APIXABAN- apixaban_tablet

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. As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose, however, are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of apixaban. The Rotachrom registered This test is not recommended for assessing the anticoagulant effect of apixaban. Effect of PCCs on Pharmacodynamics of Apixaban There is no clinical experience to reverse bleeding with the use of 4-factor PCC products in individuals who have received apixaban. Effects of 4-factor PCCs on the pharmacodynamics of apixaban were studied in healthy subjects. Following administration of apixaban dosed to steady state, endogenous thrombin potential (ETP) returned to pre-apixaban levels 4 hours after the initiation of a 30-minute PCC infusion, compared to 45 hours with placebo. Mean ETP levels continued to increase and exceeded pre-apixaban levels reaching a maximum (34% to 51% increase over pre-apixaban levels) at 21 hours after initiating PCC and remained elevated (21% to 27% increase) at the end of the study (69 hours after initiation of PCC). The clinical relevance of this increase in ETP is unknown. Pharmacodynamic Drug Interaction Studies Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin and clopidogrel, prasugrel, enoxaparin, and naproxen were conducted. No pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel [see Warnings and Precautions (5. 2)] Specific Populations Renal impairment: Hepatic impairment: Cardiac Electrophysiology Apixaban has no effect on the QTc interval in humans at doses up to 50 mg. Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 mg. Absorption The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of apixaban. Food does not affect the bioavailability of apixaban. Maximum concentrations (C max max Distribution Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters. Metabolism Approximately 25% of an orally administered apixaban dose is recovered in urine and feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Unchanged apixaban is the major drug-related component in human plasma; there are no active circulating metabolites. Elimination Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces. Apixaban has a total clearance of approximately 3. 3 L/hour and an apparent half-life of approximately 12 hours following oral administration. Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance protein. Drug Interaction Studies In in vitro The effects of coadministered drugs on the pharmacokinetics of apixaban are summarized in Figure 2 [see also Warnings and Precautions ( 5. 2 7 Figure 2: Effect of Coadministered Drugs on the Pharmacokinetics of Apixaban In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, and enoxaparin did not meaningfully alter the pharmacokinetics of apixaban. In studies conducted in healthy subjects, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid. Specific Populations The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of apixaban are summarized in Figure 3. Figure 3: Effect of Specific Populations on the Pharmacokinetics of Apixaban * dagger double dagger Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations. section No dose adjustment is recommended for nonvalvular atrial fibrillation patients unless at least 2 of the following patient 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) are present. Gender: Race: Hemodialysis in ESRD subjects: The systemic exposure to apixaban administered 2 hours prior to a 4-hour hemodialysis session with a dialysate flow rate of 500 mL/min and a blood flow rate in the range of 350 to 500 mL/min is 17% higher compared to those with normal renal function. The dialysis clearance of apixaban is approximately 18 mL/min. The systemic exposure of apixaban is 14% lower on dialysis when compared to not on dialysis. Protein binding was similar (92% to 94%) between healthy controls and ESRD subjects during the on-dialysis and off-dialysis periods. Image Image.

Apixaban is a factor Xa inhibitor indicated: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 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. 2 for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following initial therapy. 5 Apixaban tablets are indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 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. Apixaban tablets are indicated for the treatment of DVT. Apixaban tablets are indicated for the treatment of PE. Apixaban tablets are 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. 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. 1 Prophylaxis of DVT following hip or knee replacement surgery: The recommended dose is 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. 1) Reduction in the risk of recurrent DVT and PE following initial therapy: The recommended dose is 2. 5 mg taken orally twice daily. 1 Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation The recommended dose of apixaban tablets for most patients is 5 mg taken orally twice daily. The recommended dose of apixaban tablets are 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 apixaban tablets are 2. 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 apixaban tablets are 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 apixaban tablets are 2. 5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE [see Clinical Studies ( 14. 3 If a dose of apixaban tablets are 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. Apixaban tablets 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 Switching from warfarin to apixaban: Switching from apixaban to warfarin: Switching from apixaban to anticoagulants other than warfarin (oral or parenteral): Switching from anticoagulants other than warfarin (oral or parenteral) to apixaban: For patients receiving apixaban tablets doses of 5 mg or 10 mg twice daily, reduce the dose by 50% when apixaban tablets are coadministered with drugs that are combined P-glycoprotein (P-gp) and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e. , ketoconazole, itraconazole, ritonavir) [see Clinical Pharmacology ( 12. 3 In patients already taking 2. 5 mg twice daily, avoid coadministration of apixaban tablets with combined P-gp and strong CYP3A4 inhibitors [see Drug Interactions ( 7. 1 For patients who are unable to swallow whole tablets, 5 mg and 2. 5 mg apixaban 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 [see Clinical Pharmacology (12. 3)] Crushed apixaban tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours.

