`These highlights do not include all the information needed to use
`ELIQUIS safely and effectively. See full prescribing information for
`ELIQUIS.
`
`ELIQUIS (apixaban) tablets for oral use
`Initial U.S. Approval: 2012
`
`
`WARNING: DISCONTINUING ELIQUIS IN PATIENTS
`
`
`WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION
`
`
`INCREASES RISK OF STROKE
`
`
`See full prescribing information for complete boxed warning.
`
`Discontinuing ELIQUIS places patients at an increased risk of
`
`thrombotic events. An increased rate of stroke was observed following
`discontinuation of ELIQUIS in clinical trials in patients with
`
`nonvalvular atrial fibrillation. If anticoagulation with ELIQUIS must
`be discontinued for a reason other than pathological bleeding,
`coverage with another anticoagulant should be strongly considered.
`(2.4, 5.1)
`
`
`---------------------------INDICATIONS AND USAGE----------------------------
`ELIQUIS is a factor Xa inhibitor anticoagulant indicated to reduce the risk of
`stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
`(1)
`------------------------DOSAGE AND ADMINISTRATION----------------------
`
` The recommended dose is 5 mg orally twice daily. (2.1)
`
`
` In patients with at least 2 of the following characteristics: age 80 years,
`
`body weight 60 kg, or serum creatinine 1.5 mg/dL, the recommended
`
`
`dose is 2.5 mg orally twice daily. (2.2)
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
` Tablets: 2.5 mg and 5 mg (3)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: DISCONTINUING ELIQUIS IN PATIENTS WITHOUT
`
`ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES
`RISK OF STROKE
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`Recommended Dose
`2.1
`
`
`2.2
`Dosage Adjustments
`
`
`2.3
`Missed Dose
`
`
`2.4
`Discontinuation for Surgery and Other Interventions
`
`
`
`2.5
`Converting from or to ELIQUIS
`
`
`
`2.6
`Hepatic Impairment
`
`
`2.7
`Renal Impairment
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Increased Risk of Stroke with Discontinuation of ELIQUIS
`5.1
`
`
`5.2
`Bleeding
`
`
`5.3
`Patients with Prosthetic Heart Valves
`
`
`6 ADVERSE REACTIONS
`
`
`Clinical Trials Experience
`6.1
`
`
`7 DRUG INTERACTIONS
`
`
`Strong Dual Inhibitors of CYP3A4 and P-gp
`7.1
`
`
`7.2
`Strong Dual Inducers of CYP3A4 and P-gp
`
`
`
`
`------------------------------CONTRAINDICATIONS-------------------------------
`
` Active pathological bleeding (4)
`
`
` Severe hypersensitivity to ELIQUIS (4)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`
` ELIQUIS can cause serious, potentially fatal bleeding. Promptly evaluate
`
`signs and symptoms of blood loss. (5.2)
`
`
` Prosthetic heart valves: ELIQUIS use not recommended. (5.3)
`
`-------------------------------ADVERSE REACTIONS------------------------------
`Most common adverse reactions (>1%) are related to bleeding. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`or FDA
`Squibb
`at
`1-800-721-5072
`at
`1-800-FDA-1088
`or
`
`www.fda.gov/medwatch
`
`--------------------------------DRUG INTERACTIONS-----------------------------
`
` Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of
`
`apixaban: Reduce ELIQUIS dose to 2.5 mg or avoid concomitant use. (2.2,
`7.1, 12.3)
`
`
` Simultaneous use of strong inducers of CYP3A4 and P-gp reduces blood
`
`levels of apixaban: Avoid concomitant use. (7.2, 12.3)
`
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
` Nursing Mothers: Discontinue drug or discontinue nursing. (8.3)
`
`
`
` Pregnancy: Not recommended. (8.1)
`
`
`
` Severe Hepatic Impairment: Not recommended. (12.2)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide
`
`
`Revised: 12/2012
`
`
`
`
`
`
`
`Anticoagulants and Antiplatelet Agents
`7.3
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2
`Labor and Delivery
`
`
`8.3
`Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`ARISTOTLE
`14.1
`
`
`14.2
`AVERROES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`* Sections or subsections omitted from the full prescribing information
`are not listed
`
`Reference ID: 3237516
`
`1
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: DISCONTINUING ELIQUIS IN PATIENTS WITHOUT ADEQUATE
`
`CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE
`
`
`
` Discontinuing ELIQUIS places patients at an increased risk of thrombotic events. An
`
` increased rate of stroke was observed following discontinuation of ELIQUIS in clinical
` trials in patients with nonvalvular atrial fibrillation. If anticoagulation with ELIQUIS
`
` must be discontinued for a reason other than pathological bleeding, coverage with another
`
`anticoagulant should be strongly considered [see Dosage and Administration (2.4) and
`
` Warnings and Precautions (5.1)].
