2.1 Recommended Dose

The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily.

2.2 Dosage Adjustments

The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with any 2 of the following characteristics:

• age ≥80 years
• body weight ≤60 kg
• serum creatinine ≥1.5 mg/dL

CYP3A4 and P-gp inhibitors: When ELIQUIS is coadministered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin), the recommended dose is 2.5 mg twice daily [see Clinical Pharmacology (12.3)].

In patients already taking 2.5 mg twice daily, coadministration of ELIQUIS with strong dual inhibitors of CYP3A4 and P-gp should be avoided.

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 Discontinuation 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. 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.

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 INR measurements during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. If continuous anticoagulation is necessary, 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 between ELIQUIS and anticoagulants other than warfarin: Discontinue one being taken and begin the other at the next scheduled dose.

2.6 Hepatic Impairment

No dose adjustment is required in patients with mild hepatic impairment.

Because patients with moderate hepatic impairment may have intrinsic coagulation abnormalities and there is limited clinical experience with ELIQUIS in these patients, dosing recommendations cannot be provided [see Clinical Pharmacology (12.2)].

ELIQUIS is not recommended in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

2.7 Renal Impairment

The dosing adjustment for moderate renal impairment is described above [see Dosage and Administration (2.2)]. No data inform use in patients with creatinine clearance <15 mL/min or on dialysis.

5.1 Increased Risk of Stroke with Discontinuation of ELIQUIS

Discontinuing ELIQUIS in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ELIQUIS to warfarin in clinical trials in patients with nonvalvular atrial fibrillation. If ELIQUIS must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant [see Dosage and Administration (2.3)].

5.2 Bleeding

ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitor, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3)].

Patients should be made aware of signs and symptoms of blood loss and instructed to report them immediately or go to an emergency room. ELIQUIS should be discontinued in patients with active pathological hemorrhage.

There is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for about 24 hours after the last dose, i.e., for about two half-lives. A specific antidote for ELIQUIS is not available. Because of high plasma protein binding, apixaban is not expected to be dialyzable [see Clinical Pharmacology (12.3)]. Protamine sulfate and vitamin K would not be expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is neither scientific rationale for reversal nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving apixaban. Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa may be considered but has not been evaluated in clinical studies. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration [see Overdosage (10)].

5.3 Patients with Prosthetic Heart Valves

The safety and efficacy of ELIQUIS has not been studied in patients with prosthetic heart valves. Therefore, use of ELIQUIS is not recommended in these patients.

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.

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 patients-years).

The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on ELIQUIS and aspirin, respectively.

Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES

Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment period and the bleeding rate (percentage of subjects with at least one bleeding event per year) in ARISTOTLE and AVERROES.

Major bleeding was defined as clinically overt bleeding that was accompanied by one or more of the following: a decrease in hemoglobin of 2 g/dL or more; a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; or bleeding that was fatal. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

Table 1:     Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE

	ELIQUIS N=9088 n (%/year)	Warfarin N=9052 n (%/year)	Hazard Ratio (95% CI*)	P-value
*  Confidence interval.
†   International Society on Thrombosis and Hemostasis (ISTH) major bleed assessed by sequential testing strategy for superiority designed to control the overall type I error in the trial.
‡   GI bleed includes upper GI, lower GI, and rectal bleeding.
§   Intraocular bleed is within the corpus of the eye (a conjunctival bleed is not an intraocular bleed).
¶   Fatal bleed is an adjudicated death because of bleeding during the treatment period and includes both fatal extracranial bleeds and fatal hemorrhagic stroke.
** CRNM = clinically relevant nonmajor bleeding.
Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.
Major†	327 (2.13)	462 (3.09)	0.69 (0.60, 0.80)	<0.0001
Gastrointestinal (GI)‡	128 (0.83)	141 (0.93)	0.89 (0.70, 1.14)	-
Intracranial	52 (0.33)	125 (0.82)	0.41 (0.30, 0.57)	-
Intraocular§	32 (0.21)	22 (0.14)	1.42 (0.83, 2.45)	-
Fatal¶	10 (0.06)	37 (0.24)	0.27 (0.13, 0.53)	-
CRNM**	318 (2.08)	444 (3.00)	0.70 (0.60, 0.80)	<0.0001

In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic region, ELIQUIS dose, type of AF, and aspirin use at randomization (Figure 1). Subjects treated with apixaban with diabetes bled more (3.0%/year) than did subjects without diabetes (1.9%/year).

