`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`202155Orig1s002
`LABELING
`
`
`
`

`

`-------------------------------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 dual 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: 01/2014
`
`
`
`
`
` 
` 
`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
` 
`8.6
`End-Stage Renal Disease Patients Maintained with
`
` 
`Hemodialysis
` 
` 
`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
` 
` 
`14.1
`ARISTOTLE
` 
` 
`AVERROES
`14.2
` 
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 
` 
`17 PATIENT COUNSELING INFORMATION
`
`
`* Sections or subsections omitted from the full prescribing information
`are not listed.
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`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
` 
` 
`1
`INDICATIONS AND USAGE
` 
` 
`2 DOSAGE AND ADMINISTRATION
`
` 
` 
`Recommended Dose
`2.1
` 
` 
`2.2
`Dosage Adjustments
` 
` 
`2.3
`Missed Dose
` 
`2.4
`Temporary Interruption for Surgery and Other
`
` 
`Interventions
`
` 
` 
`2.5
`Converting from or to ELIQUIS
`
` 
` 
`Hepatic Impairment
`2.6
` 
` 
`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
` 
` 
`6.1
`Clinical Trials Experience
` 
` 
`7 DRUG INTERACTIONS
` 
` 
`7.1
`Strong Dual Inhibitors of CYP3A4 and P-gp
` 
` 
`Strong Dual Inducers of CYP3A4 and P-gp
`7.2
`
` 
` 
`7.3
`Anticoagulants and Antiplatelet Agents
`
`
`
`Reference ID: 3445066
`
`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: 3445066
`
`

`

`
`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
`
`Temporary Interruption 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. Bridging anticoagulation during the 24 to 48 hours after stopping
`ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted
`after the surgical or other procedures as soon as adequate hemostasis has been established.
`
`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 initial INR measurements
`
`during the transition to 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.
`
`3
`
`
`Reference ID: 3445066
`
`

`

`
`
`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)]. The recommended dose for patients with end-stage renal disease (ESRD)
`maintained on hemodialysis is 5 mg twice daily. Reduce dose to 2.5 mg twice daily if one of the
`
`following patient characteristics (age 80 years or body weight 60 kg) is present [see Use in
`
`Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`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 (e.g., 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
`
`4
`
`
`Reference ID: 3445066
`
`

`

`
`ELIQUIS to warfarin in clinical trials in patients with nonvalvular atrial fibrillation [see Clinical
`Studies (14.1)]. If ELIQUIS must be discontinued for a reason other than pathological bleeding,
`consider coverage with another anticoagulant [see Dosage and Administration (2.5)].
`
`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 at least 24 hours after the last dose, i.e., for about two half-lives. A
`specific antidote for ELIQUIS is not available. Hemodialysis does not appear to have a
`substantial impact on apixaban exposure [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 have not been studied in patients with prosthetic heart
`valves. Therefore, use of ELIQUIS is not recommended in these patients.
`
`5
`
`
`Reference ID: 3445066
`
`

`

`
`6
`
`ADVERSE REACTIONS
`
`The most serious adverse reactions reported with ELIQUIS were related to bleeding [see
`Warnings and Precautions (5.2)].
`
`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: 3445066
`
`

`

`
`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 (0.06)
`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 atrial fibrillation (AF), and aspirin use at randomization (Figure 1).
`Subjects treated with apixaban with diabetes bled more (3.0% per year) than did subjects without
`diabetes (1.9% per year).
`
`7
`
`
`Reference ID: 3445066
`
`

`

`
`Figure 1:
`
`Major Bleeding Hazard Ratios by Baseline Characteristics –
`ARISTOTLE Study
`
`
`8
`
`
`
`
`Reference ID: 3445066
`
`
`

`

`
`Table 2:
`
`Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in
`AVERROES
`
`
`
`ELIQUIS
`Aspirin
`N=2798
`N=2780
`n (%/year)
`n (%/year)
`0.07
`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.
`
`--
`
`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 twice daily, avoid coadministration with
`strong dual inhibitors of CYP3A4 and P-gp [see Dosage and Administration (2.2) and Clinical
`Pharmacology (12.3)].
`
`9
`
`
`Reference ID: 3445066
`
`
`
`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% per year with apixaban versus 0.62% per year with placebo in
`patients receiving single antiplatelet therapy and was 5.91% per year with apixaban versus
`2.50% per 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: 3445066
`
`

`

`
`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.
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`8.6
`
`End-Stage Renal Disease Patients Maintained with
`Hemodialysis
`
`
`Patients with ESRD with or without hemodialysis were not studied in clinical efficacy and safety
`studies with ELIQUIS; therefore, the dosing recommendation is based on pharmacokinetic and
`pharmacodynamic (anti-Factor Xa activity) data in subjects with ESRD maintained on dialysis.
`The recommended dose for ESRD patients maintained with hemodialysis is 5 mg orally twice
`daily. For ESRD patients maintained with hemodialysis with one of the following patient
`characteristics, age 80 years or body weight 60 kg, reduce dose to 2.5 mg twice daily [see
`
`Dosage and Administration (2.7) and Clinical Pharmacology (12.2, 12.3)].
`
`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. Thus,
`administration of activated charcoal may be useful in the management of apixaban overdose or
`
` accidental ingestion.
`
`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:
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`
`
`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.
`
` 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).
`
`12
`
`CLINICAL PHARMACOLOGY
`
`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
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` 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,
`
` 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 apixaban 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.
`
`Cardiac Electrophysiology
`
`
`Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.
`
`12.3
`
`Pharmacokinetics
`
`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 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.
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` 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 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:
`
`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, prasugrel, 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, prasugrel, or acetylsalicylic acid.
`
`the
`
`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.
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`Figure 3:
`
`Effect of Specific Populations on the Pharmacokinetics of Apixaban
`
`
`* ESRD subjects maintained with chronic and stable hemodialysis; reported PK findings are following single
`
`dose of apixaban post hemodialysis.
`† Creatinine clearance 15 to 29 mL/min.
`
`
`‡ 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.
`
`In subjects with ESRD, 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 started 2 hours after administration of a
`
`single 5 mg dose of apixaban, the AUC of apixaban was 17% greater compared to those with
`normal renal function. The dialysis clearance of apixaban is approximately 18 mL/min resulting
`in a 14% decrease in exposure due to hemodialysis compared to off-dialysis period.
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`Protein binding was similar (92%-94%) between healthy controls and the on-dialysis and off-
`dialysis periods.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`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