`
`1
`
`INDICATIONS AND USAGE
`
`
`
` ELIQUIS (apixaban) is indicated to reduce the risk of stroke and systemic embolism in patients
`with nonvalvular atrial fibrillation.
`
`2
`
`2.1
`
`DOSAGE AND ADMINISTRATION
`
`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)].
`
`2
`
`
`Reference ID: 3237516
`
`
`
`
`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)].
`
`3
`
`
`Reference ID: 3237516
`
`
`
`
`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.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`
` 2.5 mg, yellow, round, biconvex, film-coated tablets with “893” debossed on one side and
`“2½” on the other side.
`
`
` 5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894” debossed on one side and
`“5” on the other side.
`
`4
`
`CONTRAINDICATIONS
`
`ELIQUIS is contraindicated in patients with the following conditions:
`
`
` Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions
`
`(6.1)]
`
`
` Severe hypersensitivity reaction to ELIQUIS (i.e., anaphylactic reactions) [see Adverse
`
`Reactions (6.1)]
`
`
`5
`
`5.1
`
`WARNINGS AND PRECAUTIONS
`
`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)].
`
`4
`
`
`Reference ID: 3237516
`
`
`
`
`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
`
`ADVERSE REACTIONS
`
`The most serious adverse reactions reported with ELIQUIS were related to bleeding [see
`
`Warnings and Precautions (5.2)].
`
`5
`
`
`Reference ID: 3237516
`
`
`
`
`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 patient-years).
`
`The most common reason for treatment discontinuation in both studies was for bleeding-related
`adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with
`ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on ELIQUIS and
`aspirin, respectively.
`
`Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES
`
`Tables 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.
`
`6
`
`
`Reference ID: 3237516
`
`
`
`
`Table 1:
`
`
`
`Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in
`ARISTOTLE
`
`ELIQUIS
`N=9088
`n (%/year)
`
`327 (2.13)
`
`128 (0.83)
`52 (0.33)
`32 (0.21)
`10 (0.6)
`
`318 (2.08)
`
`Warfarin
`
`N=9052
`n (%/year)
`
`462 (3.09)
`
`141 (0.93)
`
`125 (0.82)
`22 (0.14)
`37 (0.24)
`
`444 (3.00)
`
`Hazard Ratio
`(95% CI*)
`
`P-value
`
`
`0.69 (0.60, 0.80)
`
`0.89 (0.70, 1.14)
`0.41 (0.30, 0.57)
`1.42 (0.83, 2.45)
`0.27 (0.13, 0.53)
`
`0.70 (0.60, 0.80)
`
`
`
`<0.0001
`-
`-
`-
`-
`
`<0.0001
`
`
`
`
`
`
`
`Major†
`
` Gastrointestinal (GI)‡
`
`
`
`Intracranial
`Intraocular§
`
`
`Fatal¶
`
`CRNM **
`
`* 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.
`
` 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).
`
`7
`
`
`Reference ID: 3237516
`
`
`
`
`Figure 1:
`
`Major Bleeding Hazard Ratios by Baseline Characteristics –
`ARISTOTLE Study
`
`8
`
`
`
`
`Reference ID: 3237516
`
`
`
`
`
`Table 2:
`
`Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in
`AVERROES
`
`
`ELIQUIS
`Aspirin
`N=2798
`N=2780
`n (%/year)
`n (%/year)
`1.54 (0.96, 2.45)
`29 (0.92)
`45 (1.41)
`Major
`0.99 (0.23, 4.29)
`5 (0.16)
`
`
`
`5 (0.16)
`Fatal
`0.99 (0.39, 2.51)
`11 (0.35)
`
`
`11 (0.34)
`Intracranial
`Events associated with each endpoint were counted once per subject, but subjects may have contributed events to
`multiple endpoints.
`
`0.07
`
`--
`
`Other Adverse Reactions
`
`Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic
`reactions, such as allergic edema) and syncope were reported in <1% of patients receiving
`ELIQUIS.
`
`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.
`
`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 daily, avoid coadministration with strong
`dual inhibitors of both CYP3A4 and P-gp [see Dosage and Administration (2.2) and Clinical
`Pharmacology (12.3)].
