•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`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 and
`•
`
`
`
`
`
`Indication (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: 05/2016
`
`
`
`
`2.5 Prophylaxis of Deep Vein Thrombosis Following
`
`
`Hip or Knee Replacement Surgery
`
`
`2.6 Discontinuation for Surgery and other
`
`
`
`
`Interventions
`
`
`
`2.7 Missed Dose
`
`
`2.8 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
`
`
`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
`
`
`6 ADVERSE REACTIONS
`
`
`
` 1
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` 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, 2.6, 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-------------------------­
`
`
`
`Warnings and Precautions (5.2, 5.4)
`05/2016
`
`
`
`----------------------------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)
`
`Nonvalvular Atrial Fibrillation:
`
`
`For patients with CrCl >50 mL/min: 20 mg orally, once daily with
`
`o
`
`
`
`
`
`
`
`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)
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`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 of Pulmonary Embolism
`
`
`1.5 Prophylaxis of Deep Vein Thrombosis Following
`
`
`Hip or Knee Replacement Surgery
`
`
`
`2 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
`
`
`
`
`Reference ID: 3927766
`
`IPR2017-00042
`Bayer Ex. 2001
`
`

`
`
`
`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
`
`
`
`Instructions for Patient Use
`
`17.1
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
` 6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Drugs that Inhibit Cytochrome P450 3A4
`
`
`Enzymes and Drug Transport Systems
`
`
`
`7.2 Drugs that Induce Cytochrome P450 3A4
`
`
`Enzymes and Drug Transport Systems
`
`
`
`
`7.3 Anticoagulants and NSAIDs/Aspirin
`
`
`7.4 Drug-Disease Interactions with Drugs that Inhibit
`
`
`
`Cytochrome P450 3A4 Enzymes and Drug
`
`
`Transport Systems
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`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
`
`
`
`
`
`Reference ID: 3927766
`
`
`
` 2
`
`IPR2017-00042
`Bayer Ex. 2001
`
`

`
`
`
`
` 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: 3927766
`
`
`
` 3
`
`IPR2017-00042
`Bayer Ex. 2001
`
`

`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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)
`
`
`
`10 mg once daily for 12 days
`
`
`
`
`
`Knee replacement:
`
`
`
`
`
`
`
`
` 2.1
`
`
` Important Food Effect Information
` 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)].
`
`
`
`
`
`
`
`
` In the nonvalvular atrial fibrillation efficacy study XARELTO was taken with the evening meal.
`
`
`
`
`
`Reference ID: 3927766
`
`
`
` 4
`
` 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:
`
`
`
`IPR2017-00042
`Bayer Ex. 2001
`
`

`
`
`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: 3927766
`
`
`
` 5
`
`IPR2017-00042
`Bayer Ex. 2001
`
`

`
`
`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, 10 mg, 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: 3927766
`
`
`
` 6
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`Bayer Ex. 2001
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`

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`
`
`
` Administration via nasogastric (NG) tube or gastric feeding tube: After confirming gastric
`
`
`
` placement of the tube, 10 mg, 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 10 mg, 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
`
`
`
`
`
` 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, 2.6) and Clinical Studies (14.1)].
`
`
`
`
`
`
`
`
`
`Reference ID: 3927766
`
`
`
` 7
`
`IPR2017-00042
`Bayer Ex. 2001
`
`

`
`
`
`
` 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, other antithrombotic agents, fibrinolytic therapy, non-
`
`steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3)], selective serotonin
`
`
`
`
`reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.
`
`
`
`
`
`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;
`
`
`
`
`Reference ID: 3927766
`
`
`
` 8
`
`IPR2017-00042
`Bayer Ex. 2001
`
`

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`
`
`
` 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.
`
`
`
`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 (2.3)]. Consider dose adjustment or discontinuation of 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.
`
`
`Reference ID: 3927766
`
`
`
` 9
`
`IPR2017-00042
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`
`

`
`
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`
` 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)].
`
`
` 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)]
`
`
`
`
`
`
`
`
`
`Reference ID: 3927766
`
`
`
` 10
`
`IPR2017-00042
`Bayer Ex. 2001
`
`

`
`
`
`
`
` 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, 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.
`
`
`
`Reference ID: 3927766
`
`
`
` 11
`
`IPR2017-00042
`Bayer Ex. 2001
`
`

`
`
`
`
`
`
`
`
` Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days
`
` Table 1:
`
`
`
` XARELTO
`
` Warfarin
` Parameter
`
`
` N = 7125
` N = 7111
`
`
` 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§
`
`Other ICH
`26 (0.2)
`19 (0.2)
`
`
`
`
` Gastrointestinal (GI)¶
`
` 140 (1.2)
` 221 (2.0)
`
`
` Fatal Bleeding#
`
` 55 (0.5)
` 27 (0.2)
`
`
`
`
`42 (0.4)
`24 (0.2)
`ICH
`
`
`13 (0.1)
`3 (0.0)
`Non-intracranial
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`treatm