ELIQUIS

ELIQUIS (apixaban), a factor Xa (FXa) inhibitor, is chemically described as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide. Its molecular formula is C 25 H 25 N 5 O 4 , which corresponds to a molecular weight of 459.5. Apixaban has the following structural formula: Apixaban is a white to pale-yellow powder. At physiological pH (1.2-6.8), apixaban does not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL. ELIQUIS tablets 2.5 mg and 5 mg are available for oral administration and contain the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets). ELIQUIS 0.5 mg film coated tablets for oral suspension are supplied in packets containing 1 (0.5 mg), 3 (1.5 mg) or 4 (2 mg) apixaban tablets. The inactive ingredients are anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and red iron oxide. ELIQUIS SPRINKLE 0.15 mg for oral suspension is supplied as a white to off-white powder in capsules, which contain 0.15 mg apixaban and the following inactive ingredients: hypromellose and sugar spheres. Apixaban Chemical Structure

ELIQUIS is a factor Xa inhibitor indicated: to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation. (1.1) for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adult 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 in adult patients following initial therapy. (1.3 , 1.4 , 1.5) Treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth and older after at least 5 days of initial anticoagulant treatment. (1.6) 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 adult 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 adult patients who have undergone hip or knee replacement surgery. 1.3 Treatment of Deep Vein Thrombosis ELIQUIS is indicated for the treatment of adults with deep vein thrombosis (DVT). 1.4 Treatment of Pulmonary Embolism ELIQUIS is indicated for the treatment of adults with pulmonary embolism (PE). 1.5 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and Pulmonary Embolism ELIQUIS is indicated to reduce the risk of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in adult patients following initial therapy. 1.6 Treatment of Venous Thromboembolism and Reduction in the Risk of Recurrent Venous Thromboembolism in Pediatric Patients ELIQUIS is indicated for the treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth and older after at least 5 days of initial anticoagulant treatment.

Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation: The recommended dose is 5 mg orally twice daily. (2.1) 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. (2.1) Prophylaxis of DVT following hip or knee replacement surgery: The recommended dose is 2.5 mg orally twice daily. (2.1) 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. (2.1) 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) Treatment of VTE and reduction in the risk of recurrent VTE in pediatric patients from birth and older after at least 5 days of initial anticoagulant treatment: See dosing recommendations in the Full Prescribing Information (2.2) 2.1 Recommended Dose in Adult Patients 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 (14.3) ] . 2.2 Recommended Dose in Pediatric Patients Treatment of Venous Thromboembolism (VTE) and Reduction in the Risk of Recurrent VTE in Pediatric Patients The recommended dose of ELIQUIS is based on the patient’s weight, see Table 1. Adjust the dose according to weight-tier as treatment progresses. Initiate ELIQUIS treatment for pediatric patients from birth to less than 18 years of age following at least 5 days of initial anticoagulation therapy. Individualize duration of overall therapy after careful assessment of the treatment benefit and the risk for bleeding. Table 1: Dose Recommendation in Pediatric Patients from Birth to less than 18 Years of Age for the Treatment of VTE and Reduction in the Risk of Recurrent VTE Days 1-7 Days 8 and beyond Presentation Body weight (kg) Dosing schedule Dosing schedule Powder in Capsule 0.15 mg For pediatric use 2.6 to less than 4 0.3 mg twice daily 0.15 mg twice daily Tablet 0.5 mg For pediatric use 4 to less than 6 1 mg twice daily 0.5 mg twice daily 6 to less than 9 2 mg twice daily 1 mg twice daily 9 to less than 12 3 mg twice daily 1.5 mg twice daily 12 to less than 18 4 mg twice daily 2 mg twice daily 18 to less than 25 6 mg twice daily 3 mg twice daily 25 to less than 35 8 mg twice daily 4 mg twice daily Tablets 2.5 mg and 5 mg greater than or equal to 35 10 mg twice daily 5 mg twice daily ELIQUIS is not recommended for use in pediatric patients less than 2.6 kg because ELIQUIS was not studied in these patients. 2.3 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. 2.4 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 (5.2) ] . 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. 2.5 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. 2.6 Combined P-gp and Strong CYP3A4 Inhibitors For adult 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 (12.3) ] . In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.1) ] . 2.7 Administration Options Adult and pediatric patients weighing greater than or equal to 35 kg. 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 (12.3) ] . Alternatively, ELIQUIS tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a 12 French nasogastric tube [see Clinical Pharmacology (12.3) ] . Following administration of the dose, the nasogastric tube should be flushed with an additional 20 mL of water or D5W. Crushed ELIQUIS tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours. Pediatric patients weighing less than 35 kg. Capsules The 0.15 mg ELIQUIS SPRINKLE capsule must be opened, and the entire contents sprinkled in water or infant formula, mixed, and administered as described in the Instructions for Use (IFU). The liquid mixtures should be administered within 2 hours. Do not swallow capsule. Tablets for oral suspension The 0.5 mg ELIQUIS tablet in a packet for oral suspension should be mixed with water, infant formula, apple juice, or apple sauce as described in the IFU. The liquid mixtures with water, infant formula or apple juice should be administered within 2 hours and the mixture in apple sauce should be administered immediately. Each packet is for single use only. For pediatric patients who have difficulty swallowing, the liquid mixture can be delivered through a 5 French, 6.5 French or 12 French nasogastric tube or gastrostomy tube. See IFU. 2.1 Recommended Dose in Adult Patients 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 (14.3) ] . 2.3 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. 2.4 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 (5.2) ] . 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. 2.5 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. 2.6 Combined P-gp and Strong CYP3A4 Inhibitors For adult 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 (12.3) ] . In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.1) ] .