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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 tablets was evaluated in the ARISTOTLE and AVERROES studies [see Clinical Studies (14)] The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1. 5% of patients treated with apixaban tablets and warfarin, respectively, and in AVERROES, in 1. 3% on apixaban tablets 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 * * dagger double dagger section paragraph ** Apixaban N=9,088 n (per 100 pt-year) Warfarin N=9,052 n (per 100 pt-year) Hazard Ratio (95% CI) P-value Major dagger 327 (2. 0001 Intracranial (ICH) double dagger 52 (0. 57) - Hemorrhagic stroke section 38 (0. 75) - Other ICH 15 (0. 51) - Gastrointestinal (GI) paragraph 128 (0. 14) - Fatal ** 10 (0. 53) - Intracranial 4 (0. 37) - Non-intracranial 6 (0. 15) - In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS 2 Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics en dash 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=2,798 n (%/year) Aspirin N=2,780 n (%/year) Hazard Ratio (95% CI) P-value Major 45 (1. 07 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 apixaban tablets. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery The safety of apixaban tablets has been evaluated in 1 Phase II and 3 Phase III studies including 5,924 patients exposed to apixaban tablets 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 tablets 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 * dagger double dagger section paragraph 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 First dose 12 to 24 hours post surgery First dose First dose 12 to 24 hours post surgery First dose First dose 12 to 24 hours post surgery First dose All treated N=2,673 N=2,659 N=1,501 N=1,508 N=1,596 N=1,588 Major (including surgical site) 22 (0. 82%) dagger 18 (0. 60%) double dagger 14 (0. 39%) Fatal 0 0 0 0 0 1 (0. 06%) Hgb decrease 13 (0. 01%) Transfusion of >=2 units RBC 16 (0. 13%) Bleed at critical site section 1 (0. 25%) Major paragraph 129 (4. 83%) 134 (5. 28%) All 313 (11. 71%) 334 (12. 56%) 104 (6. 93%) 126 (8. 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 Apixaban, n (%) 2. 5 mg po bid N=5,924 Enoxaparin, n (%) 40 mg sc qd or 30 mg sc q12h N=5,904 Nausea 153 (2. 7) Anemia (including postoperative and hemorrhagic anemia, and respective laboratory parameters) 153 (2. 0) Contusion 83 (1. 9) Hemorrhage (including hematoma, and vaginal and urethral hemorrhage) 67 (1. 4) Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel puncture-site hematoma, and catheter-site hemorrhage) 54 (0. 0) Transaminases increased (including alanine aminotransferase increased and alanine aminotransferase abnormal) 50 (0. 2) Aspartate aminotransferase increased 47 (0. 2) Gamma-glutamyltransferase increased 38 (0. 1) 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: Vascular disorders: Respiratory, thoracic, and mediastinal disorders: Gastrointestinal disorders: Hepatobiliary disorders: Renal and urinary disorders: Injury, poisoning, and procedural complications: 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 2,676 patients exposed to apixaban 10 mg twice daily, 3,359 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. 55], P-value <0. Bleeding results from the AMPLIFY study are summarized in Table 5. Table 5: Bleeding Results in the AMPLIFY Study * Apixaban N=2,676 n (%) Enoxaparin/Warfarin N=2,689 n (%) Relative Risk (95% CI) Major 15 (0. 55) CRNM * 103 (3. 0) Major + CRNM 115 (4. 7) Minor 313 (11. 8) All 402 (15. 1) Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. 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 Apixaban N=2,676 n (%) Enoxaparin/Warfarin N=2,689 n (%) Epistaxis 77 (2. 4) Contusion 49 (1. 6) Hematuria 46 (1. 8) Menorrhagia 38 (1. 1) Hematoma 35 (1. 8) Hemoptysis 32 (1. 2) Rectal hemorrhage 26 (1. 5) Gingival bleeding 26 (1. 9) 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. Table 7: Bleeding Results in the AMPLIFY-EXT Study * Apixaban 2. 