`
`
`
`Reference ID: 4845827
`
`
`
` 10
`
`

`

`
` Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction
`
`
`in the Risk of Recurrence of DVT and of PE
`
`
`
`In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are
`
`
`
`
`
`
`
`increased compared to patients with normal renal function. There are limited clinical data in
`
`
`
`
`
`
`patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs
`
`
`
`
`or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl
`
`
`<15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these
`
`
`
`
`
`patients.
`
`
`Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use
`
`
`in Specific Populations (8.6)].
`
`
`Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
`
`In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are
`
`
`
`
`
`
`
`
`increased compared to patients with normal renal function. There are limited clinical data in
`
`
`
`
`
`
`patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs
`
`
`
`
`
`or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl
`
`
`
`<15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these
`
`
`
`
`patients.
`
`
`Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use
`in Specific Populations (8.6)].
`
`
`Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for
`
`Thromboembolic Complications Not at High Risk of Bleeding
`
`
`In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are
`
`
`
`
`
`
`
` increased compared to patients with normal renal function. There are limited clinical data in
`
`
`
`
`
`
` patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs
`
`
`
`
`
` or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl
`
`
`
` <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these
`
`
`
`
` patients.
`
`
` Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use
`
`
` in Specific Populations (8.6)].
`
`
`
`
`
`
` 5.5 Use in Patients with Hepatic Impairment
`
` No clinical data are available for patients with severe hepatic impairment.
`
`
`
`
`
`
`
` Avoid 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 since drug exposure
`
`
` and bleeding risk may be increased [see Use in Specific Populations (8.7)].
`
`
`
` 11
`
`Reference ID: 4845827
`
`

`

`
` 5.6 Use with P-gp and Strong CYP3A Inhibitors or Inducers
`
`
`
` Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors
`
` [see Drug Interactions (7.2)].
`
`
`
`