Table 3:
(Continued)
Bleeding During the Treatment Period in Patients Undergoing
Elective Hip or Knee Replacement Surgery
ADVANCE-3
ADVANCE-2
ADVANCE-1
Bleeding
Hip Replacement
Knee Replacement
Knee Replacement
Endpoint*
Surgery
Surgery
Surgery
ELIQUIS Enoxaparin ELIQUIS Enoxaparin ELIQUIS Enoxaparin
2.5 mg
40 mg
2.5 mg
40 mg
2.5 mg
30 mg
po bid
sc qd
po bid
sc qd
po bid
sc q12h
35±3 days 35±3 days 12±2 days 12±2 days 12±2 days 12±2 days
First dose First dose First dose First dose First dose First dose
12 to 24
9 to 15
12 to 24
9 to 15
12 to 24 12 to 24
hours post hours prior hours post hours prior hours post hours post
surgery to surgery surgery to surgery surgery
surgery
All treated
N=2673 N=2659 N=1501 N=1508 N=1596 N=1588
Bleed at
1
1
1
2
1
4
critical site§
(0.04%)
(0.04%)
(0.07%) (0.13%)
(0.06%)
(0.25%)
Major
129
134
53
72
46
68
+ CRNM¶
(4.83%)
(5.04%)
(3.53%)
(4.77%)
(2.88%)
(4.28%)
All
313
334
104
126
85
108
(11.71%) (12.56%) (6.93%)
(8.36%)
(5.33%)
(6.80%)
* All bleeding criteria included surgical site bleeding.
† Includes 13 subjects with major bleeding events that occurred before the first dose of apixaban
(administered 12 to 24 hours post surgery).
‡ Includes 5 subjects with major bleeding events that occurred before the first dose of apixaban
(administered 12 to 24 hours post surgery).
§ Intracranial, intraspinal, intraocular, pericardial, an operated joint requiring re-operation or
intervention, intramuscular with compartment syndrome, or retroperitoneal. Bleeding into
an operated joint requiring re-operation or intervention was present in all patients with
this category of bleeding. Events and event rates include one enoxaparin-treated patient in
ADVANCE-1 who also had intracranial hemorrhage.
¶ CRNM = clinically relevant nonmajor.
Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6.
Table 6:
Adverse Reactions Occurring in ≥1% of Patients Treated for DVT and
PE in the AMPLIFY Study
ELIQUIS (apixaban)
N=2676
n (%)
ELIQUIS
N=2676
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)
Epistaxis
Contusion
Hematuria
Menorrhagia
Hematoma
Hemoptysis
Rectal hemorrhage
Gingival bleeding
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.
Table 7:
Bleeding Results in the AMPLIFY-EXT Study
ELIQUIS
2.5 mg bid
N=840
n (%)
ELIQUIS
5 mg bid
N=811
n (%)
Placebo
N=826
n (%)
In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on
ELIQUIS (apixaban) 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.
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, 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
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.
Major
2 (0.2)
1 (0.1)
4 (0.5)
Table 4:
CRNM*
25 (3.0)
34 (4.2)
19 (2.3)
Major + CRNM
27 (3.2)
35 (4.3)
22 (2.7)
Women should be instructed either to discontinue breastfeeding or to discontinue
ELIQUIS therapy, taking into account the importance of the drug to the mother.
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
Nausea
153 (2.6)
159 (2.7)
Anemia (including postoperative and
153 (2.6)
178 (3.0)
hemorrhagic anemia, and respective laboratory
parameters)
Contusion
83 (1.4)
115 (1.9)
He [ܜ