5 mg bid N=840 n (%) Apixaban 5 mg bid N=811 n (%) Placebo N=826 n (%) Major 2 (0. 5) CRNM * 25 (3. 3) Major + CRNM 27 (3. 7) Minor 75 (8. 0) All 94 (11. 0) Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. 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 Apixaban 2. 5 mg bid N=840 n (%) Apixaban 5 mg bid N=811 n (%) Placebo N=826 n (%) Epistaxis 13 (1. 1) Hematuria 12 (1. 1) Hematoma 13 (1. 2) Contusion 18 (2. 2) Gingival bleeding 12 (1. 4) 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: Gastrointestinal disorders: Injury, poisoning, and procedural complications: Musculoskeletal and connective tissue disorders: Reproductive system and breast disorders: Vascular disorders: Skin and subcutaneous tissue disorders: Eye disorders: Investigations: General disorders and administration-site conditions: Image.

Apixaban tablets are contraindicated in patients with the following conditions: Active pathological bleeding [see Warnings and Precautions ( 5. 1 Severe hypersensitivity reaction to apixaban (e. , anaphylactic reactions) [see Adverse Reactions ( 6. 1 Active pathological bleeding ( 4 Severe hypersensitivity to apixaban ( 4.

Pregnancy: Not recommended. 1 Lactation: Discontinue drug or discontinue nursing. 2 Severe Hepatic Impairment: Not recommended. 2 Risk Summary The limited available data on apixaban tablets 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. 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 tablets 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. 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) 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 to 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. 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 apixaban should be assessed in females of reproductive potential and those with abnormal uterine bleeding. Safety and effectiveness in pediatric patients have not been established. 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. 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 ( 2. 1 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 apixaban did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of apixaban at the usually recommended dose [see Dosage and Administration ( 2. 1 [see Clinical Pharmacology ( 12. 3 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 ( 2. 3 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 apixaban in these patients, dosing recommendations cannot be provided [see Clinical Pharmacology ( 12. 2 Apixaban is not recommended in patients with severe hepatic impairment (Child-Pugh class C) [see Clinical Pharmacology ( 12.

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. 3 Simultaneous use of combined P-gp and strong CYP3A4 inducers reduces blood levels of apixaban: Avoid concomitant use. 3 For patients receiving apixaban 5 mg or 10 mg twice daily, the dose of apixaban should be decreased by 50% when coadministered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e. , ketoconazole, itraconazole, ritonavir) [see Dosage and Administration ( 2. 3 For patients receiving apixaban at a dose of 2. 5 mg twice daily, avoid coadministration with combined P-gp and strong CYP3A4 inhibitors [see Dosage and Administration ( 2. 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 Avoid concomitant use of apixaban tablets with combined P-gp and strong CYP3A4 inducers (e. , rifampin, carbamazepine, phenytoin, St. John's wort) because such drugs will decrease exposure to apixaban [see Clinical Pharmacology ( 12. 3 Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. The rate of ISTH major bleeding was 2. 8% per year with apixaban versus 0. 6% per year with placebo in patients receiving single antiplatelet therapy and was 5. 9% per year with apixaban versus 2. 5% per year with placebo in those receiving dual antiplatelet therapy. In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on 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.