ELIQUIS 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 ELIQUIS (e.g., anaphylactic reactions) [see Adverse Reactions (6.1) ] Active pathological bleeding (4) Severe hypersensitivity to ELIQUIS (4)

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%) in adult patients are related to bleeding. (6.1) The most common adverse reactions (≥10%) in pediatric patients were headache, vomiting, and excessive menstrual bleeding. (6.1) 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 Adult Patients 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 (14) ] , 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 2 and 3 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 2: 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 * 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. 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) - 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 3: 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 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 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 4. Bleeding was assessed in each study beginning with the first dose of double-blind study drug. Table 4: 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 5. Table 5: 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 (2.6) 159 (2.7) Anemia (including postoperative and hemorrhagic anemia, and respective laboratory parameters) 153 (2.6) 178 (3.0) Contusion 83 (1.4) 115 (1.9) Hemorrhage (including hematoma, and vaginal and urethral hemorrhage) 67 (1.1) 81 (1.4) Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel puncture-site hematoma, and catheter-site hemorrhage) 54 (0.9) 60 (1.0) Transaminases increased (including alanine aminotransferase increased and alanine aminotransferase abnormal) 50 (0.8) 71 (1.2) Aspartate aminotransferase increased 47 (0.8) 69 (1.2) Gamma-glutamyltransferase increased 38 (0.6) 65 (1.1) 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 6. Table 6: Bleeding Results in the AMPLIFY Study * CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. ELIQUIS N=2676 n (%) Enoxaparin/Warfarin N=2689 n (%) Relative Risk (95% CI) Major 15 (0.6) 49 (1.8) 0.31 (0.17, 0.55) p<0.0001 CRNM* 103 (3.9) 215 (8.0) Major + CRNM 115 (4.3) 261 (9.7) Minor 313 (11.7) 505 (18.8) All 402 (15.0) 676 (25.1) Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 7. Table 7: 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 (2.9) 146 (5.4) Contusion 49 (1.8) 97 (3.6) Hematuria 46 (1.7) 102 (3.8) Menorrhagia 38 (1.4) 30 (1.1) Hematoma 35 (1.3) 76 (2.8) Hemoptysis 32 (1.2) 31 (1.2) Rectal hemorrhage 26 (1.0) 39 (1.5) Gingival bleeding 26 (1.0) 50 (1.9) 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 8. Table 8: Bleeding Results in the AMPLIFY-EXT Study * CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. ELIQUIS 2.5 mg bid N=840 n (%) ELIQUIS 5 mg bid N=811 n (%) Placebo N=826 n (%) Major 2 (0.2) 1 (0.1) 4 (0.5) CRNM* 25 (3.0) 34 (4.2) 19 (2.3) Major + CRNM 27 (3.2) 35 (4.3) 22 (2.7) Minor 75 (8.9) 98 (12.1) 58 (7.0) All 94 (11.2) 121 (14.9) 74 (9.0) Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in Table 9. Table 9: 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 (1.5) 29 (3.6) 9 (1.1) Hematuria 12 (1.4) 17 (2.1) 9 (1.1) Hematoma 13 (1.5) 16 (2.0) 10 (1.2) Contusion 18 (2.1) 18 (2.2) 18 (2.2) Gingival bleeding 12 (1.4) 9 (1.1) 3 (0.4) 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 Pediatric Patients Treatment of Venous Thromboembolism (VTE) and Reduction in the Risk of Recurrent VTE in Pediatric Patients The safety assessment of ELIQUIS is based on data from CV185325, a phase 3 study in 225 patients from birth and older. Patients were randomized 2:1 to receive body weight-adjusted doses of an age-appropriate formulation of ELIQUIS or standard of care. The standard of care treatments included unfractionated heparin (UFH), low molecular weight heparin (LMWH), or vitamin K antagonist (VKA). Overall, the safety profile of ELIQUIS in pediatric patients from birth and older was generally similar to that in adults and consistent across different pediatric age groups. In pediatric patients, excessive menstrual bleeding occurred in 17 (11%) patients in the ELIQUIS group and 3 (4%) patients in the standard of care group. Epistaxis occurred in 24 (16%) patients in the ELIQUIS group and 14 (19%) patients in the standard of care group. Bleeding results from Study CV185325 in pediatric patients with VTE are summarized in Table 10. Table 10: Bleeding Results in Study CV185325 – Safety Analysis Set – Main Phase * CRNM = clinically relevant nonmajor bleeding. (1) 95% Confidence Interval calculated using the Clopper-Pearson exact method Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. ** UFH/LMWH for patients less than 2 years of age and UFH/LMWH/VKA for those equal to or greater than 2 years of age. ELIQUIS N=152 Standard of care ** N=73 Major Bleeding Number (%) Subjects with Event 95% Confidence Interval (1) 0 0 CRNM* Number (%) Subjects with Event 2 (1.3) 1 (1.4) 95% Confidence Interval (1) (0.2, 4.7) (0.0, 7.4) Minor Bleeding Number (%) Subjects with Event 54 (35.5) 21 (28.8) 95% Confidence Interval (1) (27.9, 43.7) (18.8, 40.6) All Number (%) Subjects with Event 55 (36.2) 21 (28.8) 95% Confidence Interval (1) (28.6, 44.4) (18.8, 40.6) Non-bleeding adverse reactions occurring in ≥10% of patients in study CV185325 are listed in Table 11. Table 11: Other Adverse Reactions Occurring in ≥10% of Patients in Study CV185325 Number of Subjects Evaluable for Adverse Reaction ELIQUIS N=152 n (%) Standard of Care N=73 n (%) Headache 25 (16.4) 11 (15.1) Vomiting 21 (13.8) 5 (6.8) ARISTOTLE Major Bleeding Forest Plot

