ELIQUIS HCP Electronic Combo Dosing Guide - Desktop PDF

Dosing Guide
for All ELIQUIS Indications
Find out more at

hcp.eliquis.com
Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
ELIQUIS® (apixaban) INDICATIONS
Approved for 6 indications

to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial
fibrillation (NVAF)
for the treatment of deep vein thrombosis (DVT)
for the treatment of pulmonary embolism (PE)
to reduce the risk of recurrent DVT and PE following initial therapy
for the prophylaxis of DVT, which may lead to PE, in patients who have undergone hip
replacement surgery
for the prophylaxis of DVT, which may lead to PE, in patients who have undergone knee
replacement surgery
SELECTED IMPORTANT SAFETY INFORMATION
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC

EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
(A) Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk
of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than
pathological bleeding or completion of a course of therapy, consider coverage with another
anticoagulant.
(B) Epidural or spinal hematomas may occur in patients treated with ELIQUIS 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 nonsteroidal 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 ELIQUIS and neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological
compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be
anticoagulated.
Please see Important Safety Information throughout and Full Prescribing Information, 2
including Boxed WARNINGS, following page 15.
ELIQUIS® (apixaban) DOSING SUMMARY
Indication Recommended dosing

For all indications: Please see page 13 for additional dosage adjustment information on coadministration
with strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp)
5 mg twice daily in most patients
Dose adjustment for NVAF patients: 2.5 mg twice daily is

recommended for patients with at least 2 of the following
Reduction in the risk characteristics:
of stroke/systemic • age ≥80 years
embolism in NVAF • body weight ≤60 kg
• serum creatinine ≥1.5 mg/dL
10 mg twice daily for the first 7 days
 After 7 days, transition to 

Treatment of DVT/PEE
5 mg twice daily
2.5 mg twice daily after at least 6 months of treatment for

Reduction in the risk DVT or PE
of recurrent DVT/PE
following initial therapy
2.5 mg twice daily for 35 days starting 12 to 24 hours after hip

replacement surgery
Prophylaxis of DVT,
which may lead to PE, 2.5 mg twice daily for 12 days starting 12 to 24 hours after knee
following hip or knee replacement surgery
replacement surgery

CONTRAINDICATIONS
• Active pathological bleeding
• Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions)
For patients with NVAF,
DOSING FOR REDUCING THE RISK OF STROKE & SYSTEMIC EMBOLISM
5 mg taken orally twice daily recommended for most NVAF patients
Recommended dose
5 mg
In 2 Phase III NVAF clinical trials, approximately
twice
95% of ELIQUIS® (apixaban) patients received
daily this dose.
Dosage adjustment
Patients with at least 2 of the following:
a age
≥80 years
b body weight
≤60 kg
c serum creatinine
2.5 mg ≥1.5 mg/dl
twice OR
daily
For patients taking drugs that are strong dual
inhibitors of cytochrome P450 3A4 (CYP3A4)
and P-glycoprotein (P-gp) (e.g., ketoconazole,
itraconazole, ritonavir, clarithromycin).
Note: In patients already taking 2.5 mg twice
daily, avoid coadministration of ELIQUIS with
strong dual inhibitors of CYP3A4 and P-gp.
PLEASE SEE PAGES 8-14 FOR ADDITIONAL IMPORTANT DOSING INFORMATION.

WARNINGS AND PRECAUTIONS
• Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation
of any oral anticoagulant, including ELIQUIS, in the absence of adequate alternative anticoagulation
increases the risk of thrombotic events. An increased rate of stroke was observed during the transition
from ELIQUIS to warfarin in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a
reason other than pathological bleeding or completion of a course of therapy, consider coverage with
another anticoagulant.
For patients with DVT/PE,
DOSING FOR TREATING DVT/PE
10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily
recommended for the treatment of DVT and PE
Recommended dose
10 mg (two 5 mg tablets) 5 mg
twice daily twice daily
Day 1 to Day 7 Following Day 7
An example of an ELIQUIS® (apixaban) prescription for a patient starting

therapy for the treatment of DVT/PE
FOR
ADDRESS
R/
ELIQUIS 5 mg tablets
Take 2 tablets by mouth twice daily for 7 days
Followed by 1 tablet by mouth twice daily
First 30 days = 74 tablets

Subsequent prescriptions for a 30-day supply = 60 tablets (take one 5 mg tablet by mouth twice daily)

WARNINGS AND PRECAUTIONS (continued)
• Bleeding Risk: ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding.
- Concomitant use of drugs affecting hemostasis increases the risk of bleeding, including aspirin and
other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and
NSAIDs.

For patients who have experienced a DVT/PE,
REDUCING THE RISK OF RECURRENT DVT/PE FOLLOWING
INITIAL THERAPY
2.5 mg taken orally twice daily recommended for the reduction in the risk of
recurrent DVT/PE following initial therapy
Recommended dose
2.5 mg
twice
daily
Following ≥6 months
of treatment for DVT or PE
Note: For patients receiving ELIQUIS® (apixaban) doses of 5 mg or 10 mg twice daily, reduce the dose
by 50% when ELIQUIS is coadministered with drugs that are strong dual inhibitors of cytochrome P450
3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin).
In patients already taking 2.5 mg twice daily, coadministration of ELIQUIS with strong dual inhibitors of
CYP3A4 and P-gp should be avoided.

• Bleeding Risk (continued)
- Advise patients of signs and symptoms of blood loss and to report them immediately or go to an
emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage.
- There is no established way to reverse the anticoagulant effect of apixaban, which can be expected
to persist for at least 24 hours after the last dose (i.e., about two half-lives). A specific antidote for
ELIQUIS is not available.
For patients who have undergone hip or knee replacement surgery,
DOSING FOR PROPHYLAXIS OF DVT, WHICH MAY LEAD TO PE
2.5 mg taken orally twice daily recommended for hip or knee replacement
surgery patients
Recommended dose
2.5 mg
twice
daily
The initial dose should be taken 12 to 24 hours after hip or knee replacement surgery
35
DAYS
Recommended treatment duration for patients undergoing
hip replacement surgery
12
DAYS
ecommended treatment duration for patients undergoing
R
knee replacement surgery
Note: In patients already taking 2.5 mg twice daily, coadministration of ELIQUIS® (apixaban) with strong
dual inhibitors of CYP3A4 and P-gp should be avoided.

Spinal/Epidural Anesthesia or Puncture: Patients treated with ELIQUIS undergoing spinal/epidural
•
anesthesia or puncture may develop an epidural or spinal hematoma which can result in long-term or
permanent paralysis.
The risk of these events may be increased by the postoperative use of indwelling epidural catheters
or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal
catheters should not be removed earlier than 24 hours after the last administration of ELIQUIS. The next
dose of ELIQUIS should not be administered earlier than 5 hours after the removal of the catheter. The
risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture
occurs, delay the administration of ELIQUIS for 48 hours.
Monitor patients frequently and if neurological compromise is noted, urgent diagnosis and treatment is
necessary. Physicians should consider the potential benefit versus the risk of neuraxial intervention in
ELIQUIS patients.
DOSING IN PATIENTS WITH
RENAL IMPAIRMENT
ELIQUIS® (apixaban) elimination
Renal excretion
accounts for about
27%
of total clearance
• ELIQUIS is eliminated in both urine and feces. Biliary and direct intestinal excretion contributes to
elimination of ELIQUIS in the feces
No dose adjustment required for patients with renal impairment for the
following indications:
Prophylaxis of DVT, which may lead to PE, in patients who have undergone hip or
knee replacement surgery
Treatment of DVT
Treatment of PE
Reduction in the risk of recurrent DVT and PE following initial therapy

Prosthetic Heart Valves: The safety and efficacy of ELIQUIS have not been studied in patients with
•
prosthetic heart valves and is not recommended in these patients.
RENAL IMPAIRMENT
Dosing in patients with renal impairment
Renal impairment No dose adjustment
Mild
Moderate
Severe
End-stage renal disease (ESRD)*
No dose adjustment is recommended for patients with renal impairment alone, including those
with end-stage renal disease (ESRD) maintained on hemodialysis, except for NVAF patients who
meet the criteria for dosage adjustment
*Patients with ESRD (CrCl <15 mL/min) receiving or not receiving hemodialysis were not studied in
clinical efficacy and safety studies with ELIQUIS® (apixaban); therefore, the dosing recommendations
are based on pharmacokinetic and pharmacodynamic (anti-Factor Xa activity) data in subjects with
ESRD maintained on dialysis

Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or
•
Pulmonary Embolectomy: Initiation of ELIQUIS is not recommended as an alternative to unfractionated
heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may
receive thrombolysis or pulmonary embolectomy.
HEPATIC IMPAIRMENT
Dosing in patients with hepatic impairment
Moderate Severe
hepatic impairment hepatic impairment hepatic impairment
(Child-Pugh class A) (Child-Pugh class B) (Child-Pugh class C)
There is limited clinical

experience with
ELIQUIS® (apixaban)
No dose
in patients with ELIQUIS is not
adjustment
moderate hepatic recommended
required
impairment; dosing
recommendation
cannot be provided

ADVERSE REACTIONS
• The most common and most serious adverse reactions reported with ELIQUIS were related to bleeding.
DOSING CONSIDERATIONS AND
ADMINISTRATION OPTIONS
Additional dosing considerations

• Does not require routine monitoring using international normalized ratio (INR) or other
tests of coagulation
• No known dietary restrictions
• Can be taken with or without food
• Missed dose: If a dose of ELIQUIS® (apixaban) is not taken at the scheduled time, the dose
should be taken as soon as possible on the same day and twice-daily administration should
be resumed. The dose should not be doubled to make up for a missed dose
Temporary interruption for surgery and other interventions
Elective surgery or invasive procedures with moderate or high risk of

unacceptable or clinically significant bleeding
• Discontinue ELIQUIS at least 48 hours prior
Elective surgery or invasive procedures with low risk of bleeding or

bleeding in noncritical site and easily controlled
• Discontinue ELIQUIS at least 24 hours prior
Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the
intervention is not generally required. ELIQUIS should be restarted after the surgical or
other procedures as soon as adequate hemostasis has been established.

TEMPORARY INTERRUPTION FOR SURGERY AND OTHER INTERVENTIONS
• ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a
moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued
at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the
bleeding would be noncritical in location and easily controlled. Bridging anticoagulation during the 24 to
48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be
restarted after the surgical or other procedures as soon as adequate hemostasis has been established.
DOSING CONSIDERATIONS AND
ADMINISTRATION OPTIONS
Guidance for switching patients to and from ELIQUIS® (apixaban)
Switching from warfarin to ELIQUIS

• Discontinue warfarin and start ELIQUIS when the INR is <2.0
Switching from anticoagulants other than warfarin (oral or parenteral)
to ELIQUIS
• Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the usual
time of the next dose of the anticoagulant other than warfarin
Switching from ELIQUIS to anticoagulants other than
warfarin (oral or parenteral)
• Discontinue ELIQUIS and begin taking the new anticoagulant other than warfarin at the usual
time of the next dose of ELIQUIS
Switching from ELIQUIS to warfarin
• Discontinue ELIQUIS and begin both parenteral anticoagulant and warfarin at the time the
next dose would have been taken, discontinuing the parenteral anticoagulant when INR
reaches an acceptable range.
• ELIQUIS affects INR, so that initial INR measurements during transition to warfarin may not
be useful for determining the appropriate dose of warfarin.
Administration options
• For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS tablets
may be crushed and suspended in 60 mL D5W and immediately delivered through a
nasogastric tube. Information regarding the administration of crushed and suspended
ELIQUIS tablets swallowed by mouth is not available
DRUG INTERACTIONS
Strong Dual Inhibitors of CYP3A4 and P-gp: Inhibitors of cytochrome P450 3A4 (CYP3A4) and
•
P-glycoprotein (P-gp) increase exposure to apixaban and increase the risk of bleeding. For patients
receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose of ELIQUIS by 50% when ELIQUIS
is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole,
itraconazole, ritonavir, or clarithromycin). In patients already taking 2.5 mg twice daily, avoid
coadministration of ELIQUIS with strong dual inhibitors of CYP3A4 and P-gp.
DRUG INTERACTIONS
Strong dual inhibitors of CYP3A4 and P-gp

