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warnings
WARNINGS Bleeding The most common complication encountered during TNKase 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 vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or sites of recent surgical intervention. Should serious bleeding (not controlled by local pressure) occur, any concomitant heparin or antiplatelet agents should be discontinued immediately. In clinical studies of TNKase, patients were treated with both aspirin and heparin. Heparin may contribute to the bleeding risks associated with TNKase. The safety of the use of TNKase with other antiplatelet agents has not been adequately studied (see PRECAUTIONS: Drug Interactions ). Intramuscular injections and nonessential handling of the patient should be avoided for the first few hours following treatment with TNKase. Venipunctures should be performed and monitored carefully. Should an arterial puncture be necessary during the first few hours following TNKase therapy, 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. Each patient being considered for therapy with TNKase should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy. In the following conditions, the risk of TNKase therapy 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 Severe hepatic dysfunction Pregnancy Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions Septic thrombophlebitis or occluded AV cannula at seriously infected site Advanced age (see PRECAUTIONS: Geriatric Use ) Patients currently receiving oral anticoagulants, e.g., warfarin sodium Recent administration of GP IIb/IIIa inhibitors 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. 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 anti‑arrhythmic measures. It is recommended that anti‑arrhythmic therapy for bradycardia and/or ventricular irritability be available when TNKase is administered. Use with Percutaneous Coronary Intervention (PCI) In patients with large ST segment elevation myocardial infarction, physicians should choose either thrombolysis or PCI as the primary treatment strategy for reperfusion. Rescue PCI or subsequent elective PCI may be performed after administration of thrombolytic therapies if medically appropriate; however, the optimal use of adjunctive antithrombotic and antiplatelet therapies in this setting is unknown.
ADVERSE REACTIONS Bleeding The most frequent adverse reaction associated with TNKase is bleeding (see WARNINGS ). Should serious bleeding occur, concomitant heparin and antiplatelet therapy should be discontinued. Death or permanent disability can occur in patients who experience stroke or serious bleeding episodes. For TNKase-treated patients in ASSENT-2, the incidence of intracranial hemorrhage was 0.9% and any stroke was 1.8%. The incidence of all strokes, including intracranial bleeding, increases with increasing age (see PRECAUTIONS: Geriatric Use ). In the ASSENT-2 study, the following bleeding events were reported (see Table 3 ). Table 3 ASSENT-2 Non-ICH Bleeding Events TNKase (n = 8461) Accelerated Activase (n = 8488) Relative Risk for TNKase/Activase (95% CI) Major bleeding Major bleeding is defined as bleeding requiring blood transfusion or leading to hemodynamic compromise. 4.7% 5.9% 0.78 (0.69, 0.89) Minor bleeding 21.8% 23.0% 0.94 (0.89, 1.00) Units of transfused blood Any 4.3% 5.5% 0.77 (0.67, 0.89) 1–2 2.6% 3.2% >2 1.7% 2.2% Non-intracranial major bleeding and the need for blood transfusions were lower in patients treated with TNKase. Types of major bleeding reported in 1% or more of the patients were hematoma (1.7%) and gastrointestinal tract (1%). Types of major bleeding reported in less than 1% of the patients were urinary tract, puncture site (including cardiac catheterization site), retroperitoneal, respiratory tract, and unspecified. Types of minor bleeding reported in 1% or more of the patients were hematoma (12.3%), urinary tract (3.7%), puncture site (including cardiac catheterization site) (3.6%), pharyngeal (3.1%), gastrointestinal tract (1.9%), epistaxis (1.5%), and unspecified (1.3%). Allergic Reactions Allergic-type reactions (e.g., anaphylaxis, angioedema, laryngeal edema, rash, and urticaria) have rarely (< 1%) been reported in patients treated with TNKase. Anaphylaxis was reported in < 0.1% of patients treated with TNKase; however, causality was not established. When such reactions occur, they usually respond to conventional therapy. Other Adverse Reactions The following adverse reactions have been reported among patients receiving TNKase in clinical trials. These reactions are frequent sequelae of the underlying disease, and the effect of TNKase on the incidence of these events is unknown. These events include cardiogenic shock, arrhythmias, atrioventricular block, pulmonary edema, heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial reinfarction, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, thrombosis, embolism, and electromechanical dissociation. These events can be life-threatening and may lead to death. Nausea and/or vomiting, hypotension, and fever have also been reported.