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
Aggrastat Side Effects, and Drug Interactions - Tirofiban
Aggrastat Side Effects, and Drug Interactions - Tirofiban
SIDE EFFECTS
In clinical trials,
1946 patients received AGGRASTAT in combination with heparin
and 2002 patients received AGGRASTAT alone. Duration of exposure
was up to 116 hours. 43% of the population
was >65 years of age
and approximately 30% of patients were female.
BLEEDING
The most common drug-related adverse event reported during therapy
with AGGRASTAT when used concomitantly with heparin
and aspirin, was bleeding
(usually reported by the investigators as oozing or mild). The incidences
of major and minor bleeding
using the TIMI criteria in the PRISM-PLUS and RESTORE studies are
shown below.
| Bleeding
|
PRISM-PLUS*
(UAP/Non-Q-Wave MI
Study)
|
RESTORE*
(Angioplasty/Atherectomy Study)
|
| AGGRASTAT** |
AGGRASTA
|
|
+ Heparin ***
(n=773)
% (n)
|
Heparin ***
(n=797)
% (n)
|
+ Heparin
(n=1071)
% (n)
|
Heparin
(n= 1070)
% (n)
|
| Major Bleeding |
1.4 (11)
|
0.8 (6)
|
2.2 (24)
|
1.6 (17)
|
| (TIMI Criteria)
|
|
|
|
|
| Minor Bleeding |
10.5 (81)
|
8.0 (64)
|
12.0 (129)
|
6.3 (67)
|
| (TIMI Criteria)§
|
|
|
|
|
| Transfusions |
4.0 (31)
|
2.8 (22)
|
4.3 (46)
|
2.5 (27)
|
| * Patients received
aspirin unless
contraindicated. |
| **0.4 mcg/kg/min
loading infusion; 0.10 mcg/kg/min
maintenance infusion. |
| *** 5,000 U bolus
followed by 1,000 U/hr titrated to maintain an APTT of approximately
2 times control. |
| 10 mcg/kg
bolus followed by infusion
of 0.15 mcg/kg/min. |
| Bolus of 10,000
U or 150 U/kg for patients <70 kg
followed by administration
as necessary to maintain ACT in approximate
range of 300 to
400 seconds during procedure. |
| Hemoglobin drop
of >50 g/L with or without an identified site, intracranial
hemorrhage,
or cardiac tamponade. |
| § Hemoglobin drop
of >30 g/L with bleeding
from a known site, spontaneous
gross hematuria,
hematemesis or hemoptysis. |
There were no reports of
intracranial bleeding
in the PRISM-PLUS study for AGGRASTAT in combination with heparin
or in the heparin control
group. The incidence
of intracranial
bleeding in the RESTORE
study was 0.1% for AGGRASTAT in combination with heparin
and 0.3% for the control
group (which received
heparin). In the PRISM-PLUS
study, the incidences of retroperitoneal bleeding reported for AGGRASTAT
in combination with heparin, and for the heparin control
group were 0.0% and 0.1%,
respectively. In the RESTORE
study, the incidences of retroperitoneal
bleeding reported for
AGGRASTAT in combination with heparin, and the control
group were 0.6% and 0.3%
respectively. The incidences of TIMI major gastrointestinal
and genitourinary
bleeding for AGGRASTAT in combination with heparin
in the PRISM PLUS study were 0.1% and 0.1%, respectively; the incidences
in the RESTORE study for AGGRASTAT in combination with heparin
were 0.2% and 0.0% respectively.
The incidence rates
of TIMI major bleeding
in patients undergoing percutaneous procedures in PRISM-PLUS are
shown below.
| |
AGGRASTAT + Heparin |
Heparin
|
|
n
|
%n
|
n
|
%
|
| Prior to Procedures
|
2/773
|
0.3
|
1/797
|
0.1
|
| Following Angiography
|
9/697
|
1.3
|
5/708
|
0.7
|
| Following PTCA
|
6/239
|
2.5
|
5/236
|
2.2
|
The incidence rates
of TIMI major bleeding
(in some cases possibly reflecting hemodilution rather than actual
bleeding) in patients undergoing CABG
in the PRISM-PLUS and RESTORE studies within one day of discontinuation
of AGGRASTAT are shown below.
| |
AGGRASTAT +
|
Heparin
|
| |
Heparin
|
|
|
| |
n
|
%n
|
n
|
%
|
| PRISM-PLUS |
5/29
|
17.2
|
11/31
|
35.4
|
| RESTORE |
3/12
|
25.0
|
6/16
|
37.5
|
Female patients and elderly patients receiving AGGRASTAT with heparin
or heparin alone had
a higher incidence
of bleeding complications
than male patients or younger patients. The incremental risk
of bleeding in patients
treated with AGGRASTAT in combination with heparin
over the risk in patients treated with heparin
alone was comparable regardless of age or gender. No
dose adjustment
is recommended for these populations (see DOSAGE
AND ADMINISTRATION, Recommended Dosage).