For patients receiving ELIQUIS® (apixaban) doses of 5 mg or 10 mg twice daily, reduce
the dose by 50% if coadministered with drugs that are strong dual inhibitors of
CYP3A4 and P-gp, such as:
• Ketoconazole • Ritonavir
• Itraconazole • Clarithromycin
In patients already taking ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration
with strong dual inhibitors of CYP3A4 and P-gp
Strong dual inducers of CYP3A4 and P-gp

Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp, as
such drugs decrease exposure to ELIQUIS and increase the risk of stroke and other
thromboembolic events:
•R ifampin •P
henytoin
• Carbamazepine • St John’s wort
These drug categories are examples described in the Full Prescribing Information, not an all-inclusive list.
DRUG INTERACTIONS (continued)

Strong Dual Inducers of CYP3A4 and P-gp: Avoid concomitant use of ELIQUIS with strong dual inducers
•
of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will
decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events.
Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet agents, fibrinolytics,
•
heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled
clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or
the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with
apixaban compared to placebo.
DRUG INTERACTIONS
Drugs affecting hemostasis

Coadministration with these drugs increases the risk of bleeding:
• Aspirin and other antiplatelet agents
• Other anticoagulants
• Heparin
• Thrombolytic agents
• Selective serotonin reuptake inhibitors (SSRls)
• Serotonin norepinephrine reuptake inhibitors (SNRls)
• Nonsteroidal anti-inflammatory drugs (NSAIDs), when used chronically
• Fibrinolytics
These drug categories are examples described in the Full Prescribing Information, not an all-inclusive list.
Additional considerations
• Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase
exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease
exposure to apixaban and increase the risk of stroke and other thromboembolic events
Adjust ELIQUIS dose for patients taking drugs that are strong dual inhibitors of CYP3A4
and P-gp
• Famotidine, atenolol, prasugrel, and enoxaparin did not meaningfully alter the
pharmacokinetics of ELIQUIS® (apixaban) in healthy subjects
• E LIQUIS did not meaningfully alter the pharmacokinetics of digoxin, naproxen, atenolol,
prasugrel, or acetylsalicylic acid in healthy subjects
•A PPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary
syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was
terminated early due to a higher rate of bleeding with apixaban compared to placebo

PREGNANCY CATEGORY B
• There are no adequate and well-controlled studies of ELIQUIS in pregnant women. Treatment is likely to
increase the risk of hemorrhage during pregnancy and delivery. ELIQUIS should be used during pregnancy
only if the potential benefit outweighs the potential risk to the mother and fetus.
Approved for
6 Indications
Find out more at:

hcp.eliquis.com
Reference: ELIQUIS® (apixaban) Package Insert.

Bristol-Myers Squibb Company, Princeton, NJ, and Pfizer Inc, New York, NY; 2015.
Please see Important Safety Information throughout and Full Prescribing Information,
ELIQUIS® and the ELIQUIS logo are trademarks of Bristol-Myers Squibb Company.
15
© 2014 Bristol-Myers Squibb Company. All rights reserved. 432US15BR01174-01-01 10/15
HIGHLIGHTS OF PRESCRIBING INFORMATION • Prophylaxis of DVT following hip or knee replacement surgery:
These highlights do not include all the information needed to use ELIQUIS safely • The recommended dose is 2.5 mg orally twice daily. (2.1)
and effectively. See full prescribing information for ELIQUIS. • Treatment of DVT and PE:
ELIQUIS® (apixaban) tablets, for oral use
• The recommended dose is 10 mg taken orally twice daily for 7 days, followed
Initial U.S. Approval: 2012
by 5 mg taken orally twice daily. (2.1)
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS • Reduction in the risk of recurrent DVT and PE following initial therapy:
INCREASES THE RISK OF THROMBOTIC EVENTS • The recommended dose is 2.5 mg taken orally twice daily. (2.1)
(B) SPINAL/EPIDURAL HEMATOMA ------------------------ DOSAGE FORMS AND STRENGTHS -----------------------
See full prescribing information for complete boxed warning.
• Tablets: 2.5 mg and 5 mg (3)
(A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF
THROMBOTIC EVENTS: Premature discontinuation of any oral anticoagulant, -------------------------------CONTRAINDICATIONS ------------------------------
including ELIQUIS, increases the risk of thrombotic events. To reduce • Active pathological bleeding (4)
this risk, consider coverage with another anticoagulant if ELIQUIS is • Severe hypersensitivity to ELIQUIS (apixaban) (4)
discontinued for a reason other than pathological bleeding or completion
of a course of therapy. (2.4, 5.1, 14.1) --------------------------WARNINGS AND PRECAUTIONS -------------------------
(B) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas may • ELIQUIS can cause serious, potentially fatal bleeding. Promptly evaluate signs and
occur in patients treated with ELIQUIS who are receiving neuraxial symptoms of blood loss. (5.2)
anesthesia or undergoing spinal puncture. These hematomas may result in
long-term or permanent paralysis. Consider these risks when scheduling • Prosthetic heart valves: ELIQUIS use not recommended. (5.4)
patients for spinal procedures. (5.3) ------------------------------ ADVERSE REACTIONS------------------------------
Most common adverse reactions (>1%) are related to bleeding. (6.1)
---------------------------- RECENT MAJOR CHANGES --------------------------- To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at
Dosage and Administration (2.4) 6/2015 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
---------------------------- INDICATIONS AND USAGE---------------------------- -------------------------------DRUG INTERACTIONS ------------------------------
ELIQUIS is a factor Xa inhibitor indicated:
• Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of apixaban.
• to reduce the risk of stroke and systemic embolism in patients with nonvalvular
atrial fibrillation. (1.1) Reduce ELIQUIS dose or avoid coadministration. (2.5, 7.1, 12.3)
• for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary • Simultaneous use of strong dual inducers of CYP3A4 and P-gp reduces blood
embolism (PE), in patients who have undergone hip or knee replacement levels of apixaban: Avoid concomitant use. (7.2, 12.3)
surgery. (1.2)
• for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT ------------------------- USE IN SPECIFIC POPULATIONS-------------------------
and PE following initial therapy. (1.3, 1.4, 1.5) • Pregnancy: Not recommended. (8.1)
------------------------- DOSAGE AND ADMINISTRATION ------------------------ • Nursing Mothers: Discontinue drug or discontinue nursing. (8.3)
• Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation: • Severe Hepatic Impairment: Not recommended. (8.7, 12.2)
• The recommended dose is 5 mg orally twice daily. (2.1)
• In patients with at least 2 of the following characteristics: age ≥80 years,
body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, the recommended dose See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
is 2.5 mg orally twice daily. (2.1) Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS* 6 ADVERSE REACTIONS

WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES 6.1 Clinical Trials Experience
THE RISK OF THROMBOTIC EVENTS 7 DRUG INTERACTIONS
7.1 Strong Dual Inhibitors of CYP3A4 and P-gp
(B) SPINAL/EPIDURAL HEMATOMA 7.2 Strong Dual Inducers of CYP3A4 and P-gp
1 INDICATIONS AND USAGE 7.3 Anticoagulants and Antiplatelet Agents
1.1 Reduction of Risk of Stroke and Systemic Embolism in 8 USE IN SPECIFIC POPULATIONS
Nonvalvular Atrial Fibrillation 8.1 Pregnancy
1.2 Prophylaxis of Deep Vein Thrombosis Following Hip or 8.2 Labor and Delivery
8.3 Nursing Mothers
Knee Replacement Surgery
8.4 Pediatric Use
1.3 Treatment of Deep Vein Thrombosis 8.5 Geriatric Use
1.4 Treatment of Pulmonary Embolism 8.6 Renal Impairment
1.5 Reduction in the Risk of Recurrence of DVT and PE 8.7 Hepatic Impairment
2 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE
2.1 Recommended Dose 11 DESCRIPTION
2.2 Missed Dose 12 CLINICAL PHARMACOLOGY
2.3 Temporary Interruption for Surgery and Other Interventions 12.1 Mechanism of Action
12.2 Pharmacodynamics
2.4 Converting from or to ELIQUIS 12.3 Pharmacokinetics
2.5 Strong Dual Inhibitors of CYP3A4 and P-glycoprotein 13 NONCLINICAL TOXICOLOGY
2.6 Administration Options 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
3 DOSAGE FORMS AND STRENGTHS 14 CLINICAL STUDIES
4 CONTRAINDICATIONS 14.1 Reduction of Risk of Stroke and Systemic Embolism in
Nonvalvular Atrial Fibrillation
5 WARNINGS AND PRECAUTIONS 14.2 Prophylaxis of Deep Vein Thrombosis Following Hip or
5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Knee Replacement Surgery
5.2 Bleeding 14.3 Treatment of DVT and PE and Reduction in the Risk of
5.3 Spinal/Epidural Anesthesia or Puncture Recurrence of DVT and PE
5.4 Patients with Prosthetic Heart Valves 16 HOW SUPPLIED/STORAGE AND HANDLING
5.5 Acute PE in Hemodynamically Unstable Patients or Patients who 17 PATIENT COUNSELING INFORMATION
Require Thrombolysis or Pulmonary Embolectomy * Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION ELIQUIS® (apixaban)
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE • In patients undergoing hip replacement surgery, the recommended duration of
RISK OF THROMBOTIC EVENTS treatment is 35 days.
(B) SPINAL/EPIDURAL HEMATOMA
• In patients undergoing knee replacement surgery, the recommended duration of
(A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF treatment is 12 days.
THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including ELIQUIS, Treatment of DVT and PE
increases the risk of thrombotic events. If anticoagulation with ELIQUIS is
discontinued for a reason other than pathological bleeding or completion of The recommended dose of ELIQUIS is 10 mg taken orally twice daily for the first 7 days
a course of therapy, consider coverage with another anticoagulant [see of therapy. After 7 days, the recommended dose is 5 mg taken orally twice daily.
Dosage and Administration (2.4), Warnings and Precautions (5.1), and
Clinical Studies (14.1)]. Reduction in the Risk of Recurrence of DVT and PE
(B) SPINAL/EPIDURAL HEMATOMA The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least
Epidural or spinal hematomas may occur in patients treated with ELIQUIS 6 months of treatment for DVT or PE [see Clinical Studies (14.3)].
who are receiving neuraxial anesthesia or undergoing spinal puncture.
These hematomas may result in long-term or permanent paralysis. Consider 2.2 Missed Dose
these risks when scheduling patients for spinal procedures. Factors that If a dose of ELIQUIS is not taken at the scheduled time, the dose should be taken as
can increase the risk of developing epidural or spinal hematomas in these soon as possible on the same day and twice-daily administration should be resumed.
patients include: The dose should not be doubled to make up for a missed dose.
• use of indwelling epidural catheters
• concomitant use of other drugs that affect hemostasis, such as 2.3 Temporary Interruption for Surgery and Other Interventions
nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive
other anticoagulants procedures with a moderate or high risk of unacceptable or clinically significant
• a history of traumatic or repeated epidural or spinal punctures bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery
• a history of spinal deformity or spinal surgery or invasive procedures with a low risk of bleeding or where the bleeding would be
non-critical in location and easily controlled. Bridging anticoagulation during the
• optimal timing between the administration of ELIQUIS and neuraxial 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally
procedures is not known required. ELIQUIS should be restarted after the surgical or other procedures as soon
[see Warnings and Precautions (5.3)] as adequate hemostasis has been established.
Monitor patients frequently for signs and symptoms of neurological
impairment. If neurological compromise is noted, urgent treatment is 2.4 Converting from or to ELIQUIS
necessary [see Warnings and Precautions (5.3)]. Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS
Consider the benefits and risks before neuraxial intervention in patients started when the international normalized ratio (INR) is below 2.0.
anticoagulated or to be anticoagulated [see Warnings and Precautions (5.3)].
Switching from ELIQUIS to warfarin: ELIQUIS affects INR, so that initial INR
measurements during the transition to warfarin may not be useful for determining the
1 INDICATIONS AND USAGE appropriate dose of warfarin. One approach is to discontinue ELIQUIS and begin both
a parenteral anticoagulant and warfarin at the time the next dose of ELIQUIS would
have been taken, discontinuing the parenteral anticoagulant when INR reaches an
1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular acceptable range.
Atrial Fibrillation
Switching from ELIQUIS to anticoagulants other than warfarin (oral or parenteral):
ELIQUIS® (apixaban) is indicated to reduce the risk of stroke and systemic embolism Discontinue ELIQUIS and begin taking the new anticoagulant other than warfarin at
in patients with nonvalvular atrial fibrillation. the usual time of the next dose of ELIQUIS.
1.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS:
Replacement Surgery Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the
usual time of the next dose of the anticoagulant other than warfarin.
ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may
lead to pulmonary embolism (PE), in patients who have undergone hip or knee 2.5 Strong Dual Inhibitors of CYP3A4 and P-glycoprotein
replacement surgery.
For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose
1.3 Treatment of Deep Vein Thrombosis by 50% when ELIQUIS is coadministered with drugs that are strong dual inhibitors
of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole,
ELIQUIS is indicated for the treatment of DVT. itraconazole, ritonavir, clarithromycin) [see Clinical Pharmacology (12.3)].
1.4 Treatment of Pulmonary Embolism In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with
ELIQUIS is indicated for the treatment of PE. strong dual inhibitors of CYP3A4 and P-gp [see Drug Interactions (7.1)].
1.5 Reduction in the Risk of Recurrence of DVT and PE 2.6 Administration Options
ELIQUIS is indicated to reduce the risk of recurrent DVT and PE following initial therapy. For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS
tablets may be crushed and suspended in 60 mL D5W and immediately delivered
through a nasogastric tube (NGT) [see Clinical Pharmacology (12.3)]. Information
2 DOSAGE AND ADMINISTRATION regarding the administration of crushed and suspended ELIQUIS tablets swallowed
by mouth is not available.
2.1 Recommended Dose
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular 3 DOSAGE FORMS AND STRENGTHS
Atrial Fibrillation • 2.5 mg, yellow, round, biconvex, film-coated tablets with “893” debossed on
The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily. one side and “2½” on the other side.
The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with at least two • 5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894” debossed on
of the following characteristics: one side and “5” on the other side.
• age ≥80 years
4 CONTRAINDICATIONS
• body weight ≤60 kg
ELIQUIS is contraindicated in patients with the following conditions:
• serum creatinine ≥1.5 mg/dL
• Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Reactions (6.1)]
The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose • Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) [see
should be taken 12 to 24 hours after surgery. Adverse Reactions (6.1)]
ELIQUIS® (apixaban) ELIQUIS® (apixaban)
5 WARNINGS AND PRECAUTIONS 6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction
5.1 Increased Risk of Thrombotic Events after Premature Discontinuation rates observed in the clinical trials of a drug cannot be directly compared to rates in
Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence the clinical trials of another drug and may not reflect the rates observed in practice.
of adequate alternative anticoagulation increases the risk of thrombotic events.
An increased rate of stroke was observed during the transition from ELIQUIS to Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial
warfarin in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a Fibrillation
reason other than pathological bleeding or completion of a course of therapy, consider The safety of ELIQUIS was evaluated in the ARISTOTLE and AVERROES studies
coverage with another anticoagulant [see Dosage and Administration (2.4) and [see Clinical Studies (14)], including 11,284 patients exposed to ELIQUIS 5 mg twice
Clinical Studies (14.1)]. daily and 602 patients exposed to ELIQUIS 2.5 mg twice daily. The duration of ELIQUIS
5.2 Bleeding exposure was ≥12 months for 9375 patients and ≥24 months for 3369 patients in the
two studies. In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000
ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, patient-years). In AVERROES, the mean duration of exposure was approximately
bleeding [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. 59 weeks (>3000 patient-years).
Concomitant use of drugs affecting hemostasis increases the risk of bleeding. The most common reason for treatment discontinuation in both studies was for
These include aspirin and other antiplatelet agents, other anticoagulants, heparin, bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of
thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine patients treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5%
reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug and 1.3% on ELIQUIS and aspirin, respectively.
Interactions (7.3)].
Advise patients of signs and symptoms of blood loss and to report them immediately Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES
or go to an emergency room. Discontinue ELIQUIS in patients with active pathological Tables 1 and 2 show the number of patients experiencing major bleeding during
hemorrhage. the treatment period and the bleeding rate (percentage of subjects with at least one
bleeding event per 100 patient-years) in ARISTOTLE and AVERROES.
There is no established way to reverse the anticoagulant effect of apixaban, which
can be expected to persist for at least 24 hours after the last dose, i.e., for about Table 1: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation
two drug half-lives. A specific antidote for ELIQUIS is not available. Hemodialysis in ARISTOTLE*
does not appear to have a substantial impact on apixaban exposure [see Clinical
Pharmacology (12.3)]. Protamine sulfate and vitamin K are not expected to affect ELIQUIS Warfarin Hazard Ratio P-value
the anticoagulant activity of apixaban. There is no experience with antifibrinolytic N=9088 N=9052 (95% CI)
agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There n (per n (per
is neither scientific rationale for reversal nor experience with systemic hemostatics 100 pt-year) 100 pt-year)
(desmopressin and aprotinin) in individuals receiving apixaban. Use of procoagulant
Major† 327 (2.13) 462 (3.09) 0.69 (0.60, 0.80) <0.0001
reversal agents such as prothrombin complex concentrate, activated prothrombin
complex concentrate, or recombinant factor VIIa may be considered but has not been Intracranial (ICH)‡ 52 (0.33) 125 (0.82) 0.41 (0.30, 0.57) -
evaluated in clinical studies. Activated oral charcoal reduces absorption of apixaban,
thereby lowering apixaban plasma concentration [see Overdosage (10)]. Hemorrhagic stroke§ 38 (0.24) 74 (0.49) 0.51 (0.34, 0.75) -
Other ICH 15 (0.10) 51 (0.34) 0.29 (0.16, 0.51) -
5.3 Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural Gastrointestinal (GI)¶ 128 (0.83) 141 (0.93) 0.89 (0.70, 1.14) -
puncture is employed, patients treated with antithrombotic agents for prevention Fatal** 10 (0.06) 37 (0.24) 0.27 (0.13, 0.53) -
of thromboembolic complications are at risk of developing an epidural or spinal
hematoma which can result in long-term or permanent paralysis. Intracranial 4 (0.03) 30 (0.20) 0.13 (0.05, 0.37) -
The risk of these events may be increased by the postoperative use of indwelling epidural Non-intracranial 6 (0.04) 7 (0.05) 0.84 (0.28, 2.15) -
catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling * Bleeding events within each subcategory were counted once per subject, but subjects
epidural or intrathecal catheters should not be removed earlier than 24 hours after the may have contributed events to multiple endpoints. Bleeding events were counted
last administration of ELIQUIS. The next dose of ELIQUIS should not be administered during treatment or within 2 days of stopping study treatment (on-treatment period).
earlier than 5 hours after the removal of the catheter. The risk may also be increased † Defined as clinically overt bleeding accompanied by one or more of the following:
by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs,
delay the administration of ELIQUIS for 48 hours. a decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of packed
red blood cells, bleeding at a critical site: intracranial, intraspinal, intraocular, pericardial,
Monitor patients frequently for signs and symptoms of neurological impairment intra-articular, intramuscular with compartment syndrome, retroperitoneal or with
(e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological fatal outcome.
‡ Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid
compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial
intervention the physician should consider the potential benefit versus the risk in bleeding. Any type of hemorrhagic stroke was adjudicated and counted as an intracranial
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. major bleed.
§ On-treatment analysis based on the safety population, compared to ITT analysis
5.4 Patients with Prosthetic Heart Valves presented in Section 14.
¶ GI bleed includes upper GI, lower GI, and rectal bleeding.
The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic
heart valves. Therefore, use of ELIQUIS is not recommended in these patients. ** Fatal bleeding is an adjudicated death with the primary cause of death as intracranial
bleeding or non-intracranial bleeding during the on-treatment period.
5.5 Acute PE in Hemodynamically Unstable Patients or Patients who
Require Thrombolysis or Pulmonary Embolectomy
In ARISTOTLE, the results for major bleeding were generally consistent across most
Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to
for the initial treatment of patients with PE who present with hemodynamic instability estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use,
or who may receive thrombolysis or pulmonary embolectomy. geographic region, and aspirin use at randomization (Figure 1). Subjects treated with
apixaban with diabetes bled more (3.0% per year) than did subjects without diabetes
(1.9% per year).
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other
sections of the prescribing information.
• Increased risk of thrombotic events after premature discontinuation [see
Warnings and Precautions (5.1)]
• Bleeding [see Warnings and Precautions (5.2)]
• Spinal/epidural anesthesia or puncture [see Warnings and Precautions (5.3)]
Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics – ARISTOTLE Study

n of Events / N of Patients (% per year)
Subgroup Apixaban Warfarin Hazard Ratio (95% CI)
All Patients 327 / 9088 (2.1) 462 / 9052 (3.1) 0.69 (0.60, 0.80)
Prior Warfarin/VKA Status
Experienced (57%) 185 / 5196 (2.1) 274 / 5180 (3.2) 0.66 (0.55, 0.80)
Naive (43%) 142 / 3892 (2.2) 188 / 3872 (3.0) 0.73 (0.59, 0.91)
Age
<65 (30%) 56 / 2723 (1.2) 72 / 2732 (1.5) 0.78 (0.55, 1.11)
≥65 and <75 (39%) 120 / 3529 (2.0) 166 / 3501 (2.8) 0.71 (0.56, 0.89)
≥75 (31%) 151 / 2836 (3.3) 224 / 2819 (5.2) 0.64 (0.52, 0.79)
Sex
Male (65%) 225 / 5868 (2.3) 294 / 5879 (3.0) 0.76 (0.64, 0.90)
Female (35%) 102 / 3220 (1.9) 168 / 3173 (3.3) 0.58 (0.45, 0.74)
Weight
≤60 kg (11%) 36 / 1013 (2.3) 62 / 965 (4.3) 0.55 (0.36, 0.83)
>60 kg (89%) 290 / 8043 (2.1) 398 / 8059 (3.0) 0.72 (0.62, 0.83)
Prior Stroke or TIA
Yes (19%) 77 / 1687 (2.8) 106 / 1735 (3.9) 0.73 (0.54, 0.98)
No (81%) 250 / 7401 (2.0) 356 / 7317 (2.9) 0.68 (0.58, 0.80)
Diabetes Mellitus
Yes (25%) 112 / 2276 (3.0) 114 / 2250 (3.1) 0.96 (0.74, 1.25)
No (75%) 215 / 6812 (1.9) 348 / 6802 (3.1) 0.60 (0.51, 0.71)
CHADS2 Score
≤1 (34%) 76 / 3093 (1.4) 126 / 3076 (2.3) 0.59 (0.44, 0.78)
2 (36%) 125 / 3246 (2.3) 163 / 3246 (3.0) 0.76 (0.60, 0.96)
≥3 (30%) 126 / 2749 (2.9) 173 / 2730 (4.1) 0.70 (0.56, 0.88)
Creatinine Clearance
<30 mL/min (1%) 7 / 136 (3.7) 19 / 132 (11.9) 0.32 (0.13, 0.78)
30-50 mL/min (15%) 66 / 1357 (3.2) 123 / 1380 (6.0) 0.53 (0.39, 0.71)
>50-80 mL/min (42%) 157 / 3807 (2.5) 199 / 3758 (3.2) 0.76 (0.62, 0.94)
>80 mL/min (41%) 96 / 3750 (1.5) 119 / 3746 (1.8) 0.79 (0.61, 1.04)
Geographic Region
US (19%) 83 / 1716 (2.8) 109 / 1693 (3.8) 0.75 (0.56, 1.00)
Non-US (81%) 244 / 7372 (2.0) 353 / 7359 (2.9) 0.68 (0.57, 0.80)
Aspirin at Randomization
Yes (31%) 129 / 2846 (2.7) 164 / 2762 (3.7) 0.75 (0.60, 0.95)
No (69%) 198 / 6242 (1.9) 298 / 6290 (2.8) 0.66 (0.55, 0.79)
0.125 0.25 0.5 1 2

