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
Trasylol Warnings, Precautions, Pregnancy, Nursing, Abuse - Aprotinin
Trasylol Warnings, Precautions, Pregnancy, Nursing, Abuse - Aprotinin
WARNINGS
Anaphylactic or anaphylactoid reactions are possible when Trasylol is
administered. Hypersensitivity reactions are rare in patients with no
prior exposure to aprotinin. Hypersensitivity reactions can range
from skin eruptions, itching,
dyspnea, nausea
and tachycardia to fatal
anaphylactic shock with circulatory
failure. If a hypersensitivity
reaction occurs during injection
or infusion of Trasylol,
administration should
be stopped immediately and emergency treatment
should be initiated. It should be noted that severe (fatal) hypersensitivity
anaphylactic reactions can also occur in connection with application of
the test dose. Even when a second
exposure to aprotinin has
been tolerated without symptoms, a subsequent administration
may result in severe hypersensitivity
anaphylactic reactions.
Re-exposure to aprotinin
In a retrospective review of 387 European patient
records with documented re-exposure to Trasylol, the incidence
of hypersensitivity
anaphylactic reactions was 2.7%. Two patients who experienced hypersensitivity/anaphylactic
reactions subsequently died, 24 hours and 5 days after surgery,
respectively. The relationship of these 2 deaths to Trasylol is unclear.
This retrospective review also showed that the incidence
of a hypersensitivity
or anaphylactic reaction following re exposure
is increased when the re-exposure occurs within 6 months of the initial
administration (5.0%
for re-exposure within 6 months and 0.9% for re-exposure greater than
6 months). Other smaller studies have shown that in case
of re-exposure, the incidence
of hypersensitivity anaphylactic reactions may reach the five percent
level. Before initiating treatment with Trasylol in a patient
with a history of prior exposure
to aprotinin, or products containing aprotinin
the recommendations below should be followed to manage a potential
hypersensitivity
or anaphylactic reaction: 1) Have standard
emergency treatments for
hypersensitivity
or anaphylactic reactions readily available in the operating room
(e.g., epinephrine corticosteroids).
2) Administration of the test
dose and loading
dose should be done only when
the conditions for rapid cannulation (if necessary) are present. 3) Delay
the addition of Trasylol
into the pump prime
solution until after the
loading dose
has been safely administered. Additionally, administration of H1 and H2
blockers 15 minutes before the test
dose may be considered.
PRECAUTIONS
General
Test Dose: All patients treated with Trasylol should first
receive a test dose
to assess the potential
for allergic reactions. The
test dose of 1 mL Trasylol should
be administered intravenously at least 10 minutes prior to the loading
dose. However, even after the uneventful administration of the initial
1 mL test-dose, the therapeutic
dose may cause an anaphylactic
reaction. If this happens the infusion
of aprotinin should immediately be stopped, and standard
emergency treatment
for anaphylaxis be applied. It should be noted that hypersensitivity/anaphylactic
reactions can also occur in connection with application of the test-dose.
(see WARNINGS
)
Allergic Reactions: Patients with a history
of allergic reactions to drugs or other agents may be at greater risk
of developing a hypersensitivity
or anaphylactic reaction
upon exposure to Trasylol.
(see WARNINGS
)
Loading Dose: The loading
dose of Trasylol should be given
intravenously to patients in the supine
position over a 20-30 minute
period. Rapid intravenous
administration of Trasylol
can cause a transient
fall in blood pressure. (see
DOSAGE AND ADMINISTRATION).
Use of Trasylol in patients undergoing deep
hypothermic circulatory arrest: Two U.S. case
control studies have reported
contradictory results in patients receiving Trasylol while undergoing
deep hypothermic circulatory
arrest in connection with surgery
of the aortic arch.
The first study showed an increase in both renal
failure and mortality compared
to age-matched historical controls. Similar results were not observed,
however, in a second case control
study. The strength of this
association is uncertain because there are no
data from randomized studies to confirm or refute these findings.
