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 Side Effects, and Drug Interactions - Aprotinin
Trasylol Side Effects, and Drug Interactions - Aprotinin
SIDE EFFECTS
Studies of patients undergoing CABG
surgery, either primary
or repeat, indicate that TrasylolÒ
is generally well tolerated. The adverse events reported are frequent
sequelae of cardiac surgery
and are not necessarily attributable to TrasylolÒ
therapy. Adverse events reported, up to the time
of hospital discharge, from
patients in US placebo-controlled trials are listed in the following table.
The table lists only those events
that were reported in 2% or more of the TrasylolÒ
treated patients without regard to causal relationship.
|
INCIDENCE RATES OF ADVERSE EVENTS ( ³
2% ) BY BODY SYSTEM AND TREATMENT FOR ALL
PATIENTS FROM US PLACEBO-CONTROLLED CLINICAL TRIALS
|
| . |
Aprotinin
(n = 2002)
|
Placebo
(n = 1084)
|
| Adverse Event |
values in %
|
values in %
|
| Any Event |
76
|
77
|
| Body as a Whole |
| Fever |
15
|
14
|
| Infection |
6
|
7
|
| Chest Pain |
2
|
2
|
| Asthenia |
2
|
2
|
| Cardiovascular |
| Atrial Fibrillation |
21
|
23
|
| Hypotension |
8
|
10
|
| Myocardial Infarct |
6
|
6
|
| Atrial Flutter |
6
|
5
|
| Ventricular Extrasystoles
|
6
|
4
|
| Tachycardia |
6
|
7
|
| Ventricular Tachycardia
|
5
|
4
|
| Heart Failure |
5
|
4
|
| Pericarditis |
5
|
5
|
| Peripheral Edema |
5
|
5
|
| Hypertension |
4
|
5
|
| Arrhythmia |
4
|
3
|
| Supraventricular Tachycardia
|
4
|
3
|
| Atrial Arrhythmia |
3
|
3
|
| Digestive |
| Nausea |
11
|
9
|
| Constipation |
4
|
5
|
| Vomiting |
3
|
4
|
| Diarrhea |
3
|
2
|
| Liver Function Tests Abnormal
|
3
|
2
|
| Hemic and Lymphatic |
| Anemia |
2
|
8
|
| Metabolic Nutritional
|
| Creatine Phosphokinase
Increased |
2
|
1
|
| Musculoskeletal |
| Any Event |
2
|
3
|
| Nervous |
| Confusion |
4
|
4
|
| Insomnia |
3
|
4
|
| Respiratory |
| Lung Disorder |
8
|
8
|
| Pleural Effusion |
7
|
9
|
| Atelectasis |
5
|
6
|
| Dyspnea |
4
|
4
|
| Pneumothorax |
4
|
4
|
| Asthma |
2
|
3
|
| Hypoxia |
2
|
1
|
| Skin and Appendages |
| Rash |
2
|
2
|
| Urogenital |
| Kidney Function Abnormal
|
3
|
2
|
| Urinary Retention |
3
|
3
|
| Urinary Tract Infection
|
2
|
2
|
In comparison to the placebo
group, no increase in mortality
in patients treated with TrasylolÒ
was observed. Additional events of particular interest from controlled
US trials with an incidence
of less that 2% are listed below:
|
EVENT
|
Percentage of patients
treated with TrasylolÒ
N = 2002
|
Percentage of patients
treated with Placebo
N = 1084
|
| Thrombosis |
1.0
|
0.6
|
| Shock |
0.7
|
0.4
|
| Cerebrovascular Accident
|
0.7
|
2.1
|
| Thrombophlebitis |
0.2
|
0.5
|
| Deep Thrombophlebitis |
0.7
|
1.0
|
| Lung Edema |
1.3
|
1.5
|
| Pulmonary Embolus |
0.3
|
0.6
|
| Kidney Failure |
1.0
|
0.6
|
| Acute Kidney Failure |
0.5
|
0.6
|
| Kidney Tubular Necrosis
|
0.8
|
0.4
|
Listed below are additional events, from controlled US trials with an
incidence between 1 and 2%, and also from uncontrolled, compassionate
use trials and spontaneous
post- marketing reports. Estimates of frequency cannot be made for spontaneous
post- marketing reports (italicized).
