Genexiban Adverse Reactions

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; Bleeding; Spinal/Epidural anesthesia or puncture.
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 apixaban was evaluated in the ARISTOTLE and AVERROES studies, including 11,284 patients exposed to apixaban 5 mg twice daily and 602 patients exposed to apixaban 2.5 mg twice daily. The duration of apixaban 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 apixaban and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on apixaban 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. (See Table 1.)

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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, and aspirin use at randomization (Figure 3). Subjects treated with apixaban with diabetes bled more (3% per year) than did subjects without diabetes (1.9% per year). (See Figure 3.)

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Note: The figure as previously shown 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. (See Table 2.)

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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 apixaban.
Prophylaxis of deep vein thrombosis following hip or knee replacement surgery: The safety of apixaban has been evaluated in 1 Phase II and 3 Phase III studies including 5924 patients exposed to apixaban 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 apixaban 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. (See Table 3.)

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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. (See Table 4.)

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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 apixaban has been evaluated in the AMPLIFY and AMPLIFY-EXT studies including 2676 patients exposed to apixaban 10 mg twice daily, 3359 patients exposed to apixaban 5 mg twice daily, and 840 patients exposed to apixaban 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 apixaban was 154 days and to enoxaparin/warfarin was 152 days in the AMPLIFY study. Adverse reactions related to bleeding occurred in 417 (15.6%) apixaban-treated patients compared to 661 (24.6%) enoxaparin/warfarin-treated patients. The discontinuation rate due to bleeding events was 0.7% in the apixaban-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients in the AMPLIFY study.
In the AMPLIFY study, apixaban 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. (See Table 5.)

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Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6. (See Table 6.)

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AMPLIFY-EXT Study: The mean duration of exposure to apixaban 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%) apixaban-treated patients compared to 72 (8.7%) placebo-treated patients. The discontinuation rate due to bleeding events was approximately 1% in the apixaban-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. (See Table 7.)

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Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in Table 8. (See Table 8.)

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Other adverse reactions: Less common adverse reactions in apixaban-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.