=33 kg/m 2 In the ADVANCE-3 study, 5,407 patients undergoing elective hip replacement surgery were randomized to receive either apixaban 2. 5 mg orally twice daily or enoxaparin 40 mg subcutaneously once daily. The first dose of apixaban was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Treatment duration was 32 to 38 days. In patients undergoing elective knee replacement surgery, apixaban 2. 5 mg orally twice daily was compared to enoxaparin 40 mg subcutaneously once daily (ADVANCE-2, N=3,057) or enoxaparin 30 mg subcutaneously every 12 hours (ADVANCE-1, N=3,195). In the ADVANCE-2 study, the first dose of apixaban was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. In the ADVANCE-1 study, both apixaban and enoxaparin were initiated 12 to 24 hours post surgery. Treatment duration in both ADVANCE-2 and ADVANCE-1 was 10 to 14 days. In all 3 studies, the primary endpoint was a composite of adjudicated asymptomatic and symptomatic DVT, nonfatal PE, and all-cause death at the end of the double-blind intended treatment period. In ADVANCE-3 and ADVANCE-2, the primary endpoint was tested for noninferiority, then superiority, of apixaban to enoxaparin. In ADVANCE-1, the primary endpoint was tested for noninferiority of apixaban to enoxaparin. The efficacy data are provided in Tables 11 and 12. Table 11: Summary of Key Efficacy Analysis Results During the Intended Treatment Period for Patients Undergoing Elective Hip Replacement Surgery * * dagger double dagger ADVANCE-3 Events During 35-Day Treatment Period Apixaban Enoxaparin Relative Risk Number of Patients N=1,949 N=1,917 Total VTE dagger 27 (1. 36 Number of Patients N=2,708 N=2,699 All-cause death 3 (0. 04%) PE 3 (0. 19%) Symptomatic DVT 1 (0. 19%) Number of Patients N=2,196 N=2,190 Proximal DVT double dagger 7 (0. 91%) Number of Patients N=1,951 N=1,908 Distal DVT double dagger 20 (1. 99%) Table 12: Summary of Key Efficacy Analysis Results During the Intended Treatment Period for Patients Undergoing Elective Knee Replacement Surgery * * dagger double dagger ADVANCE-1 ADVANCE-2 Events during 12-day treatment period Apixaban 2. 5 mg po bid Enoxaparin 30 mg sc q12h Relative Risk (95% CI) P-value Apixaban 2. 5 mg po bid Enoxaparin 40 mg sc qd Relative Risk (95% CI) P-value Number of Patients N=1,157 N=1,130 N=976 N=997 Total VTE dagger 104 (8. 46) 243 (24. 62 Number of Patients N=1,599 N=1,596 N=1,528 N=1,529 All-cause death 3 (0. 52) 0 (0%) PE 16 (1. 70) 0 (0%) Symptomatic DVT 3 (0. 97) Number of Patients N=1,254 N=1,207 N=1,192 N=1,199 Proximal DVT double dagger 9 (0. 18) Number of Patients N=1,146 N=1,133 N=978 N=1,000 Distal DVT double dagger 83 (7. 78) 142 (14. 88) 239 (23. 65) The efficacy profile of apixaban was generally consistent across subgroups of interest for this indication (e. , age, gender, race, body weight, renal impairment). Efficacy and safety of apixaban for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following 6 to 12 months of anticoagulant treatment was derived from the AMPLIFY and AMPLIFY-EXT studies. Both studies were randomized, parallel-group, double-blind trials in patients with symptomatic proximal DVT and/or symptomatic PE. All key safety and efficacy endpoints were adjudicated in a blinded manner by an independent committee. AMPLIFY The primary objective of AMPLIFY was to determine whether apixaban was noninferior to enoxaparin/warfarin for the incidence of recurrent VTE (venous thromboembolism) or VTE-related death. Patients with an objectively confirmed symptomatic DVT and/or PE were randomized to treatment with apixaban 10 mg twice daily orally for 7 days followed by apixaban 5 mg twice daily orally for 6 months, or enoxaparin 1 mg/kg twice daily subcutaneously for at least 5 days (until INR >=2) followed by warfarin (target INR range 2. 