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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.
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
|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 (0.6)||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 AF, and aspirin use at randomization (Figure 1). Subjects treated with apixaban with diabetes bled more (3.0%/year) than did subjects without diabetes (1.9%/year).
Figure 1: Major Bleeding Hazard Ratios by Baseline
Characteristics – ARISTOTLE Study
Table 2: Bleeding Events in Patients with Nonvalvular
Atrial Fibrillation in AVERROES
|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
Read the Eliquis (apixaban tablets) Side Effects Center for a complete guide to possible side effects
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.
Strong Dual Inhibitors of CYP3A4 and P-gp
The dose of ELIQUIS should be decreased to 2.5 mg twice daily when it is 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].
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
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 2.77%/year with apixaban versus 0.62%/year with placebo in patients receiving single antiplatelet therapy and was 5.91%/year with apixaban versus 2.50%/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 the bleeding risk on warfarin 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: 1/10/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Eliquis Information
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