Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement surgery in
the 1 Phase II study and the 3 Phase III studies are listed in Table 4.
Table 4:
Table 7:
Bleeding Results in the AMPLIFY-EXT Study
Placebo Major 2 (0.2) 1 (0.1) 4 (0.5) CRNM* 25 (3.0) 34 (4.2) 19 (2.3) Major + CRNM 27 (3.2) 35 (4.3) 22 (2.7) Geriatric Use
Of the total subjects in the ARISTOTLE and AVERROES clinical studies, >69% were
65 and older, and >31% were 75 and older. In the ADVANCE-1, ADVANCE-2, and ADVANCE-3
clinical studies, 50% of subjects were 65 and older, while 16% were 75 and older. In the
AMPLIFY and AMPLIFY-EXT clinical studies, >32% of subjects were 65 and older and
>13% were 75 and older. No clinically significant differences in safety or effectiveness were
observed when comparing subjects in different age groups.
N=826
n (%)
Nausea 153 (2.6) 159 (2.7) Minor
75 (8.9)
98 (12.1)
58 (7.0)
Anemia (including postoperative and hemorrhagic
anemia, and respective laboratory parameters) 153 (2.6) 178 (3.0) All
94 (11.2)
121 (14.9)
74 (9.0)
Contusion 83 (1.4) 115 (1.9) Hemorrhage (including hematoma, and vaginal
and urethral hemorrhage) 67 (1.1) 81 (1.4) * CRNM = clinically relevant nonmajor bleeding.
Events associated with each endpoint were counted once per subject, but subjects may have
contributed events to multiple endpoints.
Postprocedural hemorrhage (including
postprocedural hematoma, wound hemorrhage,
vessel puncture site hematoma and catheter site
hemorrhage) 54 (0.9) 60 (1.0) Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in Table 8.
Transaminases increased (including alanine
aminotransferase increased and alanine
aminotransferase abnormal) 50 (0.8) Aspartate aminotransferase increased 47 (0.8) 69 (1.2) Gamma-glutamyltransferase increased 38 (0.6) 65 (1.1)
Table 8:
Adverse Reactions Occurring in ≥1% of Patients Undergoing Extended
Treatment for DVT and PE in the AMPLIFY-EXT Study
ELIQUIS
2.5 mg bid
N=840
n (%) ELIQUIS
5 mg bid
N=811
n (%) Placebo
Epistaxis 13 (1.5) 29 (3.6) 9 (1.1)
Hematuria 12 (1.4) 17 (2.1) 9 (1.1)
Hematoma 13 (1.5) 16 (2.0) 10 (1.2)
Contusion 18 (2.1) 18 (2.2) 18 (2.2)
Gingival bleeding 12 (1.4) 9 (1.1) 3 (0.4)
71 (1.2)
Less common adverse reactions in apixaban-treated patients undergoing hip or knee
replacement surgery occurring at a frequency of ≥0.1% to <1%:
Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases)
Vascular disorders: hypotension (including procedural hypotension)
Respiratory, thoracic, and mediastinal disorders: epistaxis
Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena),
hematochezia
It is unknown whether apixaban or its metabolites are excreted in human milk. Rats excrete
apixaban in milk (12% of the maternal dose).
ELIQUIS
5 mg bid
N=811
n (%)
Adverse Reactions Occurring in ≥1% of Patients in Either Group
Undergoing Hip or Knee Replacement Surgery
ELIQUIS (apixaban), Enoxaparin,
n (%)
n (%)
2.5 mg po bid
40 mg sc qd or
30 mg sc q12h
N=5924
N=5904
Nursing Mothers
ELIQUIS (apixaban)
2.5 mg bid
N=840
n (%)
N=826
n (%)
Women should be instructed either to discontinue breastfeeding or to discontinue
ELIQUIS (apixaban) therapy, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Renal Impairment
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular
Atrial Fibrillation
The recommended dose is 2.5 mg twice daily in patients with at least two of the following
characteristics [see Dosage and Administration (2.1) in full Prescribing Information]:
• age ≥80 years
• body weight ≤60 kg
• serum creatinine ≥1.5 mg/dL
Patients with End-Stage Renal Disease on Dialysis
Other Adverse Reactions Clinical efficacy and safety studies with ELIQUIS did not enroll patients with end-stage
renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent
hemodialysis, administration of ELIQUIS at the usually recommended dose [see Dosage and
Administration (2.1) in full Prescribing Information] will result in concentrations of apixaban
and pharmacodynamic activity similar to those observed in the ARISTOTLE study [see Clinical
Pharmacology (12.3) in full Prescribing Information]. It is not known whether these concentrations
will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was
seen in ARISTOTLE.
Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or AMPLIFY-EXT
studies occurring at a frequency of ≥0.1% to <1%: Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery, and
Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT and PE
Blood and lymphatic system disorders: hemorrhagic anemia No dose adjustment is recommended for patients with renal impairment, including those with
ESRD on dialysis [see Dosage and Administration (2.1) in full Prescribing Information].
Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase increased,
blood bilirubin increased Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, gastrointestinal
hemorrhage, hematemesis, melena, anal hemorrhage Renal and urinary disorders: hematuria (including respective laboratory parameters) Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural
hemorrhage, traumatic hematoma, periorbital hematoma Clinical efficacy and safety studies with ELIQUIS did not enroll patients with ESRD on dialysis
or patients with a CrCl <15 mL/min; therefore, dosing recommendations are based on
pharmacokinetic and pharmacodynamic (anti-FXa activity) data in subjects with ESRD
maintained on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].
Musculoskeletal and connective tissue disorders: muscle hemorrhage Hepatic Impairment
Injury, poisoning, and procedural complications: wound secretion, incision-site hemorrhage
(including incision-site hematoma), operative hemorrhage
Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class
A). Because patients with moderate hepatic impairment (Child-Pugh class B) 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) in
full Prescribing Information]. ELIQUIS is not recommended in patients with severe hepatic
impairment (Child-Pugh class C) [see Clinical Pharmacology (12.2) in full Prescribing Information].
Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT or PE Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage OVERDOSAGE
The safety of ELIQUIS has been evaluated in the AMPLIFY and AMPLIFY-EXT studies, including
2676 patients exposed to ELIQUIS 10 mg twice daily, 3359 patients exposed to ELIQUIS 5 mg
twice daily, and 840 patients exposed to ELIQUIS 2.5 mg twice daily. Investigations: blood urine present, occult blood positive, occult blood, red blood cells urine
positive There is no antidote to ELIQUIS. Overdose of ELIQUIS increases the risk of bleeding [see Warnings
and Precautions].
General disorders and administration-site conditions: injection-site hematoma, vessel
puncture-site hematoma 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.
Less common adverse reactions in apixaban-treated patients undergoing hip or knee
replacement surgery occurring at a frequency of <0.1%:
Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage
(including conjunctival hemorrhage), rectal hemorrhage
Common adverse reactions (≥1%) were gingival bleeding, epistaxis, contusion, hematuria,
rectal hemorrhage, hematoma, menorrhagia, and hemoptysis.
AMPLIFY Study
The mean duration of exposure to ELIQUIS was 154 days and to enoxaparin/warfarin was
152 days in the AMPLIFY study. Adverse reactions related to bleeding occurred in 417 (15.6%)
ELIQUIS-treated patients compared to 661 (24.6%) enoxaparin/warfarin-treated patients.
The discontinuation rate due to bleeding events was 0.7% in the ELIQUIS-treated patients
compared to 1.7% in enoxaparin/warfarin-treated patients in the AMPLIFY study.
In the AMPLIFY study, ELIQUIS was statistically superior to enoxaparin/warfarin in the primary
safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55], P-value <0.0001).
Bleeding results from the AMPLIFY study are summarized in Table 5.
Table 5:
Bleeding Results in the AMPLIFY Study
Enoxaparin/Warfarin
N=2689
n (%) Relative Risk
(95% CI)
Major 15 (0.6) 49 (1.8) 0.31 (0.17, 0.55)
p<0.0001
CRNM* 103 (3.9) 215 (8.0) 115 (4.3) 261 (9.7)
Minor 313 (11.7) 505 (18.8)
All 402 (15.0) 676 (25.1)
disorders:
vaginal
hemorrhage,
metrorrhagia,
Vascular disorders: hemorrhage
DRUG INTERACTIONS
Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase
exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease
exposure to apixaban and increase the risk of stroke and other thromboembolic events. 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.
