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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 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

[ 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 . 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 ( apixaban ) 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 bleedingrelated 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 N = 9088 n ( per 100 pt-year )

Warfarin N = 9052 n ( per 100 pt-year )

Hazard Ratio ( 95 % CI )

P-value

In ARISTOTLE , the results for major bleeding were generally consistent across most major subgroups including age , weight , CHADS 2 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 ).

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

Table 2 :

Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in AVERROES

ELIQUIS ( apixaban ) N = 2798 n (%/ year )

Aspirin N = 2780 n (%/ year )

Hazard Ratio ( 95 % CI ) P-value

Major 45 ( 1.41 ) 29 ( 0.92 ) 1.54 ( 0.96 , 2.45 ) 0.07 Fatal 5 ( 0.16 ) 5 ( 0.16 ) 0.99 ( 0.23 , 4.29 ) - Intracranial 11 ( 0.34 ) 11 ( 0.35 ) 0.99 ( 0.39 , 2.51 ) -

Events associated with each endpoint were counted once per subject , but subjects may have contributed events to multiple endpoints .

Other Adverse Reactions

Hypersensitivity reactions ( including drug hypersensitivity , such as skin rash , and 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 .

Table 3 :

Bleeding Endpoint *

Bleeding During the Treatment Period in Patients Undergoing Elective Hip or Knee Replacement Surgery

ADVANCE-3 Hip Replacement Surgery

ELIQUIS 2.5 mg po bid 35 ± 3 days

First dose 12 to 24 hours post surgery

Enoxaparin 40 mg sc qd 35 ± 3 days

First dose 9 to 15 hours prior to surgery

ADVANCE-2 Knee Replacement Surgery

ELIQUIS 2.5 mg po bid 12 ± 2 days

First dose 12 to 24 hours post surgery

Enoxaparin 40 mg sc qd 12 ± 2 days

First dose 9 to 15 hours prior to surgery

ADVANCE-1 Knee Replacement Surgery

ELIQUIS 2.5 mg po bid 12 ± 2 days

First dose 12 to 24 hours post surgery

Enoxaparin 30 mg sc q12h 12 ± 2 days

First dose 12 to 24 hours post surgery

All treated N = 2673 N = 2659 N = 1501 N = 1508 N = 1596 N = 1588

Major ( including surgical site )

22 18 ( 0.82 %) † ( 0.68 %)

9 14 ( 0.60 %) ‡ ( 0.93 %)

11 ( 0.69 %)

22 ( 1.39 %)

Hgb decrease ≥2 g / dL

Transfusion of ≥2 units RBC

13 ( 0.49 %)

16 ( 0.60 %)

Bleed at

1 critical site § ( 0.04 %)

Major

129 + CRNM ¶ ( 4.83 %)

All 313 ( 11.71 %)

10 ( 0.38 %)

14 ( 0.53 %)

1 ( 0.04 %)

134 ( 5.04 %)

334 ( 12.56 %)

8 ( 0.53 %)

5 ( 0.33 %)

1 ( 0.07 %)

53 ( 3.53 %)

104 ( 6.93 %)

9 ( 0.60 %)

9 ( 0.60 %)

2 ( 0.13 %)

72 ( 4.77 %)

126 ( 8.36 %)

10 ( 0.63 %)

9 ( 0.56 %)

1 ( 0.06 %)

46 ( 2.88 %)

85 ( 5.33 %)

16 ( 1.01 %)

18 ( 1.13 %)

4 ( 0.25 %)

68 ( 4.28 %)

108 ( 6.80 %)

* All bleeding criteria included surgical site bleeding .

†

Includes 13 subjects with major bleeding events that occurred before the first dose of apixaban ( administered 12 to 24 hours post surgery ).

‡

Includes 5 subjects with major bleeding events that occurred before the first dose of 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 an operated joint requiring re-operation or intervention was present in all patients with 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 .

0.125 0.25 0.5 1 2

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 .

Apixaban Better

Warfarin Better