Apixaban Warfarin
Better Better
Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were pre-specified, if not the groupings. 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.
Table 2: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation Table 3: Bleeding During the Treatment Period in Patients Undergoing
in AVERROES Elective Hip or Knee Replacement Surgery
ELIQUIS Aspirin Hazard Ratio P-value ADVANCE-3 ADVANCE-2 ADVANCE-1
N=2798 N=2780 (95% CI) Bleeding Hip Replacement Knee Replacement Knee Replacement
n (%/year) n (%/year) Endpoint* Surgery Surgery Surgery
Major 45 (1.41) 29 (0.92) 1.54 (0.96, 2.45) 0.07 ELIQUIS Enoxaparin ELIQUIS Enoxaparin ELIQUIS Enoxaparin
Fatal 5 (0.16) 5 (0.16) 0.99 (0.23, 4.29) - 2.5 mg po 40 mg sc 2.5 mg po 40 mg sc 2.5 mg po 30 mg sc
Intracranial 11 (0.34) 11 (0.35) 0.99 (0.39, 2.51) - bid qd bid qd bid q12h
35±3 days 35±3 days 12±2 days 12±2 days 12±2 days 12±2 days
Events associated with each endpoint were counted once per subject, but subjects may
have contributed events to multiple endpoints. First dose First dose First dose First dose First dose First dose
12 to 9 to 12 to 9 to 12 to 12 to
24 hours 15 hours 24 hours 15 hours 24 hours 24 hours
Other Adverse Reactions post prior post prior post post
Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and surgery to surgery surgery to surgery surgery surgery
anaphylactic reactions, such as allergic edema) and syncope were reported in All treated N=2673 N=2659 N=1501 N=1508 N=1596 N=1588
<1% of patients receiving ELIQUIS.
Major 22 18 9 14 11 22
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery (including (0.82%)† (0.68%) (0.60%)‡ (0.93%) (0.69%) (1.39%)
The safety of ELIQUIS has been evaluated in 1 Phase II and 3 Phase III studies including surgical site)
5924 patients exposed to ELIQUIS 2.5 mg twice daily undergoing major orthopedic Fatal 0 0 0 0 0 1
surgery of the lower limbs (elective hip replacement or elective knee replacement) (0.06%)
treated for up to 38 days.
Hgb decrease 13 10 8 9 10 16
In total, 11% of the patients treated with ELIQUIS 2.5 mg twice daily experienced ≥2 g/dL (0.49%) (0.38%) (0.53%) (0.60%) (0.63%) (1.01%)
adverse reactions.
Transfusion of 16 14 5 9 9 18
Bleeding results during the treatment period in the Phase III studies are shown in ≥2 units RBC (0.60%) (0.53%) (0.33%) (0.60%) (0.56%) (1.13%)
Table 3. Bleeding was assessed in each study beginning with the first dose of (Continued)
double-blind study drug.
Table 3: Bleeding During the Treatment Period in Patients Undergoing Injury, poisoning, and procedural complications: wound secretion, incision-site
(Continued) Elective Hip or Knee Replacement Surgery hemorrhage (including incision-site hematoma), operative hemorrhage
ADVANCE-3 ADVANCE-2 ADVANCE-1 Less common adverse reactions in apixaban-treated patients undergoing hip or knee
Bleeding Hip Replacement Knee Replacement Knee Replacement replacement surgery occurring at a frequency of <0.1%:
Endpoint* Surgery Surgery Surgery
Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular
ELIQUIS Enoxaparin ELIQUIS Enoxaparin ELIQUIS Enoxaparin hemorrhage (including conjunctival hemorrhage), rectal hemorrhage
2.5 mg po 40 mg sc 2.5 mg po 40 mg sc 2.5 mg po 30 mg sc
bid qd bid qd bid q12h Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT or PE
35±3 days 35±3 days 12±2 days 12±2 days 12±2 days 12±2 days The safety of ELIQUIS has been evaluated in the AMPLIFY and AMPLIFY-EXT studies,
First dose First dose First dose First dose First dose First dose including 2676 patients exposed to ELIQUIS 10 mg twice daily, 3359 patients exposed
12 to 9 to 12 to 9 to 12 to 12 to to ELIQUIS 5 mg twice daily, and 840 patients exposed to ELIQUIS 2.5 mg twice daily.
24 hours 15 hours 24 hours 15 hours 24 hours 24 hours Common adverse reactions (≥1%) were gingival bleeding, epistaxis, contusion,
post prior post prior post post hematuria, rectal hemorrhage, hematoma, menorrhagia, and hemoptysis.
surgery to surgery surgery to surgery surgery surgery
AMPLIFY Study
Bleed at 1 1 1 2 1 4
critical site§ (0.04%) (0.04%) (0.07%) (0.13%) (0.06%) (0.25%) The mean duration of exposure to ELIQUIS was 154 days and to enoxaparin/warfarin
was 152 days in the AMPLIFY study. Adverse reactions related to bleeding occurred in
Major 129 134 53 72 46 68 417 (15.6%) ELIQUIS-treated patients compared to 661 (24.6%) enoxaparin/warfarin-
+ CRNM¶ (4.83%) (5.04%) (3.53%) (4.77%) (2.88%) (4.28%) treated patients. The discontinuation rate due to bleeding events was 0.7% in the
All 313 334 104 126 85 108 ELIQUIS-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients
(11.71%) (12.56%) (6.93%) (8.36%) (5.33%) (6.80%) in the AMPLIFY study.
* All bleeding criteria included surgical site bleeding. In the AMPLIFY study, ELIQUIS was statistically superior to enoxaparin/warfarin in the
† Includes 13 subjects with major bleeding events that occurred before the first dose of primary safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55],
apixaban (administered 12 to 24 hours post surgery). P-value <0.0001).
‡ Includes 5 subjects with major bleeding events that occurred before the first dose of
Bleeding results from the AMPLIFY study are summarized in Table 5.
apixaban (administered 12 to 24 hours post surgery).
§ Intracranial, intraspinal, intraocular, pericardial, an operated joint requiring re-operation or
intervention, intramuscular with compartment syndrome, or retroperitoneal. Bleeding into Table 5: Bleeding Results in the AMPLIFY Study
an operated joint requiring re-operation or intervention was present in all patients with ELIQUIS Enoxaparin/Warfarin Relative Risk
this category of bleeding. Events and event rates include one enoxaparin-treated patient N=2676 N=2689 (95% CI)
in ADVANCE-1 who also had intracranial hemorrhage. n (%) n (%)
¶ CRNM = clinically relevant nonmajor.
Major 15 (0.6) 49 (1.8) 0.31 (0.17, 0.55)
p<0.0001
Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement CRNM* 103 (3.9) 215 (8.0)
surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4.
Major + CRNM 115 (4.3) 261 (9.7)
Table 4: Adverse Reactions Occurring in ≥1% of Patients in Either Group Minor 313 (11.7) 505 (18.8)
Undergoing Hip or Knee Replacement Surgery All 402 (15.0) 676 (25.1)
ELIQUIS, n (%) Enoxaparin, n (%) * CRNM = clinically relevant nonmajor bleeding.
2.5 mg po bid 40 mg sc qd or Events associated with each endpoint were counted once per subject, but subjects may
30 mg sc q12h have contributed events to multiple endpoints.
N=5924 N=5904
Nausea 153 (2.6) 159 (2.7)
Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in
Anemia (including postoperative and 153 (2.6) 178 (3.0) Table 6.
hemorrhagic anemia, and respective laboratory
parameters)
Table 6: Adverse Reactions Occurring in ≥1% of Patients Treated for
Contusion 83 (1.4) 115 (1.9) DVT and PE in the AMPLIFY Study
Hemorrhage (including hematoma, and vaginal 67 (1.1) 81 (1.4)
and urethral hemorrhage) ELIQUIS Enoxaparin/Warfarin
N=2676 N=2689
Postprocedural hemorrhage (including 54 (0.9) 60 (1.0) n (%) n (%)
postprocedural hematoma, wound
hemorrhage, vessel puncture site hematoma Epistaxis 77 (2.9) 146 (5.4)
and catheter site hemorrhage) Contusion 49 (1.8) 97 (3.6)
Transaminases increased (including alanine 50 (0.8) 71 (1.2) Hematuria 46 (1.7) 102 (3.8)
aminotransferase increased and alanine
Menorrhagia 38 (1.4) 30 (1.1)
aminotransferase abnormal)
Hematoma 35 (1.3) 76 (2.8)
Aspartate aminotransferase increased 47 (0.8) 69 (1.2)
Hemoptysis 32 (1.2) 31 (1.2)
Gamma-glutamyltransferase increased 38 (0.6) 65 (1.1)
Rectal hemorrhage 26 (1.0) 39 (1.5)
Less common adverse reactions in apixaban-treated patients undergoing hip or knee Gingival bleeding 26 (1.0) 50 (1.9)
replacement surgery occurring at a frequency of ≥0.1% to <1%:
Blood and lymphatic system disorders: thrombocytopenia (including platelet count
decreases) AMPLIFY-EXT Study
Vascular disorders: hypotension (including procedural hypotension) The mean duration of exposure to ELIQUIS was approximately 330 days and to
placebo was 312 days in the AMPLIFY-EXT study. Adverse reactions related to bleeding
Respiratory, thoracic, and mediastinal disorders: epistaxis occurred in 219 (13.3%) ELIQUIS-treated patients compared to 72 (8.7%) placebo-
Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and treated patients. The discontinuation rate due to bleeding events was approximately
melena), hematochezia 1% in the ELIQUIS-treated patients compared to 0.4% in those patients in the placebo
group in the AMPLIFY-EXT study.
Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase
increased, blood bilirubin increased Bleeding results from the AMPLIFY-EXT study are summarized in Table 7.
Renal and urinary disorders: hematuria (including respective laboratory parameters)
Table 7: Bleeding Results in the AMPLIFY-EXT Study 7.2 Strong Dual Inducers of CYP3A4 and P-gp
ELIQUIS 2.5 mg bid ELIQUIS 5 mg bid Placebo Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp
N=840 N=811 N=826 (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will
n (%) n (%) n (%) decrease exposure to apixaban [see Clinical Pharmacology (12.3)].
Major 2 (0.2) 1 (0.1) 4 (0.5) 7.3 Anticoagulants and Antiplatelet Agents
CRNM* 25 (3.0) 34 (4.2) 19 (2.3) Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic
NSAID use increases the risk of bleeding.
Major + CRNM 27 (3.2) 35 (4.3) 22 (2.7)
APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute
Minor 75 (8.9) 98 (12.1) 58 (7.0) coronary syndrome patients treated with aspirin or the combination of aspirin and
All 94 (11.2) 121 (14.9) 74 (9.0) clopidogrel, was terminated early due to a higher rate of bleeding with apixaban
compared to placebo. The rate of ISTH major bleeding was 2.8% per year with
* CRNM = clinically relevant nonmajor bleeding. apixaban versus 0.6% per year with placebo in patients receiving single antiplatelet
Events associated with each endpoint were counted once per subject, but subjects may therapy and was 5.9% per year with apixaban versus 2.5% per year with placebo in
have contributed events to multiple endpoints. those receiving dual antiplatelet therapy.
In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS
from 1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin
Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed increased the bleeding risk from 2.7% per year to 4.6% per year. In this clinical trial,
in Table 8. there was limited (2.3%) use of dual antiplatelet therapy with ELIQUIS.
Table 8: Adverse Reactions Occurring in ≥1% of Patients Undergoing 8 USE IN SPECIFIC POPULATIONS
Extended Treatment for DVT and PE in the AMPLIFY-EXT Study
ELIQUIS ELIQUIS Placebo 8.1 Pregnancy
2.5 mg bid 5 mg bid Pregnancy Category B
N=840 N=811 N=826
n (%) n (%) n (%) There are no adequate and well-controlled studies of ELIQUIS in pregnant women.
Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery.
Epistaxis 13 (1.5) 29 (3.6) 9 (1.1) ELIQUIS should be used during pregnancy only if the potential benefit outweighs the
Hematuria 12 (1.4) 17 (2.1) 9 (1.1) potential risk to the mother and fetus.
Hematoma 13 (1.5) 16 (2.0) 10 (1.2) Treatment of pregnant rats, rabbits, and mice after implantation until the end of
gestation resulted in fetal exposure to apixaban, but was not associated with increased
Contusion 18 (2.1) 18 (2.2) 18 (2.2) risk for fetal malformations or toxicity. No maternal or fetal deaths were attributed to
Gingival bleeding 12 (1.4) 9 (1.1) 3 (0.4) bleeding. Increased incidence of maternal bleeding was observed in mice, rats, and
rabbits at maternal exposures that were 19, 4, and 1 times, respectively, the human
exposure of unbound drug, based on area under plasma-concentration time curve
(AUC) comparisons at the maximum recommended human dose (MRHD) of 10 mg
Other Adverse Reactions (5 mg twice daily).
Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or 8.2 Labor and Delivery
AMPLIFY-EXT studies occurring at a frequency of ≥0.1% to <1%:
Safety and effectiveness of ELIQUIS during labor and delivery have not been studied
Blood and lymphatic system disorders: hemorrhagic anemia in clinical trials. Consider the risks of bleeding and of stroke in using ELIQUIS in this
Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, gastrointestinal setting [see Warnings and Precautions (5.2)].
hemorrhage, hematemesis, melena, anal hemorrhage Treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation
Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural Day 21) with apixaban at a dose of 1000 mg/kg (about 5 times the human exposure
hemorrhage, traumatic hematoma, periorbital hematoma based on unbound apixaban) did not result in death of offspring or death of mother
rats during labor in association with uterine bleeding. However, increased incidence
Musculoskeletal and connective tissue disorders: muscle hemorrhage of maternal bleeding, primarily during gestation, occurred at apixaban doses of
Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia, ≥25 mg/kg, a dose corresponding to ≥1.3 times the human exposure.
menometrorrhagia, genital hemorrhage
8.3 Nursing Mothers
Vascular disorders: hemorrhage
It is unknown whether apixaban or its metabolites are excreted in human milk.
Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae Rats excrete apixaban in milk (12% of the maternal dose).
Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage Women should be instructed either to discontinue breastfeeding or to discontinue
Investigations: blood urine present, occult blood positive, occult blood, red blood cells ELIQUIS therapy, taking into account the importance of the drug to the mother.
urine positive 8.4 Pediatric Use
General disorders and administration-site conditions: injection-site hematoma, vessel Safety and effectiveness in pediatric patients have not been established.
puncture-site hematoma
8.5 Geriatric Use
7 DRUG INTERACTIONS Of the total subjects in the ARISTOTLE and AVERROES clinical studies, >69%
Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp were 65 and older, and >31% were 75 and older. In the ADVANCE-1, ADVANCE-2,
increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and ADVANCE-3 clinical studies, 50% of subjects were 65 and older, while 16%
and P-gp decrease exposure to apixaban and increase the risk of stroke and other were 75 and older. In the AMPLIFY and AMPLIFY-EXT clinical studies, >32% of
thromboembolic events. subjects were 65 and older and >13% were 75 and older. No clinically significant
differences in safety or effectiveness were observed when comparing subjects in
7.1 Strong Dual Inhibitors of CYP3A4 and P-gp different age groups.
For patients receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should 8.6 Renal Impairment
be decreased by 50% when coadministered with drugs that are strong dual inhibitors
of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin) No dose adjustment is recommended for patients with renal impairment alone,
[see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. including those with end-stage renal disease (ESRD) maintained on hemodialysis,
except nonvalvular atrial fibrillation patients who meet the criteria for dosage
For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration
adjustment [see Dosage and Administration (2.1)].
with strong dual inhibitors of CYP3A4 and P-gp [see Dosage and Administration (2.5)
and Clinical Pharmacology (12.3)].
Patients with ESRD (CrCl <15 mL/min) receiving or not receiving hemodialysis
were not studied in clinical efficacy and safety studies with ELIQUIS; therefore, the
dosing recommendations are based on pharmacokinetic and pharmacodynamic A concentration-dependent increase in anti-FXa activity was observed in the dose
(anti-Factor Xa activity) data in subjects with ESRD maintained on dialysis [see Clinical range tested and was similar in healthy subjects and patients with AF.
Pharmacology (12.3)].
This test is not recommended for assessing the anticoagulant effect of apixaban.
8.7 Hepatic Impairment Pharmacodynamic Drug Interaction Studies
No dose adjustment is required in patients with mild hepatic impairment Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin
(Child-Pugh class A). and clopidogrel, prasugrel, enoxaparin, and naproxen were conducted. No
pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel
[see Warnings and Precautions (5.2)]. A 50% to 60% increase in anti-FXa activity
Because patients with moderate hepatic impairment (Child-Pugh class B) may have
was observed when apixaban was coadministered with enoxaparin or naproxen.
intrinsic coagulation abnormalities and there is limited clinical experience with
ELIQUIS in these patients, dosing recommendations cannot be provided [see Clinical Specific Populations
Pharmacology (12.2)].
Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar
ELIQUIS is not recommended in patients with severe hepatic impairment across renal function categories.
(Child-Pugh class C) [see Clinical Pharmacology (12.2)]. Hepatic impairment: Changes in anti-FXa activity were similar in patients with
mild-to-moderate hepatic impairment and healthy subjects. However, in patients with
10 OVERDOSAGE moderate hepatic impairment, there is no clear understanding of the impact of this
degree of hepatic function impairment on the coagulation cascade and its relationship
There is no antidote to ELIQUIS. Overdose of ELIQUIS increases the risk of bleeding to efficacy and bleeding. Patients with severe hepatic impairment were not studied.
[see Warnings and Precautions (5.2)].
Cardiac Electrophysiology
In controlled clinical trials, orally administered apixaban in healthy subjects at doses Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.
up to 50 mg daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for
3 days) had no clinically relevant adverse effects. 12.3 Pharmacokinetics
Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in
In healthy subjects, administration of activated charcoal 2 and 6 hours after exposure for oral doses up to 10 mg.
ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and
27%, respectively. Thus, administration of activated charcoal may be useful in the Absorption
management of apixaban overdose or accidental ingestion.
The absolute bioavailability of apixaban is approximately 50% for doses up to
10 mg of ELIQUIS. Food does not affect the bioavailability of apixaban. Maximum
11 DESCRIPTION
concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration of
ELIQUIS. At doses ≥25 mg, apixaban displays dissolution-limited absorption with
ELIQUIS (apixaban), a factor Xa (FXa) inhibitor, is chemically described as decreased bioavailability. Following administration of a crushed 5 mg ELIQUIS tablet
1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro- that was suspended in 60 mL D5W and delivered through a nasogastric tube (NGT),
1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Its molecular formula is C25H25N5O4, exposure was similar to that seen in other clinical trials involving healthy volunteers
which corresponds to a molecular weight of 459.5. Apixaban has the following receiving a single oral 5 mg tablet dose.
structural formula:
Distribution
Plasma protein binding in humans is approximately 87%. The volume of distribution
(Vss) is approximately 21 liters.
Metabolism
Approximately 25% of an orally administered apixaban dose is recovered in urine
and feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor
contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and
hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation.
Unchanged apixaban is the major drug-related component in human plasma; there
are no active circulating metabolites.
Elimination
Apixaban is a white to pale-yellow powder. At physiological pH (1.2–6.8), apixaban
does not ionize; its aqueous solubility across the physiological pH range is Apixaban is eliminated in both urine and feces. Renal excretion accounts for about
~0.04 mg/mL. 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination
of apixaban in the feces.
ELIQUIS tablets are available for oral administration in strengths of 2.5 mg and 5 mg of Apixaban has a total clearance of approximately 3.3 L/hour and an apparent half-life
apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline of approximately 12 hours following oral administration.
cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The
film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance
and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets). protein.
Drug Interaction Studies
12 CLINICAL PHARMACOLOGY
In vitro apixaban studies at concentrations significantly greater than therapeutic
12.1 Mechanism of Action exposures, no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8,
CYP2C9, CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of
Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for CYP1A2, CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to
antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase alter the metabolic clearance of coadministered drugs that are metabolized by these
activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits enzymes. Apixaban is not a significant inhibitor of P-gp.
platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases The effects of coadministered drugs on the pharmacokinetics of apixaban and
thrombin generation and thrombus development. associated dose recommendations are summarized in Figure 2 [see also Warnings
and Precautions (5.2) and Drug Interactions (7)].
12.2 Pharmacodynamics
As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin
time (PT), INR, and activated partial thromboplastin time (aPTT). Changes observed
in these clotting tests at the expected therapeutic dose, however, are small, subject
to a high degree of variability, and not useful in monitoring the anticoagulation effect
of apixaban.
The Rotachrom® Heparin chromogenic assay was used to measure the effect of
apixaban on FXa activity in humans during the apixaban development program.
Figure 2: Effect of Coadministered Drugs on the Pharmacokinetics of Hemodialysis in ESRD subjects: Following a 4-hour hemodialysis session with
Apixaban a dialysate flow rate of 500 mL/min and a blood flow rate in the range of 350 to
500 mL/min started 2 hours after administration of a single 5 mg dose of apixaban,
Interacting Drug PK Fold Change and 90% CI the AUC of apixaban was 17% greater compared to those with normal renal function.
Strong CYP3A4 and P-gp Inhibitor The dialysis clearance of apixaban is approximately 18 mL/min resulting in a 14%
decrease in exposure due to hemodialysis compared to off-dialysis period.
Ketoconazole 400 mg Cmax
AUC Protein binding was similar (92%-94%) between healthy controls and the on-dialysis
and off-dialysis periods.
Other CYP3A4 and P-gp Inhibitors 13 NONCLINICAL TOXICOLOGY