Strong Dual Inhibitors of CYP3A4 and P-gp PATIENT COUNSELING INFORMATION
For patients receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should be
decreased by 50% 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 (2.5) and Clinical Pharmacology (12.3) in full Prescribing Information]. Advise patients to read the FDA-approved patient labeling (Medication Guide).
For patients r eceiving 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 (2.5) and
Clinical Pharmacology (12.3) in full Prescribing Information].
Strong Dual Inducers of CYP3A4 and P-gp
ELIQUIS
N=2676
n (%) Major + CRNM
Reproductive system and breast
menometrorrhagia, genital hemorrhage
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) in full Prescribing Information].
Anticoagulants and Antiplatelet Agents
Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use
increases the risk of bleeding.
* CRNM = clinically relevant nonmajor bleeding.
Events associated with each endpoint were counted once per subject, but subjects may have
contributed events to multiple endpoints.
APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute coronary
syndrome patients treated with aspirin or the combination of aspirin and clopidogrel,
was terminated early due to a higher rate of bleeding with apixaban compared to placebo.
The rate of ISTH major bleeding was 2.8% per year with apixaban versus 0.6% per year with
placebo in patients receiving single antiplatelet therapy and was 5.9% per year with apixaban
versus 2.5% per year with placebo in those receiving dual antiplatelet therapy.
Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6. In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS from
1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin increased
the bleeding risk from 2.7% per year to 4.6% per year. In this clinical trial, there was limited
(2.3%) use of dual antiplatelet therapy with ELIQUIS.
Table 6: USE IN SPECIFIC POPULATIONS
Adverse Reactions Occurring in ≥1% of Patients Treated for DVT and PE in
the AMPLIFY Study
ELIQUIS
N=2676
n (%) Enoxaparin/Warfarin
N=2689
n (%)
Epistaxis 77 (2.9) 146 (5.4)
Contusion 49 (1.8) 97 (3.6)
Hematuria 46 (1.7) 102 (3.8)
Menorrhagia 38 (1.4) 30 (1.1)
Hematoma 35 (1.3) 76 (2.8)
Hemoptysis 32 (1.2) 31 (1.2)
Rectal hemorrhage 26 (1.0) 39 (1.5)
Gingival bleeding 26 (1.0) 50 (1.9)
AMPLIFY-EXT Study
The mean duration of exposure to ELIQUIS was approximately 330 days and to placebo
was 312 days in the AMPLIFY-EXT study. Adverse reactions related to bleeding occurred
in 219 (13.3%) ELIQUIS-treated patients compared to 72 (8.7%) placebo-treated patients.
The discontinuation rate due to bleeding events was approximately 1% in the ELIQUIS-treated
patients compared to 0.4% in those patients in the placebo group in the AMPLIFY-EXT study.
Bleeding results from the AMPLIFY-EXT study are summarized in Table 7.
ELUR17CDNY10266_2017_VTE_Jrnl_Ad_Tabloid_Size_BS_r12.indd 2
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, 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).
Advise patients of the following:
• Not to discontinue ELIQUIS without talking to their physician first.
• That it might take longer than usual for bleeding to stop, and they may bruise or
bleed more easily when treated with ELIQUIS. Advise patients about how to recognize
bleeding or symptoms of hypovolemia and of the urgent need to report any unusual bleeding
to their physician.
• To tell their physicians and dentists they are taking ELIQUIS, and/or any other product
known to affect bleeding (including nonprescription products, such as aspirin or NSAIDs),
before any surgery or medical or dental procedure is scheduled and before any new drug
is taken.
• If the patient is having neuraxial anesthesia or spinal puncture, inform the patient to watch
for signs and symptoms of spinal or epidural hematomas [see Warnings and Precautions].
If any of these symptoms occur, advise the patient to seek emergent medical attention.
• To tell their physicians if they are pregnant or plan to become pregnant or are
breastfeeding or intend to breastfeed during treatment with ELIQUIS [see Use in Specific
Populations].
• How to take ELIQUIS if they cannot swallow, or require a nasogastric tube [see Dosage and
Administration (2.6) in full Prescribing Information].
• What to do if a dose is missed [see Dosage and Administration (2.2) in full Prescribing
Information].
Marketed by:
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
and
Pfizer Inc
New York, New York 10017 USA
1356615A2 / 1356514A1
Rev July 2016
432US1603587-13-01
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].
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.
7/17/17 12:09 PM