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for All ELIQUIS Indications Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
ELIQUIS® (apixaban) INDICATIONS to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial
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
for the prophylaxis of DVT, which may lead to PE, in patients who have undergone knee
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
Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
ELIQUIS® (apixaban) DOSING SUMMARY 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
Reduction in the risk
recommended for patients with at least 2 of the following 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
2.5 mg twice daily after at least 6 months of treatment for Reduction in the risk
of recurrent DVT/PE
fol owing 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 SELECTED IMPORTANT SAFETY INFORMATION
• Active pathological bleeding • Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
For patients with NVAF, DOSING FOR REDUCING THE RISK OF STROKE & SYSTEMIC EMBOLISM 5 mg taken oral y twice daily recommended for most NVAF patients In 2 Phase III NVAF clinical trials, approximately 95% of ELIQUIS® (apixaban) patients received Dosage adjustmentPatients with at least 2 of the following: b body weight
c serum creatinine
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.
SELECTED IMPORTANT SAFETY 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 fibril ation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
For patients with DVT/PE, DOSING FOR TREATING DVT/PE 10 mg taken oral y twice daily for 7 days, fol owed by 5 mg taken oral y twice daily recommended for the treatment of DVT and PE 10 mg (two 5 mg tablets) 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 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 tabletsSubsequent prescriptions for a 30-day supply = 60 tablets (take one 5 mg tablet by mouth twice daily) PLEASE SEE PAGES 8-14 FOR ADDITIONAL IMPORTANT DOSING INFORMATION.
SELECTED IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS (continued)
• Bleeding Risk: ELIQUIS increases the risk of bleeding and can cause serious, potential y 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 Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
For patients who have experienced a DVT/PE, REDUCING THE RISK OF RECURRENT DVT/PE FOLLOWING 2.5 mg taken oral y twice daily recommended for the reduction in the risk of recurrent DVT/PE fol owing initial therapy 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.
SELECTED IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS (continued)
• 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.
Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
For patients who have undergone hip or knee replacement surgery, DOSING FOR PROPHYLAXIS OF DVT, WHICH MAY LEAD TO PE 2.5 mg taken oral y twice daily recommended for hip or knee replacement The initial dose should be taken 12 to 24 hours after hip or knee replacement surgery 35 Recommended treatment duration for patients undergoing DAYS hip replacement surgery
12 Recommended treatment duration for patients undergoing DAYS 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.
PLEASE SEE PAGES 8-14 FOR ADDITIONAL IMPORTANT DOSING INFORMATION.
SELECTED IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS (continued)
• 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 The risk of these events may be increased by the postoperative use of indwel ing epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwel ing 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.
Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
DOSING IN PATIENTS WITH ELIQUIS® (apixaban) elimination accounts for about 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 fol owing indications: SELECTED IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS (continued)
• 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.
Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
DOSING IN PATIENTS WITH Dosing in patients with renal impairment No dose adjustment Moderate
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 SELECTED IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS (continued)
• 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.
Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
DOSING IN PATIENTS WITH HEPATIC IMPAIRMENT SELECTED IMPORTANT SAFETY INFORMATION
ADVERSE REACTIONS
• The most common and most serious adverse reactions reported with ELIQUIS were related to bleeding.
Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
DOSING CONSIDERATIONS AND ADMINISTRATION OPTIONS Temporary interruption for surgery and other interventions SELECTED IMPORTANT SAFETY INFORMATION
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 clinical y 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 control ed. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not general y required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
DOSING CONSIDERATIONS AND ADMINISTRATION OPTIONS Guidance for switching patients to and from ELIQUIS® (apixaban) Administration options • For patients who are unable to sw allow whole tablets, 5 mg and 2.5 mg ELIQUIS tablets or patients who are unable to sw may be crushed and suspended in 60 mL D5W and immediately delivered through a may be crushed and suspended in 60 mL D5W and immediately delivered thr nasogastric tube. Information regarding the administration of crushed and suspended nasogastric tube. Information regarding the administr ELIQUIS tablets swallowed by mouth is not a ELIQUIS tablets sw allowed by mouth is not a ailable SELECTED IMPORTANT SAFETY INFORMATION
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.
Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
DRUG INTERACTIONS These drug categories are examples described in the Full Prescribing Information, not an al -inclusive list.
SELECTED IMPORTANT SAFETY INFORMATION
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 wil 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-control ed 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.
Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
DRUG INTERACTIONS These drug categories are examples described in the Full Prescribing Information, not an al -inclusive list.
SELECTED IMPORTANT SAFETY INFORMATION
PREGNANCY CATEGORY B
• There are no adequate and wel -control ed 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.
Please see Important Safety Information throughout and Full Prescribing Information, including Boxed WARNINGS, following page 15.
Find out more at: 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, including Boxed WARNINGS, following page 15.
ELIQUIS® and the ELIQUIS logo are trademarks of Bristol-Myers Squibb Company. 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
Initial U.S. Approval: 2012
• The recommended dose is 10 mg taken orally twice daily for 7 days, followed 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,
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)
(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) 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
---------------------------- INDICATIONS AND USAGE ----------------------------
ELIQUIS is a factor Xa inhibitor indicated:• to reduce the risk of stroke and systemic embolism in patients with nonvalvular • Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of apixaban. 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) • 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) FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES
Clinical Trials Experience THE RISK OF THROMBOTIC EVENTS
Strong Dual Inhibitors of CYP3A4 and P-gp (B) SPINAL/EPIDURAL HEMATOMA
Strong Dual Inducers of CYP3A4 and P-gp INDICATIONS AND USAGE
Anticoagulants and Antiplatelet Agents Reduction of Risk of Stroke and Systemic Embolism in USE IN SPECIFIC POPULATIONS
Nonvalvular Atrial Fibrillation Prophylaxis of Deep Vein Thrombosis Following Hip or Labor and Delivery Knee Replacement Surgery Treatment of Deep Vein Thrombosis Treatment of Pulmonary Embolism Reduction in the Risk of Recurrence of DVT and PE Hepatic Impairment DOSAGE AND ADMINISTRATION
12 CLINICAL PHARMACOLOGY
Temporary Interruption for Surgery and Other Interventions Mechanism of Action 12.2 Pharmacodynamics Converting from or to ELIQUIS 12.3 Pharmacokinetics Strong Dual Inhibitors of CYP3A4 and P-glycoprotein 13 NONCLINICAL TOXICOLOGY
Administration Options Carcinogenesis, Mutagenesis, Impairment of Fertility DOSAGE FORMS AND STRENGTHS
14 CLINICAL STUDIES
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation WARNINGS AND PRECAUTIONS
Prophylaxis of Deep Vein Thrombosis Following Hip or Increased Risk of Thrombotic Events after Premature Discontinuation Knee Replacement Surgery Treatment of DVT and PE and Reduction in the Risk of Spinal/Epidural Anesthesia or Puncture Recurrence of DVT and PE Patients with Prosthetic Heart Valves 16 HOW SUPPLIED/STORAGE AND HANDLING
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
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
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. 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
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 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
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 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 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular
have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.
ELIQUIS® (apixaban) is indicated to reduce the risk of stroke and systemic embolism Switching from ELIQUIS to anticoagulants other than warfarin (oral or parenteral): 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.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee
Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS: Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may usual time of the next dose of the anticoagulant other than warfarin.
lead to pulmonary embolism (PE), in patients who have undergone hip or knee Strong Dual Inhibitors of CYP3A4 and P-glycoprotein
For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose 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)].
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)].
Reduction in the Risk of Recurrence of DVT and PE
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 DOSAGE AND ADMINISTRATION
regarding the administration of crushed and suspended ELIQUIS tablets swallowed by mouth is not available.
