ELIQUIS SIDE EFFECTS
- Generic Name: apixaban tablets
- Brand Name: Eliquis
- Drug Class: Anticoagulants, Cardiovascular, Factor Xa Inhibitors
The following clinically significant adverse reactions are discussed in greater detail in other sections of the prescribing information.
- Increased Risk of Thrombotic Events After Premature Discontinuation
- Spinal/Epidural Anesthesia or Puncture
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, 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*
N=9088 n (per 100 pt-year)
N=9052 n (per 100 pt-year)
|Hazard Ratio (95% CI)||P-value|
|Major†||327 (2.13)||462 (3.09)||0.69
|Intracranial (ICH)‡||52 (0.33)||125 (0.82)||0.41
|Hemorrhagic stroke§||38 (0.24)||74 (0.49)||0.51
|Other ICH||15 (0.10)||51 (0.34)||0.29
|Gastrointestinal (GI)¶||128 (0.83)||141 (0.93)||0.89
|Fatal**||10 (0.06)||37 (0.24)||0.27
|Intracranial||4 (0.03)||30 (0.20)||0.13
|Non-intracranial||6 (0.04)||7 (0.05)||0.84
|* 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 ELIQUIS with diabetes bled more (3% per year) than did subjects without diabetes (1.9% per year).
Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics – ARISTOTLE Study
Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were prespecified, 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.
Table 2: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in AVERROES
N=2798 n (%/year)
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|
|Major (including surgical site)||22 (0.82%)†||18 (0.68%)||9 (0.60%)‡||14 (0.93%)||11 (0.69%)||22 (1.39%)|
|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 ELIQUIS (administered 12 to 24 hours post-surgery).
† Includes 5 subjects with major bleeding events that occurred before the first dose of ELIQUIS (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.
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
|Enoxaparin, n (%) 40 mg sc qd or 30 mg sc q12h
|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 ELIQUIS-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 ELIQUIS-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
Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT or PE
The safety of ELIQUIS has been evaluated in the AMPLIFY and AMPLIFY-EXT studies, 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.
Common adverse reactions (≥1%) were gingival bleeding, epistaxis, contusion, hematuria, rectal hemorrhage, hematoma, menorrhagia, and hemoptysis.
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 in the AMPLIFY study.
In the AMPLIFY study, ELIQUIS was statistically superior to enoxaparin/warfarin in the primary safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55], P-value <0.0001).
Bleeding results from the AMPLIFY study are summarized in Table 5.
Table 5: Bleeding Results in the AMPLIFY Study
N=2676 n (%)
N=2689 n (%)
|Relative Risk (95% CI)|
|Major||15 (0.6)||49 (1.8)||0.31 (0.17, 0.55) p<0.0001|
|CRNM*||103 (3.9)||215 (8.0)|
|Major + CRNM||115 (4.3)||261 (9.7)|
|Minor||313 (11.7)||505 (18.8)|
|All||402 (15.0)||676 (25.1)|
|* CRNM = clinically relevant nonmajor bleeding.
Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.
Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6.
Table 6: Adverse Reactions Occurring in ≥1% of Patients Treated for DVT and PE in the AMPLIFY Study
N=2676 n (%)
N=2689 n (%)
|Epistaxis||77 (2.9)||146 (5.4)|
|Contusion||49 (1.8)||97 (3.6)|
|Hematuria||46 (1.7)||102 (3.8)|
|Menorrhagia||38 (1.4)||30 (1.1)|
|Hematoma||35 (1.3)||76 (2.8)|
|Hemoptysis||32 (1.2)||31 (1.2)|
|Rectal hemorrhage||26 (1.0)||39 (1.5)|
|Gingival bleeding||26 (1.0)||50 (1.9)|
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 occurred in 219 (13.3%) ELIQUIS-treated patients compared to 72 (8.7%) placebo-treated patients. The discontinuation rate due to bleeding events was approximately 1% in the ELIQUIS-treated patients compared to 0.4% in those patients in the placebo group in the AMPLIFY-EXT study.
Bleeding results from the AMPLIFY-EXT study are summarized in Table 7.
Table 7: Bleeding Results in the AMPLIFY-EXT Study
|ELIQUIS 2.5 mg bid
|ELIQUIS 5 mg bid
|Major||2 (0.2)||1 (0.1)||4 (0.5)|
|CRNM*||25 (3.0)||34 (4.2)||19 (2.3)|
|Major + CRNM||27 (3.2)||35 (4.3)||22 (2.7)|
|Minor||75 (8.9)||98 (12.1)||58 (7.0)|
|All||94 (11.2)||121 (14.9)||74 (9.0)|
|* CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.|
Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in Table 8.
Table 8: Adverse Reactions Occurring in ≥1% of Patients Undergoing Extended Treatment for DVT and PE in the AMPLIFY-EXT Study
|ELIQUIS 2.5 mg bid
N=840 n (%)
|ELIQUIS 5 mg bid
N=811 n (%)
N=826 n (%)
|Epistaxis||13 (1.5)||29 (3.6)||9 (1.1)|
|Hematuria||12 (1.4)||17 (2.1)||9 (1.1)|
|Hematoma||13 (1.5)||16 (2.0)||10 (1.2)|
|Contusion||18 (2.1)||18 (2.2)||18 (2.2)|
|Gingival bleeding||12 (1.4)||9 (1.1)||3 (0.4)|
Other Adverse Reactions
Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or AMPLIFY-EXT studies occurring at a frequency of ≥0.1% to <1%:
Blood and lymphatic system disorders: hemorrhagic anemia
Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, melena, anal hemorrhage
Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural hemorrhage, traumatic hematoma, periorbital hematoma
Musculoskeletal and connective tissue disorders: muscle hemorrhage
Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia, menometrorrhagia, genital hemorrhage
Vascular disorders: hemorrhage
Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae
Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage
Investigations: blood urine present, occult blood positive, occult blood, red blood cells urine positive
General disorders and administration-site conditions: injection-site hematoma, vessel puncture-site hematoma.
SRC: NLM .