Combined P-gp and strong CYP3A4 inhibitors increase blood levels of apixaban. Reduce ELIQUIS dose or avoid coadministration. ( 2.6 , 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) 7.1 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 (2.6) and Clinical Pharmacology (12.3) ] . 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 (2.6) and Clinical Pharmacology (12.3) ] . Concomitant administration of combined P-gp and strong CYP3A4 inhibitors has not been studied in pediatric patients. Apixaban is a substrate of both CYP3A4 and P-gp. Concomitant use with drugs that are combined P-gp and strong CYP3A4 inhibitors increases exposure to apixaban [see Clinical Pharmacology (12.3) ] which increases the risk for bleeding. 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 (12.3) ] . 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 (12.3) ] . Apixaban is a substrate of both CYP3A4 and P-gp. Concomitant use with drugs that are combined P-gp and strong CYP3A4 inducers decreases exposure to apixaban [see Clinical Pharmacology (12.3) ] which increases the risk for stroke and other thromboembolic events. 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. 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 (2.6) and Clinical Pharmacology (12.3) ] . 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 (2.6) and Clinical Pharmacology (12.3) ] . Concomitant administration of combined P-gp and strong CYP3A4 inhibitors has not been studied in pediatric patients. Apixaban is a substrate of both CYP3A4 and P-gp. Concomitant use with drugs that are combined P-gp and strong CYP3A4 inhibitors increases exposure to apixaban [see Clinical Pharmacology (12.3) ] which increases the risk for bleeding. 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 (12.3) ] . 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 (12.3) ] . Apixaban is a substrate of both CYP3A4 and P-gp. Concomitant use with drugs that are combined P-gp and strong CYP3A4 inducers decreases exposure to apixaban [see Clinical Pharmacology (12.3) ] which increases the risk for stroke and other thromboembolic events. 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.

Storage and Handling Store ELIQUIS and ELIQUIS SPRINKLE at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Storage and Handling Store ELIQUIS and ELIQUIS SPRINKLE at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].