Apixaban

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.

1 INDICATIONS & USAGE Apixaban is a factor Xa inhibitor indicated: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. ( 1.1 ) for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. ( 1.2 ) for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following initial therapy. ( 1.3 , 1.4 , 1.5 ) 1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation Apixaban tablets are indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 1.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Apixaban tablets are indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. 1.3 Treatment of Deep Vein Thrombosis Apixaban tablets are indicated for the treatment of DVT. 1.4 Treatment of Pulmonary Embolism Apixaban tablets are indicated for the treatment of PE. 1.5 Reduction in the Risk of Recurrence of DVT and PE Apixaban tablets are indicated to reduce the risk of recurrent DVT and PE following initial therapy.

2 DOSAGE & ADMINISTRATION 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 ) 2.1 Recommended Dose 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 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 apixaban tablets 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 apixaban tablets 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 apixaban tablets 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 Missed Dose If a dose of apixaban tablets 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 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)] . Apixaban tablets 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 apixaban tablets and prior to the intervention is not generally required. Apixaban tablets should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. 2.4 Converting from or to apixaban Switching from warfarin to apixaban: Warfarin should be discontinued and apixaban started when the international normalized ratio (INR) is below 2.0. Switching from apixaban to warfarin: apixaban 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 apixaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range. Switching from apixaban to anticoagulants other than warfarin (oral or parenteral): Discontinue apixaban and begin taking the new anticoagulant other than warfarin at the usual time of the next dose of apixaban. Switching from anticoagulants other than warfarin (oral or parenteral) to apixaban: Discontinue the anticoagulant other than warfarin and begin taking apixaban 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 apixaban tablets doses of 5 mg or 10 mg twice daily, reduce the dose by 50% when apixaban tablet 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 apixaban tablets with combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitors [see Drug Interactions ( 7.1) ]. 2.6 Administration Options 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 apple

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the prescribing information. • Increased risk of thrombotic events after premature discontinuation [see Warnings and Precautions ( 5.1 )] • Bleeding [see Warnings and Precautions ( 5.2 )] • Spinal/epidural anesthesia or puncture [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (>1%) are related to bleeding. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Indoco Remedies Limited at +1-855-642-2594 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 apixaban tablets was evaluated in the ARISTOTLE and AVERROES studies [see Clinical Studies ( 14 )] , including 11,284 patients exposed to apixaban tablets 5 mg twice daily and 602 patients exposed to apixaban tablets 2.5 mg twice daily. The duration of apixaban tablets exposure was ≥12 months for 9375 patients and ≥24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000 patient-years). In AVERROES, the mean duration of exposure was approximately 59 weeks (>3000 patient-years). The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with apixaban tablets and warfarin, respectively, and in AVERROES, in 1.5% and 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* Apixaban N=9088 n(per 100 pt-year) Warfarin N=9052 n(per 100 pt-year) Hazard Ratio (95% CI) P-value Major † 327(2.13) 462(3.09) 0.69(0.60,0.80) <0.0001 Intracranial(ICH) ‡ 52( 0.33) 125(0.82) 0.41(0.30,0.57) - Hemorrhagic stroke § 38 (0.24) 74(0.49) 0.51(0.34,0.75) - Other ICH 15 (0.10) 51(0.34) 0.29(0.16,0.51) - Gastrointestinal(GI) ¶ 128 (0.83) 141(0.93) 0.89(0.70,1.14) - Fatal** 10 (0.06) 37(0.24) 0.27(0.13,0.53) - Intracranial 4 (0.03) 30(0.20) 0.13(0.05,0.37) - Non-intracranial 6 (0.04) 7(0.05) 0.84(0.28,2.15) - * Bleeding events within each subcategory were counted once per subject, but subjects may have contributed events to multiple endpoints. Bleeding events were counted during treatment or within 2 days of stopping study treatment (on-treatment period). † Defined as clinically overt bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal or with fatal outcome. ‡ Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type of hemorrhagic stroke was adjudicated and counted as an intracranial major bleed. § On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14. ¶ GI bleed includes upper GI, lower GI, and rectal bleeding. ** Fatal bleeding is an adjudicated death with the primary cause of death as intracranial bleeding or non-intracranial bleeding during the on-treatment period. In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS 2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic region, and aspirin use at randomization (Figure 1). Subjects treated with apixaban with diabetes bled more (3% per year) than did subjects without diabetes (1.9% per year). Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics – ARISTOTLE Study Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were prespecified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Table 2: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in AVERROES Apixaban N=2798 n(%/year) Aspirin N=27

7 DRUG INTERACTIONS Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events. Combined P-gp and strong CYP3A4 inhibitors increase blood levels of apixaban. Reduce apixaban dose or avoid coadministration. ( 2.5 , 7.1 , 12.3 ) Simultaneous use of combined P-gp and strong CYP3A4 inducers reduces blood levels of apixaban: Avoid concomitant use. ( 7.2 , 12.3 ) 7.1 Combined P-gp Strong CYP3A4 Inhibitors 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.g., ketoconazole, itraconazole, ritonavir) [see Dosage and Administration (2.5) and Clinical Pharmacology ( 12.3) ]. For patients receiving apixaban at a dose of 2.5 mg twice daily, avoid coadministration with combined P-gp and strong CYP3A4 inhibitors [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )]. Clarithromycin Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with apixaban [see Clinical Pharmacology ( 12.3) ]. 7.2 Combined P-gp Strong CYP3A4 Inducers Avoid concomitant use of apixaban tablets with combined P-gp and strong CYP3A4 Inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban [see Clinical Pharmacology ( 12.3 )]. 7.3 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 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.