ADVERSE REACTIONS
Bleeding
The most frequent adverse reaction associated with Activase in all approved indications is bleeding (see WARNINGS).15,16
Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial) occur, Activase therapy should be discontinued immediately, along with any concomitant therapy with heparin. Death and permanent disability are not uncommonly reported in patients that have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.
In the GUSTO trial for the treatment of acute myocardial infarction, using the accelerated infusion regimen the incidence of all strokes for the Activase-treated patients was 1.6%, while the incidence of nonfatal stroke was 0.9%. The incidence of hemorrhagic stroke was 0.7%, not all of which were fatal. The incidence of all strokes, as well as that for hemorrhagic stroke, increased with increasing age (see CLINICAL PHARMACOLOGY: Accelerated Infusion in AMI Patients). Data from previous trials utilizing a 3‑hour infusion of ≤ 100 mg indicated that the incidence of total stroke in six randomized double-blind placebo-controlled trials2,7‑11,17 was 1.2% (37/3161) in Alteplase‑treated patients compared with 0.9% (27/3092) in placebo-treated patients.
For the 3‑hour infusion regimen, the incidence of significant internal bleeding (estimated as > 250 cc blood loss) has been reported in studies in over 800 patients. These data do not include patients treated with the Alteplase accelerated infusion.
| |
Total Dose ≤ 100 mg |
| gastrointestinal |
5% |
| genitourinary |
4% |
| ecchymosis |
1% |
| retroperitoneal |
< 1% |
| epistaxis |
< 1% |
| gingival |
< 1% |
The incidence of intracranial hemorrhage (ICH) in acute myocardial infarction patients treated with Activase is as follows:
| Dose |
Number of Patients |
ICH (%) |
| 100 mg, 3-hour |
3272 |
0.4 |
| ≤ 100 mg, accelerated |
10,396 |
0.7 |
| 150 mg |
1779 |
1.3 |
| 1–1.4 mg/kg |
237 |
0.4 |
These data indicate that a dose of 150 mg of Activase should not be used in the treatment of AMI because it has been associated with an increase in intracranial bleeding.18
For acute massive pulmonary embolism, bleeding events were consistent with the general safety profile observed with Activase in acute myocardial infarction patients receiving the 3‑hour infusion regimen.
The incidence of ICH, especially symptomatic ICH, in patients with acute ischemic stroke was higher in Activase‑treated patients than placebo patients (see CLINICAL PHARMACOLOGY).
A study of another alteplase product, Actilyse, in acute ischemic stroke, suggested that doses greater than 0.9 mg/kg may be associated with an increased incidence of ICH.19
Doses greater than 0.9 mg/kg (maximum 90 mg) should not be used in the management of acute ischemic stroke.
Bleeding events other than ICH were noted in the studies of acute ischemic stroke and were consistent with the general safety profile of Activase. In The NINDS t‑PA Stroke Trial (Parts 1 and 2), the frequency of bleeding requiring red blood cell transfusions was 6.4% for Activase-treated patients compared to 3.8% for placebo (p=0.19, using Mantel-Haenszel Chi‑Square).
Fibrin which is part of the hemostatic plug formed at needle puncture sites will be lysed during Activase therapy. Therefore, Activase therapy requires careful attention to potential bleeding sites, e.g., catheter insertion sites, and arterial puncture sites.
Allergic Reactions
Allergic‑type reactions, e.g., anaphylactoid reaction, laryngeal edema, orolingual angioedema, rash, and urticaria have been reported. A cause and effect relationship to Activase therapy has not been established. When such reactions occur, they usually respond to conventional therapy.
There have been post‑marketing reports of orolingual angioedema associated with the use of Activase. Most reports were of patients treated for acute ischemic stroke, some reports were of patients treated for acute myocardial infarctions (see PRECAUTIONS: General). Many of these patients received concomitant angiotensin‑converting enzyme inhibitors (see PRECAUTIONS: Drug Interactions). Most cases resolved with prompt treatment; there have been rare fatalities as a result of upper airway hemorrhage from intubation trauma.
Other Adverse Reactions
The following adverse reactions have been reported among patients receiving Activase in clinical trials and in post-marketing experience. These reactions are frequent sequelae of the underlying disease and the effect of Activase on the incidence of these events is unknown.
Use in Acute Myocardial Infarction: Arrhythmias, AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia, myocardial reinfarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema. These events may be life threatening and may lead to death. Nausea and/or vomiting, hypotension and fever have also been reported.
Use in Pulmonary Embolism: Pulmonary reembolization, pulmonary edema, pleural effusion, thromboembolism, hypotension. These events may be life threatening and may lead to death. Fever has also been reported.
Use in Acute Ischemic Stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke. These events may be life threatening and may lead to death.
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