Side Effects of Eliquis (apixaban)

Eliquis (apixaban) is an anticoagulant (blood thinner) used to reduce the risk of blood clots in the heart and strokes in patients with atrial fibrillation who have no problems with their heart valves (nonvalvular atrial fibrillation). Eliquis is also used to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have undergone hip or knee replacement surgery.

Common side effects of Eliquis include

• skin rash,
• allergic reactions,
• fainting,
• nausea, and
• anemia.

Serious side effects of Eliquis include

• bleeding in the stomach, intestines, brain, and eyes, which may be fatal. 

Drug interactions of Eliquis include other medicines that increase your risk of bleeding, including aspirin or aspirin-containing products, long-term (chronic) use of nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, any medicine that contains heparin, selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), and other medicines to help prevent or treat blood clots.

People who take a blood thinner like Eliquis, and have medicine injected into their spinal and epidural area, or have a spinal puncture have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis).

There are no adequate studies of Eliquis in pregnant women. Use of Eliquis during pregnancy may increase the risk of bleeding during pregnancy and delivery. Eliquis should be avoided during pregnancy.

It is unknown if Eliquis is excreted in breast milk. Nursing mothers should discontinue Eliquis or discontinue breastfeeding.

The most common side effects of Eliquis involves bleeding in the:

• stomach,
• intestines,
• brain, and
• eyes.

Bleeding due to Eliquis may be fatal.

Major bleeding events were fewer in patients who received Eliquis when compared to a similar group that received warfarin (Coumadin, Jantoven), another widely used drug for preventing blood clots.

Rash and serious allergic reactions also may occur.

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
• Bleeding
• 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*

• 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 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

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

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

• 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

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

• 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

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

• 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

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

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.

Combined P-Gp And Strong CYP3A4 Inhibitors

• 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 combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir).
• For patients receiving Eliquis at a dose of 2.5 mg twice daily, avoid coadministration with combined P-gp and strong CYP3A4 inhibitors.

Clarithromycin

• Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with Eliquis.

Combined P-Gp And Strong CYP3A4 Inducers

• Avoid concomitant use of Eliquis with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) because such drugs will decrease exposure to apixaban.

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.