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warnings
WARNINGS Bleeding: The most common complication encountered during Retavase ® therapy is bleeding. The sites of bleeding include both internal bleeding sites (intracranial, retroperitoneal, gastrointestinal, genitourinary, or respiratory) and superficial bleeding sites (venous cutdowns, arterial punctures, sites of recent surgical intervention). The concomitant use of heparin anticoagulation may contribute to bleeding. In clinical trials some of the hemorrhage episodes occurred one or more days after the effects of Retavase ® had dissipated, but while heparin therapy was continuing. As fibrin is lysed during Retavase ® 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). Noncompressible arterial puncture must be avoided and internal jugular and subclavian venous punctures should be avoided to minimize bleeding from noncompressible sites. Should an arterial puncture be necessary during the administration of Retavase ® , 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. Intramuscular injections and nonessential handling of the patient should be avoided during treatment with Retavase ® . Venipunctures should be performed carefully and only as required. Should serious bleeding (not controllable by local pressure) occur, concomitant anticoagulant therapy should be terminated immediately. In addition, the second bolus of Retavase ® should not be given if serious bleeding occurs before it is administered. Each patient being considered for therapy with Retavase ® should be carefully evaluated and anticipated benefits weighed against the potential risks associated with therapy. In the following conditions, the risks of Retavase ® 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 or renal dysfunction Pregnancy Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions Septic thrombophlebitis or occluded AV cannula at a seriously infected site Advanced age 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 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 should be managed with standard antiarrhythmic measures. It is recommended that antiarrhythmic therapy for bradycardia and/or ventricular irritability be available when Retavase ® is administered.
ADVERSE REACTIONS Bleeding: The most frequent adverse reaction associated with Retavase ® is bleeding (see WARNINGS ). The types of bleeding events associated with thrombolytic therapy may be broadly categorized as either intracranial hemorrhage or other types of hemorrhage. Intracranial hemorrhage (see CLINICAL PHARMACOLOGY ) In the INJECT clinical trial the rate of in-hospital, intracranial hemorrhage among all patients treated with Retavase ® was 0.8% (23 of 2,965 patients). As seen with Retavase ® and other thrombolytic agents, the risk for intracranial hemorrhage is increased in patients with advanced age or with elevated blood pressure. Other types of hemorrhage The incidence of other types of bleeding events in clinical studies of Retavase ® varied depending upon the use of arterial catheterization or other invasive procedures and whether the study was performed in Europe or the USA. The overall incidence of any bleeding event in patients treated with Retavase ® in clinical studies (n = 3,805) was 21.1%. The rates for bleeding events, regardless of severity, for the 10 + 10 unit Retavase ® regimen from controlled clinical studies are summarized in Table 3. Table 3 Retavase ® Hemorrhage Rates Bleeding Site INJECT RAPID 1 and RAPID 2 Europe n = 2,965 USA n = 210 Europe n =113 *includes the arterial catheterization site (all patients in the RAPID studies underwent arterial catheterization). Injection Site* 4.6% 48.6% 19.5% Gastrointestinal 2.5% 9.0% 1.8% Genitourinary 1.6% 9.5% 0.9% Anemia, site unknown 2.6% 1.4% 0.9% In these studies the severity and sites of bleeding events were comparable for Retavase ® and the comparison thrombolytic agents. Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial) occur, any concomitant heparin should be terminated immediately. In addition, the second bolus of Retavase ® should not be given if the serious bleeding occurs before it is administered. Death and permanent disability are not uncommonly reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes. Fibrin which is part of the hemostatic plug formed at needle puncture sites will be lysed during Retavase ® therapy. Therefore, Retavase ® therapy requires careful attention to potential bleeding sites (e.g., catheter insertion sites, arterial puncture sites). Allergic Reactions: Among the 2,965 patients receiving Retavase ® in the INJECT trial, serious allergic reactions were noted in 3 patients, with one patient experiencing dyspnea and hypotension. No anaphylactoid reactions were observed among the 3,856 patients treated with Retavase ® in initial clinical trials. In an ongoing clinical trial two anaphylactoid reactions have been reported among approximately 2,500 patients receiving Retavase ® . Other Adverse Reactions: Patients administered Retavase ® as treatment for myocardial infarction have experienced many events which are frequent sequelae of myocardial infarction and may or may not be attributable to Retavase ® therapy. These events include cardiogenic shock, arrhythmias (e.g., sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation), AV block, pulmonary edema, heart failure, cardiac arrest, recurrent ischemia, reinfarction, myocardial rupture, mitral regurgitation, pericardial effusion, pericarditis, cardiac tamponade, venous thrombosis and embolism, and electromechanical dissociation. These events can be life-threatening and may lead to death. Other adverse events have been reported, including nausea and/or vomiting, hypotension, and fever.