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular DOSAGE FORMS AND STRENGTHS
• 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 • 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)] WARNINGS AND PRECAUTIONS
Clinical Trials Experience
Increased Risk of Thrombotic Events after Premature Discontinuation
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in 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 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 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 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 Bleeding Events in Patients with Nonvalvular Atrial Fibrillation
two drug half-lives. A specific antidote for ELIQUIS is not available. Hemodialysis 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 Warfarin
Hazard Ratio
the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There 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 reversal agents such as prothrombin complex concentrate, activated prothrombin 0.69 (0.60, 0.80) <0.0001 complex concentrate, or recombinant factor VIIa may be considered but has not been Intracranial (ICH)‡ 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§ 0.51 (0.34, 0.75) Spinal/Epidural Anesthesia or Puncture
0.29 (0.16, 0.51) When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural Gastrointestinal (GI)¶ 0.89 (0.70, 1.14) puncture is employed, patients treated with antithrombotic agents for prevention 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.
0.13 (0.05, 0.37) The risk of these events may be increased by the postoperative use of indwelling epidural Non-intracranial 0.84 (0.28, 2.15) 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 Bleeding events within each subcategory were counted once per subject, but subjects 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 by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, Defined as clinically overt bleeding accompanied by one or more of the following: 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.
compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial ‡ Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid 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 Patients with Prosthetic Heart Valves
presented in Section 14.
The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic ¶ GI bleed includes upper GI, lower GI, and rectal bleeding.
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.
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).
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)
Hazard Ratio (95% CI)
0.69 (0.60, 0.80) Prior Warfarin/VKA Status Experienced (57%) 0.66 (0.55, 0.80) 0.73 (0.59, 0.91) 0.78 (0.55, 1.11) ≥65 and <75 (39%) 0.71 (0.56, 0.89) 0.64 (0.52, 0.79) 0.76 (0.64, 0.90) 0.58 (0.45, 0.74) 0.55 (0.36, 0.83) 0.72 (0.62, 0.83) Prior Stroke or TIA 0.73 (0.54, 0.98) 0.68 (0.58, 0.80) Diabetes Mellitus 0.96 (0.74, 1.25) 215 / 6812 (1.9) 0.60 (0.51, 0.71) 0.59 (0.44, 0.78) 0.76 (0.60, 0.96) 0.70 (0.56, 0.88) Creatinine Clearance <30 mL/min (1%) 0.32 (0.13, 0.78) 30-50 mL/min (15%) 0.53 (0.39, 0.71) >50-80 mL/min (42%) 0.76 (0.62, 0.94) >80 mL/min (41%) 0.79 (0.61, 1.04) Geographic Region 0.75 (0.56, 1.00) 0.68 (0.57, 0.80) Aspirin at Randomization 0.75 (0.60, 0.95) 0.66 (0.55, 0.79) 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.
Bleeding Events in Patients with Nonvalvular Atrial Fibrillation
Bleeding During the Treatment Period in Patients Undergoing
in AVERROES
Elective Hip or Knee Replacement Surgery
Hazard Ratio P-value
ADVANCE-3
ADVANCE-2
ADVANCE-1
Bleeding
Hip Replacement
Knee Replacement
Knee Replacement
n (%/year)
n (%/year)
1.54 (0.96, 2.45) ELIQUIS Enoxaparin ELIQUIS Enoxaparin ELIQUIS Enoxaparin 0.99 (0.23, 4.29) 0.99 (0.39, 2.51) 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 24 hours 15 hours 24 hours 15 hours 24 hours 24 hours Other Adverse Reactions Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and surgery to surgery surgery to surgery surgery anaphylactic reactions, such as allergic edema) and syncope were reported in <1% of patients receiving ELIQUIS.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery The safety of ELIQUIS has been evaluated in 1 Phase II and 3 Phase III studies including 5924 patients exposed to ELIQUIS 2.5 mg twice daily undergoing major orthopedic surgery of the lower limbs (elective hip replacement or elective knee replacement) treated for up to 38 days.
In total, 11% of the patients treated with ELIQUIS 2.5 mg twice daily experienced adverse reactions.
Bleeding results during the treatment period in the Phase III studies are shown in Table 3. Bleeding was assessed in each study beginning with the first dose of double-blind study drug.