0) orally for 6 months. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent, and patients with creatinine clearance <25 mL/min, significant liver disease, an existing heart valve or atrial fibrillation, or active bleeding were excluded from the AMPLIFY study. Patients were allowed to enter the study with or without prior parenteral anticoagulation (up to 48 hours). A total of 5,244 patients were evaluable for efficacy and were followed for a mean of 154 days in the apixaban group and 152 days in the enoxaparin/warfarin group. The mean age was 57 years. The AMPLIFY study population was 59% male, 83% Caucasian, 8% Asian, and 4% Black. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2. Approximately 90% of patients enrolled in AMPLIFY had an unprovoked DVT or PE at baseline. The remaining 10% of patients with a provoked DVT or PE were required to have an additional ongoing risk factor in order to be randomized, which included previous episode of DVT or PE, immobilization, history of cancer, active cancer, and known prothrombotic genotype. Apixaban was shown to be noninferior to enoxaparin/warfarin in the AMPLIFY study for the primary endpoint of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy (Table 13). Table 13: Efficacy Results in the AMPLIFY Study * dagger Apixaban N=2,609 n Enoxaparin/Warfarin N=2,635 n Relative Risk (95% CI) VTE or VTE-related death * 59 (2. 18) DVT dagger 22 (0. 3%) PE dagger 27 (1. 9%) VTE-related death dagger 12 (0. 6%) VTE or all-cause death 84 (3. 08) VTE or CV-related death 61 (2. 11) In the AMPLIFY study, patients were stratified according to their index event of PE (with or without DVT) or DVT (without PE). Efficacy in the initial treatment of VTE was consistent between the two subgroups. AMPLIFY-EXT Patients who had been treated for DVT and/or PE for 6 to 12 months with anticoagulant therapy without having a recurrent event were randomized to treatment with apixaban 2. 5 mg orally twice daily, apixaban 5 mg orally twice daily, or placebo for 12 months. Approximately one-third of patients participated in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study. A total of 2,482 patients were randomized to study treatment and were followed for a mean of approximately 330 days in the apixaban group and 312 days in the placebo group. The mean age in the AMPLIFY-EXT study was 57 years. The study population was 57% male, 85% Caucasian, 5% Asian, and 3% Black. The AMPLIFY-EXT study enrolled patients with either an unprovoked DVT or PE at baseline (approximately 92%) or patients with a provoked baseline event and one additional risk factor for recurrence (approximately 8%). However, patients who had experienced multiple episodes of unprovoked DVT or PE were excluded from the AMPLIFY-EXT study. In the AMPLIFY-EXT study, both doses of apixaban were superior to placebo in the primary endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE), or all-cause death (Table 14). Table 14: Efficacy Results in the AMPLIFY-EXT Study * Apixaban 2. 5 mg bid N=840 Apixaban 5 mg bid N=813 Placebo N=829 Relative Risk (95% CI) Apixaban 2. 5 mg bid vs Placebo Apixaban 5 mg bid vs Placebo n (%) Recurrent VTE or all-cause death 32 (3. 53) DVT * 19 (2. 7) PE * 23 (2. 5) All-cause death 22 (2. 0) Image Image.">OVERDOSAGE
Overdose of apixaban tablets increases the risk of bleeding [see Warnings and Precautions ( 5.2 In controlled clinical trials, orally administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) had no clinically relevant adverse effects. In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion. An agent to reverse the anti-factor Xa activity of apixaban is available.
