Eliquis apixaban 5 mg Tablet, Film Coated, 30-count — NDC 70518-4462-0 (Billing 70518-4462-00)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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 ® Heparin chromogenic assay was used to measure the effect of apixaban on FXa activity in humans primarily during the apixaban adult development program.

A concentration-dependent increase in anti-FXa activity was observed in the dose range tested and was similar in healthy subjects and patients with AF. This test is not recommended for assessing the anticoagulant effect of apixaban. Effect of PCCs on Pharmacodynamics of ELIQUIS There is no clinical experience to reverse bleeding with the use of 4-factor PCC products in individuals who have received ELIQUIS.

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%-51% increase over pre-apixaban levels) at 21 hours after initiating PCC and remained elevated (21%-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) ] .

A 50% to 60% increase in anti-FXa activity was observed when ELIQUIS was coadministered with enoxaparin or naproxen. Specific Populations Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across renal function categories. Hepatic impairment: Changes in anti-FXa activity were similar in patients with mild-to-moderate hepatic impairment and healthy subjects.

However, in patients with moderate hepatic impairment, there is no clear understanding of the impact of this degree of hepatic function impairment on the coagulation cascade and its relationship to efficacy and bleeding. Patients with severe hepatic impairment were not studied. Pediatric patients: In pediatric patients treated with apixaban, the correlation between anti-FXa activity and plasma concentration is linear with a slope close to 1.

Cardiac Electrophysiology Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.

12.3Pharmacokinetics 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 ELIQUIS. Food does not affect the bioavailability of apixaban.

Maximum concentrations (C max ) of apixaban appear 3 to 4 hours after oral administration of ELIQUIS. At doses ≥25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability. Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was similar to that after oral administration of 2 intact 5 mg tablets.

Following oral administrati… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics 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 ELIQUIS. Food does not affect the bioavailability of apixaban.

Maximum concentrations (C max ) of apixaban appear 3 to 4 hours after oral administration of ELIQUIS. At doses ≥25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability. Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was similar to that after oral administration of 2 intact 5 mg tablets.

Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets mixed with 30 g of applesauce, the C max and AUC were 20% and 16% lower, respectively, when compared to administration of 2 intact 5 mg tablets. Following administration of a crushed 5 mg ELIQUIS tablet that was suspended in 60 mL D5W and delivered through a nasogastric tube, exposure was similar to that seen in other clinical trials involving healthy volunteers receiving a single oral 5 mg tablet dose. 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

3.3L/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 i n vitro apixaban studies at concentrations significantly greater than therapeutic exposures, no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of CYP1A2, CYP2B6, or CYP3A4/5 were observed.

Therefore, apixaban is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp. The effects of coadministered drugs on the pharmacokinetics of apixaban are summarized in Figure 2 [see also Warnings and Precautions (5.2) and Drug Interactions (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. Effect of Coadministered Drugs on Pharmacokinetics of Apixaban 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 * ESRD subjects treated with intermittent hemodialysis; reported PK findings are following single dose of apixaban posthemodialysis. † Results reflect CrCl of 15 mL/min based on regression analysis. ‡ Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations. § No dose adjustment is recommended for nonvalvular atrial fibrillation patients unless at least 2 of the follow… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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 ® Heparin chromogenic assay was used to measure the effect of apixaban on FXa activity in humans primarily during the apixaban adult development program.

A concentration-dependent increase in anti-FXa activity was observed in the dose range tested and was similar in healthy subjects and patients with AF. This test is not recommended for assessing the anticoagulant effect of apixaban. Effect of PCCs on Pharmacodynamics of ELIQUIS There is no clinical experience to reverse bleeding with the use of 4-factor PCC products in individuals who have received ELIQUIS.

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%-51% increase over pre-apixaban levels) at 21 hours after initiating PCC and remained elevated (21%-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) ] .