Bleeding During the Treatment Period in Patients Undergoing
Injury, poisoning, and procedural complications: wound secretion, incision-site 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%: Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular ELIQUIS Enoxaparin ELIQUIS Enoxaparin ELIQUIS Enoxaparin hemorrhage (including conjunctival hemorrhage), rectal hemorrhage 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 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, hematuria, rectal hemorrhage, hematoma, menorrhagia, and hemoptysis.
surgery to surgery surgery to surgery surgery 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 417 (15.6%) ELIQUIS-treated patients compared to 661 (24.6%) enoxaparin/warfarin- treated patients. The discontinuation rate due to bleeding events was 0.7% in the ELIQUIS-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients (11.71%) (12.56%) 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).
‡ 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 Bleeding Results in the AMPLIFY Study
an operated joint requiring re-operation or intervention was present in all patients with Relative Risk
this category of bleeding. Events and event rates include one enoxaparin-treated patient in ADVANCE-1 who also had intracranial hemorrhage.
¶ CRNM = clinically relevant nonmajor.
0.31 (0.17, 0.55) Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4.
Adverse Reactions Occurring in ≥1% of Patients in Either Group
Undergoing Hip or Knee Replacement Surgery
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.
Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Anemia (including postoperative and hemorrhagic anemia, and respective laboratory Adverse Reactions Occurring in ≥1% of Patients Treated for
DVT and PE in the AMPLIFY Study
Hemorrhage (including hematoma, and vaginal and urethral hemorrhage) Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel puncture site hematoma and catheter site hemorrhage) Transaminases increased (including alanine aminotransferase increased and alanine Aspartate aminotransferase increased Rectal hemorrhage Less common adverse reactions in apixaban-treated patients undergoing hip or knee Gingival bleeding replacement surgery occurring at a frequency of ≥0.1% to <1%:Blood and lymphatic system disorders: thrombocytopenia (including platelet count 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) Bleeding Results in the AMPLIFY-EXT Study
Strong Dual Inducers of CYP3A4 and P-gp
ELIQUIS 2.5 mg bid ELIQUIS 5 mg bid
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 [see Clinical Pharmacology (12.3)].
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. 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.
Adverse Reactions Occurring in ≥1% of Patients Undergoing
USE IN SPECIFIC POPULATIONS
Extended Treatment for DVT and PE in the AMPLIFY-EXT Study
2.5 mg bid
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.
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 risk for fetal malformations or toxicity. No maternal or fetal deaths were attributed to bleeding. Increased incidence of maternal bleeding was observed in mice, rats, and Gingival bleeding 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 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 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 ELIQUIS therapy, taking into account the importance of the drug to the mother.
Investigations: blood urine present, occult blood positive, occult blood, red blood cells General disorders and administration-site conditions: injection-site hematoma, vessel Safety and effectiveness in pediatric patients have not been established.
puncture-site hematoma Of the total subjects in the ARISTOTLE and AVERROES clinical studies, >69% were 65 and older, and >31% were 75 and older. In the ADVANCE-1, ADVANCE-2, Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp and ADVANCE-3 clinical studies, 50% of subjects were 65 and older, while 16% increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 were 75 and older. In the AMPLIFY and AMPLIFY-EXT clinical studies, >32% of and P-gp decrease exposure to apixaban and increase the risk of stroke and other 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 different age groups.
Strong Dual Inhibitors of CYP3A4 and P-gp
For patients receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should 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.
This test is not recommended for assessing the anticoagulant effect of apixaban.
Pharmacodynamic Drug Interaction StudiesPharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin No dose adjustment is required in patients with mild hepatic impairment and clopidogrel, prasugrel, enoxaparin, and naproxen were conducted. No (Child-Pugh class A).
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 Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across renal function categories.
ELIQUIS is not recommended in patients with severe hepatic impairment (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 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)].
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.
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 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 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 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: DistributionPlasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
MetabolismApproximately 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.