NON-BLEEDING
The incidences of non-bleeding adverse events that occurred at
an incidence of >1%
and numerically higher than control, regardless of drug
relationship, are shown below:
| |
AGGRASTAT + |
|
| |
Heparin
|
Heparin
|
| |
(n=1953)
|
(n=1887)
|
| |
%
|
%
|
| Body as a Whole
|
|
|
| Edema/ swelling
|
2
|
1
|
| Pain, pelvic
|
6
|
5
|
| Reaction, vasovagal
|
2
|
1
|
| Cardiovascular
System |
|
|
| Bradycardia |
4
|
3
|
| Dissection, coronary
artery |
5
|
4
|
| Musculoskeletal
System |
|
|
| Pain, leg
|
3
|
2
|
| Nervous System/
Psychiatric |
|
|
| Dizziness |
3
|
2
|
| Skin and Skin
Appendage |
|
|
| Sweating |
2
|
1
|
Other non-bleeding side
effects (considered at least possibly related to treatment) reported
at a >1% rate with AGGRASTAT
administered concomitantly with heparin
were nausea, fever,
and headache; these side
effects were reported at a similar rate
in the heparin group.
In clinical studies,
the incidences of adverse events were generally similar among different
races, patients with or without hypertension,
patients with or without diabetes
mellitus, and patients with or without hypercholesteremia.
The overall incidence
of non-bleeding adverse events was higher in female patients (compared
to male patients) and older
patients (compared to younger patients). However, the incidences
of non-bleeding adverse events in these patients were comparable
between the AGGRASTAT with heparin
and the heparin alone groups. (See above for bleeding
adverse events).
Allergic Reactions/Readministration: No patients in the
clinical database developed anaphylaxis
and/or hives requiring
discontinuation of the infusion
of tirofiban. No information
is available regarding the development of antibodies to tirofiban;
very few patients received tirofiban twice.
Laboratory Findings: The most frequently observed laboratory
adverse events in patients receiving AGGRASTAT concomitantly with
heparin were related to bleeding. Decreases in hemoglobin
(2.1%) and hematocrit (2.2%) were observed in the group
receiving AGGRASTAT compared to 3.1% and 2.6%, respectively, in
the heparin group. Increases
in the presence of urine
and fecal occult blood
were also observed (10.7% and 18.3%, respectively) in the group
receiving AGGRASTAT compared to 7.8% and 12.2%, respectively, in
the heparin group.
Patients treated with AGGRASTAT, with heparin, were more likely
to experience decreases in platelet
counts than the control
group. These decreases were reversible upon discontinuation of AGGRASTAT.
The percentage of patients with a decrease of platelets to <90,000/mm3
was 1.5%, compared with 0.6% in the patients who received heparin
alone. The percentage of patients with a decrease of platelets to
<50,000/mm3 was 0.3%, compared with 0.1% of the patients
who received heparin
alone.
DRUG INTERACTIONS
AGGRASTAT has been studied on a background of aspirin
and heparin.
The use of AGGRASTAT, in combination with heparin
and aspirin, has been associated with an increase in bleeding
compared to heparin
and aspirin alone (see SIDE EFFECTS
).
Caution should be employed when AGGRASTAT is used with other drugs
that affect hemostasis
(e.g., warfarin). No information
is available about the concomitant
use of AGGRASTAT with thrombolytic
agents (see PRECAUTIONS, Bleeding
Precautions).
In a sub-set of patients (n=762) in the PRISM study, the plasma
clearance of tirofiban in patients receiving one of the following
drugs was compared to that in patients not receiving that drug.
There were no clinically
significant effects of co-administration of these drugs on the plasma
clearance of tirofiban:
acebutolol, acetaminophen, alprazolam, amlodipine, aspirin
preparations, atenolol, bromazepam, captopril, diazepam, digoxin,
diltiazem, docusate sodium, enalapril, furosemide, glyburide, heparin,
insulin, isosorbide,
lorazepam, lovastatin, metoclopramide, metoprolol, morphine, nifedipine,
nitrate preparations, oxazepam, potassium
chloride, propranolol, ranitidine, simvastatin, sucralfate
and temazepam. Patients who received levothyroxine or omeprazole
along with AGGRASTAT had a higher rate
of clearance of AGGRASTAT.
The clinical significance
of this is unknown.
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