WARNINGS
Bleeding
The most common complication encountered during Activase therapy is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into two broad categories:
- Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts.
- Superficial or surface bleeding, observed mainly at invaded or disturbed sites (e.g., venous cutdowns, arterial punctures, sites of recent surgical intervention).
The concomitant use of heparin anticoagulation may contribute to bleeding. Some of the hemorrhage episodes occurred 1 or more days after the effects of Activase had dissipated, but while heparin therapy was continuing.
As fibrin is lysed during Activase therapy, bleeding from recent puncture sites may occur. Therefore, thrombolytic therapy requires careful attention to all potential bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites, and needle puncture sites).
Intramuscular injections and nonessential handling of the patient should be avoided during treatment with Activase. Venipunctures should be performed carefully and only as required.
Should an arterial puncture be necessary during an infusion of Activase, it is preferable to use an upper extremity vessel that is accessible to manual compression. Pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.
Should serious bleeding (not controllable by local pressure) occur, the infusion of Activase and any concomitant heparin should be terminated immediately.
Each patient being considered for therapy with Activase should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy.
In the following conditions, the risks of Activase therapy for all approved indications may be increased and should be weighed against the anticipated benefits:
- Recent major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels
- Cerebrovascular disease
- Recent gastrointestinal or genitourinary bleeding
- Recent trauma
- Hypertension: systolic BP ≥175 mm Hg and/or diastolic BP ≥110 mm Hg
- High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
- Acute pericarditis
- Subacute bacterial endocarditis
- Hemostatic defects including those secondary to severe hepatic or renal disease
- Significant hepatic dysfunction
- Pregnancy
- Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions
- Septic thrombophlebitis or occluded AV cannula at seriously infected site
- Advanced age (e.g., over 75 years old)
- Patients currently receiving oral anticoagulants, e.g., warfarin sodium
- Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location
Cholesterol Embolization
Cholesterol embolism has been reported rarely in patients treated with all types of thrombolytic agents; the true incidence is unknown. This serious condition, which can be lethal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. Clinical features of cholesterol embolism may include livedo reticularis, "purple toe" syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.
Use in Acute Myocardial Infarction
In a small subgroup of AMI patients who are at low risk for death from cardiac causes (i.e., no previous myocardial infarction, Killip class I) and who have high blood pressure at the time of presentation, the risk for stroke may offset the survival benefit produced by thrombolytic therapy. 14
Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) are not different from those often seen in the ordinary course of acute myocardial infarction and may be managed with standard antiarrhythmic measures. It is recommended that antiarrhythmic therapy for bradycardia and/or ventricular irritability be available when infusions of Activase are administered.
Use in Acute Ischemic Stroke
In addition to the previously listed conditions, the risks of Activase therapy to treat acute ischemic stroke may be increased in the following conditions and should be weighed against the anticipated benefits:
- Patients with severe neurological deficit (e.g., NIHSS > 22) at presentation. There is an increased risk of intracranial hemorrhage in these patients.
- Patients with major early infarct signs on a computerized cranial tomography (CT) scan (e.g., substantial edema, mass effect, or midline shift).
In patients without recent use of oral anticoagulants or heparin, Activase treatment can be initiated prior to the availability of coagulation study results. However, infusion should be discontinued if either a pretreatment International Normalized Ratio (INR) > 1.7 or a prothrombin time (PT) > 15 seconds or an elevated activated partial thromboplastin time (aPTT) is identified.
Treatment should be limited to facilities that can provide appropriate evaluation and management of ICH.
In acute ischemic stroke, neither the incidence of intracranial hemorrhage nor the benefits of therapy are known in patients treated with Activase more than 3 hours after the onset of symptoms. Therefore, treatment of patients with acute ischemic stroke more than 3 hours after symptom onset is not recommended.
Due to the increased risk for misdiagnosis of acute ischemic stroke, special diligence is required in making this diagnosis in patients whose blood glucose values are < 50 mg/dL or > 400 mg/dL. The safety and efficacy of treatment with Activase in patients with minor neurological deficit or with rapidly improving symptoms prior to the start of Activase administration has not been evaluated. Therefore, treatment of patients with minor neurological deficit or with rapidly improving symptoms is not recommended.