Apixaban is a white to pale-yellow powder. At physiological pH (1.2–6.8), apixaban Apixaban is eliminated in both urine and feces. Renal excretion accounts for about does not ionize; its aqueous solubility across the physiological pH range is 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination 0.04 mg/mL.
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 Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).
Drug Interaction Studies In vitro apixaban studies at concentrations significantly greater than therapeutic exposures, no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, Mechanism of Action
CYP2C9, CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of CYP1A2, CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for alter the metabolic clearance of coadministered drugs that are metabolized by these antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase enzymes. Apixaban is not a significant inhibitor of P-gp.
activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits 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)].
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 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, 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 Protein binding was similar (92%-94%) between healthy controls and the on-dialysis and off-dialysis periods.
Other CYP3A4 and P-gp Inhibitors
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Apixaban was not carcinogenic when administered to mice and rats for up to 2 years. The systemic exposures (AUCs) of unbound apixaban in male 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 10 mg/day. Systemic exposures of unbound apixaban in male and female rats at the Strong CYP3A4 and P-gp Inducer
highest dose tested (600 mg/kg/day) were 2 and 4 times, respectively, the human 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 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.
Figure 3:
Effect of Specific Populations on the Pharmacokinetics of
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular
ARISTOTLEEvidence 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.
A total of 18,201 patients were randomized and followed on study treatment for a * ESRD subjects maintained with chronic and stable hemodialysis; reported PK findings are median of 89 weeks. Forty-three percent of patients were vitamin K antagonist (VKA) following single dose of apixaban post hemodialysis.
"naive," defined as having received ≤30 consecutive days of treatment with warfarin † Results reflect CrCl of 15 mL/min based on regression analysis.
or another VKA before entering the study. The mean age was 69 years and the mean ‡ Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores 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 Key Efficacy Outcomes in Patients with Nonvalvular Atrial
Fibrillation in ARISTOTLE (Intent-to-Treat Analysis)
Warfarin
Hazard Ratio P-value
n (%/year) n (%/year)
Stroke or systemic embolism 265 (1.60) 0.79 (0.66, 0.95) 250 (1.51) 0.79 (0.65, 0.95) Ischemic without 136 (0.82) 1.02 (0.81, 1.29) hemorrhagic conversion 0.60 (0.29, 1.23) All-cause death was assessed using a sequential testing strategy that allowed testing 0.51 (0.35, 0.75) for superiority if effects on earlier endpoints (stroke plus systemic embolus and major 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 0.87 (0.44, 1.75) a reduction in cardiovascular death, particularly stroke deaths. Non-vascular death rates were similar in the treatment arms.
The primary endpoint was based on the time to first event (one per subject). Component 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)
Hazard Ratio (95% CI)
0.79 (0.66, 0.95) Prior Warfarin/VKA Status Experienced (57%) 0.73 (0.57, 0.95) 0.86 (0.66, 1.11) 1.16 (0.77, 1.73) ≥65 and <75 (39%) 0.72 (0.54, 0.96) 0.71 (0.53, 0.95) 0.82 (0.65, 1.04) 0.74 (0.56, 1.00) 0.63 (0.41, 0.97) 0.83 (0.68, 1.01) Prior Stroke or TIA 0.76 (0.56, 1.03) 0.82 (0.65, 1.03) Diabetes Mellitus 0.75 (0.53, 1.05) 155 / 6836 (1.2) 0.81 (0.65, 1.00) 0.85 (0.57, 1.27) 0.90 (0.66, 1.23) 0.70 (0.54, 0.91) Creatinine Clearance <30 mL/min (1%) 0.55 (0.20, 1.53) 30-50 mL/min (15%) 0.83 (0.57, 1.21) >50-80 mL/min (42%) 0.74 (0.56, 0.97) >80 mL/min (41%) 0.88 (0.64, 1.21) Geographic Region 0.79 (0.50, 1.27) 0.79 (0.65, 0.96) Aspirin at Randomization 0.72 (0.53, 0.98) 0.83 (0.67, 1.04) 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 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 21 stroke or systemic embolism events in the 6791 patients (0.3%) in the ELIQUIS arm compared to 5 in the 6569 patients (0.1%) in the warfarin arm [see Dosage and Number of Patients
Total VTE†/All-cause death In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates for warfarin therapy were randomized to treatment with ELIQUIS 5 mg orally twice 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
for preventing the composite outcome of stroke or systemic embolism. AVERROES was stopped early on the basis of a prespecified interim analysis showing a significant 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 Table 10:
Key Efficacy Outcomes in Patients with Nonvalvular Atrial
Fibrillation in AVERROES
Number of Patients
Hazard Ratio
n (%/year) n (%/year)
Number of Patients
Stroke or systemic embolism 113 (3.63) 0.45 (0.32, 0.62) <0.0001 0.44 (0.31, 0.63) * 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.
