`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, and
`
`(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, 2.6, 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--------------------------
`03/2014
`Boxed Warning
`
`01/2014
`Dosage and Administration (2.5)
`
`01/2014
`Warnings and Precautions (5.2, 5.6, 5.9)
`
`03/2014
`Warnings and Precautions (5.3)
`
`----------------------------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), pulmonary embolism
`(PE), and for the reduction in the risk of recurrence of DVT and of PE (1.2,
`1.3, 1.4)
` for the prophylaxis of DVT, which may lead to PE in patients undergoing
`knee or hip replacement surgery (1.5)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`Take 15 mg and 20 mg tablets with food; take 10 mg tablets with or
`
`without food (2.1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`
`2
`
`WARNING: (A) PREMATURE DISCONTINUATION OF
`XARELTO INCREASES THE RISK OF THROMBOTIC
`EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
`INDICATIONS AND USAGE
`Reduction of Risk of Stroke and Systemic
`1.1
`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 of Pulmonary Embolism
`1.5
`Prophylaxis of Deep Vein Thrombosis Following
`Hip or Knee Replacement Surgery
`DOSAGE AND ADMINISTRATION
`Important Food Effect Information
`2.1
`2.2
`Switching to and from XARELTO
`2.3
`Nonvalvular Atrial Fibrillation
`2.4
`Treatment of Deep Vein Thrombosis (DVT),
`Pulmonary Embolism (PE), and Reduction in the
`Risk of Recurrence of DVT and of PE
`Prophylaxis of Deep Vein Thrombosis Following
`Hip or Knee Replacement Surgery
`
`2.5
`
`
`
`
`
`
`
`Nonvalvular Atrial Fibrillation:
`o
`For patients with CrCl >50 mL/min: 20 mg orally, once daily with
`the evening meal (2.3)
`o
`For patients with CrCl 15 - 50 mL/min: 15 mg orally, once daily
`with the evening meal (2.3)
`Treatment of DVT, PE, and Reduction in the Risk of Recurrence of
`DVT and of PE: 15 mg orally twice daily with food for the first 21 days
`for the initial treatment of acute DVT or PE. After the initial treatment
`period, 20 mg orally once daily with food for the remaining treatment
`and the long-term reduction in the risk of recurrence of DVT and of PE.
`(2.4)
`Prophylaxis of DVT Following Hip or Knee Replacement Surgery:
`10 mg orally, once daily with or without food (2.5)
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`Tablets: 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. (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 CYP3A4 inhibitors and inducers: Avoid
`
`concomitant use (7.1, 7.2)
`Anticoagulants: Avoid concomitant use (7.3)
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`Nursing mothers: discontinue drug or discontinue nursing (8.3)
`
`Renal impairment: Avoid or adjust dose based on CrCl (8.7)
`
`Hepatic impairment: Avoid use in patients with Child-Pugh B and C
`
`hepatic impairment or with any degree of hepatic disease associated with
`coagulopathy (8.8)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 12/2014
`
`Discontinuation for Surgery and other
`
`2.6
`Interventions
`
`2.7 Missed Dose
`Administration Options
`2.8
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`Increased Risk of Thrombotic Events after
`5.1
`Premature Discontinuation
`5.2
`Risk of Bleeding
`5.3
`Spinal/Epidural Anesthesia or Puncture
`5.4
`Use in Patients with Renal Impairment
`5.5
`Use in Patients with Hepatic Impairment
`5.6
`Use with P-gp and Strong CYP3A4 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
`ADVERSE REACTIONS
`Clinical Trials Experience
`6.1
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`
`6
`
`7
`
`Reference ID: 3676584
`
`1
`
`
`
`7.1
`7.2
`7.3
`7.4
`
`Drugs that Inhibit Cytochrome P450 3A4
`
`Enzymes and Drug Transport Systems
`
`Drugs that Induce Cytochrome P450 3A4
`
`Enzymes and Drug Transport Systems
`