A 50% to 60% increase in anti-FXa activity was observed when ELIQUIS was coadministered with enoxaparin or naproxen. Specific Populations Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across renal function categories. Hepatic impairment: Changes in anti-FXa activity were similar in patients with mild-to-moderate hepatic impairment and healthy subjects.

However, in patients with moderate hepatic impairment, there is no clear understanding of the impact of this degree of hepatic function impairment on the coagulation cascade and its relationship to efficacy and bleeding. Patients with severe hepatic impairment were not studied. Pediatric patients: In pediatric patients treated with apixaban, the correlation between anti-FXa activity and plasma concentration is linear with a slope close to 1.

Cardiac Electrophysiology Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.

Effect of PCCs on Pharmacodynamics of ELIQUIS There is no clinical experience to reverse bleeding with the use of 4-factor PCC products in individuals who have received ELIQUIS. 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%-51% increase over pre-apixaban levels) at 21 hours after initiating PCC and remained elevated (21%-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) ] . A 50% to 60% inc… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation ARISTOTLE Evidence for the efficacy and safety of ELIQUIS was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular AF comparing the effects of ELIQUIS and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. In ARISTOTLE, patients were randomized to ELIQUIS 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 2.0-3.0).

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 ELIQUIS 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 ELIQUIS 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 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk) was 2.1. The population was 65% male, 83% Caucasian, 14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 19% of patients.

Concomitant diseases of patients in this study included hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular ejection fraction ≤40%) 35%, and prior myocardial infarction 14%. Patients treated with warfarin in ARISTOTLE had a mean percentage of time in therapeutic range (INR 2.0-3.0) of 62%. ELIQUIS was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Table 13 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. ELIQUIS also showed significantly fewer major bleeds than warfarin [see Adverse Reactions (6.1) ] .

Table 13: Key Efficacy Outcomes in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE (Intent-to-Treat Analysis) ELIQUIS N=9120 n (%/year) Warfarin N=9081 n (%/year) Hazard Ratio (95% CI) P-value 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. Stroke or systemic embolism 212 (1.27) 265 (1.60) 0.79 (0.66, 0.95)

0.01Stroke 199 (1.19) 250 (1.51) 0.79 (0.65, 0.95) Ischemic without hemorrhage 140 (0.83) 136 (0.82) 1.02 (0.81, 1.29) Ischemic with hemorrhagic conversion 12 (0.07) 20 (0.12) 0.60 (0.29, 1.23) Hemorrhagic 40 (0.24) 78 (0.47) 0.51 (0.35, 0.75) Unknown 14 (0.08) 21 (0.13) 0.65 (0.33, 1.29) Systemic embolism 15 (0.09) 17 (0.10) 0.87 (0.44, 1.75) 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.

ELIQUIS treatment resulted in a significantly low… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Apixaban was not carcinogenic when administered to mice and rats for up to 2 years. The systemic exposures (AUCs) of unbound apixaban in male and female mice at the highest doses tested (1500 and 3000 mg/kg/day) were 9 and 20 times, respectively, the human exposure of unbound drug at the MRHD of 10 mg/day. Systemic exposures of unbound apixaban in male and female rats at the highest dose tested (600 mg/kg/day) were 2 and 4 times, respectively, the human exposure.

Mutagenesis: Apixaban was neither mutagenic in the bacterial reverse mutation (Ames) assay, nor clastogenic in Chinese hamster ovary cells in vitro , in a 1-month in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes, or in a rat micronucleus study in vivo . Impairment of Fertility: Apixaban had no effect on fertility in male or female rats when given at doses up to 600 mg/kg/day, a dose resulting in unbound apixaban exposure levels that are 3 and 4 times, respectively, the human exposure. Apixaban administered to female rats at doses up to 1000 mg/kg/day from implantation through the end of lactation produced no adverse findings in male offspring (F1 generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure to unbound apixaban that is 5 times the human exposure.

Adverse effects in the F1-generation female offspring were limited to decreased mating and fertility indices at ≥200 mg/kg/day (a dose resulting in exposure to unbound apixaban that is ≥5 times the human exposure).