NONCLINICAL TOXICOLOGY
Carcinogenesis: Mutagenesis: in vitro in vivo in vitro in vivo Impairment of Fertility: Apixaban administered to female rats at doses up to 1,000 mg/kg/day from implantation through the end of lactation produced no adverse findings in male offspring (F 1 1
CLINICAL STUDIES
ARISTOTLE Evidence for the efficacy and safety of apixaban was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular AF comparing the effects of apixaban and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. In ARISTOTLE, patients were randomized to apixaban 5 mg orally twice daily (or 2. 5 mg twice daily in subjects 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) or to warfarin (targeted to an INR range of 2. Patients had to have one or more of the following additional risk factors for stroke: prior stroke or transient ischemic attack (TIA) prior systemic embolism age greater than or equal to 75 years arterial hypertension requiring treatment diabetes mellitus heart failure >=New York Heart Association Class 2 left ventricular ejection fraction <=40% The primary objective of ARISTOTLE was to determine whether apixaban 5 mg twice daily (or 2. 5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of apixaban to warfarin was also examined for the primary endpoint (rate of stroke and systemic embolism), major bleeding, and death from any cause. A total of 18,201 patients were randomized and followed on study treatment for a median of 89 weeks. Forty-three percent of patients were vitamin K antagonist (VKA) "naive," defined as having received <=30 consecutive days of treatment with warfarin or another VKA before entering the study. The mean age was 69 years and the mean CHADS 2 Apixaban was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Table 9 and Figure 4). Superiority to warfarin was primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs. Apixaban also showed significantly fewer major bleeds than warfarin [see Adverse Reactions ( 6. 1 Table 9: Key Efficacy Outcomes in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE (Intent-to-Treat Analysis) Apixaban N=9,120 n (%/year) Warfarin N=9,081 n (%/year) Hazard Ratio (95% CI) P-value Stroke or systemic embolism 212 (1. 01 Stroke 199 (1. 95) Ischemic without hemorrhage 140 (0. 29) Ischemic with hemorrhagic conversion 12 (0. 23) Hemorrhagic 40 (0. 75) Unknown 14 (0. 29) Systemic embolism 15 (0. 75) The primary endpoint was based on the time to first event (one per subject). Component counts are for subjects with any event, not necessarily the first. Figure 4: Kaplan-Meier Estimate of Time to First Stroke or Systemic Embolism in ARISTOTLE (Intent-to-Treat Population) All-cause death was assessed using a sequential testing strategy that allowed testing for superiority if effects on earlier endpoints (stroke plus systemic embolus and major bleeding) were demonstrated. Apixaban treatment resulted in a significantly lower rate of all-cause death (p = 0. 046) than did treatment with warfarin, primarily because of a reduction in cardiovascular death, particularly stroke deaths. Non vascular death rates were similar in the treatment arms. In ARISTOTLE, the results for the primary efficacy endpoint were generally consistent across most major subgroups including weight, CHADS 2 Figure 5: Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics en dash 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. At the end of the ARISTOTLE study, warfarin patients who completed the study were generally maintained on a VKA with no interruption of anticoagulation. Apixaban patients who completed the study were generally switched to a VKA with a 2-day period of coadministration of apixaban and VKA, so that some patients may not have been adequately anticoagulated after stopping apixaban tablets until attaining a stable and therapeutic INR. During the 30 days following the end of the study, there were 21 stroke or systemic embolism events in the 6,791 patients (0. 3%) in the apixaban arm compared to 5 in the 6,569 patients (0. 1%) in the warfarin arm [see Dosage and Administration ( 2. 4 AVERROES In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates for warfarin therapy were randomized to treatment with apixaban 5 mg orally twice daily (or 2. 