`These highlights do not include all the information needed to use
`XARELTO® (rivaroxaban) 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.
`
`
`(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 (1.6)
`10/2018
`Dosage and Administration (2.1, 2.4)
`10/2018
`Warnings and Precautions (5.2)
`07/2018
`----------------------------INDICATIONS AND USAGE---------------------------
`XARELTO is a factor Xa inhibitor indicated:
`to reduce the risk of stroke and systemic embolism in patients with
`
`nonvalvular atrial fibrillation (1.1)
`for the treatment of deep vein thrombosis (DVT) (1.2)
`for the treatment of pulmonary embolism (PE) (1.3)
`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 (1.4)
`for the prophylaxis of DVT, which may lead to PE in patients
`undergoing knee or hip replacement surgery (1.5)
`in combination with aspirin, to reduce the risk of major cardiovascular
`events (cardiovascular (CV) death, myocardial infarction (MI) and
`stroke) in patients with chronic coronary artery disease (CAD) or
`peripheral artery disease (PAD) (1.6)
`
`
`
`
`
`
`1
`
`
`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 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 Reduction of Risk of Major Cardiovascular Events
`in Patients with Chronic Coronary Artery Disease
`(CAD) or Peripheral Artery Disease (PAD)
`
`Reference ID: 4376293
`
`
`
`
`
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`Nonvalvular Atrial Fibrillation:
`
`o For patients with CrCl >50 mL/min: 20 mg orally, once daily with
`the evening meal (2.1)
`o For patients with CrCl ≤50 mL/min: 15 mg orally, once daily with
`the evening meal (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)
`Reduction of Risk of Major Cardiovascular Events (CV Death, MI, and
`Stroke) in chronic 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.
`
`Promptly evaluate signs and symptoms of blood loss. An agent to
`reverse the anti-factor Xa 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. Promptly evaluate signs and symptoms of blood loss.
`(5.7)
`Prosthetic heart valves: XARELTO use not recommended (5.8)
`
`------------------------------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----------------------------
`Combined P-gp and strong CYP3A inhibitors and inducers: Avoid
`
`concomitant use (7.2, 7.3)
`Anticoagulants: Avoid concomitant use (7.4)
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`Renal impairment: Avoid or adjust dose based on CrCl and
`
`Indication (8.6)
`Hepatic impairment: Avoid use in patients with Child-Pugh B and C
`hepatic impairment or with any degree of hepatic disease associated with
`coagulopathy (8.7)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`
`
`
`
`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
`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
`
`Revised: 1/2019
`
`1
`
`
`
`
`
`5.8 Patients with Prosthetic Heart Valves
`5.9 Acute PE in Hemodynamically Unstable Patients
`or Patients Who Require Thrombolysis or
`Pulmonary Embolectomy
`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 Reduction of Risk of Major Cardiovascular Events
`in Patients with Chronic CAD or 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: 4376293
`
`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: 4376293
`
`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 Reduction of Risk of Major Cardiovascular Events in Patients with Chronic
`Coronary Artery Disease (CAD) or Peripheral Artery Disease (PAD)
`XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular
`events (cardiovascular (CV) death, myocardial infarction (MI) and stroke) in patients with
`chronic coronary artery disease (CAD) or peripheral artery disease (PAD).
