XARELTO- rivaroxaban tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
RIVAROXABAN (UNII: 9NDF7JZ4M3) (RIVAROXABAN - UNII:9NDF7JZ4M3)
Available from:
A-S Medication Solutions
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 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)]. XARELTO is indicated for the treatment of deep vein thrombosis (DVT). XARELTO is indicated for the treatment of pulmonary embolism (PE). 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. XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery. 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 periph
Product summary:
Product: 50090-4469 NDC: 50090-4469-0 90 TABLET, FILM COATED in a BOTTLE
Authorization status:
New Drug Application
Authorization number:
50090-4469-0

A-S Medication Solutions

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This Medication Guide has been approved by the U.S. Food and Drug Administration

Revised: 10/2018

MEDICATION GUIDE

XARELTO® (zah-REL-toe)

(rivaroxaban)

tablets

What is the most important information I should know about XARELTO?

XARELTO may cause serious side effects, including:

Increased risk of blood clots if you stop taking XARELTO.

People with atrial fibrillation (a type of irregular heart beat) that is not caused by a heart valve

problem (non-valvular) are at an increased risk of forming a blood clot in the heart, which can travel

to the brain, causing a stroke, or to other parts of the body. XARELTO lowers your chance of having

a stroke by helping to prevent clots from forming. If you stop taking XARELTO, you may have

increased risk of forming a clot in your blood.

Do not stop taking XARELTO without talking to the doctor who prescribes it for you. Stopping

XARELTO increases your risk of having a stroke.

If you have to stop taking XARELTO, your doctor may prescribe another blood thinner medicine to

prevent a blood clot from forming.

Increased risk of bleeding. XARELTO can cause bleeding which can be serious, and may lead to

death. This is because XARELTO is a blood thinner medicine (anticoagulant) that lowers blood

clotting. During treatment with XARELTO you are likely to bruise more easily and it may take

longer for bleeding to stop.

You may have a higher risk of bleeding if you take XARELTO and take other medicines that

increase your risk of bleeding, including:

aspirin or aspirin containing products

long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs)

warfarin sodium (Coumadin®, Jantoven®)

any medicine that contains heparin

clopidogrel (Plavix®)

selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake

inhibitors (SNRIs)

other medicines to prevent or treat blood clots

Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your

medicine is one listed above.

Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:

unexpected bleeding or bleeding that lasts a long time, such as:

nose bleeds that happen often

unusual bleeding from the gums

menstrual bleeding that is heavier than normal or vaginal bleeding

bleeding that is severe or you cannot control

red, pink or brown urine

bright red or black stools (looks like tar)

cough up blood or blood clots

vomit blood or your vomit looks like "coffee grounds"

headaches, feeling dizzy or weak

pain, swelling, or new drainage at wound sites

Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine (anticoagulant)

like XARELTO, and have medicine injected into their spinal and epidural area, or have a spinal

puncture have a risk of forming a blood clot that can cause long-term or permanent loss of the ability

to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:

a thin tube called an epidural catheter is placed in your back to give you certain medicine

you take NSAIDs or a medicine to prevent blood from clotting

you have a history of difficult or repeated epidural or spinal punctures

you have a history of problems with your spine or have had surgery on your spine

If you take XARELTO and receive spinal anesthesia or have a spinal puncture, your doctor should

watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if you

have back pain, tingling, numbness, muscle weakness (especially in your legs and feet), loss of

control of the bowels or bladder (incontinence).

XARELTO is not for use in people with artificial heart valves.

What is XARELTO?

XARELTO is a prescription medicine used to:

reduce the risk of stroke and blood clots in people who have a medical condition called atrial

fibrillation that is not caused by a heart valve problem. With atrial fibrillation, part of the heart does

not beat the way it should. This can lead to the formation of blood clots, which can travel to the

brain, causing a stroke, or to other parts of the body.

treat blood clots in the veins of your legs (deep vein thrombosis or DVT) or lungs (pulmonary

embolism or PE)

reduce the risk of blood clots happening again in people who continue to be at risk for DVT or PE

after receiving treatment for blood clots for at least 6 months.

help prevent a blood clot in the legs and lungs of people who have just had hip or knee replacement

surgery.

XARELTO is used with low dose aspirin to:

reduce the risk of serious heart problems, heart attack and stroke in patients with coronary artery

disease (a condition where the blood supply to the heart is reduced or blocked) or peripheral artery

disease (a condition where the blood flow to the legs is reduced).

It is not known if XARELTO is safe and effective in children.

Do not take XARELTO if you:

currently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO if

you currently have unusual bleeding.

are allergic to rivaroxaban or any of the ingredients in XARELTO. See the end of this Medication

Guide for a complete list of ingredients in XARELTO.

Before taking XARELTO, tell your doctor about all of your medical conditions, including if you:

have ever had bleeding problems

have liver or kidney problems

are pregnant or plan to become pregnant. It is not known if XARELTO will harm your unborn baby.

Tell your doctor right away if you become pregnant during treatment with XARELTO.

Taking XARELTO while you are pregnant may increase the risk of bleeding in you or in your

unborn baby.

If you take XARELTO during pregnancy tell your doctor right away if you have any signs or

symptoms of bleeding or blood loss. See "What is the most important information I should

know about XARELTO?" for signs and symptoms of bleeding.

are breastfeeding or plan to breastfeed. XARELTO can pass into your breast milk. Talk to your

doctor about the best way to feed your baby during treatment with XARELTO.

Tell all of your doctors and dentists that you are taking XARELTO. They should talk to the doctor who

prescribed XARELTO for you before you have any surgery, medical or dental procedure.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines,

vitamins, and herbal supplements.

Some of your other medicines may affect the way XARELTO works, causing side effects. Certain medicines

may increase your risk of bleeding. See "What is the most important information I should know about

XARELTO?"

Especially tell your doctor if you take:

ketoconazole

erythromycin

phenytoin

St. John's wort

ritonavir

carbamazepine

rifampin

How should I take XARELTO?

Take XARELTO exactly as prescribed by your doctor.

Do not change your dose or stop taking XARELTO unless your doctor tells you to.

Your doctor may change your dose if needed.

If you take XARELTO for:

atrial fibrillation that is not caused by a heart valve problem:

Take XARELTO 1 time a day with your evening meal.

If you miss a dose of XARELTO, take it as soon as you remember on the same day.

Take your next dose at your regularly scheduled time.

blood clots in the veins of your legs or lungs:

Take XARELTO 1 or 2 times a day as prescribed by your doctor.

For the 15 mg and 20 mg doses, XARELTO should be taken with food.

For the 10 mg dose, XARELTO may be taken with or without food.

Take your XARELTO doses at the same time each day.

If you miss a dose:

If you take the 15 mg dose of XARELTO 2 times a day (a total of 30 mg of

XARELTO in 1 day): Take XARELTO as soon as you remember on the same

day. You may take 2 doses at the same time to make up for the missed dose.

Take your next dose at your regularly scheduled time.

If you take XARELTO 1 time a day: Take XARELTO as soon as you remember

on the same day. Take your next dose at your regularly scheduled time.

hip or knee replacement surgery:

Take XARELTO 1 time a day with or without food.

If you miss a dose of XARELTO, take it as soon as you remember on the same day.

Take your next dose at your regularly scheduled time.

reducing the risk of serious heart problems, heart attack and stroke in coronary artery disease

or peripheral artery disease:

Take XARELTO 2 times a day with or without food.

If you miss a dose of XARELTO, take your next dose at your regularly scheduled

time.

If you have difficulty swallowing the XARELTO tablet whole, talk to your doctor about other ways

to take XARELTO.

Your doctor will decide how long you should take XARELTO.

XARELTO may need to be stopped, if possible for one or more days before any surgery or medical

or dental procedure. If you need to stop taking XARELTO for any reason, talk to the doctor who

prescribed XARELTO to you to find out when you should stop taking it. Do not stop taking

XARELTO without first talking to the doctor who prescribes it to you. Your doctor will tell you

when to start taking XARELTO again after your surgery or procedure.

Do not run out of XARELTO. Refill your prescription of XARELTO before you run out. When

leaving the hospital following a hip or knee replacement, be sure that you will have XARELTO

available to avoid missing any doses.

If you take too much XARELTO, go to the nearest hospital emergency room or call your doctor right

away.

What are the possible side effects of XARELTO?

The most common side effect of XARELTO was bleeding.

See "What is the most important information I should know about XARELTO?"

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 800-FDA-

1088.

How should I store XARELTO?

Store XARELTO at room temperature between 68°F to 77°F (20°C to 25°C).

Keep XARELTO and all medicines out of the reach of children.

General information about the safe and effective use of XARELTO.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use

XARELTO for a condition for which it was not prescribed. Do not give XARELTO to other people, even if

they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for

information about XARELTO that is written for health professionals.

