Information for: ACTIVASE

The most common complication encountered during Activase®, Alteplase, recombinant 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 180 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 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.

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®, Alteplase, recombinant are administered.

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 pre-treatment prothrombin time (PT) > 15 seconds or an elevated activate partial thromboplastin time (aPTT) is identified.

Treatment should be limited to facilities that can provide appropriate evaluation and management of I.H.

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.

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.

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.

Standard management of myocardial infarction or pulmonary embolism should be implemented concomitantly with Activase^®, Alteplase, recombinant, 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.

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.

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.

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.

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 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 monitored for 24 hours and was actively controlled (¾ 185/110 mm Hg) during this period with appropriate medication.

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.

Animal reproduction studies have not been conducted with Activase. It is also not known whether Activase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Activase should be given to a pregnant woman only if clearly needed.

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.

Safety and effectiveness of Activase in pediatric patients have not been established.