`Anticoagulants and NSAIDs/Aspirin
`
`Drug-Disease Interactions with Drugs that Inhibit
`
`Cytochrome P450 3A4 Enzymes and Drug
`
`Transport Systems
`
`8 USE IN SPECIFIC POPULATIONS
`Pregnancy
`
`8.1
`8.2
`Labor and Delivery
`
`8.3
`Nursing Mothers
`
`8.4
`Pediatric Use
`
`8.5 Geriatric Use
`
`8.6
`Females of Reproductive Potential
`
`8.7
`Renal Impairment
`
`8.8
`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),
`
`Pulmonary Embolism (PE), and Reduction in the
`
`Risk of Recurrence of DVT and of PE
`
`14.3 Prophylaxis of Deep Vein Thrombosis Following
`
`Hip or Knee Replacement Surgery
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1
`Instructions for Patient Use
`
`17.2 Bleeding Risks
`
`17.3
`Invasive or Surgical Procedures
`
`17.4 Concomitant Medication and Herbals
`
`17.5 Pregnancy and Pregnancy-Related Hemorrhage
`
`17.6 Nursing
`
`17.7 Females of Reproductive Potential
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`Reference ID: 3676584
`
`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, 2.6), Warnings and
`Precautions (5.1), and Clinical Studies (14.1)].
`
`B. SPINAL/EPIDURAL HEMATOMA
`Epidural or spinal hematomas have occurred in patients treated with XARELTO who are
`receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may
`result in long-term or permanent paralysis. Consider these risks when scheduling patients
`for spinal procedures. Factors that can increase the risk of developing epidural or spinal
`hematomas in these patients include:
` use of indwelling epidural catheters
` concomitant use of other drugs that affect hemostasis, such as non-steroidal
`anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
` a history of traumatic or repeated epidural or spinal punctures
` a history of spinal deformity or spinal surgery
` optimal timing between the administration of XARELTO and neuraxial procedures is
`not known
`[see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2)].
`
`Monitor patients frequently for signs and symptoms of neurological impairment. If
`neurological compromise is noted, urgent treatment is necessary [see Warnings and
`Precautions (5.3)].
`
`Consider the benefits and risks before neuraxial intervention in patients anticoagulated or
`to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.3)].
`
`INDICATIONS AND USAGE
`1
`1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial
`Fibrillation
`XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with
`nonvalvular atrial fibrillation.
`
`Reference ID: 3676584
`
`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 of
`Pulmonary Embolism
`XARELTO is indicated for the reduction in the risk of recurrence of deep vein thrombosis and of
`pulmonary embolism following initial 6 months treatment for DVT and/or PE.
`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.
`
`2 DOSAGE AND ADMINISTRATION
`
`Indication
`Reduction in Risk of Stroke in
`Nonvalvular Atrial Fibrillation
`(2.3)
`Treatment of DVT (2.4)
`Treatment of PE (2.4)
`
`CrCl >50 mL/min:
`
`Dosage
`20 mg once daily with the evening meal
`
`CrCl 15 to 50 mL/min:
`
`15 mg once daily with the evening meal
`
`15 mg twice daily with food, for first 21 days
`▼after 21 days, transition to ▼
`20 mg once daily with food, for remaining treatment
`
`Reduction in the Risk of
`Recurrence of DVT and of PE (2.4) 20 mg once daily with food
`Hip replacement:
`10 mg once daily for 35 days
`Prophylaxis of DVT Following Hip
`or Knee Replacement Surgery (2.5)
`
`Knee replacement:
`
`10 mg once daily for 12 days
`
`Important Food Effect Information
`2.1
`The 15 mg and 20 mg XARELTO tablets should be taken with food, while the 10 mg tablet can
`be taken with or without food [see Clinical Pharmacology (12.3)].
`
`4
`
`Reference ID: 3676584
`
`
`
`In the nonvalvular atrial fibrillation efficacy study XARELTO was taken with the evening meal.