`
`Reference ID: 4376293
`
`4
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`Table 1:
`Recommended Dosage
`Indication
`Renal
`Considerations*
`CrCl >50 mL/min
`
`CrCl ≤50 mL/min
`
`CrCl ≥30 mL/min
`
`Reduction in Risk of
`Stroke in
`Nonvalvular Atrial
`Fibrillation
`Treatment of DVT
`and/or PE
`
`Dosage
`
`20 mg once daily
`
`15 mg once daily
`
`15 mg twice daily
`▼ after 21 days, transition to ▼
`20 mg once daily
`
`CrCl <30 mL/min
`
`Avoid Use
`
`Food/Timing†
`
`Take with evening meal
`
`Take with evening meal
`
`Take with food,
`at the same time each day
`
`Reduction in the Risk
`of Recurrence of
`DVT and/or PE in
`patients at continued
`risk for DVT and/or
`PE
`Prophylaxis of DVT Following:
`
`
`CrCl ≥30 mL/min
`
`CrCl <30 mL/min
`
`CrCl ≥30 mL/min
`
`CrCl <30 mL/min
`
`CrCl ≥30 mL/min
`
`CrCl <30 mL/min
`
`- Hip
`Replacement
`Surgery‡
`
`- Knee
`Replacement
`Surgery‡
`
`10 mg once daily, after at least 6
`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, 6-10
`hours after surgery once hemostasis has
`been established
`
`Avoid Use
`
`Take with or without food
`
`Take with or without food
`
`2.5 mg twice daily, plus aspirin (75-
`100 mg) once daily
`
`Take with or without food
`
`No dose adjustment
`needed based on CrCl
`
`
`See Use in Specific Populations (8.6)
`See Clinical Pharmacology (12.3)
`See Dosage and Administration (2.3)
`
`Reduction of Risk of
`Major
`Cardiovascular
`Events (CV Death,
`MI, and Stroke) in
`Chronic CAD or
`PAD
`*
`†
`‡
`
`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.
`
`Reference ID: 4376293
`
`5
`
`
`
`
`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.
` 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.
`
`Reference ID: 4376293
`
`6
`
`
`
`
`2.5 Administration Options
`For patients who are unable to swallow whole tablets, XARELTO tablets 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 [see Clinical Pharmacology (12.3)].
`
`Administration via nasogastric (NG) tube or gastric feeding tube: After confirming gastric
`placement of the tube, XARELTO tablets 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 [see Clinical Pharmacology (12.3)].
`
`Crushed XARELTO tablets 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
` 10 mg tablets: Round, light red, biconvex and film-coated with a triangle pointing down
`above a “10” marked on one side and “Xa” on the other side
` 15 mg tablets: Round, red, biconvex, and film-coated with a triangle pointing down above a
`“15” marked on one side and “Xa” on the other side
` 20 mg tablets: Triangle-shaped, dark red, and film-coated with a triangle pointing down
`above a “20” marked on one side and “Xa” on the other side
`
`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)]
`5 WARNINGS AND PRECAUTIONS
`5.1
`Increased Risk of Thrombotic Events after Premature Discontinuation
`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
`
`7
`
`Reference ID: 4376293
`
`
`
`
`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)].
`
`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 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
`
`8
`
`Reference ID: 4376293
`
`
`
`
`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)].
`
`Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction
`in the Risk of Recurrence of DVT and of PE
`Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in
`rivaroxaban exposure and pharmacodynamic effects in this patient population [see Use in
`Specific Populations (8.6)].
`
`Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
`Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in
`rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely
`and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to
`
`Reference ID: 4376293
`
`9
`
`
`
`
`50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the
`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)].
`
`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)].
`
`Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong
`CYP3A inducers [see Drug Interactions (7.3)].
`
`5.7 Risk of Pregnancy-Related Hemorrhage
`In pregnant women, XARELTO should be used only if the potential benefit justifies the potential
`risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The
`anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing.
`Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin
`and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions (5.2)].
`
`5.8 Patients with Prosthetic Heart Valves
`The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart
`valves. Therefore, use of XARELTO is not recommended in these patients.
`
`5.9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require
`Thrombolysis or Pulmonary Embolectomy
`Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin
`in patients with pulmonary embolism who present with hemodynamic instability or who may
`receive thrombolysis or pulmonary embolectomy.
`
`6 ADVERSE REACTIONS
`The following clinically significant adverse reactions are also discussed in other sections of the
`labeling:
`
`
`
`Increased risk of stroke after discontinuation in nonvalvular atrial fibrillation [see Boxed
`Warning and Warnings and Precautions (5.1)]
` Bleeding risk [see Warnings and Precautions (5.2, 5.4, 5.5, 5.6, 5.7)]
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` Spinal/epidural hematoma [see Boxed Warning and Warnings and Precautions (5.3)]
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`of another drug and may not reflect the rates observed in clinical practice.
`
`During clinical development for the approved indications, 27,694 patients were exposed to
`XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once
`daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of
`stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 6962 patients
`who received XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally
`once daily to treat DVT or PE (EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once
`daily (EINSTEIN Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT
`and/or PE; 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of
`DVT following hip or knee replacement surgery (RECORD 1-3); and 9134 patients who
`received XARELTO 2.5 mg orally twice daily, in combination with aspirin 100 mg once daily,
`for the reduction in risk of major cardiovascular events in patients with chronic CAD or PAD
`(COMPASS).
