Actilyse

Alteplase is a serine protease responsible for fibrin-enhanced conversion of plasminogen to plasmin. It produces limited conversion of plasminogen in the absence of fibrin. When introduced into the systemic circulation at pharmacologic concentration, alteplase binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin. This initiates local fibrinolysis with limited systemic proteolysis.

Pharmacodynamics: Following administration of 100 mg Alteplase, there is a decrease (16%-36%) in circulating fibrinogen. In a controlled trial, 8 of 73 patients (11%) receiving Alteplase (1.25 mg/kg body weight over 3 hours) experienced a decrease in fibrinogen to below 100 mg/dL.

Pharmacokinetics: Alteplase in acute myocardial infarction (AMI) patients is rapidly cleared from the plasma with an initial half-life of less than 5 minutes. There is no difference in the dominant initial plasma half-life between the 3-hour and accelerated regimens for AMI. The plasma clearance of alteplase is 380-570 mL/min, primarily mediated by the liver. The initial volume of distribution approximates plasma volume.

The interaction of Alteplase with other cardioactive or cerebroactive drugs has not been studied. Anticoagulants and antiplatelet drugs increase the risk of bleeding if administered prior to, during, or after Alteplase therapy. In the post-marketing setting, there have been reports of orolingual angioedema in patients (primarily patients with AIS) receiving concomitant angiotensin-converting enzyme inhibitors.

The following adverse reactions are:

• Bleeding
• Orolingual Angioedema
• Cholesterol Embolization
• Reembolization of Deep Venous Thrombi during Treatment for Acute Massive Pulmonary
• Embolism.

Pregnancy Category C. Alteplase is embryocidal in rabbits when intravenously administered in doses of approximately two times (3 mg/kg) the human dose for AMI. No maternal or fetal toxicity was evident at 0.65 times (1 mg/kg) the human dose in pregnant rats and rabbits dosed during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women. It is not known whether Alteplase is excreted in human milk. Many drugs are excreted in human milk.

• Increases the risk of bleeding. Avoid intramuscular injections. Monitor for bleeding. If serious bleeding occurs, discontinue Alteplase.
• Monitor patients during and for several hours after infusion for orolingual angioedema. If angioedema develops, discontinue Alteplase.
• Cholesterol embolism has been reported rarely in patients treated with thrombolytic agents.
• Consider the risk of reembolization from the lysis of underlying deep venous thrombi in patients with pulmonary embolism.

Pediatric Use: Safety and effectiveness of Alteplase in pediatric patients have not been established.

Geriatric Use:

• Acute Ischemic Stroke: In exploratory, multivariate analyses of Studies 1 and 2, age greater than 77 years was one of several interrelated baseline characteristics associated with an increased risk of intracranial hemorrhage. Efficacy results suggest a reduced but still favorable clinical outcome for Alteplase-treated elderly.
• Acute Myocardial Infarction: In a large trial of accelerated-infusion Alteplase that enrolled 41,021 patients with AMI to one of four thrombolytic regimens [see Clinical Studies (14.2)], patients over 75 years of age, a predefined subgroup, comprised 12% of enrolment. In these patients, the incidence of stroke was 4.0% for the Alteplase accelerated infusion group, 2.8% for streptokinase IV [SK (IV)], and 3.2% for streptokinase SQ [SK (SQ)]. The incidence of combined 30-day mortality or nonfatal stroke was 20.6% for accelerated infusion of Alteplase, 21.5% for SK (IV), and 22.0% for SK (SQ).

Anti-platelet drugs, Fibrinolytics (Thrombolytics)

Store lyophilized Alteplase at controlled room temperature not to exceed 30°C, or under refrigeration (2-8°C). Protect the lyophilized material during extended storage from excessive exposure to light. If stored between 2-30°C, Alteplase may be used within 8 hours following reconstitution. Discard any unused solution after administration is complete. Do not use beyond the expiration date stamped on the vial.