Diltiazem 360 mg Cmax
AUC 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Apixaban was not carcinogenic when administered to mice and
Naproxen 500 mg Cmax rats for up to 2 years. The systemic exposures (AUCs) of unbound apixaban in male
AUC and female mice at the highest doses tested (1500 and 3000 mg/kg/day) were
9 and 20 times, respectively, the human exposure of unbound drug at the MRHD of
Strong CYP3A4 and P-gp Inducer 10 mg/day. Systemic exposures of unbound apixaban in male and female rats at the
highest dose tested (600 mg/kg/day) were 2 and 4 times, respectively, the human
Rifampin 600 mg Cmax exposure.
AUC
Mutagenesis: Apixaban was neither mutagenic in the bacterial reverse mutation
(Ames) assay, nor clastogenic in Chinese hamster ovary cells in vitro, in a 1-month
0.5 1.0 1.5 2.0 in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes, or in a rat
micronucleus study in vivo.
Change Relative to Reference
Impairment of Fertility: Apixaban had no effect on fertility in male or female rats
In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, when given at doses up to 600 mg/kg/day, a dose resulting in exposure levels that are
and enoxaparin did not meaningfully alter the pharmacokinetics of apixaban. 3 and 4 times, respectively, the human exposure.
In studies conducted in healthy subjects, apixaban did not meaningfully alter the Apixaban administered to female rats at doses up to 1000 mg/kg/day from
pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid. implantation through the end of lactation produced no adverse findings in male
offspring (F1 generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure
Specific Populations that is 5 times the human exposure. Adverse effects in the F1-generation female
The effects of level of renal impairment, age, body weight, and level of hepatic offspring were limited to decreased mating and fertility indices at 1000 mg/kg/day.
impairment on the pharmacokinetics of apixaban are summarized in Figure 3.
14 CLINICAL STUDIES
Figure 3: Effect of Specific Populations on the Pharmacokinetics of
Apixaban
14.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular
Atrial Fibrillation
ARISTOTLE
Evidence for the efficacy and safety of ELIQUIS was derived from ARISTOTLE,
a multinational, double-blind study in patients with nonvalvular AF comparing the
effects of ELIQUIS and warfarin on the risk of stroke and non-central nervous system
(CNS) systemic embolism. In ARISTOTLE, patients were randomized to ELIQUIS 5 mg
orally twice daily (or 2.5 mg twice daily in subjects with at least 2 of the following
characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL)
or to warfarin (targeted to an INR range of 2.0–3.0). Patients had to have one or more
of the following additional risk factors for stroke:
• prior stroke or transient ischemic attack (TIA)
• prior systemic embolism
• age ≥75 years
• arterial hypertension requiring treatment
• diabetes mellitus
• heart failure ≥New York Heart Association Class 2
• left ventricular ejection fraction ≤40%
The primary objective of ARISTOTLE was to determine whether ELIQUIS 5 mg twice
daily (or 2.5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk
of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of ELIQUIS
to warfarin was also examined for the primary endpoint (rate of stroke and systemic
embolism), major bleeding, and death from any cause.
* ESRD subjects maintained with chronic and stable hemodialysis; reported PK findings are A total of 18,201 patients were randomized and followed on study treatment for a
following single dose of apixaban post hemodialysis. median of 89 weeks. Forty-three percent of patients were vitamin K antagonist (VKA)
† Results reflect CrCl of 15 mL/min based on regression analysis. “naive,” defined as having received ≤30 consecutive days of treatment with warfarin
‡ Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing
or another VKA before entering the study. The mean age was 69 years and the mean
CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores
recommendations. predicting greater risk) was 2.1. The population was 65% male, 83% Caucasian,
§ No dose adjustment is recommended for nonvalvular atrial fibrillation patients unless at
14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS systemic
least 2 of the following patient characteristics (age ≥80 years, body weight ≤60 kg, or embolism in 19% of patients. Concomitant diseases of patients in this study included
serum creatinine ≥1.5 mg/dL) are present. hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular ejection
fraction ≤40%) 35%, and prior myocardial infarction 14%. Patients treated with
Gender: A study in healthy subjects comparing the pharmacokinetics in males and warfarin in ARISTOTLE had a mean percentage of time in therapeutic range (INR
females showed no meaningful difference. 2.0–3.0) of 62%.
Race: The results across pharmacokinetic studies in normal subjects showed no
differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/
African American subjects. No dose adjustment is required based on race/ethnicity.
ELIQUIS was superior to warfarin for the primary endpoint of reducing the risk of Figure 4: Kaplan-Meier Estimate of Time to First Stroke or Systemic
stroke and systemic embolism (Table 9 and Figure 4). Superiority to warfarin was Embolism in ARISTOTLE (Intent-to-Treat Population)
primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with
hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with
similar rates on both drugs.
ELIQUIS also showed significantly fewer major bleeds than warfarin [see Adverse
Reactions (6.1)].
Table 9: Key Efficacy Outcomes in Patients with Nonvalvular Atrial