Use in Pulmonary Embolism
It should be recognized that the treatment of pulmonary embolism with Activase has not been shown to constitute adequate clinical treatment of underlying deep vein thrombosis. Furthermore, the possible risk of reembolization due to the lysis of underlying deep venous thrombi should be considered.
PRECAUTIONS
General
Standard management of myocardial infarction or pulmonary embolism should be implemented concomitantly with Activase treatment. Noncompressible arterial puncture must be avoided and internal jugular and subclavian venous punctures should be avoided to minimize bleeding from noncompressible sites. Arterial and venous punctures should be minimized. In the event of serious bleeding, Activase and heparin should be discontinued immediately. Heparin effects can be reversed by protamine.
Orolingual angioedema has been observed in post-market experience in patients treated for acute ischemic stroke and in patients treated for acute myocardial infarction (see PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Allergic Reactions). Onset of angioedema occurred during and up to 2 hours after infusion of Activase. In many cases, patients were receiving concomitant Angiotensin-converting enzyme inhibitors. Patients treated with Activase should be monitored during and for several hours after infusion for signs of orolingual angioedema. If angioedema is noted, promptly institute appropriate therapy (e.g. antihistamines, intravenous corticosteroids or epinephrine) and consider discontinuing the Activase infusion. Rare fatal cases of hemorrhage associated with traumatic intubation in patients administered Activase have been reported.
Readministration
There is no experience with readministration of Activase. If an anaphylactoid reaction occurs, the infusion should be discontinued immediately and appropriate therapy initiated.
Although sustained antibody formation in patients receiving one dose of Activase has not been documented, readministration should be undertaken with caution. Detectable levels of antibody (a single point measurement) were reported in one patient, but subsequent antibody test results were negative.
Drug/Laboratory Test Interactions
During Activase therapy, if coagulation tests and/or measures of fibrinolytic activity are performed, the results may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Activase is an enzyme that when present in blood in pharmacologic concentrations remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. Collection of blood samples in the presence of aprotinin (150–200 units/mL) can to some extent mitigate this phenomenon.
Drug Interactions
The interaction of Activase with other cardioactive or cerebroactive drugs has not been studied. In addition to bleeding associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole and Abciximab) may increase the risk of bleeding if administered prior to, during, or after Activase therapy.
There have been post-marketing reports of orolingual angioedema associated with the use of Activase. Many patients, primarily acute ischemic stroke patients, were receiving concomitant Angiotensin-converting enzyme inhibitors. (See PRECAUTIONS: General and ADVERSE REACTIONS: Allergic Reactions).
Use of Antithrombotics
Aspirin and heparin have been administered concomitantly with and following infusions of Activase in the management of acute myocardial infarction or pulmonary embolism. Because heparin, aspirin, or Activase may cause bleeding complications, careful monitoring for bleeding is advised, especially at arterial puncture sites.
The concomitant use of heparin or aspirin during the first 24 hours following symptom onset were prohibited in The NINDS t-PA Stroke Trial. The safety of such concomitant use with Activase for the management of acute ischemic stroke is unknown.
Blood Pressure Control
Blood pressure should be monitored frequently and controlled during and following Activase administration in the management of acute ischemic stroke. In The NINDS t‑PA Stroke Trial, blood pressure was actively controlled (≤ 185/110 mm Hg) for 24 hours. Blood pressure was monitored during the hospital stay.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long‑term studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility. Short‑term studies, which evaluated tumorigenicity of Activase and effect on tumor metastases in rodents, were negative.
Studies to determine mutagenicity (Ames test) and chromosomal aberration assays in human lymphocytes were negative at all concentrations tested. Cytotoxicity, as reflected by a decrease in mitotic index, was evidenced only after prolonged exposure and only at the highest concentrations tested.
Pregnancy (Category C)
Activase has been shown to have an embryocidal effect in rabbits when intravenously administered in doses of approximately two times (3 mg/kg) the human dose for AMI. No maternal or fetal toxicity was evident at 0.65 times (1 mg/kg) the human dose in pregnant rats and rabbits dosed during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women. Activase should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether Activase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Activase is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Activase in pediatric patients have not been established.
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