AMPLIFY Study
The mean duration of exposure to ELIQUIS (apixaban) 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.
For patients receiving ELIQUIS (apixaban) 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) in full Prescribing Information].
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) in full Prescribing Information].
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).
Anticoagulants and Antiplatelet Agents
Bleeding results from the AMPLIFY study are summarized in Table 5.
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.
Table 5:
Bleeding Results in the AMPLIFY Study
Major
CRNM*
Major + CRNM
Minor
All
ELIQUIS
N=2676
n (%)
Enoxaparin/
Warfarin
N=2689
n (%)
15 (0.6)
49 (1.8)
103 (3.9)
115 (4.3)
313 (11.7)
402 (15.0)
215 (8.0)
261 (9.7)
505 (18.8)
676 (25.1)
Relative Risk
(95% CI)
0.31 (0.17, 0.55)
p<0.0001
Pregnancy
Pregnancy Category B
Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6.
Adverse Reactions Occurring in ≥1% of Patients Treated for DVT and PE in
the AMPLIFY Study
Epistaxis
Contusion
Hematuria
Menorrhagia
Hematoma
Hemoptysis
Rectal hemorrhage
Gingival bleeding
ELIQUIS
N=2676
n (%)
Enoxaparin/Warfarin
N=2689
n (%)
77 (2.9)
49 (1.8)
46 (1.7)
38 (1.4)
35 (1.3)
32 (1.2)
26 (1.0)
26 (1.0)
146 (5.4)
97 (3.6)
102 (3.8)
30 (1.1)
76 (2.8)
31 (1.2)
39 (1.5)
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 in the AMPLIFY-EXT Study
Major
CRNM*
Major + CRNM
Minor
All
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 attribu ted 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).
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.
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.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Bleeding results from the AMPLIFY-EXT study are summarized in Table 7.
Table 7:
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.
USE IN SPECIFIC POPULATIONS
* CRNM = clinically relevant nonmajor bleeding.
Events associated with each endpoint were counted once per subject, but subjects may have
contributed events to multiple endpoints.
Table 6:
Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID
use increases the risk of bleeding.
ELIQUIS
2.5 mg
N=840
n (%)
ELIQUIS
5 mg
N=811
n (%)
Placebo
2 (0.2)
25 (3.0)
27 (3.2)
75 (8.9)
94 (11.2)
1 (0.1)
34 (4.2)
35 (4.3)
98 (12.1)
121 (14.9)
4 (0.5)
19 (2.3)
22 (2.7)
58 (7.0)
74 (9.0)
N=826
n (%)
* CRNM = clinically relevant nonmajor bleeding.
Events associated with each endpoint were counted once per subject, but subjects may have
contributed events to multiple endpoints.
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.
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 for patients with
nonvalvular atrial fibrillation is based on pharmacokinetic and pharmacodynamic (antiFactor 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) in full Prescribing Information].
OVERDOSAGE
Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in Table 8.
There is no antidote to ELIQUIS. Overdose of ELIQUIS increases the risk of bleeding [see
Warnings and Precautions].
Table 8:
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.
Adverse Reactions Occurring in ≥1% of Patients Undergoing Extended
Treatment for DVT and PE in the AMPLIFY-EXT Study
Epistaxis
Hematuria
Hematoma
Contusion
Gingival bleeding
ELIQUIS
2.5 mg
N=840
n (%)
ELIQUIS
5 mg
N=811
n (%)
Placebo
13 (1.5)
12 (1.4)
13 (1.5)
18 (2.1)
12 (1.4)
29 (3.6)
17 (2.1)
16 (2.0)
18 (2.2)
9 (1.1)
9 (1.1)
9 (1.1)
10 (1.2)
18 (2.2)
3 (0.4)
N=826
n (%)
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.
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide).
Advise patients of the following:
•
They should not discontinue ELIQUIS without talking to their physician first.
•
They should be informed 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.
•
They should 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, such as
numbness or weakness of the legs, or bowel or bladder dysfunction [see Warnings
and Precautions]. If any of these symptoms occur, the patient should contact his or
her physician immediately.
•
They should 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].
•
If a dose is missed, 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.
Other Adverse Reactions
Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or AMPLIFYEXT studies occurring at a frequency of ≥0.1% to <1%:
Blood and lymphatic system disorders: hemorrhagic anemia
Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, gastrointestinal
hemorrhage, hematemesis, melena, anal hemorrhage
Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural
hemorrhage, traumatic hematoma, periorbital hematoma
Musculoskeletal and connective tissue disorders: muscle hemorrhage
Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia,
menometrorrhagia, genital hemorrhage
Vascular disorders: hemorrhage
Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae
Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage
Investigations: blood urine present, occult blood positive, occult blood, red blood cells urine
positive
General disorders and administration-site conditions: injection-site hematoma, vessel
puncture-site hematoma
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.
Strong Dual Inhibitors of CYP3A4 and P-gp
For patients receiving ELIQUIS doses greater than 2.5 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 (2.2) and Clinical Pharmacology (12.3) in full Prescribing
Information].
Manufactured by:
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
Marketed by:
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
and
Pfizer Inc
New York, New York 10017 USA
1289808A1 / 1289807A1 / 1298500A1
Rev August 2014
432US14BR00804-05-01