Drug Interactions
Trasylol is known to have antifibrinolytic activity
and therefore, may inhibit the effects of fibrinolytic agents. In
study of nine patients with untreated hypertension,
Trasylol infused intravenously in a dose
of 2 million KIU over two hours blocked the acute
hypotensive effect
of 100mg of captopril.
Trasylol, in the presence of heparin
has been found to prolong the activated clotting time
(ACT) as measured by a celite surface
activation method. The
kaolin activated clotting
time appears to be much less
affected. However, Trasylol should not be viewed as a heparin
sparing agent. (see Laboratory
Monitoring of Anticoagulation During Cardiopulmonary Bypass).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term animal
studies to evaluate the carcinogenic
potential of Trasylol or
studies to determine the effect
of Trasylol on fertility
have not been performed. Results of microbial in vitro tests using
Salmonella typhimurium and Bacillus
subtilisindicate that Trasylol is not a mutagen.
Pregnancy: Teratogenic Effects: Pregnancy Category B
Reproduction studies have been performed in rats at intravenous
doses up to 200,000 KIU/kg/day for 11 days, and in rabbits at intravenous
doses up to 100,000 KIU/kg/day for 13 days, 2.4 and 1.2 times the human
dose on a mg/kg basis and 0.37
and 0.36 times the human mg/m
2 dose. They have revealed no
evidence of impaired fertility
or harm to the fetus due to Trasylol .There are, however, no
adequate and well- controlled studies in pregnant
women. Because animal reproduction
studies are not always predictive of human
response, this drug should be
used during pregnancy only
if clearly needed.
Nursing Mother
Not applicable.
Pediatric Use
Safety and effectiveness
in pediatric patient(s)
have not been established.
Laboratory Monitoring of Anticoagulation during Cardiopulmonary Bypass
Trasylol prolongs whole blood
clotting times by a different
mechanism than heparin. In the
presence of aprotinin, prolongation is dependent on the type
of whole blood clotting
test employed. If an activated
clotting time (ACT) is used to determine the effectiveness
of heparin anticoagulation,
the prolongation of the ACT by aprotinin
may lead to an overestimation
of the degree of anticoagulation,
thereby leading to inadequate anticoagulation. During extended extracorporeal
circulation, patients
may require additional heparin, even in the presence of ACT levels that
appear adequate. In patients undergoing
CPB with Trasylol therapy
one of the following methods may be employed to maintain adequate anticoagulation:
1) ACT- An ACT is not a standardized
coagulation test, and different formulations of the assay
are affected differently by the presence of aprotinin. The test
is further influenced by variable
dilution effects and the
temperature experienced during cardiopulmonary
bypass. It has been observed that Kaolin- based ACTs are not increased
to the same degree by aprotinin
as are diatomaceous earth based (celite) ACTs. While protocols vary, a
minimal celite ACT of 750
seconds or kaolinACT of 480 seconds, independent of the effects of hemodilution
and hypothermia, is recommended
in the presence of aprotinin. Consult the manufacturer of the ACT test
regarding the interpretation
of the assay in the presence
of Trasylol.
2) Fixed Heparin Dosing- A standard
loading dose
of heparin, administered prior to cannulation of the heart,
plus the quantity of heparin
added to the prime volume
of the CPB circuit, should total at least 350 IU/kg. Additional heparin
should be administered in a fixed-dose regimen
based on patient weight and duration
of CPB.
3) Heparin Titration- Protamine titration,
a method that is not affected
by aprotinin, can be used to measure
heparin levels. A heparin
dose response, assessed by protamine
titration, should be performed
prior to administration of aprotinin
to determine the heparin loading
dose. Additional heparin should be administered on the basis
of heparin levels measured
by protamine titration. Heparin levels during bypass
should not be allowed to drop
below 2.7 U/mL (2.0 mg/kg) or below the level indicated by heparin
dose response testing performed
prior to administration
of aprotinin.
Protamine Administration: In
patients treated with Trasylol, the amount of protamine
administered, to reverse heparin
activity should be based
on the actual amount of heparin
administered, and not on the ACT values.
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