apixaban

1 INDICATIONS AND USAGE ELIQUIS is a factor Xa inhibitor indicated:

• to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
• 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.
• for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following initial therapy. 1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 1.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery ELIQUIS is 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. 1.3 Treatment of Deep Vein Thrombosis ELIQUIS is indicated for the treatment of DVT.

Treatment of Pulmonary Embolism ELIQUIS is indicated for the treatment of PE.

1.5 Reduction in the Risk of Recurrence of DVT and PE ELIQUIS is indicated to reduce the risk of recurrent DVT and PE following initial therapy.

• Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation:
• The recommended dose is 5 mg orally twice daily.
• In patients with at least 2 of the following characteristics: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or serum creatinine greater than or equal to 1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily.
• Prophylaxis of DVT following hip or knee replacement surgery:
• The recommended dose is 2.5 mg orally twice daily.
• Treatment of DVT and PE:
• The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.
• Reduction in the risk of recurrent DVT and PE following initial therapy:
• The recommended dose is 2.5 mg taken orally twice daily. 2.1 Recommended Dose Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily. The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with at least two of the following characteristics:
• age greater than or equal to 80 years
• body weight less than or equal to 60 kg
• serum creatinine greater than or equal to 1.5 mg/dL Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.
• In patients undergoing hip replacement surgery, the recommended duration of treatment is 35 days.
• In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days. Treatment of DVT and PE The recommended dose of ELIQUIS is 10 mg taken orally twice daily for the first 7 days of therapy. After 7 days, the recommended dose is 5 mg taken orally twice daily. Reduction in the Risk of Recurrence of DVT and PE The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE [see Clinical Studies ] . 2.2 Missed Dose If a dose of ELIQUIS is not taken at the scheduled time, the dose should be taken as soon as possible on the same day and twice-daily administration should be resumed. The dose should not be doubled to make up for a missed dose. 2.3 Temporary Interruption for Surgery and Other Interventions ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding [see Warnings and Precautions ] . ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. 2.4 Converting from or to ELIQUIS Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS started when the international normalized ratio (INR) is below 2.0. Switching from ELIQUIS to warfarin: ELIQUIS affects INR, so that initial INR measurements during the transition to warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue ELIQUIS and begin both a parenteral anticoagulant and warfarin at the time the next dose of ELIQUIS would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range. Switching from ELIQUIS to anticoagulants other than warfarin (oral or parenteral): Discontinue ELIQUIS and begin taking the new anticoagulant other than warfarin at the usual time of the next dose of ELIQUIS. Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS: Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the usual time of the next dose of the anticoagulant other than warfarin. 2.5 Combined P-gp and Strong CYP3A4 Inhibitors For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose by 50% when ELIQUIS is coadministered with drugs that are combined P-glycoprotein (P-gp) and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, itraconazole, ritonavir) [see Clinical Pharmacology ] . In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined P-gp and strong CYP3A4 inhibitors [see Drug Interactions ] . 2.6 Administration Options For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS tablets may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, or mixed with applesauce and promptly administered orally [see Clinical Pharmacology ] . Alternatively, ELIQUIS tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube [see Clinical Pharmacology ] . Crushed ELIQUIS tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours.

