ADVERSE REACTIONS
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.
| PRISM-PLUS
(UAP/Non-Q-Wave MI Study) | RESTORE
(Angioplasty/Atherectomy Study) |
| Bleeding | AGGRASTAT
+ Heparin
(n=773)
%(n) | Heparin
(n=797)
%(n) | AGGRASTAT
+ Heparin
(n=1071)
%(n) | Heparin
(n=1070)
%(n) |
| Major Bleeding (TIMI Criteria)Hemoglobin drop of >50 g/L with or without an identified site, intracranial hemorrhage, or cardiac tamponade. | 1.4 (11) | 0.8 (6) | 2.2 (24) | 1.6 (17) |
| Minor Bleeding (TIMI Criteria)Hemoglobin drop of >30 g/L with bleeding from a known site, spontaneous gross hematuria, hematemesis or hemoptysis. | 10.5 (81) | 8.0 (64) | 12.0 (129) | 6.3 (67) |
| Transfusions | 4.0 (31) | 2.8 (22) | 4.3 (46) | 2.5 (27) |
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 | % |
| 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 | % |
| 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
(n=1953)
% | Heparin
(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
Although no patients in the clinical trial database developed anaphylaxis and/or hives requiring discontinuation of the infusion of tirofiban, anaphylaxis has been reported in post-marketing experience (see also Post-Marketing Experience, Hypersensitivity). No information is available regarding the development of antibodies to tirofiban.
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. Platelet decreases have been observed in patients with no prior history of thrombocytopenia upon readministration of GP IIb/IIIa receptor antagonists.
Post-Marketing Experience
The following additional adverse reactions have been reported in post-marketing experience: Bleeding: Intracranial bleeding, retroperitoneal bleeding, hemopericardium, pulmonary (alveolar) hemorrhage, and spinal-epidural hematoma. Fatal bleeding events have been reported; Body as a Whole: Acute and/or severe decreases in platelet counts which may be associated with chills, low-grade fever, or bleeding complications (see Laboratory Findings above); Hypersensitivity: Severe allergic reactions including anaphylactic reactions. The reported cases have occurred during the first day of tirofiban infusion, during initial treatment, and during readministration of tirofiban. Some cases have been associated with severe thrombocytopenia (platelet counts <10,000/mm3).
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