`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 (7.3)].
`
`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 Nonvalvular Atrial Fibrillation
`For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO
`is 20 mg taken orally once daily with the evening meal. For patients with CrCl 15 to 50 mL/min,
`the recommended dose is 15 mg once daily with the evening meal [see Use in Specific
`Populations (8.7)].
`2.4 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and
`Reduction in the Risk of Recurrence of DVT and of PE
`The recommended dose of XARELTO for the initial treatment of acute DVT and/or PE is 15 mg
`
`taken orally twice daily with food for the first 21 days. After this initial treatment period, the
`recommended dose of XARELTO is 20 mg taken orally once daily with food, at approximately
`the same time each day. The recommended dose of XARELTO for reduction in the risk of
`recurrence of DVT or PE is 20 mg taken orally once daily with food at approximately the same
`time each day [see Clinical Studies (14.2)].
`
`
`Reference ID: 3676584
`
`5
`
`
`
`2.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
`Surgery
`The recommended dose of XARELTO is 10 mg taken orally once daily with or without food.
`The initial dose should be taken 6 to 10 hours after surgery provided that hemostasis has been
`
`established [see Dosage and Administration (2.6)].
`
` For patients undergoing hip replacement surgery, treatment duration of 35 days is
`recommended.
` For patients undergoing knee replacement surgery, treatment duration of 12 days is
`recommended.
`2.6 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.
`
`2.7 Missed Dose
`If a dose of XARELTO is not taken at the scheduled time, administer the dose as soon as
`possible on the same day as follows:
`
` For patients receiving 15 mg twice daily: The patient should take XARELTO
`immediately to ensure intake of 30 mg XARELTO per day. In this particular instance,
`two 15 mg tablets may be taken at once. The patient should continue with the regular
`15 mg twice daily intake as recommended on the following day.
` For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the
`
`missed XARELTO dose immediately.
`
`2.8 Administration Options
`For patients who are unable to swallow whole tablets, 15 mg or 20 mg 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 Dosage and Administration (2.1, 2.3, 2.4) and Clinical
`Pharmacology (12.3)].
`
`Reference ID: 3676584
`
`6
`
`
`
`Administration via nasogastric (NG) tube or gastric feeding tube: After confirming gastric
`placement of the tube, 15 mg or 20 mg 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 15 mg or 20 mg 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
` 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
`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, 2.6) 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.
`
`Reference ID: 3676584
`
`7
`
`
`
`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, other antithrombotic agents, fibrinolytic therapy, and
`non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3)].
`
`Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g., ketoconazole
`and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug
`Interactions (7.1)].
`
`Reversal of Anticoagulant Effect:
`
`A specific antidote for rivaroxaban is not available. Because of high plasma protein binding,
`rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3)]. Protamine
`sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Partial
`reversal of prothrombin time prolongation has been seen after administration of prothrombin
`complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant reversal
`agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa
`(rFVIIa) has not been evaluated.
`
`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 rivaroxaban and
`epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile
`of rivaroxaban [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter
`or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low;
`however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not
`known.
`
`An epidural catheter should not be removed earlier than 18 hours after the last administration of
`XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the
`removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be
`delayed for 24 hours.
`
`Reference ID: 3676584
`
`8
`
`
`
`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
`Avoid the use of XARELTO in patients with CrCl <15 mL/min since drug exposure is increased.
`Periodically assess renal function as clinically indicated (i.e., more frequently in situations in
`
`which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO in
`
`patients who develop acute renal failure while on XARELTO [see Use in Specific Populations
`(8.7)].
`
`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 (8.7)].
`
`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
`50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the
`treatment [see Use in Specific Populations (8.7)].
`
`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 (8.8)].
`
`Reference ID: 3676584
`
`9
`
`
`
`5.6 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers
`Avoid concomitant use of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g.,
`ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, and conivaptan) [see Drug
`Interactions (7.1)].
