August 29, 2015
Recommended Topic Related To:

Eliquis

"May 31, 2013 -- More than 2 million Americans have an abnormal heart rhythm known as atrial fibrillation, raising their risk of blood clots leading to stroke. For many years, the blood thinner Coumadin (warfarin) was the only game in town to help"...

Eliquis




Side Effects
Interactions

SIDE EFFECTS

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.

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], 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.

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

Major Bleeding Hazard Ratios by Baseline Characteristics – ARISTOTLE Study - Illustration

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* All treated 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
N=2673
First dose 9 to 15 hours prior to surgery
N=2659
First dose 12 to 24 hours post surgery
N=1501
First dose 9 to 15 hours prior to surgery
N=1508
First dose 12 to 24 hours post surgery
N=1596
First dose 12 to 24 hours post surgery
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.

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
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

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.

AMPLIFY Study

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

  ELIQUIS
N=2676
n (%)
Enoxaparin/Warfarin
N=2689
n (%)
Major 15 (0.6) 49 (1.8)
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

  ELIQUIS
N=2676
n (%)
Enoxaparin/Warfarin
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)

AMPLIFY-EXT Study

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
N=840
n (%)
ELIQUIS 5 mg bid
N=811
n (%)
Placebo
N=826
n (%)
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 (%)
Placebo
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 AMPLIFYEXT 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

Read the Eliquis (apixaban tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events.

Strong Dual Inhibitors Of CYP3A4 And P-gp

For patients receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should be decreased by 50% when coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Strong Dual Inducers Of CYP3A4 And P-gp

Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) because such drugs will decrease exposure to apixaban [see CLINICAL PHARMACOLOGY].

Anticoagulants And Antiplatelet Agents

Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding.

APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. The rate of ISTH major bleeding was 2.8% per year with apixaban versus 0.6% per year with placebo in patients receiving single antiplatelet therapy and was 5.9% per year with apixaban versus 2.5% per year with placebo in those receiving dual antiplatelet therapy.

In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS from 1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin increased the bleeding risk from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet therapy with ELIQUIS.

Last reviewed on RxList: 7/8/2015
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions

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