ELIQUIS® (apixaban) tablets, for oral use
Brief Summary of Prescribing Information. For complete prescribing information consult
official package insert.
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF
THROMBOTIC EVENTS
(B) SPINAL/EPIDURAL HEMATOMA
(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. 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 [see Dosage and Administration, Warnings and Precautions, and Clinical
Studies (14.1) in full Prescribing Information].
(B) SPINAL/EPIDURAL HEMATOMA
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 patient s 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
[see Warnings and Precautions]
Monitor patients frequently for signs and symptoms of neurological impairment.
If neurological compromise is noted, urgent treatment is necessary [see Warnings and
Precautions].
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to
be anticoagulated [see Warnings and Precautions].
INDICATIONS AND USAGE
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation—
ELIQUIS® (apixaban) is indicated to reduce the risk of stroke and systemic embolism in patients with
nonvalvular atrial fibrillation.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery—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 replacement surgery.
Treatment of Deep Vein Thrombosis—ELIQUIS is indicated for the treatment of DVT.
Treatment of Pulmonary Embolism—ELIQUIS is indicated for the treatment of PE.
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.
DOSAGE AND ADMINISTRATION (Selected 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 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 non-critical 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. (For complete Dosage and Administration section, see full Prescribing Information.)
CONTRAINDICATIONS
ELIQUIS is contraindicated in patients with the following conditions:
• Active pathological bleeding [see Warnings and Precautions and Adverse Reactions]
• Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) [see Adverse Reactions]
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 [see Dosage and Administration (2.4) and Clinical
Studies (14.1) in full Prescribing Information].
Bleeding
ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see Dosage and
Administration (2.1) in full Prescribing Information and Adverse Reactions].
Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin
and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin
reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory
drugs (NSAIDs) [see Drug Interactions].
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., for about 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) in full Prescribing Information]. Protamine sulfate and
vitamin K are not expected to affect 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 (desmopressin and
aprotinin) in individuals receiving apixaban. Use of procoagulant reversal agents such as prothrombin
complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa may be
considered but has not been evaluated in clinical studies. Activated oral charcoal reduces absorption of
apixaban, thereby lowering apixaban plasma concentration [see Overdosage].
Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed,
patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk
of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
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 (apixaban). 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 for signs and symptoms of neurological impairment (e.g., numbness
or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent
diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider
the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for
thromboprophylaxis.
Patients with Prosthetic Heart Valves
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.
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.
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]
• Bleeding [see Warnings and Precautions]
• Spinal/epidural anesthesia or puncture [see Warnings and Precautions]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation
The safety of ELIQUIS was evaluated in the ARISTOTLE and AVERROES studies [see Clinical Studies
(14) in full Prescribing Information], including 11,284 patients exposed to ELIQUIS 5 mg twice 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 patient-years). In AVERROES, the mean duration of exposure was
approximately 59 weeks (>3000 patient-years).
The most common reason for treatment discontinuation in both studies was for bleeding-related adverse
reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with ELIQUIS and warfarin,
respectively, and in AVERROES, in 1.5% and 1.3% on ELIQUIS and aspirin, respectively.
Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES
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.
Table 1:
Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE*
ELIQUIS
Warfarin
Hazard Ratio
P-value
N=9088
N=9052
(95% CI)
n (per
n (per
100 pt-year)
100 pt-year)
Major†
327 (2.13)
462 (3.09)
0.69 (0.60, 0.80)
<0.0001
52 (0.33)
125 (0.82)
0.41 (0.30, 0.57)
Intracranial (ICH)‡
38 (0.24)
74 (0.49)
0.51 (0.34, 0.75)
Hemorrhagic stroke§
Other ICH
15 (0.10)
51 (0.34)
0.29 (0.16, 0.51)
128 (0.83)
141 (0.93)
0.89 (0.70, 1.14)
Gastrointestinal (GI)¶
10 (0.06)
37 (0.24)
0.27 (0.13, 0.53)
Fatal**
Intracranial
4 (0.03)
30 (0.20)
0.13 (0.05, 0.37)
Non-intracranial
6 (0.04)
7 (0.05)
0.84 (0.28, 2.15)
* Bleeding events within each subcategory were counted once per subject, but subjects may have
contributed events to multiple endpoints. Bleeding events were counted during treatment or within
2 days of stopping study treatment (on-treatment period).
† Defined as clinically overt bleeding accompanied by one or more of the following: 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, intra-articular, intramuscular with compartment
syndrome, retroperitoneal or with fatal outcome.
‡ Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type
of hemorrhagic stroke was adjudicated and counted as an intracranial major bleed.
§ On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14.
¶ GI bleed includes upper GI, lower GI, and rectal bleeding.
** Fatal bleeding is an adjudicated death with the primary cause of death as intracranial bleeding or
non-intracranial bleeding during the on-treatment period.
In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups
including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher
scores predicting greater risk), prior warfarin use, 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).