12.1 Mechanism of Action Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development.

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 ]
• Bleeding [see Warnings and Precautions ]
• Spinal/Epidural Anesthesia or Puncture [see Warnings and Precautions ] Most common adverse reactions (>1%) are related to bleeding. To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 100 patient-years) in ARISTOTLE and AVERROES. Table 1: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE* ELIQUIS N=9088 n (per 100 pt-year) Warfarin N=9052 n (per 100 pt-year) Hazard Ratio (95% CI) P-value Major † 327 462 0.69 < 0.0001 Intracranial (ICH) ‡ 52 125 0.41 - Hemorrhagic stroke § 38 74 0.51 - Other ICH 15 51 0.29 - Gastrointestinal (GI) ¶ 128 141 0.89 - Fatal** 10 37 0.27 - Intracranial 4 30 0.13 - Non-intracranial 6 7 0.84 - * 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 ELIQUIS 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 ELIQUIS N=2798 n (%/year) Aspirin N=2780 n (%/year) Hazard Ratio (95% CI) P-value Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. Major 45 29 1.54 0.07 Fatal 5 5 0.99 - Intracranial 11 11 0.99 - 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 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* ADVANCE-3 Hip Replacement Surgery ADVANCE-2 Knee Replacement Surgery ADVANCE-1 Knee Replacement Surgery * All bleeding criteria included surgical site bleeding. † Includes 13 subjects with major bleeding events that occurred before the first dose of ELIQUIS (administered 12 to 24 hours post-surgery). ‡ Includes 5 subjects with major bleeding events that occurred before the first dose of ELIQUIS (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. 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 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%) 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 153 159 Anemia (including postoperative and hemorrhagic anemia, and respective laboratory parameters) 153 178 Contusion 83 115 Hemorrhage (including hematoma, and vaginal and urethral hemorrhage) 67 81 Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel puncture-site hematoma, and catheter-site hemorrhage) 54 60 Transaminases increased (including alanine aminotransferase increased and alanine aminotransferase abnormal) 50 71 Aspartate aminotransferase increased 47 69 Gamma-glutamyltransferase increased 38 65 Less common adverse reactions in ELIQUIS-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 ELIQUIS-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 (%) Relative Risk (95% CI) * CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. Major 15 49 0.31 p< 0.0001 CRNM* 103 215 Major + CRNM 115 261 Minor 313 505 All 402 676 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 77 146 Contusion 49 97 Hematuria 46 102 Menorrhagia 38 30 Hematoma 35 76 Hemoptysis 32 31 Rectal hemorrhage 26 39 Gingival bleeding 26 50 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 (%) * CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. Major 2 1 4 CRNM* 25 34 19 Major + CRNM 27 35 22 Minor 75 98 58 All 94 121 74 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 29 9 Hematuria 12 17 9 Hematoma 13 16 10 Contusion 18 18 18 Gingival bleeding 12 9 3 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 increase blood levels of apixaban. Reduce ELIQUIS dose or avoid coadministration.
• Simultaneous use of combined P-gp and strong CYP3A4 inducers reduces blood levels of apixaban: Avoid concomitant use. 7.1 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) [see Dosage and Administration and Clinical Pharmacology ] . For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with combined P-gp and strong CYP3A4 inhibitors [see Dosage and Administration and Clinical Pharmacology ] . 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 [see Clinical Pharmacology ] . 7.2 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 [see Clinical Pharmacology ] . 7.3 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 ELIQUIS 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 ELIQUIS compared to placebo. The rate of ISTH major bleeding was 2.8% per year with ELIQUIS versus 0.6% per year with placebo in patients receiving single antiplatelet therapy and was 5.9% per year with ELIQUIS 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.

• Pregnancy: Not recommended.
• Lactation: Discontinue drug or discontinue nursing.
• Severe Hepatic Impairment: Not recommended. 8.1 Pregnancy Risk Summary The limited available data on ELIQUIS 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 ELIQUIS, 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. ELIQUIS 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 ] . 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. 8.2 Lactation Risk Summary There are no data on the presence of apixaban or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Apixaban and/or its metabolites were present in the milk of rats (see Data). Because human exposure through milk is unknown, breastfeeding is not recommended during treatment with ELIQUIS. Data Animal Data Maximal plasma concentrations were observed after 30 minutes following a single oral administration of a 5 mg dose to lactating rats. Maximal milk concentrations were observed 6 hours after dosing. The milk to plasma AUC (0-24) ratio is 30:1 indicating that apixaban can accumulate in milk. The concentrations of apixaban in animal milk does not necessarily predict the concentration of drug in human milk. 8.3 Females and Males of Reproductive Potential Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including ELIQUIS should be assessed in females of reproductive potential and those with abnormal uterine bleeding. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the total subjects in the ARISTOTLE and AVERROES clinical studies, >69% were 65 years of age and older, and >31% were 75 years of age and older. In the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical studies, 50% of subjects were 65 years of age and older, while 16% were 75 years of age and older. In the AMPLIFY and AMPLIFY-EXT clinical studies, >32% of subjects were 65 years of age and older and >13% were 75 years of age and older. No clinically significant differences in safety or effectiveness were observed when comparing subjects in different age groups. 8.6 Renal Impairment Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation The recommended dose is 2.5 mg twice daily in patients with at least two of the following characteristics [see Dosage and Administration ] :
• age greater than or equal to 80 years
• body weight less than or equal to 60 kg
• serum creatinine greater than or equal to 1.5 mg/dL Patients with End-Stage Renal Disease on Dialysis Clinical efficacy and safety studies with ELIQUIS did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of ELIQUIS at the usually recommended dose [see Dosage and Administration ] will result in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study [see Clinical Pharmacology ] . It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ARISTOTLE. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery, and Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT and PE No dose adjustment is recommended for patients with renal impairment, including those with ESRD on dialysis [see Dosage and Administration ] . Clinical efficacy and safety studies with ELIQUIS did not enroll patients with ESRD on dialysis or patients with a CrCl <15 mL/min; therefore, dosing recommendations are based on pharmacokinetic and pharmacodynamic (anti-FXa activity) data in subjects with ESRD maintained on dialysis [see Clinical Pharmacology ] . 8.7 Hepatic Impairment No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A). Because patients with moderate hepatic impairment (Child-Pugh class B) may have intrinsic coagulation abnormalities and there is limited clinical experience with ELIQUIS in these patients, dosing recommendations cannot be provided [see Clinical Pharmacology ] . ELIQUIS is not recommended in patients with severe hepatic impairment (Child-Pugh class C) [see Clinical Pharmacology ] .