The most serious adverse reactions reported with ELIQUIS were related to bleeding [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 Nonvalvular Atrial Fibrillation
The safety of ELIQUIS was evaluated in the ARISTOTLE and AVERROES studies [see Clinical Studies], 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 year) in ARISTOTLE and AVERROES.
Major bleeding was defined as clinically overt bleeding that was accompanied by one or more of the following: a decrease in hemoglobin of 2 g/dL or more; a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; or bleeding that was fatal. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.
Table 1: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE
| ELIQUIS N=9088 n (%/year) |
Warfarin N=9052 n (%/year) |
Hazard Ratio (95% CI*) | P-value | |
| Major† | 327 (2.13) | 462 (3.09) | 0.69 (0.60, 0.80) | < 0.0001 |
| Gastrointestinal (GI)‡ | 128 (0.83) | 141 (0.93) | 0.89 (0.70, 1.14) | - |
| Intracranial | 52 (0.33) | 125 (0.82) | 0.41 (0.30, 0.57) | - |
| Intraocular§ | 32 (0.21) | 22 (0.14) | 1.42 (0.83, 2.45) | - |
| Fatal¶ | 10 (0.06) | 37 (0.24) | 0.27 (0.13, 0.53) | - |
| CRNM ** | 318 (2.08) | 444 (3.00) | 0.70 (0.60, 0.80) | < 0.0001 |
| * Confidence interval. † International Society on Thrombosis and Hemostasis (ISTH) major bleed assessed by sequential testing strategy for superiority designed to control the overall type I error in the trial. ‡ GI bleed includes upper GI, lower GI, and rectal bleeding. § Intraocular bleed is within the corpus of the eye (a conjunctival bleed is not an intraocular bleed). ¶Fatal bleed is an adjudicated death because of bleeding during the treatment period and includes both fatal extracranial bleeds and fatal hemorrhagic stroke. **CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. |
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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, ELIQUIS dose, type of atrial fibrillation (AF), 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 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 During the Treatment Period in Patients Undergoing Elective Hip or Knee Replacement Surgery
| Bleeding Endpoint* | ADVANCE-3 Hip Replacement Surgery | ADVANCE-2 Knee Replacement Surgery | ADVANCE-1 Knee Replacement Surgery | |||
| ELIQUIS 2.5 mg po bid 35±3 days | Enoxaparin 40 mg sc qd 35±3 days | ELIQUIS 2.5 mg po bid 12±2 days | Enoxaparin 40 mg sc qd 12±2 days | ELIQUIS 2.5 mg po bid 12±2 days | Enoxaparin 30 mg sc q12h 12±2 days | |
| First dose 12 to 24 hours post surgery | First dose 9 to 15 hours prior to surgery | First dose 12 to 24 hours post surgery | First dose 9 to 15 hours prior to surgery | First dose 12 to 24 hours post surgery | 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 (0.82%)† | 18 (0.68%) | 9 (0.60%)‡ | 14 (0.93%) | 11 (0.69%) | 22 (1.39%) |
| Fatal | 0 | 0 | 0 | 0 | 0 | 1 (0.06%) |
| Hgb decrease ≥ 2 g/dL | 13 (0.49%) | 10 (0.38%) | 8 (0.53%) | 9 (0.60%) | 10 (0.63%) | 16 (1.01%) |
| Transfusion of ≥ 2 units RBC | 16 (0.60%) | 14 (0.53%) | 5 (0.33%) | 9 (0.60%) | 9 (0.56%) | 18 (1.13%) |
| Bleed at critical site§ | 1 (0.04%) | 1 (0.04%) | 1 (0.07%) | 2 (0.13%) | 1 (0.06%) | 4 (0.25%) |
| Major + CRNM¶ | 129 (4.83%) | 134 (5.04%) | 53 (3.53%) | 72 (4.77%) | 46 (2.88%) | 68 (4.28%) |
| All | 313 (11.71%) | 334 (12.56%) | 104 (6.93%) | 126 (8.36%) | 85 (5.33%) | 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. |
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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.
Table 4: Adverse Reactions Occurring in ≥ 1% of Patients in Either Group Undergoing Hip or Knee Replacement Surgery
| ELIQUIS, n (%) 2.5 mg po bid N=5924 |
Enoxaparin, n (%) 40 mg sc qd or 30 mg sc q12h N=5904 |
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| Nausea | 153 (2.6) | 159 (2.7) |
| Anemia (including postoperative and hemorrhagic anemia, and respective laboratory parameters) | 153 (2.6) | 178 (3.0) |
| Contusion | 83 (1.4) | 115 (1.9) |
| Hemorrhage (including hematoma, and vaginal and urethral hemorrhage) | 67 (1.1) | 81 (1.4) |
| Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel puncture site hematoma and catheter site hemorrhage) | 54 (0.9) | 60 (1.0) |
| Transaminases increased (including alanine aminotransferase increased and alanine aminotransferase abnormal) | 50 (0.8) | 71 (1.2) |
| Aspartate aminotransferase increased | 47 (0.8) | 69 (1.2) |
| Gamma-glutamyltransferase increased | 38 (0.6) | 65 (1.1) |
Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of ≥ 0.1% to < 1%:
Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases)
Vascular disorders: hypotension (including procedural hypotension)
Respiratory, thoracic, and mediastinal disorders: epistaxis Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena), hematochezia
Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased
Renal and urinary disorders: hematuria (including respective laboratory parameters)
Injury, poisoning, and procedural complications: wound secretion, incision-site hemorrhage (including incision-site hematoma), operative hemorrhage
Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of < 0.1%:
Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage (including conjunctival hemorrhage), rectal hemorrhage