5 mg twice daily in selected patients) or aspirin 81 to 324 mg once daily. The primary objective of the study was to determine if apixaban was superior to aspirin for preventing the composite outcome of stroke or systemic embolism. AVERROES was stopped early on the basis of a prespecified interim analysis showing a significant reduction in stroke and systemic embolism for apixaban compared to aspirin that was associated with a modest increase in major bleeding (Table 10) [see Adverse Reactions ( 6. 1 Table 10: Key Efficacy Outcomes in Patients with Nonvalvular Atrial Fibrillation in AVERROES Apixaban N=2,807 n (%/year) Aspirin N=2,791 n (%/year) Hazard Ratio (95% CI) P-value Stroke or systemic embolism 51 (1. 0001 Stroke Ischemic or undetermined 43 (1. 63) - Hemorrhagic 6 (0. 88) - Systemic embolism 2 (0. 68) - MI 24 (0. 48) - All-cause death 111 (3. 068 Vascular death 84 (2. 17) - The clinical evidence for the effectiveness of apixaban is derived from the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical trials in adult patients undergoing elective hip (ADVANCE-3) or knee (ADVANCE-2 and ADVANCE-1) replacement surgery. A total of 11,659 patients were randomized in 3 double-blind, multi-national studies. Included in this total were 1,866 patients age 75 or older, 1,161 patients with low body weight (<=60 kg), 2,528 patients with Body Mass Index >=33 kg/m 2 In the ADVANCE-3 study, 5,407 patients undergoing elective hip replacement surgery were randomized to receive either apixaban 2. 5 mg orally twice daily or enoxaparin 40 mg subcutaneously once daily. The first dose of apixaban was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Treatment duration was 32 to 38 days. In patients undergoing elective knee replacement surgery, apixaban 2. 5 mg orally twice daily was compared to enoxaparin 40 mg subcutaneously once daily (ADVANCE-2, N=3,057) or enoxaparin 30 mg subcutaneously every 12 hours (ADVANCE-1, N=3,195). In the ADVANCE-2 study, the first dose of apixaban was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. In the ADVANCE-1 study, both apixaban and enoxaparin were initiated 12 to 24 hours post surgery. Treatment duration in both ADVANCE-2 and ADVANCE-1 was 10 to 14 days. In all 3 studies, the primary endpoint was a composite of adjudicated asymptomatic and symptomatic DVT, nonfatal PE, and all-cause death at the end of the double-blind intended treatment period. In ADVANCE-3 and ADVANCE-2, the primary endpoint was tested for noninferiority, then superiority, of apixaban to enoxaparin. In ADVANCE-1, the primary endpoint was tested for noninferiority of apixaban to enoxaparin. The efficacy data are provided in Tables 11 and 12. Table 11: Summary of Key Efficacy Analysis Results During the Intended Treatment Period for Patients Undergoing Elective Hip Replacement Surgery * * dagger double dagger ADVANCE-3 Events During 35-Day Treatment Period Apixaban Enoxaparin Relative Risk Number of Patients N=1,949 N=1,917 Total VTE dagger 27 (1. 36 Number of Patients N=2,708 N=2,699 All-cause death 3 (0. 04%) PE 3 (0. 19%) Symptomatic DVT 1 (0. 19%) Number of Patients N=2,196 N=2,190 Proximal DVT double dagger 7 (0. 91%) Number of Patients N=1,951 N=1,908 Distal DVT double dagger 20 (1. 99%) Table 12: Summary of Key Efficacy Analysis Results During the Intended Treatment Period for Patients Undergoing Elective Knee Replacement Surgery * * dagger double dagger ADVANCE-1 ADVANCE-2 Events during 12-day treatment period Apixaban 2. 5 mg po bid Enoxaparin 30 mg sc q12h Relative Risk (95% CI) P-value Apixaban 2. 5 mg po bid Enoxaparin 40 mg sc qd Relative Risk (95% CI) P-value Number of Patients N=1,157 N=1,130 N=976 N=997 Total VTE dagger 104 (8. 46) 243 (24. 62 Number of Patients N=1,599 N=1,596 N=1,528 N=1,529 All-cause death 3 (0. 52) 0 (0%) PE 16 (1. 70) 0 (0%) Symptomatic DVT 3 (0. 97) Number of Patients N=1,254 N=1,207 N=1,192 N=1,199 Proximal DVT double dagger 9 (0. 18) Number of Patients N=1,146 N=1,133 N=978 N=1,000 Distal DVT double dagger 83 (7. 78) 142 (14. 88) 239 (23. 