Fibrillation in ARISTOTLE (Intent-to-Treat Analysis)
ELIQUIS Warfarin Hazard Ratio P-value
N=9120 N=9081 (95% CI)
n (%/year) n (%/year)
Stroke or systemic embolism 212 (1.27) 265 (1.60) 0.79 (0.66, 0.95) 0.01
Stroke 199 (1.19) 250 (1.51) 0.79 (0.65, 0.95)
Ischemic without
140 (0.83) 136 (0.82) 1.02 (0.81, 1.29)
hemorrhage
Ischemic with
12 (0.07) 20 (0.12) 0.60 (0.29, 1.23)
hemorrhagic conversion
All-cause death was assessed using a sequential testing strategy that allowed testing
Hemorrhagic 40 (0.24) 78 (0.47) 0.51 (0.35, 0.75) for superiority if effects on earlier endpoints (stroke plus systemic embolus and major
Unknown 14 (0.08) 21 (0.13) 0.65 (0.33, 1.29) bleeding) were demonstrated. ELIQUIS treatment resulted in a significantly lower rate
of all-cause death (p = 0.046) than did treatment with warfarin, primarily because of
Systemic embolism 15 (0.09) 17 (0.10) 0.87 (0.44, 1.75) a reduction in cardiovascular death, particularly stroke deaths. Non-vascular death
The primary endpoint was based on the time to first event (one per subject). Component rates were similar in the treatment arms.
counts are for subjects with any event, not necessarily the first. In ARISTOTLE, the results for the primary efficacy endpoint were generally consistent
across most major subgroups including weight, CHADS2 score (a scale from 0 to 6
used to predict risk of stroke in patients with AF, with higher scores predicting greater
risk), prior warfarin use, level of renal impairment, geographic region, and aspirin use
at randomization (Figure 5).
Figure 5: Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics – ARISTOTLE Study
n of Events / N of Patients (% per year)
Subgroup Apixaban Warfarin Hazard Ratio (95% CI)
All Patients 212 / 9120 (1.3) 265 / 9081 (1.6) 0.79 (0.66, 0.95)
Prior Warfarin/VKA Status
Experienced (57%) 102 / 5208 (1.1) 138 / 5193 (1.5) 0.73 (0.57, 0.95)
Naive (43%) 110 / 3912 (1.5) 127 / 3888 (1.8) 0.86 (0.66, 1.11)
Age
<65 (30%) 51 / 2731 (1.0) 44 / 2740 (0.9) 1.16 (0.77, 1.73)
≥65 and <75 (39%) 82 / 3539 (1.3) 112 / 3513 (1.7) 0.72 (0.54, 0.96)
≥75 (31%) 79 / 2850 (1.6) 109 / 2828 (2.2) 0.71 (0.53, 0.95)
Sex
Male (65%) 132 / 5886 (1.2) 160 / 5899 (1.5) 0.82 (0.65, 1.04)
Female (35%) 80 / 3234 (1.3) 105 / 3182 (1.8) 0.74 (0.56, 1.00)
Weight
≤60 kg (11%) 34 / 1018 (2.0) 52 / 967 (3.2) 0.63 (0.41, 0.97)
>60 kg (89%) 177 / 8070 (1.2) 212 / 8084 (1.4) 0.83 (0.68, 1.01)
Prior Stroke or TIA
Yes (19%) 73 / 1694 (2.5) 98 / 1742 (3.2) 0.76 (0.56, 1.03)
No (81%) 139 / 7426 (1.0) 167 / 7339 (1.2) 0.82 (0.65, 1.03)
Diabetes Mellitus
Yes (25%) 57 / 2284 (1.4) 75 / 2263 (1.9) 0.75 (0.53, 1.05)
No (75%) 155 / 6836 (1.2) 190 / 6818 (1.5) 0.81 (0.65, 1.00)
CHADS2 Score
≤1 (34%) 44 / 3100 (0.7) 51 / 3083 (0.9) 0.85 (0.57, 1.27)
2 (36%) 74 / 3262 (1.2) 82 / 3254 (1.4) 0.90 (0.66, 1.23)
≥3 (30%) 94 / 2758 (2.0) 132 / 2744 (2.8) 0.70 (0.54, 0.91)
Creatinine Clearance
<30 mL/min (1%) 6 / 137 (2.8) 10 / 133 (5.1) 0.55 (0.20, 1.53)
30-50 mL/min (15%) 48 / 1365 (2.0) 59 / 1382 (2.5) 0.83 (0.57, 1.21)
>50-80 mL/min (42%) 87 / 3817 (1.2) 116 / 3770 (1.7) 0.74 (0.56, 0.97)
>80 mL/min (41%) 70 / 3761 (1.0) 79 / 3757 (1.1) 0.88 (0.64, 1.21)
Geographic Region
US (19%) 31 / 1720 (0.9) 39 / 1697 (1.2) 0.79 (0.50, 1.27)
Non-US (81%) 181 / 7400 (1.3) 226 / 7384 (1.7) 0.79 (0.65, 0.96)
Aspirin at Randomization
Yes (31%) 70 / 2859 (1.3) 94 / 2773 (1.9) 0.72 (0.53, 0.98)
No (69%) 142 / 6261 (1.2) 171 / 6308 (1.5) 0.83 (0.67, 1.04)
0.25 0.5 1 2
Apixaban Warfarin
Better Better
Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were pre-specified, if not the groupings. 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.
At the end of the ARISTOTLE study, warfarin patients who completed the study Table 11: Summary of Key Efficacy Analysis Results During the Intended
were generally maintained on a VKA with no interruption of anticoagulation. ELIQUIS Treatment Period for Patients Undergoing Elective Hip
patients who completed the study were generally switched to a VKA with a 2-day Replacement Surgery*
period of coadministration of ELIQUIS and VKA, so that some patients may not have
been adequately anticoagulated after stopping ELIQUIS until attaining a stable and ADVANCE-3
therapeutic INR. During the 30 days following the end of the study, there were Events During 35-Day ELIQUIS Enoxaparin Relative Risk
21 stroke or systemic embolism events in the 6791 patients (0.3%) in the ELIQUIS Treatment Period 2.5 mg po bid 40 mg sc qd (95% CI)
arm compared to 5 in the 6569 patients (0.1%) in the warfarin arm [see Dosage and P-value
Administration (2.4)].
Number of Patients N=1949 N=1917
AVERROES
Total VTE†/All-cause death 27 (1.39%) 74 (3.86%) 0.36
In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates (0.95, 2.02) (3.08, 4.83) (0.22, 0.54)
for warfarin therapy were randomized to treatment with ELIQUIS 5 mg orally twice p<0.0001
daily (or 2.5 mg twice daily in selected patients) or aspirin 81 to 324 mg once daily.
The primary objective of the study was to determine if ELIQUIS was superior to aspirin Number of Patients N=2708 N=2699
for preventing the composite outcome of stroke or systemic embolism. AVERROES All-cause death 3 (0.11%) 1 (0.04%)
was stopped early on the basis of a prespecified interim analysis showing a significant (0.02, 0.35) (0.00, 0.24)
reduction in stroke and systemic embolism for ELIQUIS compared to aspirin that
was associated with a modest increase in major bleeding (Table 10) [see Adverse PE 3 (0.11%) 5 (0.19%)
Reactions (6.1)]. (0.02, 0.35) (0.07, 0.45)
Symptomatic DVT 1 (0.04%) 5 (0.19%)
(0.00, 0.24) (0.07, 0.45)
Table 10: Key Efficacy Outcomes in Patients with Nonvalvular Atrial
Fibrillation in AVERROES Number of Patients N=2196 N=2190
ELIQUIS Aspirin Hazard Ratio P-value Proximal DVT‡ 7 (0.32%) 20 (0.91%)
N=2807 N=2791 (95% CI) (0.14, 0.68) (0.59, 1.42)
n (%/year) n (%/year)
Number of Patients N=1951 N=1908
Stroke or systemic embolism 51 (1.62) 113 (3.63) 0.45 (0.32, 0.62) <0.0001 Distal DVT‡ 20 (1.03%) 57 (2.99%)
Stroke (0.66, 1.59) (2.31, 3.86)
* Events associated with each endpoint were counted once per subject but subjects may
Ischemic or 43 (1.37) 97 (3.11) 0.44 (0.31, 0.63) -
undetermined have contributed events to multiple endpoints.
† Total VTE includes symptomatic and asymptomatic DVT and PE.
Hemorrhagic 6 (0.19) 9 (0.28) 0.67 (0.24, 1.88) - ‡ Includes symptomatic and asymptomatic DVT.
Systemic embolism 2 (0.06) 13 (0.41) 0.15 (0.03, 0.68) -

