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. Reversal of Anticoagulant Effect A specific antidote for ELIQUIS is not available, and there is no established way to reverse the bleeding in patients taking ELIQUIS. The pharmacodynamic effect of ELIQUIS can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical studies [see Clinical Pharmacology (12.2) in full Prescribing Information] . When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not useful and is not recommended. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration [see Overdosage] . 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 no experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving apixaban and they are not expected to be effective as a reversal agent. 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 (apixaban) 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 N=9088 n (per 100 pt-year) Major † Intracranial (ICH) ‡ Hemorrhagic stroke § Other ICH Gastrointestinal (GI) ¶ Fatal ** Intracranial Non-intracranial * 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). Table 2: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in AVERROES ELIQUIS (apixaban) Aspirin N=2798 N=2780 Hazard Ratio n (%/year) n (%/year) (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 ADVANCE-2 ADVANCE-1 Hip Replacement Knee Replacement Knee Replacement Surgery Surgery Surgery ELIQUIS Enoxaparin ELIQUIS Enoxaparin ELIQUIS Enoxaparin 2.5 mg 40 mg 2.5 mg 40 mg 2.5 mg 30 mg po bid sc qd po bid sc qd po bid sc q12h 35±3 days 35±3 days 12±2 days 12±2 days 12±2 days 12±2 days First dose First dose First dose First dose First dose First dose 12 to 24 9 to 15 12 to 24 9 to 15 12 to 24 12 to 24 hours post hours prior hours post hours prior hours post hours post surgery to surgery surgery to surgery surgery surgery N=2673 N=2659 N=1501 N=1508 N=1596 N=1588 22 (0.82%) † 0 13 (0.49%) 16 (0.60%) 1 (0.04%) 129 (4.83%) 313 (11.71%) 18 (0.68%) 0 10 (0.38%) 14 (0.53%) 1 (0.04%) 134 (5.04%) 334 (12.56%) 9 (0.60%) ‡ 0 8 (0.53%) 5 (0.33%) 1 (0.07%) 53 (3.53%) 104 (6.93%) 14 (0.93%) 0 9 (0.60%) 9 (0.60%) 2 (0.13%) 72 (4.77%) 126 (8.36%) 11 (0.69%) 0 10 (0.63%) 9 (0.56%) 1 (0.06%) 46 (2.88%) 85 (5.33%) 22 (1.39%) 1 (0.06%) 16 (1.01%) 18 (1.13%) 4 (0.25%) 68 (4.28%) 108 (6.80%) Warfarin N=9052 n (per 100 pt-year) 462 (3.09) 125 (0.82) 74 (0.49) 51 (0.34) 141 (0.93) 37 (0.24) 30 (0.20) 7 (0.05) Hazard Ratio (95% CI) 0.69 (0.60, 0.80) 0.41 (0.30, 0.57) 0.51 (0.34, 0.75) 0.29 (0.16, 0.51) 0.89 (0.70, 1.14) 0.27 (0.13, 0.53) 0.13 (0.05, 0.37) 0.84 (0.28, 2.15) P-value All treated <0.0001 -------Major (including surgical site) Fatal Hgb decrease ≥2 g/dL Transfusion of ≥2 units RBC Bleed at critical site § Major + CRNM ¶ All 327 (2.13) 52 (0.33) 38 (0.24) 15 (0.10) 128 (0.83) 10 (0.06) 4 (0.03) 6 (0.04) 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. Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics – ARISTOTLE Study * 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. n of Events / N of Patients (% per year) Subgroup All Patients Prior Warfarin/VKA Status Experienced (57%) Naive (43%) Age <65 (30%) ≥65 and <75 (39%) ≥75 (31%) Sex Male (65%) Female (35%) Weight ≤60 kg (11%) >60 kg (89%) Prior Stroke or TIA Yes (19%) No (81%) Diabetes Mellitus Yes (25%) No (75%) CHADS 2 Score ≤1 (34%) 2 (36%) ≥3 (30%) Creatinine Clearance <30 mL/min (1%) 30-50 mL/min (15%) >50-80 mL/min (42%) >80 mL/min (41%) Geographic Region US (19%) Non-US (81%) Aspirin at Randomization Yes (31%) No (69%) Apixaban 327 / 9088 (2.1) 185 / 5196 (2.1) 142 / 3892 (2.2) 56 / 2723 (1.2) 120 / 3529 (2.0) 151 / 2836 (3.3) 225 / 5868 (2.3) 102 / 3220 (1.9) 36 / 1013 (2.3) 290 / 8043 (2.1) 77 / 1687 (2.8) 250 / 7401 (2.0) 112 / 2276 (3.0) 215 / 6812 (1.9) 76 / 3093 (1.4) 125 / 3246 (2.3) 126 / 2749 (2.9) 7 / 136 (3.7) 66 / 1357 (3.2) 157 / 3807 (2.5) 96 / 3750 (1.5) 83 / 1716 (2.8) 244 / 7372 (2.0) 129 / 2846 (2.7) 198 / 6242 (1.9) Warfarin 462 / 9052 (3.1) 274 / 5180 (3.2) 188 / 3872 (3.0) 72 / 2732 (1.5) 166 / 3501 (2.8) 224 / 2819 (5.2) 294 / 5879 (3.0) 168 / 3173 (3.3) 62 / 965 (4.3) 398 / 8059 (3.0) 106 / 1735 (3.9) 356 / 7317 (2.9) 114 / 2250 (3.1) 348 / 6802 (3.1) 126 / 3076 (2.3) 163 / 3246 (3.0) 173 / 2730 (4.1) 19 / 132 (11.9) 123 / 1380 (6.0) 199 / 3758 (3.2) 119 / 3746 (1.8) 109 / 1693 (3.8) 353 / 7359 (2.9) 164 / 2762 (3.7) 298 / 6290 (2.8) Hazard Ratio (95% CI) 0.69 (0.60, 0.80) 0.66 (0.55, 0.80) 0.73 (0.59, 0.91) 0.78 (0.55, 1.11) 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) 0.73 (0.54, 0.98) 0.68 (0.58, 0.80) 0.96 (0.74, 1.25) 0.60 (0.51, 0.71) 0.59 (0.44, 0.78) 0.76 (0.60, 0.96) 0.70 (0.56, 0.88) 0.32 (0.13, 0.78) 0.53 (0.39, 0.71) 0.76 (0.62, 0.94) 0.79 (0.61, 1.04) 0.75 (0.56, 1.00) 0.68 (0.57, 0.80) 0.75 (0.60, 0.95) 0.66 (0.55, 0.79) 0.125 0.25 0.5 1 2 Warfarin Better Apixaban Better Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were pre-specified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.