What are the ingredients in XARELTO?

Active ingredient: rivaroxaban

Inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate,

microcrystalline cellulose, and sodium lauryl sulfate.

The proprietary film coating mixture for XARELTO 2.5 mg tablets is Opadry® Light Yellow and contains:

ferric oxide yellow, hypromellose, polyethylene glycol 3350, and titanium dioxide.

The proprietary film coating mixture for XARELTO 10 mg tablets is Opadry® Pink and contains: ferric

oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.

The proprietary film coating mixture for XARELTO 15 mg tablets is Opadry® Red and contains: ferric

oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.

The proprietary film coating mixture for XARELTO 20 mg tablets is Opadry® II Dark Red and contains:

ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium

dioxide.

Finished Product Manufactured by: Janssen Ortho LLC Gurabo, PR 00778 or Bayer AG 51368 Leverkusen,

Germany

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer HealthCare AG

51368 Leverkusen, Germany

© 2011 Janssen Pharmaceutical Companies

Trademarks are property of their respective owners.

For more information go to www.XARELTO-US.com or call 1-800-526-7736.

Revised: 8/2019

Document Id: dca2f612-0851-4377-84b3-0cd138c3e3c8

34391-3

Set id: 65727928-9421-4df8-bff2-f72a9cc78069

Version: 2

Effective Time: 20190829

A-S Medication Solutions

XARELTO- rivaroxaban tablet, film coated

A-S Medication Solutions

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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, 2.3,

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)

DOSAGE AND ADMINISTRATION

Nonvalvular Atrial Fibrillation:

For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal (2.1)

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

®

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.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE

RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

1 INDICATIONS AND USAGE

1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

1.2 Treatment of Deep Vein Thrombosis

1.3 Treatment of Pulmonary Embolism

1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism

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)

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

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

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

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.

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).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

Table 1: Recommended Dosage

Indication

Renal

Cons iderations

Dos age

Food/Timing

Reduction in Risk

of Stroke in

Nonvalvular Atrial

Fibrillation

CrCl >50 mL/min 20 mg once daily

Take with evening

meal

CrCl ≤50 mL/min 15 mg once daily

Take with evening

meal

Treatment of

DVT and/or PE

CrCl ≥30 mL/min

15 mg twice daily

▼ after 21 days, transition to ▼

20 mg once daily

Take with food, at

the same time

each day

CrCl <30 mL/min

Avoid Use

Reduction in the

Risk of

Recurrence of

DVT and/or PE in

patients at

continued risk for

DVT and/or PE

CrCl ≥30 mL/min

10 mg once daily, after at least 6

months of standard anticoagulant

treatment

Take with or

without food

CrCl <30 mL/min

Avoid Use

Prophylaxis of DVT Following:

CrCl ≥30 mL/min

10 mg once daily for 35 days, 6–10

hours after surgery once

hemostasis has been established

Take with or

without food

CrCl <30 mL/min

Avoid Use

CrCl ≥30 mL/min

10 mg once daily for 12 days, 6–10

hours after surgery once

hemostasis has been established

Take with or

without food

CrCl <30 mL/min

Avoid Use

Reduction of Risk

of Major

Cardiovas cular

Events (CV

Death, MI, and

Stroke) in

Chronic CAD or

No dose

adjustment needed

based on CrCl

2.5 mg twice daily, plus aspirin

(75–100 mg) once daily

Take with or

without food

*

Hip

Replacement

Surgery

Knee

Replacement

Surgery

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.

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.

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

See Use in Specific Populations (8.6)

See Clinical Pharmacology (12.3)

See Dosage and Administration (2.3)

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 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, P2Y

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 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 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)]

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.

Table 2: Bleeding Events in ROCKET AF - On Treatment Plus 2 Days

Parameter

XARELTO

N=7111

n (%/year)

Warfarin

N=7125

n (%/year)

XARELTO vs.

Warfarin HR

(95% CI)

Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM =

Clinically Relevant Non-Major.

Major Bleeding

395 (3.6)

386 (3.5)

1.04 (0.90, 1.20)

Intracranial

Hemorrhage (ICH)

55 (0.5)

84 (0.7)

0.67 (0.47, 0.93)

Hemorrhagic

Stroke

36 (0.3)

58 (0.5)

0.63 (0.42, 0.96)

Other ICH

19 (0.2)

26 (0.2)

0.74 (0.41, 1.34)

Gastrointestinal

(GI)

221 (2.0)

140 (1.2)

1.61 (1.30, 1.99)

Fatal Bleeding

27 (0.2)

55 (0.5)

0.50 (0.31, 0.79)

24 (0.2)

42 (0.4)

0.58 (0.35, 0.96)

Non-intracranial

3 (0.0)

13 (0.1)

0.23 (0.07, 0.82)

Figure 1 shows the risk of major bleeding events across major subgroups.

*

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.

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.

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

Parameter

XARELTO

N=4130

n (%)

Enoxaparin/VKA

N=4116

n (%)

Major bleeding event

40 (1.0)

72 (1.7)

Fatal bleeding

3 (<0.1)

8 (0.2)

*

Intracranial

2 (<0.1)

4 (<0.1)

Non-fatal critical organ bleeding

10 (0.2)

29 (0.7)

Intracranial

3 (<0.1)

10 (0.2)

Retroperitoneal

1 (<0.1)

8 (0.2)

Intraocular

3 (<0.1)

2 (<0.1)

Intra-articular

4 (<0.1)

Non-fatal non-critical organ

bleeding

27 (0.7)

37 (0.9)

Decrease in Hb ≥ 2 g/dL

28 (0.7)

42 (1.0)

Transfusion of ≥2 units of whole

blood or packed red blood cells

18 (0.4)

25 (0.6)

Clinically relevant non-major bleeding

357 (8.6)

357 (8.7)

Any bleeding

1169 (28.3)

1153 (28.0)

Reduction in the Risk of Recurrence of DVT and/or PE

EINSTEIN CHOICE Study

In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with

permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10

mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of

treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated

patients.

Table 4 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.

Table 4: Bleeding Events

in EINSTEIN CHOICE

Parameter

XARELTO

10 mg

N=1127

n (%)

Acetyls alicylic

Acid (aspirin)

100 mg

N=1131

n (%)

Major bleeding event

5 (0.4)

3 (0.3)

Fatal bleeding

1 (<0.1)

Non-fatal critical organ bleeding

2 (0.2)

1 (<0.1)

Non-fatal non-critical organ

bleeding

3 (0.3)

1 (<0.1)

Clinically relevant non-major (CRNM)

bleeding

22 (2.0)

20 (1.8)

Any bleeding

151 (13.4)

138 (12.2)

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

*

Bleeding event occurred after the first dose and up to 2 days after the last dose of

In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and

CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg

groups.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent

treatment discontinuation was 3.7% with XARELTO.

The rates of major bleeding events and any bleeding events observed in patients in the RECORD

clinical trials are shown in Table 5.

Table 5: Bleeding Events

in Patients Undergoing Hip or Knee

Replacement Surgeries (RECORD 1–3)

XARELTO 10 mg

Enoxaparin

Total treated patients

N=4487

n (%)

N=4524

n (%)

Major bleeding event

14 (0.3)

9 (0.2)

Fatal bleeding

1 (<0.1)

Bleeding into a critical

organ

2 (<0.1)

3 (0.1)

Bleeding that required

re-operation

7 (0.2)

5 (0.1)

Extra-surgical site

bleeding requiring

transfusion of >2 units of

whole blood or packed

cells

4 (0.1)

1 (<0.1)

Any bleeding event

261 (5.8)

251 (5.6)

Hip Surgery Studies

N=3281

n (%)

N=3298

n (%)

Major bleeding event

7 (0.2)

3 (0.1)

Fatal bleeding

1 (<0.1)

Bleeding into a critical

organ

1 (<0.1)

1 (<0.1)

Bleeding that required

re-operation

2 (0.1)

1 (<0.1)

Extra-surgical site

bleeding requiring

transfusion of >2 units of

whole blood or packed

cells

3 (0.1)

1 (<0.1)

study drug. Although a patient may have had 2 or more events, the patient is counted

only once in a category.

Treatment schedule: XARELTO 10 mg once daily or aspirin 100 mg once daily.

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.

Bleeding which was clinically overt, did not meet the criteria for major bleeding, but

was associated with medical intervention, unscheduled contact with a physician,

temporary cessation of treatment, discomfort for the patient, or impairment of

activities of daily life.

*

cells

Any bleeding event

201 (6.1)

191 (5.8)

Knee Surgery Study

N=1206

n (%)

N=1226

n (%)

Major bleeding event

7 (0.6)

6 (0.5)

Fatal bleeding

Bleeding into a critical

organ

1 (0.1)

2 (0.2)

Bleeding that required

re-operation

5 (0.4)

4 (0.3)

Extra-surgical site

bleeding requiring

transfusion of >2 units of

whole blood or packed

cells

1 (0.1)

Any bleeding event

60 (5.0)

60 (4.9)

Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during

the first week after surgery.