Body as a Whole: Sepsis, death,
multi system organ
failure, immune system disorder,
hemoperitoneum.
Cardiovascular: Ventricular fibrillation,
heart arrest, bradycardia, congestive
heart failure, hemorrhage,
bundle branch
block, myocardial ischemia,
ventricular tachycardia,
heart block, pericardial effusion,
ventricular arrhythmia,
shock, pulmonary hypertension.
Digestive: Dyspepsia, gastrointestinal
hemorrhage, jaundice, hepatic
failure.
Hematologic and Lymphatic: Although thrombosis
was not reported more frequently in aprotinin
versus placebo-treated patients in controlled trials, it has been reported
in uncontrolled trials, compassionate use trials, and spontaneous
post-marketing reporting. These reports of thrombosis encompass the following
terms: thrombosis, occlusion,
arterial thrombosis, pulmonary thrombosis, coronary
occlusion, embolus, pulmonary
embolus, thrombophlebitis,
deep thrombophlebitis,
cerebrovascular accident,
cerebral embolism. Other hematologic events reported include leukocytosis,
thrombocytopenia, coagulation disorder
(which includes disseminated
intravascular coagulation) decreased prothombin.
Metabolic and Nutritional: Hyperglycemia, hypokalemia,
hypervolemia, acidosis.
Musculoskeletal: Arthralgia.
Nervous: Agitation, dizziness,
anxiety, convulsion.
Respiratory: Pneumonia, apnea,
increased cough, lung edema.
Skin: Skin discoloration.
Urogenital: Oliguria, kidney
failure, acute kidney
failure, kidney tubular necrosis.
Myocardial Infarction: In the pooled analysis
of all patients undergoing CABG
surgery, there was no
significant difference
in the incidence of investigator- reported myocardial
infarction (MI) in TrasylolÒ
treated patients as compared to placebo
treated patients. However, because no uniform
criteria for the diagnosis
of myocardial infarction
were utilized by investigators, this issue
was addressed prospectively in three later studies (two studies evaluated
Regimen A, Regimen B and Pump Prime Regimen; one study evaluated only
Regimen A), in which data were analyzed by a blinded consultant employing
an algorithm for possible,
probable or definite MI. Utilizing this method, the incidence
of definite myocardial
infarction was 5.9% in the aprotinin- treated patients versus 4.7% in
the placebo treated patients. This difference in the incidence
rates was not statistically significant. Data from these three studies
are summarized below.
Incidence of Myocardial Infarctions by Treatment Group Population
All CABG Patients Valid for
Safety Anaylsis
| Treatment |
Definite MI% |
Definite or Probable MI% |
Definite, Probable or Possible
MI % |
| Pooled Data from Three Studies
that Evaluated Regimen A |
| TrasylolÒ
Regimen A
n = 646
|
4.6
|
10.7
|
14.1
|
| Placebo
n =661
|
4.7
|
11.3
|
13.4
|
| Pooled Data from Two Studies
that Evaluated Regimen B and Pump Prime Regimen |
| TrasylolÒ
Regimen B
n =241
|
8.7
|
15.9
|
18.7
|
| TrasylolÒ
Pump Prime Regimen
n =239
|
6.3
|
15.7
|
18.1
|
| Placebo
n = 240
|
6.3
|
15.1
|
15.8
|
Graft Patency: In a recently
completed multi-center, multi-national study to determine the effects
of TrasylolÒ
Regimen A vs. placebo on saphenous
vein graft
patency in patients undergoing
primary CABG surgery,
patients were subjected to routine postoperative angiography. Of the 13
study sites, 10 were in the United States and three were non-U. S. centers
(Denmark (1), Israel (2). The results of this study are summarized below.
