A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Integrilin Warnings, Precautions, Pregnancy, Nursing, Abuse - Eptifibatide
Integrilin Warnings, Precautions, Pregnancy, Nursing, Abuse - Eptifibatide
WARNINGS
Bleeding
Bleeding is the most common complication
encountered during eptifibatide therapy. Administration of eptifibatide
is associated with an increase in major and minor
bleeding, as classified
by the criteria of the Thrombolysis in Myocardial Infarction Study
group (TIMI), (see ADVERSE
REACTIONS). Most major bleeding
associated with eptifibatide has been at the arterial
access site for cardiac
catheterization
or from the gastrointestinal
or genitourinary
tract.
In patients undergoing percutaneous
coronary interventions,
patients receiving eptifibatide experience
an increased incidence
of major bleeding compared
to those receiving placebo. Special care should be employed to minimize
the risk of bleeding
among these patients (see PRECAUTIONS
).
If bleeding cannot
be controlled with pressure,
infusion of eptifibatide
and concomitant
heparin should be stopped
immediately.
PRECAUTIONS
Bleeding Precautions
Care of the Femoral Artery Access Site in Patients Undergoing Percutaneous
Coronary Intervention (PCI)
In patients undergoing PCI, treatment
with eptifibatide is associated with an increase in major and minor
bleeding at the site
of arterial sheath
placement. After PCI, eptifibatide infusion
should be continued for 20-24 hours. The femoral
artery sheath
may be removed during treatment
with eptifibatide, but only after heparin
has been discontinued and its effects largely reversed. In
the IMPACT II study, heparin
use was discouraged after the PCI procedure
if the coronary lesion
appeared angiographically stable. Early sheath
removal was encouraged in both the IMPACT II and the PURSUIT studies
while study drug was being
infused. Prior to removing the sheath, it was recommended that heparin
be discontinued for 3-4 hours and that an aPTT of <45 seconds
be documented. In any case,
both heparin and eptifibatide
should be discontinued and sheath
hemostasis should
be achieved by standard
compressive techniques at least 4 hours before hospital
discharge.
Use of Thrombolytics, Anticoagulants, and Other Antiplatelet
Agents. In the IMPACT
II and PURSUIT studies, eptifibatide was used concomitantly with
heparin and aspirin
(see CINICAL STUDIES).
Because eptifibatide inhibits platelet
aggregation, caution should be employed when it is used with other
drugs that affect hemostasis,
including thrombolytics, oral
anticoagulants, non-steroidal anti-inflammatory
drugs, dipyridamole, ticlopidine, and clopidogrel. To
avoid potentially additive
pharmacologic effects, concomitant
treatment with other
inhibitors of platelet
receptor GP IIb/IIIa
should be avoided.
There is only a small experience
with concomitant
use of eptifibatide and thrombolytics. In
a study of 180 patients with acute
myocardial infarction
(AMI), eptifibatide (in regimens up to a bolus
of 180 mcg/kg followed by a continuous infusion
of 0.75 mcg/kg/min for 24 hours) was administered concomitantly with
the approved "accelerated" regimen
of alteplase, a thrombolytic
agent. The studied regimens of eptifibatide did not increase the
incidence of major
bleeding or transfusion
compared to the incidence
seen when alteplase was given alone.
In the IMPACT II study, 15 patients received a thrombolytic
agent in conjunction with
the 135/0.5 dosing regimen, 2 of whom experienced a major bleed.
In the PURSUIT study, 40
patients who received eptifibatide at the 180/2.0 dosing regimen
received a thrombolytic
agent, 10 of whom experienced
a major bleed.
In another AMI study involving
181 patients, eptifibatide (in regimens up to a bolus
of 180 mcg/kg followed by a continuous infusion
of up to 2.0 mcg/kg/min for up to 72 hours) was administered concomitantly
with streptokinase
(1.5 million units over 60 minutes), another thrombolytic
agent. At the highest studied
infusion rates (1.3
µg/kg/min and 2.0 µg/kg/min), eptifibatide was
associated with an increase in the incidence
of bleeding and transfusions
compared to the incidence
seen when streptokinase
was given alone.
These limited data on the use of eptifibatide in patients receiving
thrombolytic agents
do not allow an estimate of the bleeding
risk associated with concomitant
use of thrombolytics. Systemic thrombolytic
therapy should be used
with caution in patients who have received eptifibatide.
Minimization of Vascular and Other Trauma. Arterial and
venous punctures, intramuscular
injections, and the use of urinary
catheters, nasotracheal intubation,
and nasogastric
tubes should be minimized. When obtaining intravenous
access, non-compressible sites (e.g., subclavian
or jugular veins) should
be avoided.
