warnings and cautions
5 WARNINGS AND PRECAUTIONS Increases the risk of bleeding. Avoid intramuscular injections. Monitor for bleeding. If serious bleeding occurs, discontinue Activase. ( 5.1 ) Monitor patients during and for several hours after infusion for hypersensitivity. If signs of hypersensitivity develop, discontinue Activase. ( 5.2 ) Consider the risk of reembolization from the lysis of underlying deep venous thrombi in patients with pulmonary embolism. ( 5.3 ) Cholesterol embolism has been reported rarely in patients treated with thrombolytic agents. ( 5.4 ) 5.1 Bleeding Activase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Avoid intramuscular injections and trauma to the patient while on Activase. Perform venipunctures carefully and only as required. To minimize bleeding from noncompressible sites, avoid internal jugular and subclavian venous punctures. If an arterial puncture is necessary during Activase infusion, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. Because of the higher risk of intracranial hemorrhage in patients treated for acute ischemic stroke, limit treatment to facilities that can provide timely access to appropriate evaluation and management of intracranial hemorrhage. Fatal cases of hemorrhage associated with traumatic intubation in patients administered Activase have been reported. Aspirin and heparin have been administered concomitantly with and following infusions of Activase in the management of acute myocardial infarction and pulmonary embolism, but the concomitant administration of heparin and aspirin with and following infusions of Activase for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or Activase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of Activase, while patients are still receiving anticoagulant therapy. If serious bleeding occurs, terminate the Activase infusion and treat appropriately. In the following conditions, the risks of bleeding with Activase therapy for all approved indications are increased and should be weighed against the anticipated benefits: Recent major surgery or procedure, (e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels) Cerebrovascular disease Recent intracranial hemorrhage Recent gastrointestinal or genitourinary bleeding Recent trauma Hypertension: systolic BP above 175 mm Hg or diastolic BP above 110 mm Hg 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 [see Use in Specific Populations (8.5) ] Patients currently receiving 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. 5.2 Hypersensitivity Hypersensitivity, including urticarial / anaphylactic reactions, have been reported after administration of Activase (e.g., laryngeal edema, rash and shock). Rare fatal outcome for hypersensitivity was reported. Angioedema has been observed during and up to 2 hours after Activase infusion in patients treated for acute ischemic stroke and acute myocardial infarction. In many cases, patients received concomitant angiotensin-converting enzyme inhibitors [see Drug Interactions (7) ] . Monitor patients treated with Activase during and for several hours after infusion for hypersensitivity. If signs of hypersensitivity occur, e.g. anaphylactoid reaction or angioedema develops, discontinue the Activase infusion and promptly institute appropriate therapy (e.g., antihistamines, intravenous corticosteroids, epinephrine). 5.3 Thromboembolism The use of thrombolytics can increase the risk of thrombo-embolic events in patients with high likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation. Activase has not been shown to treat adequately underlying deep vein thrombosis in patients with PE. Consider the possible risk of re-embolization due to the lysis of underlying deep venous thrombi in this setting. 5.4 Cholesterol Embolization Cholesterol embolism has been reported rarely in patients treated with thrombolytic agents; the true incidence is unknown. Cholesterol embolism may present with livedo reticularis, "purple toe" syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, or rhabdomyolysis and can be fatal. It is associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. 5.5 Coagulation Tests May Be Unreliable during Activase Therapy Coagulation tests and measures of fibrinolytic activity may be unreliable during Activase therapy, unless specific precautions are taken to prevent in vitro artifacts. When present in blood at pharmacologic concentrations, Activase remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.