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD

In the COMPASS trial, the most frequent adverse reactions associated with permanent drug

discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily

in combination with aspirin 100 mg once daily vs. 1.2% for aspirin 100 mg once daily.

Table 6 shows the number of patients experiencing various types of major bleeding events in the

COMPASS trial.

Table 6: Major Bleeding Events

in COMPASS - On Treatment Plus 2 days

XARELTO plus

aspirin

N=9134

Aspirin alone

N=9107

XARELTO plus

aspirin vs.

Aspirin alone

Parameter

n (%/year)

n (%/year)

HR (95 % CI)

Modified ISTH Major Bleeding

263 (1.6)

144 (0.9)

1.84 (1.50, 2.26)

- Fatal bleeding event

12 (<0.1)

8 (<0.1)

1.51 (0.62, 3.69)

Intracranial hemorrhage (ICH)

6 (<0.1)

3 (<0.1)

2.01 (0.50, 8.03)

Non-intracranial

6 (<0.1)

5 (<0.1)

1.21 (0.37, 3.96)

- Symptomatic bleeding in critical

organ (non-fatal)

58 (0.3)

43 (0.3)

1.36 (0.91, 2.01)

23 (0.1)

21 (0.1)

1.09 (0.61, 1.98)

Hemorrhagic Stroke

18 (0.1)

13 (<0.1)

1.38 (0.68, 2.82)

Other ICH

6 (<0.1)

9 (<0.1)

0.67 (0.24, 1.88)

- Bleeding into the surgical site

requiring reoperation (non-fatal, not

7 (<0.1)

6 (<0.1)

1.17 (0.39, 3.48)

Bleeding events occurring any time following the first dose of double-blind study

medication (which may have been prior to administration of active drug) until two

days after the last dose of double-blind study medication. Patients may have more

than one event.

Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 4 0

mg once daily (RECORD 1–3)

Includes major bleeding events

*

CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and

Hemostasis

in critical organ)

- Bleeding leading to hospitalization

(non-fatal, not in critical organ, not

requiring reoperation)

188 (1.1)

91 (0.5)

2.08 (1.62, 2.67)

Major GI bleeding

117 (0.7)

49 (0.3)

2.40 (1.72, 3.35)

Figure 2 shows the risk of modified ISTH major bleeding events across major subgroups.

Figure 2: Risk of Modified ISTH Major Bleeding Events by Baseline Characteristics in

COMPASS – On Treatment Plus 2 Days

Other Adverse Reactions

Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN

DVT and EINSTEIN PE studies are shown in Table 7.

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.

Treatment schedule: XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily, or aspirin 100 mg

once daily

Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as

intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular,

respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into

the surgical site requiring reoperation, or iv) bleeding leading to hospitalization.

Table 7: Other Adverse Reactions

Reported by ≥1% of XARELTO-

Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies

Body System

Adverse Reaction

EINSTEIN DVT Study

XARELTO 20

mg

N=1718

n (%)

Enoxaparin/VKA

N=1711

n (%)

Gastrointestinal disorders

Abdominal pain

46 (2.7)

25 (1.5)

General disorders and

administration site conditions

Fatigue

24 (1.4)

15 (0.9)

Musculoskeletal and connective

tissue disorders

Back pain

50 (2.9)

31 (1.8)

Muscle spasm

23 (1.3)

13 (0.8)

Nervous system disorders

Dizziness

38 (2.2)

22 (1.3)

Psychiatric disorders

Anxiety

24 (1.4)

11 (0.6)

Depression

20 (1.2)

10 (0.6)

Insomnia

28 (1.6)

18 (1.1)

EINSTEIN PE Study

XARELTO 20

mg

N=2412

n (%)

Enoxaparin/VKA

N=2405

n (%)

Skin and subcutaneous tissue

dis orders

Pruritus

53 (2.2)

27 (1.1)

Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1–3

studies are shown in Table 8.

Table 8: Other Adverse Drug Reactions

Reported by ≥1% of

XARELTO-Treated Patients in RECORD 1–3 Studies

Body System

Adverse Reaction

XARELTO

10 mg

N=4487

n (%)

Enoxaparin

N=4524

n (%)

Injury, poisoning and

procedural

complications

Wound secretion

125 (2.8)

89 (2.0)

Musculoskeletal and

connective tissue

dis orders

*

Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator

*

Pain in extremity

74 (1.7)

55 (1.2)

Muscle spasm

52 (1.2)

32 (0.7)

Nervous system

dis orders

Syncope

55 (1.2)

32 (0.7)

Skin and subcutaneous

tissue disorders

Pruritus

96 (2.1)

79 (1.8)

Blister

63 (1.4)

40 (0.9)

Other clinical trial experience: In an investigational study of acute medically ill patients being treated with

XARELTO 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with

bronchiectasis were observed.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of XARELTO.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia

Gastrointestinal disorders: retroperitoneal hemorrhage

Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury)

Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema

Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and

systemic symptoms (DRESS)

7 DRUG INTERACTIONS

7.1 General Inhibition and Induction Properties

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2)

transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may

increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to

rivaroxaban and may increase the risk of thromboembolic events.

7.2 Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems

Interaction with Combined P-gp and Strong CYP3A Inhibitors

Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A

inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions (5.6) and Clinical

Pharmacology (12.3)].

Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data

suggests that no precautions are necessary with concomitant administration with XARELTO as the

change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology (12.3)].

Adverse reaction occurring any time following the first dose of double-blind

medication, which may have been prior to administration of active drug, until two

days after the last dose of double-blind study medication

Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 4 0

mg once daily (RECORD 1–3)

Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment

XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant

combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies

the potential risk [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

7.3 Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers

(e.g., carbamazepine, phenytoin, rifampin, St. John's wort) [see Warnings and Precautions (5.6) and

Clinical Pharmacology (12.3)].

7.4 Anticoagulants and NSAIDs/Aspirin

Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the

risk of bleeding [see Clinical Pharmacology (12.3)].

Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless

benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated

concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and

Precautions (5.2)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The limited available data on XARELTO in pregnant women are insufficient to inform a drug-

associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients

because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant

effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the

benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing

XARELTO to a pregnant woman [see Warnings and Precautions (5.2, 5.7)].

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.

The estimated background risk of major birth defects and miscarriage for the indicated populations is

unknown. In the U.S. general population, the estimated background risk of major birth defects and

miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with

inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased

risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the

risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.

Fetal/Neonatal Adverse Reactions

Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta,

bleeding may occur at any site in the fetus and/or neonate.

Labor or Delivery

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk

may be increased during labor or delivery [see Warnings and Precautions (5.7)]. The risk of bleeding

should be balanced with the risk of thrombotic events when considering the use of XARELTO in this

setting.

Data

Human Data

There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for

pregnant women has not been established. Post-marketing experience is currently insufficient to

determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta

perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.

Animal Data

Rivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased

resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits

were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose

corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the

highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were

given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14

times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal

death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the

unbound drug at the human dose of 20 mg/day).

8.2 Lactation

Risk Summary

Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of

rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were

present in the milk of rats. The developmental and health benefits of breastfeeding should be considered

along with the mother's clinical need for XARELTO and any potential adverse effects on the breastfed

infant from XARELTO or from the underlying maternal condition (see Data).

Data

Animal Data

Following a single oral administration of 3 mg/kg of radioactive [

C]-rivaroxaban to lactating rats

between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples

collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32

hours after administration was 2.1% of the maternal dose.

8.3 Females and Males of Reproductive Potential

Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with

their physician.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in the RECORD 1–3 clinical studies evaluating XARELTO, about 54%

were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were

65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical

studies approximately 37% were 65 years and over and about 16% were >75 years. In EINSTEIN

CHOICE, approximately 39% were 65 years and over and about 12% were >75 years. In the COMPASS

study, approximately 76% were 65 years and over and about 17% were >75 years. In clinical trials the

efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger

than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-

benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies

(14)].

8.6 Renal Impairment

In pharmacokinetic studies, compared to healthy subjects with normal creatinine clearance, rivaroxaban

exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in

pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3)].

Nonvalvular Atrial Fibrillation

Patients with Chronic Kidney Disease not on Dialysis

In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once

daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients

with better renal function administered XARELTO 20 mg once daily. Patients with CrCl ≤30 mL/min

were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum

concentrations of rivaroxaban similar to those in patients with moderate renal impairment [see Clinical

Pharmacology (12.3)].