Laboratory Tests. Before infusion
of eptifibatide, the following laboratory
tests should be performed to identify pre-existing hemostatic
abnormalities: hematocrit
or hemoglobin, platelet
count, serum creatinine,
and PT/aPTT. In patients
undergoing PCI, the activated clotting
time (ACT) should also
be measured.
Maintaining Target aPTT and ACT. The aPTT should be maintained
between 50 and 70 seconds unless PCI is to be performed. During
PCI, the ACT should be maintained between 300 and 350 seconds.
The aPTT should be checked prior to arterial
sheath removal. The sheath
should not be removed unless the aPTT is < 45 seconds. In
patients treated with heparin, bleeding
can be minimized by close monitoring of the aPTT. Table 6 displays
the risk of major bleeding
according to the maximum
aPTT attained within 72 hours in the PURSUIT study.
Table 6
Major Bleeding by Maximal aPTT Within 72 Hours in
the PURSUIT Study
| |
Placebo
n (%)
|
Eptifibatide
180/ 1.3*
n (%)
|
Eptifibatide
180/ 2.0
n (%)
|
|
Maximum aPTT (seconds)
|
|
|
|
|
< 50
|
44/ 721 (6.1%)
|
21/ 244 (8.6%)
|
44/ 743 (5.9%)
|
|
50 - 70
|
92/ 908 (10.1%)
|
28/ 259 (10.8%)
|
99/ 883 (11.2%)
|
|
(recommended)
|
|
|
|
|
> 70
|
281/ 2786 (10.1%)
|
99/ 891 (11.1%)
|
345/ 2811 (12.3%)
|
- * Administered only until the first interim
analysis
Thrombocytopenia. If the patient
experiences a confirmed platelet
decrease to <100,000/mm3, INTEGRILIN and heparin
should be discontinued and the condition
appropriately monitored and treated.
Renal Insufficiency. Based on results of clinical
studies with eptifibatide (which did not adjust dose
for renal function) and
the fact that the drug
is cleared equally by renal
and nonrenal mechanisms, dose
adjustment is unnecessary
for patients with mild to moderate renal
impairment (serum
creatinine <2
mg/dL for the 180 µg/kg bolus
and the 2.0 µg/kg/min infusion
and <4 mg/dL for the 135 µg/kg bolus
and the 0.5 µg/kg/min infusion). Plasma eptifibatide levels
are expected to be higher in patients with more severe renal
impairment, but no
data are available for such
patients or for patients on renal
dialysis. In vitro studies
have indicated that eptifibatide may be cleared from plasma
by dialysis.
Geriatric Use
The PURSUIT and IMPACT II clinical
studies enrolled patients up to the age
of 94 years (45% were age
65 and over; 12% were age
75 and older). There was no
apparent difference
in efficacy between
older and younger patients treated with eptifibatide. The incidence
of bleeding complications
was higher in the elderly in both placebo
and eptifibatide groups, and the incremental risk
of eptifibatide-associated bleeding
was greater in the older patients. No
dose adjustment
was made for elderly patients, but patients over 75 years of age
had to weigh at least 50 kg
to be enrolled in the PURSUIT study because of concern about an
increased risk of bleeding
in this subgroup (see also ADVERSE
REACTIONS).
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate
the carcinogenic
potential of eptifibatide.
Eptifibatide was not genotoxic
in the Ames test, the mouse
lymphoma cell
(L 5178Y, TK+/-) forward mutation
test, the human lymphocyte
chromosome aberration
test, or the mouse micronucleus
test. Administered by continuous intravenous
infusion at total daily
doses up to 72 mg/kg/day (about 4 times the recommended maximum
daily human dose
on a body surface
area basis), eptifibatide
had no effect
on fertility and reproductive
performance of male
and female rats.
Pregnancy
Pregnancy Category B. Teratology studies have been
performed by continuous intravenous
infusion of eptifibatide
in pregnant rats at
total daily doses of up to 72 mg/kg/day (about 4 times the recommended
maximum daily human
dose on a body
surface area
basis) and in pregnant
rabbits at total daily doses of up to 36 mg/kg/day (also about 4
times the recommended maximum
daily human dose
on a body surface
area basis). These studies
revealed no evidence
of harm to the fetus due
to eptifibatide. There are, however, no
adequate and well-controlled studies in pregnant
women with eptifibatide. Because animal
reproduction studies
are not always predictive of human
response, eptifibatide should be used during pregnancy
only if clearly needed.
Pediatric Use
Safety and effectiveness
of eptifibatide in pediatric
patients have not been studied.
Nursing Mothers
It is not known whether eptifibatide is excreted in human
milk. Because many drugs are excreted in human
milk, caution should be exercised when eptifibatide is administered
to a nursing mother.
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