Incidence of Graft Closure Myocardial Infarction and Death by Treatment
Group
| |
Overall Closure
Rates* |
Incidence of MI** |
Incidence of Death*** |
| |
All Centers
n =703
|
U.S. Centers
n =381
|
All Centers
n =831
|
All Centers
n =870
|
| TrasylolÒ |
15.4 |
9.4 |
2.9 |
1.4 |
| Placebo |
10.9 |
9.5 |
3.8 |
1.6 |
| CI for the Difference %
(Drug- Placebo)
|
(1.3, 9.6)+ |
(-3.8, 5.9)+ |
-3.3 to 1.5++ |
-1.9 to 1.4++ |
| * Population: all patients
with assessable saphenous
vein grafts
** Population: all patients assessable by blinded
consultant
*** All patients
+ 90%; per
protocol
++ 95%; not specified in protocol
|
Although there was a statistically significantly increased risk
of graft closure for TrasylolÒ
treated patients compared to patients who received placebo
(p = 0.035), further analysis
showed a significant treatment
by site interaction for one of
the non-U.S. sites vs. the U.S. centers. When the analysis
of graft closures was repeated for U.S. centers only, there was no
statistically significant difference in graft
closure rates in patients
who received TrasylolÒ
vs. placebo. These results are the same whether analyzed as the proportion
of patients who experienced at least one graft
closure postoperatively or
as the proportion of grafts closed. There were no
differences between treatment groups in the incidence
of myocardial infarction
as evaluated by the blinded consultant
(2.9% TrasylolÒ vs.
3.8% placebo) or of death (1.4%
Trasylol vs. 1.6% placebo) in this study.
Hypersensitivity and Anaphylaxis (See WARNINGS)
Hypersensitivity and anaphylactic reactions during surgery
were rarely reported in U.S. controlled clinical
studies in patients with no prior
exposure to TrasylolÒ (1/1424
patients or <0.1% on Trasylol vs. 1/861 patients or 0.1% on placebo).
In case of re-exposure the incidence
of hypersensitivity/anaphylactic reactions has been reported to reach
the 5% level. A review of 387 European patient records involving re-exposure
to TrasylolÒ
showed that the incidence
of hypersensitivity
or anaphylactic reactions was 5.0% for re-exposure within 6 months and
0.9% for re-exposure greater than 6 months.
Laboratory Findings
Serum Creatinine: Data pooled from all patients undergoing
CABG surgery in U.S. placebo-controlled
trials showed no statistically
or clinically significant
increase in the incidence
of postoperative renal dysfunction in patients treated with TrasylolÒ.
The incidence of serum
creatinine elevations >0.5
mg/dL above pre-treatment levels was 9% in the Trasylol group
vs. 8% in the placebo group
(p= 0.248), while the incidence
of elevations >2.0 mg/dL above baseline
was only 1%in each group (p=
0.883). In the majority of instances,
postoperative renal dysfunction
was not severe and was reversible. Patients with baseline elevations in
serum creatinine
were not at increased risk of
developing postoperative renal
dysfunction following
Trasylol treatment.
Serum Transaminases: Data pooled from all patients undergoing
CABG surgery in U.S. placebo-controlled
trials showed no evidence
of an increase in the incidence
of post-operative hepatic
dysfunction in patients
treated with Trasylol. The incidence
of treatment emergent
increases in ALT (formerly SGPT) >1.8 times the upper limit
of normal was 14% in both the
TrasylolÒ
and placebo-treated patients (p= 0.687), while the incidence
of increases >3 times the upper limit
of normal was 5% in both groups
(p= 0.847).
Other Laboratory Findings: The incidence
of treatment-emergent elevations in plasma
glucose, AST
(formerly SGOT), LDH, alkaline
phosphatase, and CPK-MB was not notably different between TrasylolÒ
and placebo treated patients
undergoing CABG surgery. Significant
elevations in the partial thromboplastin
time (PTT) and celite Activated
Clotting Time (celite ACT) are expected in TrasylolÒ
treated patients in the hours after surgery
due to circulating concentrations of TrasylolÒ
which are known to inhibit activation
of the intrinsic clotting
system by contact with a foreign
material (e.g. celite), a
method used in these tests.
(see Laboratory Monitoring of Anticoagulation During Cardiopulmonary Bypass).
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,
TrasylolÒ
infused intravenously in a dose
of 2 million KIU over two hours blocked the acute
hypotensive effect
of 100mg of captopril. TrasylolÒ
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, TrasylolÒ
should not be viewed as a heparin
sparing agent. (see Laboratory
Monitoring of Anticoagulation During Cardiopulmonary Bypass).
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