0.67 (0.24, 1.88) ‡ Includes symptomatic and asymptomatic DVT.
Systemic embolism 0.15 (0.03, 0.68) 0.86 (0.50, 1.48) Table 12:
Summary of Key Efficacy Analysis Results During the Intended
Treatment Period for Patients Undergoing Elective Knee
140 (4.42) 0.79 (0.62, 1.02) 0.87 (0.65, 1.17) ELIQUIS Enoxaparin Relative Enoxaparin Relative Risk 2.5 mg po bid 40 mg sc qd Prophylaxis of Deep Vein Thrombosis Following Hip or Knee
The clinical evidence for the effectiveness of ELIQUIS is derived from the ADVANCE-1, Number of
ADVANCE-2, and ADVANCE-3 clinical trials in adult patients undergoing elective hip (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 (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 severe or moderate renal impairment.
Number of
In the ADVANCE-3 study, 5407 patients undergoing elective hip replacement surgery were randomized to receive either ELIQUIS 2.5 mg orally twice daily or enoxaparin 3 (0.19%) 3 (0.19%) 40 mg subcutaneously once daily. The first dose of ELIQUIS was given 12 to 24 hours (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.
16 (1.0%) 7 (0.44%) (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%) (ADVANCE-2, N=3057) or enoxaparin 30 mg subcutaneously every 12 hours (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
12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to 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 9 (0.72%) 11 (0.91%) 9 (0.76%) 26 (2.17%) 10 to 14 days.
(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
and symptomatic DVT, nonfatal PE, and all-cause death at the end of the double-blind intended treatment period. In ADVANCE-3 and ADVANCE-2, the primary endpoint was 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 (5.88, 8.91) (6.58, 9.78) primary endpoint was tested for noninferiority of ELIQUIS to enoxaparin.
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).
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
treatment was derived from the AMPLIFY and AMPLIFY-EXT studies. Both studies were 2.5 mg bid 5 mg bid
2.5 mg bid
randomized, parallel-group, double-blind trials in patients with symptomatic proximal vs Placebo
vs Placebo
DVT and/or symptomatic PE. All key safety and efficacy endpoints were adjudicated in a blinded manner by an independent committee.
Recurrent VTE or 34 (4.2) 96 (11.6) 0.33 (0.22, 0.48) 0.36 (0.25, 0.53) The primary objective of AMPLIFY was to determine whether ELIQUIS was noninferior to enoxaparin/warfarin for the incidence of recurrent VTE (venous thromboembolism) 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 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 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. The mean age was 57 years. The AMPLIFY study population was 59% male, 83% Package Size
Caucasian, 8% Asian, and 4% Black. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2.0-3.0) was 60.9%.
"893" on one side Hospital Unit-Dose 0003-0893-31 Approximately 90% of patients enrolled in AMPLIFY had an unprovoked DVT or PE at on the other side baseline. The remaining 10% of patients with a provoked DVT or PE were required to have an additional ongoing risk factor in order to be randomized, which included previous episode of DVT or PE, immobilization, history of cancer, active cancer, and known prothrombotic genotype.
"894" on one side Hospital Unit-Dose 0003-0894-31 ELIQUIS was shown to be noninferior to enoxaparin/warfarin in the AMPLIFY study for on the other side the primary endpoint of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or 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 (59°F-86°F) [see USP Controlled Room Temperature].