Patients with End-Stage Renal Disease on Dialysis

Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease

(ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of

XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity

similar to those observed in the ROCKET AF study [see Clinical Pharmacology (12.2, 12.3)]. It is not

known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients

with ESRD on dialysis as was seen in ROCKET AF.

Treatment of DVT and/or PE and Reduction in the Risk of Recurrence of DVT and/or PE

In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the

studies. Avoid the use of XARELTO in patients with CrCl <30 mL/min.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

The combined analysis of the RECORD 1–3 clinical efficacy studies did not show an increase in

bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous

thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of

blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl

<30 mL/min.

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD

Patients with Chronic Kidney Disease not on Dialysis

Patients with a CrCl <15 mL/min at screening were excluded from COMPASS, and limited data are

available for patients with a CrCl of 15–30 mL/min. In patients with CrCl ≤30 mL/min, a dose of 2.5 mg

XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal

impairment [see Clinical Pharmacology (12.3)], whose efficacy and safety outcomes were similar to

those with preserved renal function.

Patients with End-Stage Renal Disease on Dialysis

No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on

dialysis since these patients were not enrolled in COMPASS. In patients with ESRD maintained on

intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations

of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired

patients in the COMPASS study [see Clinical Pharmacology (12.2, 12.3)]. It is not known whether these

concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis

as was seen in COMPASS.

8.7 Hepatic Impairment

In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of

127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).

The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been

evaluated [see Clinical Pharmacology (12.3)].

Avoid the 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.

10 OVERDOSAGE

Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate

therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is

not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to

reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein

binding, rivaroxaban is not dialyzable [see Warnings and Precautions (5.2) and Clinical Pharmacology

(12.3)]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma

products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

11 DESCRIPTION

Rivaroxaban, a factor Xa (FXa) inhibitor, is the active ingredient in XARELTO Tablets with the

chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-

yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C

H ClN O S and the

molecular weight is 435.89. The structural formula is:

Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder.

Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is

practically insoluble in water and aqueous media.

Each XARELTO tablet contains 2.5 mg, 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive

ingredients of XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium

stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating

mixture used for XARELTO 2.5 mg is Opadry

Light Yellow, containing ferric oxide yellow,

hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 10 mg tablets is

Opadry

Pink and for XARELTO 15 mg tablets is Opadry

Red, both containing ferric oxide red,

hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is

Opadry

II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol

(partially hydrolyzed), talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

XARELTO is a selective inhibitor of FXa. It does not require a cofactor (such as Anti-thrombin III) for

activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on

platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa,

rivaroxaban decreases thrombin generation.

12.2 Pharmacodynamics

Dose-dependent inhibition of FXa activity was observed in humans. Neoplastin

prothrombin time (PT),

activated partial thromboplastin time (aPTT) and HepTest

are also prolonged dose-dependently. Anti-

factor Xa activity is also influenced by rivaroxaban.

Specific Populations

Renal Impairment

The relationship between systemic exposure and pharmacodynamic activity of rivaroxaban was altered

in subjects with renal impairment relative to healthy control subjects [see Use in Specific Populations

(8.6)].

Table 9: Percentage Increase in Rivaroxaban PK and PD Measures in Subjects with

Renal Impairment Relative to Healthy Subjects from Clinical Pharmacology Studies

Creatinine Clearance (mL/min)

Meas ure

Parameter

50–79

30–49

15–29

ESRD (on

dialys is )

ESRD (post-

dialys is )

PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the plasma

concentration-time curve; AUEC = Area under the effect-time curve

Exposure

FXa Inhibition

AUEC

PT Prolongation

AUEC

Hepatic Impairment

Anti-Factor Xa activity was similar in subjects with normal hepatic function and in mild hepatic

impairment (Child-Pugh A class). There is no clear understanding of the impact of hepatic impairment

beyond this degree on the coagulation cascade and its relationship to efficacy and safety.

12.3 Pharmacokinetics

Absorption

The absolute bioavailability of rivaroxaban is dose-dependent. For the 2.5 mg and 10 mg dose, it is

estimated to be 80% to 100% and is not affected by food. XARELTO 2.5 mg and 10 mg tablets can be

taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is

approximately 66%. Coadministration of XARELTO with food increases the bioavailability of the 20

mg dose (mean AUC and C

increasing by 39% and 76% respectively with food). XARELTO 15 mg

and 20 mg tablets should be taken with food [see Dosage and Administration (2.1)].

The maximum concentrations (C

) of rivaroxaban appear 2 to 4 hours after tablet intake. The

pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of

XARELTO (30 mg single dose) with the H -receptor antagonist ranitidine (150 mg twice daily), the

antacid aluminum hydroxide/magnesium hydroxide (10 mL) or XARELTO (20 mg single dose) with the

*

*

Separate stand-alone study.

antacid aluminum hydroxide/magnesium hydroxide (10 mL) or XARELTO (20 mg single dose) with the

PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of

rivaroxaban (see Figure 4).

Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56%

decrease in AUC and C

compared to tablet was reported when rivaroxaban granulate is released in

the proximal small intestine. Exposure is further reduced when drug is released in the distal small

intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result

in reduced absorption and related drug exposure.

In a study with 44 healthy subjects, both mean AUC and C

values for 20 mg rivaroxaban administered

orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However,

for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal,

only mean AUC was comparable to that after the whole tablet, and C

was 18% lower.

Distribution

Plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin

being the main binding component. The steady-state volume of distribution in healthy subjects is

approximately 50 L.

Metabolism

Approximately 51% of an orally administered [

C]-rivaroxaban dose was recovered as inactive

metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2

and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant

moiety in plasma with no major or active circulating metabolites.

Excretion

In a Phase 1 study, following the administration of [

C]-rivaroxaban, approximately one-third (36%)

was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces.

Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via

glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter

proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxaban's affinity for influx transporter proteins

is unknown.

Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy

volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5

to 9 hours in healthy subjects aged 20 to 45 years.

Specific Populations

The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the

pharmacokinetics of rivaroxaban are summarized in Figure 3.

Figure 3: Effect of Specific Populations on the Pharmacokinetics of Rivaroxaban

Gender

Gender did not influence the pharmacokinetics or pharmacodynamics of XARELTO.

Race

Healthy Japanese subjects were found to have 20 to 40% on average higher exposures compared to

other ethnicities including Chinese. However, these differences in exposure are reduced when values

are corrected for body weight.

Elderly

The terminal elimination half-life is 11 to 13 hours in the elderly subjects aged 60 to 76 years [see Use

in Specific Populations (8.5)].

Renal Impairment

The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in

healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see

Figure 3). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure

increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed

[see Use in Specific Populations (8.6)].

Hemodialysis in ESRD subjects: Systemic exposure to rivaroxaban administered as a single 15 mg dose

in ESRD subjects dosed 3 hours after the completion of a 4-hour hemodialysis session (post-dialysis)

is 56% higher when compared to subjects with normal renal function (see Table 9). The systemic

exposure to rivaroxaban administered 2 hours prior to a 4-hour hemodialysis session with a dialysate

flow rate of 600 mL/min and a blood flow rate in the range of 320 to 400 mL/min is 47% higher

compared to those with normal renal function. The extent of the increase is similar to the increase in

patients with CrCl 15 to 50 mL/min taking XARELTO 15 mg. Hemodialysis had no significant impact on

rivaroxaban exposure. Protein binding was similar (86% to 89%) in healthy controls and ESRD subjects

in this study.

Hepatic Impairment

The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in

healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Figure 3). No

patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects

with normal liver function, significant increases in rivaroxaban exposure were observed in subjects

with moderate hepatic impairment (Child-Pugh B) (see Figure 3). Increases in pharmacodynamic effects

were also observed [see Use in Specific Populations (8.7)].

Drug Interactions

In vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2,

2C8, 2C9, 2C19, 2D6, 2J2, and 3A nor induces CYP1A2, 2B6, 2C19, or 3A. In vitro data also indicates a

low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters.

The effects of coadministered drugs on the pharmacokinetics of rivaroxaban exposure are summarized

in Figure 4 [see Drug Interactions (7)].

Figure 4: Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban

Anticoagulants

In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg)

given concomitantly resulted in an additive effect on anti-factor Xa activity. In another study, single

doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition

and PT. Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban (see Figure 4).

NSAIDs/Aspirin

In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the

double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known

to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with

XARELTO. Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban (see Figure 4).

Clopidogrel

In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily

maintenance dose) and XARELTO (15 mg single dose) were coadministered in healthy subjects, an

increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in

these studies, respectively. The change in bleeding time was approximately twice the maximum increase

seen with either drug alone. There was no change in the pharmacokinetics of either drug.

Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport

Systems

In a pharmacokinetic trial, XARELTO was administered as a single dose in subjects with mild (CrCl =

50 to 79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving multiple doses of

erythromycin (a combined P-gp and moderate CYP3A inhibitor). Compared to XARELTO administered

alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal

impairment concomitantly receiving erythromycin reported a 76% and 99% increase in AUC

and a

56% and 64% increase in C

, respectively. Similar trends in pharmacodynamic effects were also

observed.

12.6 QT/QTc Prolongation

In a thorough QT study in healthy men and women aged 50 years and older, no QTc prolonging effects

were observed for XARELTO (15 mg and 45 mg, single-dose).

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Rivaroxaban was not carcinogenic when administered by oral gavage to mice or rats for up to 2 years.

The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose

tested (60 mg/kg/day) were 1- and 2-times, respectively, the human exposure of unbound drug at the

human dose of 20 mg/day. Systemic exposures of unbound drug in male and female rats at the highest

dose tested (60 mg/kg/day) were 2- and 4-times, respectively, the human exposure.

Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in V79 Chinese hamster lung

cells in vitro or in the mouse micronucleus test in vivo.

No impairment of fertility was observed in male or female rats when given up to 200 mg/kg/day of

rivaroxaban orally. This dose resulted in exposure levels, based on the unbound AUC, at least 13 times

the exposure in humans given 20 mg rivaroxaban daily.

14 CLINICAL STUDIES

14.1 Stroke Prevention in Nonvalvular Atrial Fibrillation

The evidence for the efficacy and safety of XARELTO was derived from Rivaroxaban Once-daily oral

direct factor Xa inhibition Compared with vitamin K antagonist for the prevention of stroke and

Embolism Trial in Atrial Fibrillation (ROCKET AF) [NCT00403767], a multi-national, double-blind

study comparing XARELTO (at a dose of 20 mg once daily with the evening meal in patients with CrCl

>50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to 50 mL/min) to

warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS)

systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more

of the following additional risk factors for stroke:

a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic

embolism, or

2 or more of the following risk factors:

age ≥75 years,

hypertension,

heart failure or left ventricular ejection fraction ≤35%, or

diabetes mellitus

ROCKET AF was a non-inferiority study designed to demonstrate that XARELTO preserved more than

50% of warfarin's effect on stroke and non-CNS systemic embolism as established by previous

placebo-controlled studies of warfarin in atrial fibrillation.

A total of 14264 patients were randomized and followed on study treatment for a median of 590 days.

The mean age was 71 years and the mean CHADS score was 3.5. The population was 60% male, 83%

Caucasian, 13% Asian and 1.3% Black. There was a history of stroke, TIA, or non-CNS systemic

embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6

weeks at time of screening. Concomitant diseases of patients in this study included hypertension 91%,

diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of

patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on

clopidogrel. Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia,

and New Zealand (15%); Western Europe (15%); and Latin America (13%). Patients randomized to

warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the

first few months of the study.

In ROCKET AF, XARELTO was demonstrated non-inferior to warfarin for the primary composite

endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism [HR (95% CI):

0.88 (0.74, 1.03)], but superiority to warfarin was not demonstrated. There is insufficient experience to

determine how XARELTO and warfarin compare when warfarin therapy is well-controlled.

Table 10 displays the overall results for the primary composite endpoint and its components.

Table 10: Primary Composite Endpoint Results in ROCKET AF Study (Intent-to-Treat

Population)

XARELTO

Warfarin

XARELTO vs.

Warfarin

Event

N=7081

n (%)

Event Rate

(per 100 Pt-

yrs )

N=7090

n (%)

Event Rate

(per 100 Pt-

yrs )

Hazard Ratio

(95% CI)

Primary

Composite

Endpoint

269 (3.8)

306 (4.3)

0.88 (0.74, 1.03)

Stroke

253 (3.6)

281 (4.0)

Hemorrhagic

Stroke

33 (0.5)

57 (0.8)

Ischemic Stroke

206 (2.9)

208 (2.9)

Unknown Stroke

Type

19 (0.3)

18 (0.3)

Non-CNS

Systemic

Embolism

20 (0.3)

27 (0.4)

Figure 5 is a plot of the time from randomization to the occurrence of the first primary endpoint event in

the two treatment arms.

The primary endpoint was the time to first occurrence of stroke (any type) or non-CNS systemic

embolism. Data are shown for all randomized patients followed to site notification that the study

would end.

Defined as primary hemorrhagic strokes confirmed by adjudication in all randomized patients followed

up to site notification

Figure 5: Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by

Treatment Group (Intent-to-Treat Population)

Figure 6 shows the risk of stroke or non-CNS systemic embolism across major subgroups.

Figure 6: Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in

ROCKET AF (Intent-to-Treat Population)

*

The efficacy of XARELTO was generally consistent across major subgroups.

The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but

warfarin patients who completed the study were generally maintained on warfarin. XARELTO patients

were generally switched to warfarin without a period of coadministration of warfarin and XARELTO,

so that they were not adequately anticoagulated after stopping XARELTO until attaining a therapeutic

INR. During the 28 days following the end of the study, there were 22 strokes in the 4637 patients

taking XARELTO vs. 6 in the 4691 patients taking warfarin.

Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation. The utility of

XARELTO for preventing post-cardioversion stroke and systemic embolism is unknown.

14.2 Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE)

EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism Studies

XARELTO for the treatment of DVT and/or PE was studied in EINSTEIN DVT [NCT00440193] and

EINSTEIN PE [NCT00439777], multi-national, open-label, non-inferiority studies comparing

XARELTO (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by

XARELTO 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with

VKA and then continued with VKA only after the target INR (2.0–3.0) was reached. Patients who

required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with

creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the

studies. The intended treatment duration was 3, 6, or 12 months based on investigator's assessment prior

to randomization.

Data are shown for all randomized patients followed to site notification that the study would end.

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.

A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and

followed on study treatment for a mean of 208 days in the XARELTO group and 204 days in the

enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70%

Caucasian, 9% Asian and about 3% Black. About 73% and 92% of XARELTO-treated patients in the

EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant

treatment for a median duration of 2 days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and

EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days.

Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of

patients in both treatment groups. Patients randomized to VKA had an unadjusted mean percentage of time

in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study,

with the lower values occurring during the first month of the study.

In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at

baseline. Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma

(18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic conditions

(6%), or active cancer (5%).

In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated to be non-inferior to

enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or

non-fatal or fatal PE [EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI):

1.12 (0.75, 1.68)]. In each study the conclusion of non-inferiority was based on the upper limit of the

95% confidence interval for the hazard ratio being less than 2.0.

Table 11 displays the overall results for the primary composite endpoint and its components for

EINSTEIN DVT and EINSTEIN PE studies.

Table 11: Primary Composite Endpoint Results

in EINSTEIN DVT and EINSTEIN PE

Studies – Intent-to-Treat Population

Event

XARELTO 20

mg

Enoxaparin/VKA

XARELTO vs.

Enoxaparin/VKA

Hazard Ratio

(95% CI)

EINSTEIN DVT Study

N=1731

n (%)

N=1718

n (%)

Primary Composite

Endpoint

36 (2.1)

51 (3.0)

0.68 (0.44, 1.04)

Death (PE)

1 (<0.1)

Death (PE cannot be

excluded)

3 (0.2)

6 (0.3)

Symptomatic PE and DVT

1 (<0.1)

Symptomatic recurrent PE

only

20 (1.2)

18 (1.0)

Symptomatic recurrent

DVT only

14 (0.8)

28 (1.6)

EINSTEIN PE Study

N=2419

n (%)

N=2413

n (%)

Primary Composite

Endpoint

50 (2.1)

44 (1.8)

1.12 (0.75, 1.68)

Death (PE)

3 (0.1)

1 (<0.1)

Death (PE cannot be

excluded)

8 (0.3)

6 (0.2)

Symptomatic PE and DVT

2 (<0.1)

*

Symptomatic recurrent PE

only

23 (1.0)

20 (0.8)

Symptomatic recurrent

DVT only

18 (0.7)

17 (0.7)

Figures 7 and 8 are plots of the time from randomization to the occurrence of the first primary efficacy

endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively.

Figure 7: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE

by Treatment Group (Intent-to-Treat Population) – EINSTEIN DVT Study

Figure 8: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE

by Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study

For the primary efficacy analysis, all confirmed events were considered from randomization up to the

end of intended treatment duration (3, 6 or 12 months) irrespective of the actual treatment duration. If

the same patient had several events, the patient may have been counted for several components.

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)]

14.3 Reduction in the Risk of Recurrence of DVT and/or PE

EINSTEIN CHOICE Study

XARELTO for reduction in the risk of recurrence of DVT and of PE was evaluated in the EINSTEIN

CHOICE study [NCT02064439], a multi-national, double-blind, superiority study comparing

XARELTO (10 or 20 mg once daily with food) to 100 mg acetylsalicylic acid (aspirin) once daily in

patients who had completed 6 to 12 months of anticoagulant treatment for DVT and/or PE following the

acute event. The intended treatment duration in the study was up to 12 months. Patients with an indication

for continued therapeutic-dose anticoagulation were excluded.

