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.

General

Standard management of myocardial infarction should be implemented concomitantly with Retavase® treatment. Arterial and venous punctures should be minimized (see WARNINGS). In addition, the second bolus of Retavase® should not be given if the serious bleeding occurs before it is administered. In the event of serious bleeding, any concomitant heparin should be terminated immediately. Heparin effects can be reversed by protamine.

Readministration

There is no experience with patients receiving repeat courses of therapy with Retavase®. Retavase® did not induce the formation of Retavase® specific antibodies in any of the approximately 2,400 patients who were tested for antibody formation in clinical trials. If an anaphylactoid reaction occurs, the second bolus of Retavase® should not be given, and appropriate therapy should be initiated.

Drug Interactions

The interaction of Retavase® with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as aspirin, dipyridamole, and abciximab) may increase the risk of bleeding if administered prior to or after Retavase® therapy.

Drug/Laboratory Test Interactions

Administration of Retavase® may cause decreases in plasminogen and fibrinogen. During Retavase® therapy, if coagulation tests and/or measurements of fibrinolytic activity are performed, the results may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Retavase® 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 PPACK (chloromethylketone) at 2 µM concentrations was used in clinical trials of prevent in vitro fibrinolytic artifacts. ⁶

Use of Antithrombotics

Heparin and aspirin have been administered concomitantly with and following the administration of Retavase® in the management of acute myocardial infarction. Because heparin, aspirin, or Retavase® may cause bleeding complications, careful monitoring for bleeding is advised, especially at arterial puncture sites.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Retavase®. Studies to determine mutagenicity, chromosomal aberrations, gene mutations, and micronuclei induction were negative at all concentrations tested. Reproductive toxicity studies in rats revealed no effects on fertility at doses up to 15 times the human dose (4.31 U/kg).

Pregnancy Category C

Reteplase has been shown to have an abortifacient effect in rabbits when given in doses 3 times the human dose (0.86 U/kg). Reproduction studies performed in rats at doses up to 15 times the human dose (4.31 U/kg) revealed no evidence of fetal anomalies; however, Reteplase administered to pregnant rabbits resulted in hemorrhaging in the genital tract, leading to abortions in mid-gestation. There are no adequate and well-controlled studies in pregnant women. The most common complication of thrombolytic therapy is bleeding and certain conditions, including pregnancy, can increase this risk. Reteplase should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether Retavase® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Retavase® is administered to a nursing woman.

Pediatric Use

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

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