Figure 1:     Major Bleeding Hazard Ratios by Baseline Characteristics – ARISTOTLE Study

Table 2:     Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in AVERROES

	ELIQUIS N=2978 n (%/year)	Aspirin N=2780 n (%/year)	Hazard Ratio (95% CI)	P-value
Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.
Major	45 (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)	-

7.1 Strong Dual Inhibitors of CYP3A4 and P-gp

The dose of ELIQUIS should be decreased to 2.5 mg twice daily when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp, (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

In patients already taking ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of both CYP3A4 and P-gp [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

7.2 Strong Dual Inducers of CYP3A4 and P-gp

Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp (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 2.77%/year with apixaban versus 0.62%/year with placebo in patients receiving single antiplatelet therapy and was 5.91%/year with apixaban versus 2.50%/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 the bleeding risk on warfarin 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.

8.1 Pregnancy

8.2 Labor and Delivery

Safety and effectiveness of ELIQUIS during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using ELIQUIS in this setting [see Warnings and Precautions (5.2)].

Treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with apixaban at a dose of 1000 mg/kg (about 5 times the human exposure based on unbound apixaban) did not result in death of offspring or death of mother rats during labor in association with uterine bleeding. However, increased incidence of maternal bleeding, primarily during gestation, occurred at apixaban doses of ≥25 mg/kg, a dose corresponding to ≥1.3 times the human exposure.

8.3 Nursing Mothers

It is unknown whether apixaban or its metabolites are excreted in human milk. Rats excrete apixaban in milk (12% of the maternal dose).

Women should be instructed either to discontinue breastfeeding or to discontinue ELIQUIS therapy, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total subjects in clinical studies of apixaban, >69% were 65 and older, and >31% were 75 and older. The effects of ELIQUIS on the risk of stroke and major bleeding compared to warfarin were maintained in geriatric subjects.

12.1 Mechanism of Action

Apixaban is an oral, reversible, and selective active site 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.

12.2 Pharmacodynamics

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 during the apixaban 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.

12.3 Pharmacokinetics

Apixaban displays prolonged absorption. Thus, despite a short clearance half-life of about 6 hours, the apparent half-life during repeat dosing is about 12 hours, which allows twice-daily dosing to provide effective anticoagulation, but it also means that when the drug is stopped for surgery, anticoagulation persists for at least a day.

Drug Interaction Studies

In 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 and associated dose recommendations 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

*  Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations. Dosing recommendations were also informed by clinical considerations [see Warnings and Precautions (5.2) and Drug Interactions (7)].

In dedicated studies conducted in healthy subjects, famotidine, atenolol, 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, or acetylsalicylic acid.

Specific Populations

The effects of level of renal impairment, age, body weight, level of hepatic impairment, gender, and ethnic origin on the pharmacokinetics of apixaban are summarized in Figure 3.

Figure 3:     Effect of Specific Populations on the Pharmacokinetics of Apixaban

*  Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations.

A study in healthy subjects comparing the pharmacokinetics in males and females showed no meaningful difference.

The results across pharmacokinetic studies in normal subjects showed no differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/African American subjects. No dose adjustment is required based on race/ethnicity.

13.1 Carcinogenesis, 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 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 that is 5 times the human exposure. Adverse effects in the F1-generation female offspring were limited to decreased mating and fertility indices at 1000 mg/kg/day.

14.1 ARISTOTLE

Evidence for the efficacy and safety of ELIQUIS was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular atrial fibrillation (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 ≥80 years, body weight ≤60 kg, or serum creatinine ≥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 ≥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 CHADS2 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 3 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)].

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 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, CHADS2 score (a scale from 0 to 6 used to predict risk of stroke in patients with AF, with higher scores predicting greater risk), prior warfarin use, level of renal impairment, geographic region, ELIQUIS dose, type of AF, and aspirin use at randomization (Figure 5).

Figure 5:     Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics – ARISTOTLE Study

14.2 AVERROES

In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates for warfarin therapy were randomized to treatment with ELIQUIS 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 ELIQUIS 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 ELIQUIS compared to aspirin that was associated with a modest increase in major bleeding (Table 4); [see Adverse Reactions (6.1)].