Because the benefit-risk assessment favored the 10 mg dose versus aspirin compared to the 20 mg dose

versus aspirin, only the data concerning the 10 mg dose is discussed below.

A total of 2275 patients were randomized and followed on study treatment for a mean of 290 days for the

XARELTO and aspirin treatment groups. The mean age was approximately 59 years. The population

was 56% male, 70% Caucasian, 14% Asian and 3% Black. In the EINSTEIN CHOICE study, 51% of

patients had DVT only, 33% had PE only, and 16% had PE and DVT combined. Other risk factors

included idiopathic VTE (43%), previous episode of DVT/PE (17%), recent surgery or trauma (12%),

prolonged immobilization (10%), use of estrogen containing drugs (5%), known thrombophilic

conditions (6%), Factor V Leiden gene mutation (4%), or active cancer (3%).

In the EINSTEIN CHOICE study, XARELTO 10 mg was demonstrated to be superior to aspirin 100 mg

for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal

Table 12 displays the overall results for the primary composite endpoint and its components.

Table 12: Primary Composite Endpoint and its Components Results

in EINSTEIN

CHOICE Study – Full Analysis Set

*

Event

XARELTO

10 mg

N=1,127

n (%)

Acetyls alicylic

Acid (Aspirin)

100 mg

N=1,131

n (%)

XARELTO 10 mg

vs. Aspirin

100 mg

Hazard Ratio

(95% CI)

Primary Composite Endpoint

13 (1.2)

50 (4.4)

0.26

(0.14, 0.47)

p<0.0001

Symptomatic recurrent DVT

8 (0.7)

29 (2.6)

Symptomatic recurrent PE

5 (0.4)

19 (1.7)

Death (PE)

1 (<0.1)

Death (PE cannot be excluded)

1 (<0.1)

Figure 9 is a plot of the time from randomization to the occurrence of the first primary efficacy

endpoint event in the two treatment groups.

Figure 9: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE

by Treatment Group (Full Analysis Set) – EINSTEIN CHOICE Study

14.4 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

XARELTO was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in

the REgulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE, Controlled, Double-

For the primary efficacy analysis, all confirmed events were considered from randomization up to the

end of intended treatment duration (12 months) irrespective of the actual treatment duration. The

individual component of the primary endpoint represents the first occurrence of the event.

blind, Randomized Study of BAY 59-7939 in the Extended Prevention of VTE in Patients Undergoing

Elective Total Hip or Knee Replacement (RECORD 1, 2, and 3) [NCT00329628, NCT00332020,

NCT00361894] studies.

The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective

total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6 to 8 hours

(about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily

started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579

received study drug. The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years

with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were

White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged

bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine

clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1,

the mean exposure duration (± SD) to active XARELTO and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3

days, respectively. In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was

33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin

group for the remainder of the double-blind study duration. The efficacy data for RECORD 1 and 2 are

provided in Table 13.

Table 13: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Hip

Replacement Surgery - Modified Intent-to-Treat Population

RECORD 1

RECORD 2

Treatment

Dosage and

Duration

XARELTO

10 mg once

daily

Enoxaparin

40 mg once

daily

RRR ,

p-value

XARELTO

10 mg once

daily

Enoxaparin

40 mg once

daily

RRR ,

p-value

Number of

Patients

N=1513

N=1473

N=834

N=835

Total VTE

17 (1.1%)

57 (3.9%)

(95% CI:

50, 83),

p<0.001

17 (2.0%)

70 (8.4%)

(95% CI:

59, 86),

p<0.001

Components of Total VTE

Proximal

1 (0.1%)

31 (2.1%)

5 (0.6%)

40 (4.8%)

Distal DVT

12 (0.8%)

26 (1.8%)

11 (1.3%)

43 (5.2%)

Non-fatal PE

3 (0.2%)

1 (0.1%)

1 (0.1%)

4 (0.5%)

Death (any

cause)

4 (0.3%)

4 (0.3%)

2 (0.2%)

4 (0.5%)

Number of

Patients

N=1600

N=1587

N=928

N=929

Major VTE

3 (0.2%)

33 (2.1%)

91% (95%

CI: 71, 97),

p<0.001

6 (0.7%)

45 (4.8%)

87% (95%

CI: 69, 94),

p<0.001

Number of

Patients

N=2103

N=2119

N=1178

N=1179

Symptomatic

VTE

5 (0.2%)

11 (0.5%)

3 (0.3%)

15 (1.3%)

*

*

Relative Risk Reduction; CI = confidence interval

Includes the placebo-controlled period of RECORD 2

Proximal DVT, nonfatal PE or VTE-related death

One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee

replacement surgery compared XARELTO 10 mg once daily started at least 6 to 8 hours (about 90% of

patients dosed 6 to 10 hours) after wound closure versus enoxaparin. In RECORD 3, the enoxaparin

regimen was 40 mg once daily started 12 hours preoperatively. The mean age (± SD) of patients in the

study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight percent (68%) of

patients were female. Eighty-one percent (81%) of patients were White, less than 7% were Asian, and

less than 2% were Black. The study excluded patients with severe renal impairment defined as an

estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or

cirrhosis). The mean exposure duration (± SD) to active XARELTO and enoxaparin was 11.9 ± 2.3 and

12.5 ± 3.0 days, respectively. The efficacy data are provided in Table 14.

Table 14: Summary of Key Efficacy Analysis Results for Patients Undergoing Total

Knee Replacement Surgery - Modified Intent-to-Treat Population

RECORD 3

Treatment Dosage

and Duration

XARELTO

10 mg once daily

Enoxaparin

40 mg once daily

RRR ,

p-value

Number of Patients

N=813

N=871

Total VTE

79 (9.7%)

164 (18.8%)

(95% CI: 34, 60),

p<0.001

Components of events contributing to Total VTE

Proximal DVT

9 (1.1%)

19 (2.2%)

Distal DVT

74 (9.1%)

154 (17.7%)

Non-fatal PE

4 (0.5%)

Death (any cause)

2 (0.2%)

Number of Patients

N=895

N=917

Major VTE

9 (1.0%)

23 (2.5%)

60% (95% CI: 14, 81),

p = 0.024

Number of Patients

N=1206

N=1226

Symptomatic VTE

8 (0.7%)

24 (2.0%)

14.5 Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD

The evidence for the efficacy and safety of XARELTO for the reduction in the risk of stroke,

myocardial infarction, or cardiovascular death in patients with coronary artery disease (CAD) or

peripheral artery disease (PAD) was derived from the double-blind Cardiovascular OutcoMes for

People using Anticoagulation StrategieS trial (COMPASS) [NCT10776424]. A total of 27,395 patients

were evenly randomized to rivaroxaban 2.5 mg orally twice daily plus aspirin 100 mg once daily,

rivaroxaban 5 mg orally twice daily alone, or aspirin 100 mg once daily alone. Because the 5 mg dose

alone was not superior to aspirin alone, only the data concerning the 2.5 mg dose plus aspirin are

discussed below.

Patients with established CAD or PAD were eligible. Patients with CAD who were younger than 65

years of age were also required to have documentation of atherosclerosis involving at least two

vascular beds or to have at least two additional cardiovascular risk factors (current smoking, diabetes

mellitus, an estimated glomerular filtration rate [eGFR] <60 mL per minute, heart failure, or non-lacunar

ischemic stroke ≥1 month earlier). Patients with PAD were either symptomatic with ankle brachial index

<0.90 or had asymptomatic carotid artery stenosis ≥50%, a previous carotid revascularization

procedure, or established ischemic disease of one or both lower extremities. Patients were excluded

*

Relative Risk Reduction; CI = confidence interval

Proximal DVT, nonfatal PE or VTE-related death

for use of dual antiplatelet, other non-aspirin antiplatelet, or oral anticoagulant therapies, ischemic, non-

lacunar stroke within 1 month, hemorrhagic or lacunar stroke at any time, or eGFR <15 mL/min. [see

Warnings and Precautions (5.2)].

The mean age was 68 years and 21% of the subject population were ≥75 years. Of the included patients,

91% had CAD, 27% had PAD, and 18% had both CAD and PAD. Of the patients with CAD, 69% had

prior MI, 60% had prior percutaneous transluminal coronary angioplasty (PTCA)/atherectomy/

percutaneous coronary intervention (PCI), and 26% had history of coronary artery bypass grafting

(CABG) prior to study. Of the patients with PAD, 49% had intermittent claudication, 27% had peripheral

artery bypass surgery or peripheral percutaneous transluminal angioplasty, 26% had asymptomatic

carotid artery stenosis > 50%, and 4% had limb or foot amputation for arterial vascular disease.

