Apixaban tablets are a factor Xa inhibitor indicated: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. (1.1) for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. (1.2) for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following initial therapy.
(1.3 , 1.4 , 1.5)
1.1Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
Apixaban tablets are indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
1.2Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
Apixaban tablets are indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.
1.3Treatment of Deep Vein Thrombosis
Apixaban tablets are indicated for the treatment of DVT.
1.4Treatment of Pulmonary Embolism
Apixaban tablets are indicated for the treatment of PE.
1.5Reduction in the Risk of Recurrence of DVT and PE
Apixaban tablets are indicated to reduce the risk of recurrent DVT and PE following initial therapy.
Contraindications
Apixaban is contraindicated in patients with the following conditions: Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] Severe hypersensitivity reaction to apixaban (e.g., anaphylactic reactions) [see Adverse Reactions (6.1) ] Active pathological bleeding. (4) Severe hypersensitivity to apixaban. (4)
Apixaban tablets can cause serious, potentially fatal, bleeding. Promptly evaluate signs and symptoms of blood loss. An agent to reverse the anti-factor Xa activity of apixaban is available. (5.2) Prosthetic heart valves: Apixaban use not recommended. (5.4) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: Apixaban use not recommended. ( 5.6 )
5.1Increased Risk of Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including apixaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from apixaban to warfarin in clinical trials in atrial fibrillation patients. If apixaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.4) and Clinical Studies (14.1) ] .
5.2Bleeding
Apixaban increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see Dosage and Administration (2.1) and Adverse Reactions (6.1) ] . Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3) ] .
Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue apixaban in patients with active pathological hemorrhage. Reversal of Anticoagulant Effect An agent to reverse the anti-factor Xa activity of apixaban is available. The pharmacodynamic effect of apixaban can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives.
Prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa may be considered, but have not been evaluated in clinical studies [see Clinical Pharmacology (12.2) ] . When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not useful and is not recommended. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration [see Overdosage (10) ] .
Hemodialysis does not appear to have a substantial impact on apixaban exposure [see Clinical Pharmacology (12.3) ] . Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is no experience with systemic hemostatics (desmopressin) in individuals receiving apixaban, and they are not expected to be effective as a reversal agent.
5.3Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis.
Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of apixaban. The next dose of apixaban should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of apixaban for 48 hours. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, or bowel or bladder dysfunction).
If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
5.4Patients with Prosthetic Heart Valves
The safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves. Therefore, use of apixaban is not recommended in these patients.
5.5 Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy Initiation of apixaban is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
5.6Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome
Direct-acting oral anticoagulants (DOACs), including apixaban, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti–beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
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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. Combined P-gp and strong CYP3A4 inhibitors increase blood levels of apixaban. Reduce apixaban dose or avoid coadministration. (2.5 , 7.1 , 12.3) Simultaneous use of combined P-gp and strong CYP3A4 inducers reduces blood levels of apixaban: Avoid concomitant use.
(7.2 , 12.3)
7.1Combined P-gp and Strong CYP3A4 Inhibitors
For patients receiving apixaban 5 mg or 10 mg twice daily, the dose of apixaban should be decreased by 50% when co-administered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . For patients receiving apixaban at a dose of 2.5 mg twice daily, avoid co-administration with combined P-gp and strong CYP3A4 inhibitors [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] .
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 apixaban [see Clinical Pharmacology (12.3)].
7.2Combined P-gp and Strong CYP3A4 Inducers
Avoid concomitant use of apixaban 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 [see Clinical Pharmacology (12.3) ] .
7.3Anticoagulants and Antiplatelet Agents Co-administration
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 apixaban 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 apixaban.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
The limited available data on apixaban use in pregnant women are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse developmental outcomes. Treatment may increase the risk of bleeding during pregnancy and delivery. In animal reproduction studies, no adverse developmental effects were seen when apixaban was administered to rats (orally), rabbits (intravenously) and mice (orally) during organogenesis at unbound apixaban exposure levels up to 4, 1 and 19 times, respectively, the human exposure based on area under plasma-concentration time curve (AUC) at the Maximum Recommended Human Dose (MRHD) of 5 mg twice daily.
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnancy confers an increased risk of thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions.
Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy. Fetal/Neonatal adverse reactions Use of anticoagulants, including apixaban, may increase the risk of bleeding in the fetus and neonate. Labor or delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Apixaban use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas.
Consider use of a shorter acting anticoagulant as delivery approaches [see Warnings and Precautions (5.3)] . Data Animal Data No developmental toxicities were observed when apixaban was administered during organogenesis to rats (orally), rabbits (intravenously) and mice (orally) at unbound apixaban exposure levels 4, 1, and 19 times, respectively, the human exposures at the MRHD. There was no evidence of fetal bleeding, although conceptus exposure was confirmed in rats and rabbits.
Oral administration of apixaban to rat dams from gestation day 6 through lactation day 21 at maternal unbound apixaban exposures ranging from 1.4 to 5 times the human exposures at the MRHD was not associated with reduced maternal mortality or reduced conceptus/neonatal viability, although increased incidences of peri-vaginal bleeding were observed in dams at all doses. There was no evidence of neonatal bleeding.
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 [see Warnings and Precautions (5.1) ]. Bleeding [see Warnings and Precautions (5.2) ]. Spinal/Epidural Anesthesia or Puncture [see Warnings and Precautions (5.3) ]. Most common adverse reactions (>1%) are related to bleeding.
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Impax Laboratories, Inc. at 1-800-934-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 apixaban was evaluated in the ARISTOTLE and AVERROES studies [see Clinical Studies (14) ] , 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. Table 1: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE* Apixaban N=9088 n (per 100 pt-year) Warfarin N=9052 n (per 100 pt-year) Hazard Ratio (95% CI) P-value Major † 327 (2.13) 462 (3.09) 0.69 (0.60, 0.80) <0.0001 Intracranial (ICH) ‡ 52 (0.33) 125 (0.82) 0.41 (0.30, 0.57) - Hemorrhagic stroke § 38 (0.24) 74 (0.49) 0.51 (0.34, 0.75) - Other ICH 15 (0.10) 51 (0.34) 0.29 (0.16, 0.51) - Gastrointestinal (GI) ¶ 128 (0.83) 141 (0.93) 0.89 (0.70, 1.14) - Fatal** 10 (0.06) 37 (0.24) 0.27 (0.13, 0.53) - Intracranial 4 (0.03) 30 (0.20) 0.13 (0.05, 0.37) - Non-intracranial 6 (0.04) 7 (0.05) 0.84 (0.28, 2.15) - * 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, CHADS 2 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% 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 Apixaban 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)
0.07Fatal 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. ARISTOTLE Major Bleeding Forest Plot 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. 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 Apixaban 2.5 mg po bid 35±3 days Enoxaparin 40 mg sc qd 35±3 days Apixaban 2.5 mg po bid 12±2 days Enoxaparin 40 mg sc qd 12±2 days Apixaban 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 All treated N=2673 N=2659 N=1501 N=1508 N=1596 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 in
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Composition
Active ingredients
APIXABAN 2.5MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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