MI 24 (0.76) 28 (0.89) 0.86 (0.50, 1.48) - Table 12: Summary of Key Efficacy Analysis Results During the Intended
Treatment Period for Patients Undergoing Elective Knee
All-cause death 111 (3.51) 140 (4.42) 0.79 (0.62, 1.02) 0.068 Replacement Surgery*
Vascular death 84 (2.65) 96 (3.03) 0.87 (0.65, 1.17) - ADVANCE-1 ADVANCE-2
Events during ELIQUIS Enoxaparin Relative ELIQUIS Enoxaparin Relative
12-day 2.5 mg po 30 mg sc Risk 2.5 mg po bid 40 mg sc qd Risk
14.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee treatment bid q12h (95% CI) (95% CI)
Replacement Surgery period P-value P-value
The clinical evidence for the effectiveness of ELIQUIS is derived from the ADVANCE-1, Number of N=1157 N=1130 N=976 N=997
ADVANCE-2, and ADVANCE-3 clinical trials in adult patients undergoing elective hip Patients
(ADVANCE-3) or knee (ADVANCE-2 and ADVANCE-1) replacement surgery. A total of
11,659 patients were randomized in 3 double-blind, multi-national studies. Included Total VTE†/All- 104 (8.99%) 100 (8.85%) 1.02 147 (15.06%) 243 (24.37%) 0.62
in this total were 1866 patients age 75 or older, 1161 patients with low body weight cause death (7.47, 10.79) (7.33, 10.66) (0.78, 1.32) (12.95, 17.46) (21.81, 27.14) (0.51, 0.74)
(≤60 kg), 2528 patients with Body Mass Index ≥33 kg/m2, and 625 patients with NS p<0.0001
severe or moderate renal impairment. Number of N=1599 N=1596 N=1528 N=1529
In the ADVANCE-3 study, 5407 patients undergoing elective hip replacement surgery Patients
were randomized to receive either ELIQUIS 2.5 mg orally twice daily or enoxaparin All-cause 3 (0.19%) 3 (0.19%) 2 (0.13%) 0 (0%)
40 mg subcutaneously once daily. The first dose of ELIQUIS was given 12 to 24 hours death (0.04, 0.59) (0.04, 0.59) (0.01, 0.52) (0.00, 0.31)
post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Treatment
duration was 32 to 38 days. PE 16 (1.0%) 7 (0.44%) 4 (0.26%) 0 (0%)
(0.61, 1.64) (0.20, 0.93) (0.08, 0.70) (0.00, 0.31)
In patients undergoing elective knee replacement surgery, ELIQUIS 2.5 mg orally
twice daily was compared to enoxaparin 40 mg subcutaneously once daily Symptomatic 3 (0.19%) 7 (0.44%) 3 (0.20%) 7 (0.46%)
(ADVANCE-2, N=3057) or enoxaparin 30 mg subcutaneously every 12 hours DVT (0.04, 0.59) (0.20, 0.93) (0.04, 0.61) (0.20, 0.97)
(ADVANCE-1, N=3195). In the ADVANCE-2 study, the first dose of ELIQUIS was given Number of N=1254 N=1207 N=1192 N=1199
12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to Patients
surgery. In the ADVANCE-1 study, both ELIQUIS and enoxaparin were initiated 12 to
24 hours post surgery. Treatment duration in both ADVANCE-2 and ADVANCE-1 was Proximal 9 (0.72%) 11 (0.91%) 9 (0.76%) 26 (2.17%)
10 to 14 days. DVT‡ (0.36, 1.39) (0.49, 1.65) (0.38, 1.46) (1.47, 3.18)
In all 3 studies, the primary endpoint was a composite of adjudicated asymptomatic Number of N=1146 N=1133 N=978 N=1000
and symptomatic DVT, nonfatal PE, and all-cause death at the end of the double-blind Patients
intended treatment period. In ADVANCE-3 and ADVANCE-2, the primary endpoint was Distal 83 (7.24%) 91 (8.03%) 142 (14.52%) 239 (23.9%)
tested for noninferiority, then superiority, of ELIQUIS to enoxaparin. In ADVANCE-1, the DVT‡ (5.88, 8.91) (6.58, 9.78) (12.45, 16.88) (21.36,
primary endpoint was tested for noninferiority of ELIQUIS to enoxaparin. 26.65)
The efficacy data are provided in Tables 11 and 12. * Events associated with each endpoint were counted once per subject but subjects may
have contributed events to multiple endpoints.
† Total VTE includes symptomatic and asymptomatic DVT and PE.
‡ Includes symptomatic and asymptomatic DVT.
The efficacy profile of ELIQUIS was generally consistent across subgroups of interest
for this indication (e.g., age, gender, race, body weight, renal impairment).
14.3 Treatment of DVT and PE and Reduction in the Risk of Recurrence of Table 14: Efficacy Results in the AMPLIFY-EXT Study
DVT and PE
Relative Risk (95% CI)
Efficacy and safety of ELIQUIS for the treatment of DVT and PE, and for the reduction
in the risk of recurrent DVT and PE following 6 to 12 months of anticoagulant ELIQUIS ELIQUIS Placebo ELIQUIS ELIQUIS
treatment was derived from the AMPLIFY and AMPLIFY-EXT studies. Both studies were 2.5 mg bid 5 mg bid 2.5 mg bid 5 mg bid
randomized, parallel-group, double-blind trials in patients with symptomatic proximal N=840 N=813 N=829 vs Placebo vs Placebo
DVT and/or symptomatic PE. All key safety and efficacy endpoints were adjudicated in n (%)
a blinded manner by an independent committee.
Recurrent VTE or 32 (3.8) 34 (4.2) 96 (11.6) 0.33 (0.22, 0.48) 0.36 (0.25, 0.53)
AMPLIFY all-cause death p<0.0001 p<0.0001
The primary objective of AMPLIFY was to determine whether ELIQUIS was noninferior DVT* 19 (2.3) 28 (3.4) 72 (8.7)
to enoxaparin/warfarin for the incidence of recurrent VTE (venous thromboembolism) PE* 23 (2.7) 25 (3.1) 37 (4.5)
or VTE-related death. Patients with an objectively confirmed symptomatic DVT
and/or PE were randomized to treatment with ELIQUIS 10 mg twice daily orally for All-cause death 22 (2.6) 25 (3.1) 33 (4.0)
7 days followed by ELIQUIS 5 mg twice daily orally for 6 months, or enoxaparin 1 mg/kg * Patients with more than one event are counted in multiple rows.
twice daily subcutaneously for at least 5 days (until INR ≥2) followed by warfarin (target
INR range 2.0-3.0) orally for 6 months. Patients who required thrombectomy, insertion
of a caval filter, or use of a fibrinolytic agent, and patients with creatinine clearance 16 HOW SUPPLIED/STORAGE AND HANDLING
<25 mL/min, significant liver disease, an existing heart valve or atrial fibrillation, or
active bleeding were excluded from the AMPLIFY study. Patients were allowed to enter How Supplied
the study with or without prior parenteral anticoagulation (up to 48 hours). ELIQUIS (apixaban) tablets are available as listed in the table below.
A total of 5244 patients were evaluable for efficacy and were followed for a mean
of 154 days in the ELIQUIS group and 152 days in the enoxaparin/warfarin group. Tablet Tablet Tablet
The mean age was 57 years. The AMPLIFY study population was 59% male, 83% Strength Color/Shape Markings Package Size NDC Code
Caucasian, 8% Asian, and 4% Black. For patients randomized to warfarin, the mean
2.5 mg Yellow, round, Debossed with Bottles of 60 0003-0893-21
percentage of time in therapeutic range (INR 2.0-3.0) was 60.9%. biconvex “893” on one side Bottles of 180 0003-0893-41
Approximately 90% of patients enrolled in AMPLIFY had an unprovoked DVT or PE at and “2½” Hospital Unit-Dose 0003-0893-31
baseline. The remaining 10% of patients with a provoked DVT or PE were required on the other side Blister Package
to have an additional ongoing risk factor in order to be randomized, which included of 100
previous episode of DVT or PE, immobilization, history of cancer, active cancer, and 5 mg Pink, oval, Debossed with Bottles of 60 0003-0894-21
known prothrombotic genotype. biconvex “894” on one side Bottles of 180 0003-0894-41
and “5” Hospital Unit-Dose 0003-0894-31
ELIQUIS was shown to be noninferior to enoxaparin/warfarin in the AMPLIFY study for on the other side Blister Package
the primary endpoint of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or of 100
VTE-related death over 6 months of therapy (Table 13).
Storage and Handling
Table 13: Efficacy Results in the AMPLIFY Study
Store at 20°C to 25°C (68°F-77°F); excursions permitted between 15°C and 30°C
ELIQUIS Enoxaparin/Warfarin Relative Risk (59°F-86°F) [see USP Controlled Room Temperature].
N=2609 N=2635 (95% CI)
n n 17 PATIENT COUNSELING INFORMATION
VTE or VTE-related death* 59 (2.3%) 71 (2.7%) 0.84 (0.60, 1.18)
See FDA-approved patient labeling (Medication Guide).
DVT† 22 (0.8%) 35 (1.3%) Advise patients of the following:
PE† 27 (1.0%) 25 (0.9%) • They should not discontinue ELIQUIS without talking to their physician first.
VTE-related death† 12 (0.4%) 16 (0.6%) • They should be informed that it might take longer than usual for bleeding to stop,
and they may bruise or bleed more easily when treated with ELIQUIS. Advise
VTE or all-cause death 84 (3.2%) 104 (4.0%) 0.82 (0.61, 1.08) patients about how to recognize bleeding or symptoms of hypovolemia and of the
VTE or CV-related death 61 (2.3%) 77 (2.9%) 0.80 (0.57, 1.11) urgent need to report any unusual bleeding to their physician.
* Noninferior compared to enoxaparin/warfarin (P-value <0.0001). • They should tell their physicians and dentists they are taking ELIQUIS, and/or
† Events any other product known to affect bleeding (including nonprescription products,
associated with each endpoint were counted once per subject, but subjects may such as aspirin or NSAIDs), before any surgery or medical or dental procedure is
have contributed events to multiple endpoints. scheduled and before any new drug is taken.
• If the patient is having neuraxial anesthesia or spinal puncture, inform the
In the AMPLIFY study, patients were stratified according to their index event of PE patient to watch for signs and symptoms of spinal or epidural hematomas,
(with or without DVT) or DVT (without PE). Efficacy in the initial treatment of VTE was such as numbness or weakness of the legs, or bowel or bladder dysfunction
consistent between the two subgroups. [see Warnings and Precautions (5.3)]. If any of these symptoms occur, the patient
should contact his or her physician immediately.
AMPLIFY-EXT
• They should tell their physicians if they are pregnant or plan to become pregnant
Patients who had been treated for DVT and/or PE for 6 to 12 months with anticoagulant or are breastfeeding or intend to breastfeed during treatment with ELIQUIS
therapy without having a recurrent event were randomized to treatment with ELIQUIS [see Use in Specific Populations (8.1, 8.3)].
2.5 mg orally twice daily, ELIQUIS 5 mg orally twice daily, or placebo for 12 months.
Approximately one-third of patients participated in the AMPLIFY study prior to • If a dose is missed, the dose should be taken as soon as possible on the same
enrollment in the AMPLIFY-EXT study. day and twice-daily administration should be resumed. The dose should not be
doubled to make up for a missed dose.
A total of 2482 patients were randomized to study treatment and were followed for a
mean of approximately 330 days in the ELIQUIS group and 312 days in the placebo
group. The mean age in the AMPLIFY-EXT study was 57 years. The study population Marketed by:
was 57% male, 85% Caucasian, 5% Asian, and 3% Black. Bristol-Myers Squibb Company
The AMPLIFY-EXT study enrolled patients with either an unprovoked DVT or PE at Princeton, New Jersey 08543 USA
baseline (approximately 92%) or patients with a provoked baseline event and one and
additional risk factor for recurrence (approximately 8%). However, patients who had Pfizer Inc
experienced multiple episodes of unprovoked DVT or PE were excluded from the New York, New York 10017 USA
AMPLIFY-EXT study. In the AMPLIFY-EXT study, both doses of ELIQUIS were superior Rotachrom® is a registered trademark of Diagnostica Stago.
to placebo in the primary endpoint of symptomatic, recurrent VTE (nonfatal DVT or
nonfatal PE), or all-cause death (Table 14). 1356615A0 / 1356514A0
MEDICATION GUIDE • other medicines to help prevent or treat