The mean duration of follow-up was 23 months. Relative to aspirin alone, XARELTO plus aspirin

reduced the rate of the primary composite outcome of stroke, myocardial infarction or cardiovascular

death. The benefit was observed early with a constant treatment effect over the entire treatment period

(see Table 15 and Figure 11).

A benefit-risk analysis of the data from COMPASS was performed by comparing the number of CV

events (CV deaths, myocardial infarctions and non-hemorrhagic strokes) prevented to the number of

fatal or life-threatening bleeding events (fatal bleeds + symptomatic non-fatal bleeds into a critical

organ) in the XARELTO plus aspirin group versus the aspirin group. Compared to aspirin alone, during

10,000 patient-years of treatment, XARELTO plus aspirin would be expected to result in 70 fewer CV

events and 12 additional life-threatening bleeds, indicating a favorable balance of benefits and risks.

The results in patients with PAD, CAD, and both CAD and PAD were consistent with the overall

efficacy and safety results (see Figure 10).

Figure 10 shows the risk of primary efficacy outcome across major subgroups.

Figure 10: Risk of Primary Efficacy Outcome by Baseline Characteristics in COMPASS (Intent-

to-Treat Population)

Table 15: Efficacy results from COMPASS study

Study Population

Patients with CAD or PAD

Event

Xarelto plus aspirin

N=9152

Aspirin alone

N=9126

Hazard Ratio

(95% CI)

n (%)

Event Rate

(%/year)

n (%)

Event Rate

(%/year)

Stroke, MI or CV

death

379 (4.1)

496 (5.4)

0.76 (0.66, 0.86)

- Stroke

83 (0.9)

142 (1.6)

0.58 (0.44, 0.76)

- MI

178 (1.9)

205 (2.2)

0.86 (0.70, 1.05)

- CV death

160 (1.7)

203 (2.2)

0.78 (0.64, 0.96)

Coronary heart

disease death, MI,

ischemic stroke,

acute limb

ischemia

329 (3.6)

450 (4.9)

0.72 (0.63, 0.83)

- Coronary heart

disease death

86 (0.9)

117 (1.3)

0. 7

0.73 (0.55, 0.96)

- Ischemic stroke

64 (0.7)

125 (1.4)

0.51 (0.38, 0.69)

- Acute limb

ischemia

22 (0.2)

40 (0.4)

0.55 (0.32, 0.92)

CV death , MI,

*

CHD: coronary heart disease, CI: confidence interval; CV: cardiovascular; MI: myocardial

infarction

ischemic stroke,

acute limb

ischemia

389 (4.3)

516 (5.7)

3.00

0.74 (0.65, 0.85)

All-cause

mortality

313 (3.4)

1. 8

378 (4.1)

0.82 (0.71, 0.96)

Lower extremity

amputations for

CV reasons

15 (0.2)

<0.1

31 (0.3)

0.48 (0.26, 0.89)

Patients with PAD

Acute limb

ischemia

19 (0.8)

34 (1.4)

0.56 (0.32, 0.99)

Figure 11: Time to first occurrence of primary efficacy outcome (stroke, myocardial infarction,

cardiovascular death) in COMPASS

CI: confidence interval

intention to treat analysis set, primary analyses.

Treatment schedule: XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily, or aspirin 100 mg

once daily.

vs. aspirin 100 mg

Coronary heart disease death: death due to acute MI, sudden cardiac death, or CV procedure.

Acute limb ischemia is defined as limb-threatening ischemia leading to an acute vascular intervention

(i.e., pharmacologic, peripheral arterial surgery/reconstruction, peripheral angioplasty/stent, or

amputation).

CV death includes CHD death, or death due to other CV causes or unknown death.

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50090-4469

NDC: 50090-4469-0 90 TABLET, FILM COATED in a BOTTLE

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Instructions for Patient Use

Advise patients to take XARELTO only as directed.

Remind patients to not discontinue XARELTO without first talking to their healthcare professional.

Advise patients with atrial fibrillation to take XARELTO once daily with the evening meal.

Advise patients for initial treatment of DVT and/or PE to take XARELTO 15 mg or 20 mg tablets

with food at approximately the same time every day [see Dosage and Administration (2.1)].

Advise patients who are at a continued risk of recurrent DVT and/or PE after at least 6 months of

initial treatment, to take XARELTO 10 mg once daily with or without food [see Dosage and

Administration (2.1)].

Advise patients who cannot swallow the tablet whole to crush XARELTO and combine with a small

amount of applesauce followed by food [see Dosage and Administration (2.5)].

For patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush

the XARELTO tablet and mix it with a small amount of water before administering via the tube [see

Dosage and Administration (2.5)].

If a dose is missed, advise the patient to take XARELTO as soon as possible on the same day and

continue on the following day with their recommended daily dose regimen.

Bleeding Risks

Advise patients to report any unusual bleeding or bruising to their physician. Inform patients that it

might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily

when they are treated with XARELTO [see Warnings and Precautions (5.2)].

If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking

concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal

or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle

weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to

contact his or her physician immediately [see Boxed Warning].

Invasive or Surgical Procedures

Instruct patients to inform their healthcare professional that they are taking XARELTO before any

invasive procedure (including dental procedures) is scheduled.

Concomitant Medication and Herbals

Advise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription

or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential

interactions [see Drug Interactions (7)].

Pregnancy and Pregnancy-Related Hemorrhage

Advise patients to inform their physician immediately if they become pregnant or intend to become

pregnant during treatment with XARELTO [see Use in Specific Populations (8.1)].

Advise pregnant women receiving XARELTO to immediately report to their physician any bleeding

or symptoms of blood loss [see Warnings and Precautions (5.7)].

Lactation

Advise patients to discuss with their physician the benefits and risks of XARELTO for the mother and

for the child if they are nursing or intend to nurse during anticoagulant treatment [see Use in Specific

Populations (8.2)].

Females and Males of Reproductive Potential

Advise patients who can become pregnant to discuss pregnancy planning with their physician [see Use in

Specific Populations (8.3)].

Product of Germany

Finished Product Manufactured by:

Janssen Ortho LLC

Gurabo, PR 00778

Bayer AG

51368 Leverkusen, Germany

Manufactured for:

Janssen Pharmaceuticals, Inc.

Titusville, NJ 08560

Licensed from:

Bayer HealthCare AG

51368 Leverkusen, Germany

© 2011 Janssen Pharmaceutical Companies

MEDICATION GUIDE

XARELTO (zah-REL-toe)

(rivaroxaban)

tablets

What is the most important information I should know about XARELTO?

XARELTO may cause serious side effects, including:

Increased risk of blood clots if you stop taking XARELTO.

People with atrial fibrillation (a type of irregular heart beat) that is not caused by a heart valve

problem (non-valvular) are at an increased risk of forming a blood clot in the heart, which can travel

to the brain, causing a stroke, or to other parts of the body. XARELTO lowers your chance of

having a stroke by helping to prevent clots from forming. If you stop taking XARELTO, you may

have increased risk of forming a clot in your blood.

Do not stop taking XARELTO without talking to the doctor who prescribes it for you.

Stopping XARELTO increases your risk of having a stroke.

If you have to stop taking XARELTO, your doctor may prescribe another blood thinner medicine to

prevent a blood clot from forming.

Increased risk of bleeding. XARELTO can cause bleeding which can be serious, and may lead to

death. This is because XARELTO is a blood thinner medicine (anticoagulant) that lowers blood

clotting. During treatment with XARELTO you are likely to bruise more easily and it may take

longer for bleeding to stop.

You may have a higher risk of bleeding if you take XARELTO and take other medicines that

increase your risk of bleeding, including:

aspirin or aspirin containing products

long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs)

warfarin sodium (Coumadin , Jantoven )

any medicine that contains heparin

clopidogrel (Plavix

selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors

(SNRIs)

other medicines to prevent or treat blood clots

Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure

if your medicine is one listed above.

Call your doctor or get medical help right away if you develop any of these signs or symptoms of

bleeding:

unexpected bleeding or bleeding that lasts a long time, such as:

nose bleeds that happen often

unusual bleeding from the gums

menstrual bleeding that is heavier than normal or vaginal bleeding

bleeding that is severe or you cannot control

red, pink or brown urine

bright red or black stools (looks like tar)

cough up blood or blood clots

vomit blood or your vomit looks like "coffee grounds"

headaches, feeling dizzy or weak

pain, swelling, or new drainage at wound sites

Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine

(anticoagulant) like XARELTO, and have medicine injected into their spinal and epidural area, or

have a spinal puncture have a risk of forming a blood clot that can cause long-term or permanent

loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is

higher if:

a thin tube called an epidural catheter is placed in your back to give you certain medicine

you take NSAIDs or a medicine to prevent blood from clotting

you have a history of difficult or repeated epidural or spinal punctures

you have a history of problems with your spine or have had surgery on your spine

If you take XARELTO and receive spinal anesthesia or have a spinal puncture, your doctor should

watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if

you have back pain, tingling, numbness, muscle weakness (especially in your legs and feet), loss of

control of the bowels or bladder (incontinence).