`
`9
`
`
`Reference ID: 3237516
`
`
`
`Hazard Ratio
`(95% CI)
`
`P-value
`
`
`
`
`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
`
`8.1
`
`USE IN SPECIFIC POPULATIONS
`
`
`Pregnancy
`
`Pregnancy Category B
`
`There are no adequate and well-controlled studies of ELIQUIS in pregnant women. Treatment is
`likely to increase the risk of hemorrhage during pregnancy and delivery. ELIQUIS should be
`used during pregnancy only if the potential benefit outweighs the potential risk to the mother and
`fetus.
`
`
`Treatment of pregnant rats, rabbits, and mice after implantation until the end of gestation resulted
`in fetal exposure to apixaban, but was not associated with increased risk for fetal malformations
`or toxicity. No maternal or fetal deaths were attributed to bleeding. Increased incidence of
`maternal bleeding was observed in mice, rats, and rabbits at maternal exposures that were 19, 4,
`
`10
`
`
`Reference ID: 3237516
`
`
`
`
`and 1 times, respectively, the human exposure of unbound drug, based on area under plasma-
`concentration time curve (AUC) comparisons at the maximum recommended human dose
`(MRHD) of 10 mg (5 mg twice daily).
`
`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.
`
`11
`
`
`Reference ID: 3237516
`
`
`
`
`10
`
`OVERDOSAGE
`
`
`
` There is no antidote to ELIQUIS. Overdose of ELIQUIS 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. Mean apparent
`half-life of apixaban decreased from 13.4 hours when apixaban was administered alone to 5.3
`hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours after
`apixaban, indicating that charcoal blocked the continued absorption of apixaban from the gut
`[see Clinical Pharmacology (12.3)]. Thus, administration of activated charcoal may be useful in
`
` the management of apixaban overdose or accidental ingestion by leading to a more rapid fall in
`apixaban blood levels.
`
`11
`
`DESCRIPTION
`
`ELIQUIS (apixaban), a factor Xa (FXa) inhibitor, is chemically described as 1-(4
`methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4
`c]pyridine-3-carboxamide. Its molecular formula is C25H25N5O4, which corresponds to a
`molecular weight of 459.5. Apixaban has the following structural formula:
`
`O
`
`H2N
`
`N
`
`N
`
`N
`
`O
`
`H3CO
`
`O
`
`N
`
`
`
`Apixaban is a white to pale-yellow powder. At physiological pH (1.2-6.8), apixaban does not
`ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL.
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`ELIQUIS tablets are available for oral administration in strengths of 2.5 mg and 5 mg of
`apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline cellulose,
`croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains
`
`lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg
`tablets) or red iron oxide (5 mg tablets).
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`12
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`CLINICAL PHARMACOLOGY
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`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.
`
`Pharmacodynamic Drug Interaction Studies
`
`Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin and clopidogrel,
`enoxaparin, and naproxen were conducted. No pharmacodynamic interactions were observed
`with aspirin or clopidogrel, but a 50% to 60% increase in anti-FXa activity was observed when
`apixaban was coadministered with enoxaparin or naproxen.
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`Specific Populations
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`Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across renal
`function categories.
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`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.
`
`Cardiac Electrophysiology
`
`Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.
`
`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.
`
`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 (Cmax)
`of apixaban appear 3 to 4 hours after oral administration of ELIQUIS. Apixaban is absorbed
`throughout the gastrointestinal tract with the distal small bowel and ascending colon contributing
`about 55% of apixaban absorption. Apixaban demonstrates linear pharmacokinetics with dose-
`proportional increases in exposure for oral doses up to 10 mg. At doses 25 mg, apixaban
`displays dissolution-limited absorption with decreased bioavailability.
`
`Distribution
`
`
`Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is
`approximately 21 liters.
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`Metabolism
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`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.
`
`Following intravenous administration, apixaban is eliminated with a dominant half-life of ~ 5
`hours. Following oral administration, the apparent half-life is ~12 hours because of prolonged
`absorption.
`
`
`Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance protein.
`
`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)].
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`Figure 2:
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`Effect of Coadministered Drugs on the Pharmacokinetics of Apixaban
`
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`* 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 healthy subjects, apixaban did not meaningfully alter
`In studies conducted
`pharmacokinetics of digoxin, naproxen, atenolol, or acetylsalicylic acid.
`
`the
`
`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.
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`Figure 3:
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`Effect of Specific Populations on the Pharmacokinetics of Apixaban
`
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` * Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations.
`
`
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`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.
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`13
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`NONCLINICAL TOXICOLOGY
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`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.
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`14
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`CLINICAL STUDIES
`
`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
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`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
`
`
`The primary objective of ARISTOTLE was to determine whether ELIQUIS 5 mg twice daily (or
`2.5 mg twice da