ELIQUIS® (ELL eh kwiss) blood clots
(apixaban) Tell your doctor if you take any of these
tablets medicines. Ask your doctor or pharmacist
if you are not sure if your medicine is one
What is the most important information listed above.
I should know about ELIQUIS?
While taking ELIQUIS:
• For people taking ELIQUIS for atrial
• you may bruise more easily
fibrillation:
• it may take longer than usual for any
People with atrial fibrillation (a type of
bleeding to stop
irregular heartbeat) are at an increased risk
of forming a blood clot in the heart, which Call your doctor or get medical help
can travel to the brain, causing a stroke, or right away if you have any of these
to other parts of the body. ELIQUIS lowers signs or symptoms of bleeding when
your chance of having a stroke by helping taking ELIQUIS:
to prevent clots from forming. If you stop
• unexpected bleeding, or bleeding that
taking ELIQUIS, you may have increased
lasts a long time, such as:
risk of forming a clot in your blood.
• unusual bleeding from the gums
Do not stop taking ELIQUIS without
talking to the doctor who prescribes it • nosebleeds that happen often
for you. Stopping ELIQUIS increases
• menstrual bleeding or vaginal
your risk of having a stroke.
bleeding that is heavier than normal
ELIQUIS may need to be stopped, if possible,
prior to surgery or a medical or dental • bleeding that is severe or you cannot
procedure. Ask the doctor who prescribed control
ELIQUIS for you when you should stop • red, pink, or brown urine
taking it. Your doctor will tell you when you
• red or black stools (looks like tar)
may start taking ELIQUIS again after your
surgery or procedure. If you have to stop • cough up blood or blood clots
taking ELIQUIS, your doctor may prescribe
• vomit blood or your vomit looks like
another medicine to help prevent a blood
coffee grounds
clot from forming.
• ELIQUIS can cause bleeding which can • unexpected pain, swelling, or joint pain
be serious and rarely may lead to death. • headaches, feeling dizzy or weak
This is because ELIQUIS is a blood thinner
• ELIQUIS is not for patients with
medicine that reduces blood clotting.
artificial heart valves.
You may have a higher risk of bleeding if you
take ELIQUIS and take other medicines that • Spinal or epidural blood clots
increase your risk of bleeding, including: (hematoma). People who take a blood
thinner medicine (anticoagulant) like
• aspirin or aspirin-containing products ELIQUIS, and have medicine injected into
• long-term (chronic) use of nonsteroidal their spinal and epidural area, or have a
anti-inflammatory drugs (NSAIDs) spinal puncture have a risk of forming a blood
clot that can cause long-term or permanent
• warfarin sodium (COUMADIN®, loss of the ability to move (paralysis). Your
JANTOVEN®) risk of developing a spinal or epidural blood
• any medicine that contains heparin clot is higher if:
• selective serotonin reuptake inhibitors • a thin tube called an epidural catheter is
(SSRIs) or serotonin norepinephrine placed in your back to give you certain
reuptake inhibitors (SNRIs) medicine
• you take NSAIDs or a medicine to prevent • are breastfeeding or plan to breastfeed. It

blood from clotting is not known if ELIQUIS passes into your
breast milk. You and your doctor should
• you have a history of difficult or repeated decide if you will take ELIQUIS or breastfeed.
epidural or spinal punctures You should not do both.
• you have a history of problems with your Tell all of your doctors and dentists that you are
spine or have had surgery on your spine taking ELIQUIS. They should talk to the doctor
If you take ELIQUIS and receive spinal who prescribed ELIQUIS for you, before you
anesthesia or have a spinal puncture, have any surgery, medical or dental procedure.
your doctor should watch you closely for Tell your doctor about all the medicines
symptoms of spinal or epidural blood clots or you take, including prescription and
bleeding. Tell your doctor right away if over-the-counter medicines, vitamins, and
you have tingling, numbness, or muscle herbal supplements. Some of your other
weakness, especially in your legs and feet. medicines may affect the way ELIQUIS works.
Certain medicines may increase your risk of
What is ELIQUIS? bleeding or stroke when taken with ELIQUIS. See
ELIQUIS is a prescription medicine used to: “What is the most important information
I should know about ELIQUIS?”
• reduce the risk of stroke and blood clots in
people who have atrial fibrillation. Know the medicines you take. Keep a list of
them to show your doctor and pharmacist when
• reduce the risk of forming a blood clot in the
you get a new medicine.
legs and lungs of people who have just had
hip or knee replacement surgery. How should I take ELIQUIS?
• treat blood clots in the veins of your legs • Take ELIQUIS exactly as prescribed by
(deep vein thrombosis) or lungs (pulmonary your doctor.
embolism), and reduce the risk of them • Take ELIQUIS twice every day with or
occurring again. without food.
It is not known if ELIQUIS is safe and effective • Do not change your dose or stop taking
in children. ELIQUIS unless your doctor tells you to.
Who should not take ELIQUIS? • If you miss a dose of ELIQUIS, take it as
soon as you remember. Do not take more
Do not take ELIQUIS if you:
than one dose of ELIQUIS at the same time
• currently have certain types of abnormal to make up for a missed dose.
bleeding.
• Your doctor will decide how long you should
• have had a serious allergic reaction to take ELIQUIS. Do not stop taking it
ELIQUIS. Ask your doctor if you are not sure. without first talking with your doctor.
If you are taking ELIQUIS for atrial
What should I tell my doctor before taking
fibrillation, stopping ELIQUIS may
ELIQUIS?
increase your risk of having a stroke.
Before you take ELIQUIS, tell your doctor
• Do not run out of ELIQUIS. Refill your
if you: prescription before you run out. When
• have kidney or liver problems leaving the hospital following hip or knee
replacement, be sure that you will have
• have any other medical condition
ELIQUIS available to avoid missing any
• have ever had bleeding problems doses.
• are pregnant or plan to become pregnant. • If you take too much ELIQUIS, call your
It is not known if ELIQUIS will harm your doctor or go to the nearest hospital
unborn baby. emergency room right away.
• Call your doctor or healthcare provider right What are the ingredients in ELIQUIS?
away if you fall or injure yourself, especially if
Active ingredient: apixaban.
you hit your head. Your doctor or healthcare
provider may need to check you. Inactive ingredients: anhydrous lactose,
microcrystalline cellulose, croscarmellose
What are the possible side effects of sodium, sodium lauryl sulfate, and magnesium
ELIQUIS? stearate. The film coating contains lactose
• See “What is the most important monohydrate, hypromellose, titanium dioxide,
information I should know about triacetin, and yellow iron oxide (2.5 mg tablets)
ELIQUIS?” or red iron oxide (5 mg tablets).
• ELIQUIS can cause a skin rash or severe

This Medication Guide has been approved by
allergic reaction. Call your doctor or get
the U.S. Food and Drug Administration.
medical help right away if you have any of
the following symptoms:
Marketed by:
• chest pain or tightness Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
• swelling of your face or tongue
and
• trouble breathing or wheezing Pfizer Inc
New York, New York 10017 USA
• feeling dizzy or faint
COUMADIN® is a registered trademark of
Tell your doctor if you have any side effect that
Bristol-Myers Squibb Pharma Company.
bothers you or that does not go away.
All other trademarks are property of their
These are not all of the possible side effects of respective companies.
ELIQUIS. For more information, ask your doctor
or pharmacist. 1356615A0 / 1356514A0
Call your doctor for medical advice about side 1356616 Revised June 2015
effects. You may report side effects to FDA at 432US1501679-01-01
1-800-FDA-1088.
How should I store ELIQUIS?
Store ELIQUIS at room temperature between
68°F to 77°F (20°C to 25°C).
Keep ELIQUIS and all medicines out of the
reach of children.
General Information about ELIQUIS
Medicines are sometimes prescribed for
purposes other than those listed in a Medication
Guide. Do not use ELIQUIS for a condition
for which it was not prescribed. Do not give
ELIQUIS to other people, even if they have the
same symptoms that you have. It may harm
them.
If you would like more information, talk with
your doctor. You can ask your pharmacist or
doctor for information about ELIQUIS that is
written for health professionals.
For more information, call 1-855-354-7847
(1-855-ELIQUIS) or go to www.ELIQUIS.com.

ELIQUIS HCP Electronic Combo Dosing Guide - Desktop PDF

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Dosing Guide

for All ELIQUIS Indications

Find out more at

Approved for 6 indications

for the treatment of deep vein thrombosis (DVT)

for the treatment of pulmonary embolism (PE)

SELECTED IMPORTANT SAFETY INFORMATION

WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC

Indication Recommended dosing

5 mg twice daily in most patients

Dose adjustment for NVAF patients: 2.5 mg twice daily is

10 mg twice daily for the first 7 days

 After 7 days, transition to 

2.5 mg twice daily after at least 6 months of treatment for

2.5 mg twice daily for 35 days starting 12 to 24 hours after hip

SELECTED IMPORTANT SAFETY INFORMATION

5 mg taken orally twice daily recommended for most NVAF patients

PLEASE SEE PAGES 8-14 FOR ADDITIONAL IMPORTANT DOSING INFORMATION.

SELECTED IMPORTANT SAFETY INFORMATION

An example of an ELIQUIS® (apixaban) prescription for a patient starting

First 30 days = 74 tablets

PLEASE SEE PAGES 8-14 FOR ADDITIONAL IMPORTANT DOSING INFORMATION.

SELECTED IMPORTANT SAFETY INFORMATION

SELECTED IMPORTANT SAFETY INFORMATION

PLEASE SEE PAGES 8-14 FOR ADDITIONAL IMPORTANT DOSING INFORMATION.

SELECTED IMPORTANT SAFETY INFORMATION

ELIQUIS® (apixaban) elimination

Reduction in the risk of recurrent DVT and PE following initial therapy

SELECTED IMPORTANT SAFETY INFORMATION

Dosing in patients with renal impairment

Renal impairment No dose adjustment

End-stage renal disease (ESRD)*

SELECTED IMPORTANT SAFETY INFORMATION

Dosing in patients with hepatic impairment

There is limited clinical

SELECTED IMPORTANT SAFETY INFORMATION

Additional dosing considerations

Temporary interruption for surgery and other interventions

Elective surgery or invasive procedures with moderate or high risk of

Elective surgery or invasive procedures with low risk of bleeding or

SELECTED IMPORTANT SAFETY INFORMATION

Guidance for switching patients to and from ELIQUIS® (apixaban)

Switching from warfarin to ELIQUIS

SELECTED IMPORTANT SAFETY INFORMATION

Strong dual inhibitors of CYP3A4 and P-gp

Strong dual inducers of CYP3A4 and P-gp

SELECTED IMPORTANT SAFETY INFORMATION

DRUG INTERACTIONS (continued)

Drugs affecting hemostasis

SELECTED IMPORTANT SAFETY INFORMATION

Find out more at:

Reference: ELIQUIS® (apixaban) Package Insert.

FULL PRESCRIBING INFORMATION: CONTENTS* 6 ADVERSE REACTIONS

5 WARNINGS AND PRECAUTIONS 6.1 Clinical Trials Experience

Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics – ARISTOTLE Study

0.125 0.25 0.5 1 2

Other CYP3A4 and P-gp Inhibitors 13 NONCLINICAL TOXICOLOGY

Table 9: Key Efficacy Outcomes in Patients with Nonvalvular Atrial

Systemic embolism 2 (0.06) 13 (0.41) 0.15 (0.03, 0.68) -

for the treatment of deep vein thrombosis (DVT)

Dose adjustment for NVAF patients: 2.5 mg twice daily is