XARELTO is not for use in people with artificial heart valves.

What is XARELTO?

XARELTO is a prescription medicine used to:

reduce the risk of stroke and blood clots in people who have a medical condition called atrial

fibrillation that is not caused by a heart valve problem. With atrial fibrillation, part of the heart does

not beat the way it should. This can lead to the formation of blood clots, which can travel to the

brain, causing a stroke, or to other parts of the body.

treat blood clots in the veins of your legs (deep vein thrombosis or DVT) or lungs (pulmonary

embolism or PE)

reduce the risk of blood clots happening again in people who continue to be at risk for DVT or PE

after receiving treatment for blood clots for at least 6 months.

help prevent a blood clot in the legs and lungs of people who have just had hip or knee replacement

surgery.

XARELTO is used with low dose aspirin to:

reduce the risk of serious heart problems, heart attack and stroke in patients with coronary artery

disease (a condition where the blood supply to the heart is reduced or blocked) or peripheral artery

disease (a condition where the blood flow to the legs is reduced).

It is not known if XARELTO is safe and effective in children.

Do not take XARELTO if you:

currently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO if

you currently have unusual bleeding.

are allergic to rivaroxaban or any of the ingredients in XARELTO. See the end of this Medication

Guide for a complete list of ingredients in XARELTO.

Before taking XARELTO, tell your doctor about all of your medical conditions, including if you:

have ever had bleeding problems

have liver or kidney problems

are pregnant or plan to become pregnant. It is not known if XARELTO will harm your unborn baby.

Tell your doctor right away if you become pregnant during treatment with XARELTO. Taking

XARELTO while you are pregnant may increase the risk of bleeding in you or in your unborn

baby.

If you take XARELTO during pregnancy tell your doctor right away if you have any signs or

symptoms of bleeding or blood loss. See "What is the most important information I should

know about XARELTO?" for signs and symptoms of bleeding.

are breastfeeding or plan to breastfeed. XARELTO can pass into your breast milk. Talk to your

doctor about the best way to feed your baby during treatment with XARELTO.

Tell all of your doctors and dentists that you are taking XARELTO. They should talk to the doctor who

prescribed XARELTO for you before you have any surgery, medical or dental procedure.

Tell your doctor about all the medicines you take, including prescription and over-the-counter

medicines, vitamins, and herbal supplements.

Some of your other medicines may affect the way XARELTO works, causing side effects. Certain

medicines may increase your risk of bleeding. See "What is the most important information I

should know about XARELTO?"

Especially tell your doctor if you take:

ketoconazole

erythromycin

phenytoin

St. John's wort

ritonavir

carbamazepine

rifampin

How should I take XARELTO?

Take XARELTO exactly as prescribed by your doctor.

Do not change your dose or stop taking XARELTO unless your doctor tells you to.

Your doctor may change your dose if needed.

If you take XARELTO for:

atrial fibrillation that is not caused by a heart valve problem:

Take XARELTO 1 time a day with your evening meal.

If you miss a dose of XARELTO, take it as soon as you remember on the same day. Take

your next dose at your regularly scheduled time.

blood clots in the veins of your legs or lungs:

Take XARELTO 1 or 2 times a day as prescribed by your doctor.

For the 15 mg and 20 mg doses, XARELTO should be taken with food.

For the 10 mg dose, XARELTO may be taken with or without food.

Take your XARELTO doses at the same time each day.

If you miss a dose:

If you take the 15 mg dose of XARELTO 2 times a day (a total of 30 mg of

XARELTO in 1 day): Take XARELTO as soon as you remember on the same day.

hip or knee replacement surgery:

Take XARELTO 1 time a day with or without food.

If you miss a dose of XARELTO, take it as soon as you remember on the same day. Take

your next dose at your regularly scheduled time.

reducing the risk of serious heart problems, heart attack and stroke in coronary artery

disease or peripheral artery disease:

Take XARELTO 2 times a day with or without food.

If you miss a dose of XARELTO, take your next dose at your regularly scheduled time.

If you have difficulty swallowing the XARELTO tablet whole, talk to your doctor about other ways

to take XARELTO.

Your doctor will decide how long you should take XARELTO.

XARELTO may need to be stopped, if possible for one or more days before any surgery or

medical or dental procedure. If you need to stop taking XARELTO for any reason, talk to the doctor

who prescribed XARELTO to you to find out when you should stop taking it. Do not stop taking

XARELTO without first talking to the doctor who prescribes it to you. Your doctor will tell

you when to start taking XARELTO again after your surgery or procedure.

Do not run out of XARELTO. Refill your prescription of XARELTO before you run out. When

leaving the hospital following a hip or knee replacement, be sure that you will have XARELTO

available to avoid missing any doses.

If you take too much XARELTO, go to the nearest hospital emergency room or call your doctor

right away.

What are the possible side effects of XARELTO?

The most common side effect of XARELTO was bleeding.

See "What is the most important information I should know about XARELTO?"

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 800-

FDA-1088.

How should I store XARELTO?

Store XARELTO at room temperature between 68°F to 77°F (20°C to 25°C).

Keep XARELTO and all medicines out of the reach of children.

General information about the safe and effective use of XARELTO.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use XARELTO for a condition for which it was not prescribed. Do not give XARELTO to other

people, even if they have the same symptoms that you have. It may harm them. You can ask your

pharmacist or doctor for information about XARELTO that is written for health professionals.

What are the ingredients in XARELTO?

Active ingredient: rivaroxaban

Inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate,

microcrystalline cellulose, and sodium lauryl sulfate.

The proprietary film coating mixture for XARELTO 2.5 mg tablets is Opadry

Light Yellow and

contains: ferric oxide yellow, hypromellose, polyethylene glycol 3350, and titanium dioxide.

The proprietary film coating mixture for XARELTO 10 mg tablets is Opadry

Pink and contains: ferric

oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.

The proprietary film coating mixture for XARELTO 15 mg tablets is Opadry

Red and contains: ferric

oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.

You may take 2 doses at the same time to make up for the missed dose. Take your next

dose at your regularly scheduled time.

If you take XARELTO 1 time a day: Take XARELTO as soon as you remember on

the same day. Take your next dose at your regularly scheduled time.

This Medication Guide has been approved by the U.S. Food and Drug

Administration

Revised: 10/2018

The proprietary film coating mixture for XARELTO 20 mg tablets is Opadry

II Dark Red and

contains: ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and

titanium dioxide.

Finished Product Manufactured by: Janssen Ortho LLC Gurabo, PR 00778 or Bayer AG 51368

Leverkusen, Germany

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer

HealthCare AG 51368 Leverkusen, Germany

© 2011 Janssen Pharmaceutical Companies

Trademarks are property of their respective owners.

For more information go to www.XARELTO-US.com or call 1-800-526-7736.

Storage

Store at 25°C (77°F) or room temperature; excursions permitted to 15°–30°C (59°–86°F) [see USP

Controlled Room Temperature]. Keep out of the reach of children.

rivaroxaban

XARELTO

rivaroxaban tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code

(S ource )

NDC:50 0 9 0 -446 9 (NDC:50 458 -58 0 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

RIVARO XABAN (UNII: 9 NDF7JZ4M3) (RIVAROXABAN - UNII:9 NDF7JZ4M3)

RIVAROXABAN

10 mg

A-S Medication Solutions

Inactive Ingredients

Ingredient Name

Stre ng th

micro crysta lline cellulo se (UNII: OP1R32D6 1U)

cro sca rmello se so dium (UNII: M28 OL1HH48 )

hypro mello se, unspecified (UNII: 3NXW29 V3WO)

la cto se mo no hydra te (UNII: EWQ57Q8 I5X)

ma g nesium stea ra te (UNII: 70 0 9 7M6 I30 )

so dium la uryl sulfa te (UNII: 36 8 GB5141J)

po lyethylene g lyco l 3 3 50 (UNII: G2M7P15E5P)

tita nium dio xide (UNII: 15FIX9 V2JP)

ferric o xide red (UNII: 1K0 9 F3G6 75)

Product Characteristics

Color

RED (light red)

S core

no sco re

S hap e

ROUND (bico nvex)

S iz e

6 mm

Flavor

Imprint Code

10 ;Xa

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 0 9 0 -446 9 -0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /16 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 2240 6

0 7/0 1/20 11

Labeler -

A-S Medication Solutions (830016429)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

A-S Medicatio n So lutio ns

8 30 0 16 429

RELABEL(50 0 9 0 -446 9 )

Revised: 8/2019

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