65) The efficacy profile of apixaban was generally consistent across subgroups of interest for this indication (e. , age, gender, race, body weight, renal impairment). Efficacy and safety of apixaban for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following 6 to 12 months of anticoagulant treatment was derived from the AMPLIFY and AMPLIFY-EXT studies. Both studies were randomized, parallel-group, double-blind trials in patients with symptomatic proximal DVT and/or symptomatic PE. All key safety and efficacy endpoints were adjudicated in a blinded manner by an independent committee. AMPLIFY The primary objective of AMPLIFY was to determine whether apixaban was noninferior to enoxaparin/warfarin for the incidence of recurrent VTE (venous thromboembolism) or VTE-related death. Patients with an objectively confirmed symptomatic DVT and/or PE were randomized to treatment with apixaban 10 mg twice daily orally for 7 days followed by apixaban 5 mg twice daily orally for 6 months, or enoxaparin 1 mg/kg twice daily subcutaneously for at least 5 days (until INR >=2) followed by warfarin (target INR range 2. 0) orally for 6 months. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent, and patients with creatinine clearance <25 mL/min, significant liver disease, an existing heart valve or atrial fibrillation, or active bleeding were excluded from the AMPLIFY study. Patients were allowed to enter the study with or without prior parenteral anticoagulation (up to 48 hours). A total of 5,244 patients were evaluable for efficacy and were followed for a mean of 154 days in the apixaban group and 152 days in the enoxaparin/warfarin group. The mean age was 57 years. The AMPLIFY study population was 59% male, 83% Caucasian, 8% Asian, and 4% Black. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2. Approximately 90% of patients enrolled in AMPLIFY had an unprovoked DVT or PE at baseline. The remaining 10% of patients with a provoked DVT or PE were required to have an additional ongoing risk factor in order to be randomized, which included previous episode of DVT or PE, immobilization, history of cancer, active cancer, and known prothrombotic genotype. Apixaban was shown to be noninferior to enoxaparin/warfarin in the AMPLIFY study for the primary endpoint of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy (Table 13). Table 13: Efficacy Results in the AMPLIFY Study * dagger Apixaban N=2,609 n Enoxaparin/Warfarin N=2,635 n Relative Risk (95% CI) VTE or VTE-related death * 59 (2. 18) DVT dagger 22 (0. 3%) PE dagger 27 (1. 9%) VTE-related death dagger 12 (0. 6%) VTE or all-cause death 84 (3. 08) VTE or CV-related death 61 (2. 11) In the AMPLIFY study, patients were stratified according to their index event of PE (with or without DVT) or DVT (without PE). Efficacy in the initial treatment of VTE was consistent between the two subgroups. AMPLIFY-EXT Patients who had been treated for DVT and/or PE for 6 to 12 months with anticoagulant therapy without having a recurrent event were randomized to treatment with apixaban 2. 5 mg orally twice daily, apixaban 5 mg orally twice daily, or placebo for 12 months. Approximately one-third of patients participated in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study. A total of 2,482 patients were randomized to study treatment and were followed for a mean of approximately 330 days in the apixaban group and 312 days in the placebo group. The mean age in the AMPLIFY-EXT study was 57 years. The study population was 57% male, 85% Caucasian, 5% Asian, and 3% Black. The AMPLIFY-EXT study enrolled patients with either an unprovoked DVT or PE at baseline (approximately 92%) or patients with a provoked baseline event and one additional risk factor for recurrence (approximately 8%). However, patients who had experienced multiple episodes of unprovoked DVT or PE were excluded from the AMPLIFY-EXT study. In the AMPLIFY-EXT study, both doses of apixaban were superior to placebo in the primary endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE), or all-cause death (Table 14). Table 14: Efficacy Results in the AMPLIFY-EXT Study * Apixaban 2. 5 mg bid N=840 Apixaban 5 mg bid N=813 Placebo N=829 Relative Risk (95% CI) Apixaban 2. 5 mg bid vs Placebo Apixaban 5 mg bid vs Placebo n (%) Recurrent VTE or all-cause death 32 (3. 53) DVT * 19 (2. 7) PE * 23 (2. 5) All-cause death 22 (2. 0) Image Image.

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