`
`Hemorrhage
`The most common adverse reactions with XARELTO were bleeding complications [see
`Warnings and Precautions (5.2)].
`
`Nonvalvular Atrial Fibrillation
`In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug
`discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for
`warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both
`treatment groups.
`
`Table 2 shows the number of patients experiencing various types of bleeding events in the
`ROCKET AF trial.
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`Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days
`Table 2:
`Parameter
`XARELTO
`Warfarin
`N=7111
`N=7125
`n (%/year)
`n (%/year)
`395 (3.6)
`386 (3.5)
`55 (0.5)
`84 (0.7)
`
`XARELTO vs. Warfarin
`HR
`(95% CI)
`1.04 (0.90, 1.20)
`0.67 (0.47, 0.93)
`
`Major Bleeding†
`Intracranial
`Hemorrhage (ICH) ‡
`Hemorrhagic
`Stroke§
`26 (0.2)
`19 (0.2)
`Other ICH
`140 (1.2)
`221 (2.0)
`Gastrointestinal (GI)¶
`55 (0.5)
`27 (0.2)
`Fatal Bleeding#
`42 (0.4)
`24 (0.2)
`ICH
`3 (0.0)
`Non-intracranial
`13 (0.1)
`Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major.
`* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple
`subcategories. These events occurred during treatment or within 2 days of stopping treatment.
`† Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood
`cells or whole blood, bleeding at a critical site, or with a fatal outcome.
`Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma.
`‡
`§ Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on
`treatment plus 2 days.
`¶ Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding.
`#
`Fatal bleeding is adjudicated death with the primary cause of death from bleeding.
`
`36 (0.3)
`
`58 (0.5)
`
`0.63 (0.42, 0.96)
`
`0.74 (0.41, 1.34)
`1.61 (1.30, 1.99)
`0.50 (0.31, 0.79)
`0.58 (0.35, 0.96)
`0.23 (0.07, 0.82)
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`Figure 1 shows the risk of major bleeding events across major subgroups.
`
`Figure 1:
`
`Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment
`Plus 2 Days
`
`
`
`Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of
`which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2
`score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor
`do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or
`heterogeneity among groups should not be over-interpreted.
`
`Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE)
`
`EINSTEIN DVT and EINSTEIN PE Studies
`
`In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most
`frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with
`XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%,
`respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and
`204 days for enoxaparin/VKA-treated patients.
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`Reference ID: 4376293
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`Table 3 shows the number of patients experiencing major bleeding events in the pooled analysis
`of the EINSTEIN DVT and EINSTEIN PE studies.
`
`Table 3:
`
`Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies
`Enoxaparin/
`VKA†
`N=4116
`n (%)
`72 (1.7)
`8 (0.2)
`4 (<0.1)
`29 (0.7)
`10 (0.2)
`8 (0.2)
`2 (<0.1)
`4 (<0.1)
`37 (0.9)
`42 (1.0)
`25 (0.6)
`
`XARELTO†
`N=4130
`n (%)
`40 (1.0)
`3 (<0.1)
`2 (<0.1)
`10 (0.2)
`3 (<0.1)
`1 (<0.1)
`3 (<0.1)
`0
`27 (0.7)
`28 (0.7)
`18 (0.4)
`
`Parameter
`Major bleeding event
`Fatal bleeding
`Intracranial
`Non-fatal critical organ bleeding
`Intracranial‡
`Retroperitoneal‡
`Intraocular‡
`Intra-articular‡
`Non-fatal non-critical organ bleeding§
`Decrease in Hb ≥ 2 g/dL
`Transfusion of ≥2 units of whole blood or packed red
`blood cells
`357 (8.7)
`357 (8.6)
`Clinically relevant non-major bleeding
`1153 (28.0)
`1169 (28.3)
`Any bleeding
`* Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a
`patient may have had 2 or more events, the patient is counted only once in a category.
`† Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3
`weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually
`titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)]
`‡ Treatment-emergent major bleeding events with