PATIENT COUNSELING INFORMATION
VTE or VTE-related death* 0.84 (0.60, 1.18) See FDA-approved patient labeling (Medication Guide). Advise patients of the following: • They should not discontinue ELIQUIS without talking to their physician first.
VTE-related death† • 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 0.82 (0.61, 1.08) patients about how to recognize bleeding or symptoms of hypovolemia and of the urgent need to report any unusual bleeding to their physician.
VTE or CV-related death 0.80 (0.57, 1.11) • They should tell their physicians and dentists they are taking ELIQUIS, and/or Noninferior compared to enoxaparin/warfarin (P-value <0.0001).
any other product known to affect bleeding (including nonprescription products, † Events 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.
• 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 day and twice-daily administration should be resumed. The dose should not be enrollment in the AMPLIFY-EXT study.
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 was 57% male, 85% Caucasian, 5% Asian, and 3% Black.
Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA The AMPLIFY-EXT study enrolled patients with either an unprovoked DVT or PE at baseline (approximately 92%) or patients with a provoked baseline event and one additional risk factor for recurrence (approximately 8%). However, patients who had New York, New York 10017 USA experienced multiple episodes of unprovoked DVT or PE were excluded from the 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 • other medicines to help prevent or treat ELIQUIS® (ELL eh kwiss)
(apixaban)
Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one 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 People with atrial fibrillation (a type of • it may take longer than usual for any 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 to prevent clots from forming. If you stop taking ELIQUIS, you may have increased • unexpected bleeding, or bleeding that risk of forming a clot in your blood.
lasts a long time, such as: Do not stop taking ELIQUIS without
• unusual bleeding from the gums talking to the doctor who prescribes it
• nosebleeds that happen often for you. Stopping ELIQUIS increases
your risk of having a stroke.
• menstrual bleeding or vaginal 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 ELIQUIS for you when you should stop • red, pink, or brown urine taking it. Your doctor will tell you when you may start taking ELIQUIS again after your • red or black stools (looks like tar) surgery or procedure. If you have to stop • cough up blood or blood clots taking ELIQUIS, your doctor may prescribe another medicine to help prevent a blood • vomit blood or your vomit looks like 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 medicine that reduces blood clotting.
• ELIQUIS is not for patients with
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 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) • 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 • reduce the risk of forming a blood clot in the them to show your doctor and pharmacist when 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 Do not take ELIQUIS if you:
soon as you remember. Do not take more than one dose of ELIQUIS at the same time • currently have certain types of abnormal to make up for a missed dose.
• 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.
What should I tell my doctor before taking
If you are taking ELIQUIS for atrial
fibrillation, stopping ELIQUIS may
increase your risk of having a stroke.
Before you take ELIQUIS, tell your doctor
• Do not run out of ELIQUIS. Refill your
prescription before you run out. When
• have kidney or liver problems leaving the hospital following hip or knee • have any other medical condition replacement, be sure that you will have ELIQUIS available to avoid missing any • have ever had bleeding problems • 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 you hit your head. Your doctor or healthcare Active ingredient: apixaban.
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 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) or red iron oxide (5 mg tablets).
• ELIQUIS can cause a skin rash or severe allergic reaction. Call your doctor or get This Medication Guide has been approved by medical help right away if you have any of the U.S. Food and Drug Administration.
the following symptoms: • chest pain or tightness Bristol-Myers Squibb Company • swelling of your face or tongue Princeton, New Jersey 08543 USA • trouble breathing or wheezing New York, New York 10017 USA • feeling dizzy or faint Tell your doctor if you have any side effect that COUMADIN® is a registered trademark of bothers you or that does not go away.
Bristol-Myers Squibb Pharma Company. All other trademarks are property of their These are not all of the possible side effects of ELIQUIS. For more information, ask your doctor or pharmacist.
1356615A0 / 1356514A0 Call your doctor for medical advice about side Revised June 2015 effects. You may report side effects to FDA at 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.

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