`
`Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4
`inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Drug Interactions
`(7.2)].
`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 nor
`readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in
`hemoglobin and/or hematocrit, hypotension, or fetal distress).
`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 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)]
` 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.
`
`Reference ID: 3676584
`
`10
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`
`
`During clinical development for the approved indications, 16326 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); 4728 patients
`who received either XARELTO 15 mg orally twice daily for three weeks followed by 20 mg
`orally once daily (EINSTEIN DVT, EINSTEIN PE) or 20 mg orally once daily (EINSTEIN
`Extension) to treat DVT, PE, and to reduce the risk of recurrence of DVT and of PE; and 4487
`patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip
`or knee replacement surgery (RECORD 1-3).
`
`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 1 shows the number of patients experiencing various types of bleeding events in the
`ROCKET AF trial.
`
`Event Rate
`(per 100 Pt-yrs)
`
`Event Rate
`(per 100 Pt-yrs)
`
`Warfarin
`N = 7125
`n (%)
`386 (5.4)
`133 (1.9)
`55 (0.8)
`149 (2.1)
`
`3.5
`1.2
`0.5
`1.3
`
`Table 1:
`
`Bleeding Events in ROCKET AF*
`Parameter
`XARELTO
`N = 7111
`n (%)
`395 (5.6)
`91 (1.3)
`27 (0.4)
`183 (2.6)
`
`3.6
`0.8
`0.2
`1.7
`
`Major bleeding†
`Bleeding into a critical organ‡
`Fatal bleeding
`Bleeding resulting in
`transfusion of ≥2 units of whole
`blood or packed red blood cells
`1.2
`140 (2.0)
`2.0
`221 (3.1)
`Gastrointestinal bleeding
`* For all sub-types of major bleeding, single events may be represented in more than one row, and individual
`patients may have more than one event.
`† Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2
`units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.
`Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding
`strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin.
`‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intra-
`articular, intramuscular with compartment syndrome, or retroperitoneal.
`
`Reference ID: 3676584
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`11
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`Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and to Reduce
`the Risk of Recurrence of DVT and of 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.
`
`Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis
`of the EINSTEIN DVT and EINSTEIN PE studies.
`
`Table 2:
`
`Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies
`Parameter
`XARELTO†
`Enoxaparin/
`N = 4130
`VKA†
`N = 4116
`n (%)
`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)
`
`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)
`
`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 ≥ 2g/dL
`Transfusion of ≥2 units of whole blood or packed red
`blood cells
`Clinically relevant non-major bleeding
`357 (8.7)
`357 (8.6)
`Any bleeding
`1153 (28.0)
`1169 (28.3)
`* 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 at least >2 subjects in any pooled treatment group
`§ Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or
`
`transfusion of ≥2 units of whole blood or packed red blood cells
`
`
`EINSTEIN Extension Study
`
`Reference ID: 3676584
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`12
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`In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with
`permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for
`XARELTO vs. 0.2% for placebo treatment groups. The mean duration of treatment was 190 days
`for both XARELTO and placebo treatment groups.
`
`Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN Extension
`study.
`
`Table 3:
`
`Bleeding Events* in EINSTEIN Extension Study
`Parameter
`
`Placebo†
`N = 590
`n (%)
`
`XARELTO†
`20 mg
`N = 598
`n (%)
`4 (0.7)
`4 (0.7)
`2 (0.3)
`
`Major bleeding event‡
`Decrease in Hb ≥2 g/dL
`Transfusion of ≥2 units of whole blood or packed red
`blood cells
`0
`3 (0.5)
`Gastrointestinal
`0
`1 (0.2)
`Menorrhagia
`7 (1.2)
`32 (5.4)
`Clinically relevant non-major bleeding
`63 (10.7)
`104 (17.4)
`Any bleeding
`* Bleeding event occurred after the first dose and up t