Actilyse

Acute Ischemic Stroke: Actilyse is indicated for the treatment of acute ischemic stroke. Exclude intracranial hemorrhage as the primary cause of stroke signs and symptoms prior to initiation of treatment. Initiate treatment as soon as possible but within 3 hours after symptom onset.

Acute Myocardial Infarction: Actilyse is indicated for use in acute myocardial infarction (AMI) for the reduction of mortality and the reduction of the incidence of heart failure.

Pulmonary Embolism: Actilyse is indicated for the lysis of acute massive pulmonary embolism, defined as:

• Acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments.
• Acute pulmonary emboli accompanied by unstable hemodynamics, e.g., failure to maintain blood pressure without supportive measures.

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.

Acute Ischemic Stroke: Administer Alteplase as soon as possible but within 3 hours after onset of symptoms. The recommended dose is 0.9 mg/kg (not to exceed 90 mg total dose), with 10% of the total dose administered as an initial intravenous bolus over 1 minute and the remainder infused over 60 minutes. During and following Alteplase administration for the treatment of acute ischemic stroke, frequently monitor and control blood pressure. In patients without recent use of oral anticoagulants or heparin, Alteplase treatment can be initiated prior to the availability of coagulation study results. Discontinue Alteplase if the pretreatment International Normalized Ratio (INR) is greater than 1.7 or the activated partial thromboplastin time (aPTT) is elevated.

Acute Myocardial Infarction: Administer Alteplase as soon as possible after the onset of symptoms. The recommended total doses for acute myocardial infarction (AMI) is based on patient weight, not to exceed 100 mg, regardless of the selected administration regimen (accelerated or 3 hour). There are two Alteplase dose regimens (accelerated and 3-hour) for use in the management of AMI; there are no controlled studies to compare clinical outcomes with these regimens

Pulmonary Embolism (PE): The recommended dose is 100 mg administered by IV infusion over 2 hours. Institute parenteral anticoagulation near the end of or immediately following the Alteplase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less.

Following bolus dose, if indicated:

• 50 mg vials: administer using either a polyvinyl chloride bag or glass vial and infusion set.
• 100 mg vials: remove from the vial any quantity of drug in excess of that specified for patient treatment. Insert the spike end of an infusion set through the same puncture site created by the transfer device in the stopper of the vial of reconstituted Alteplase. Peel the clear plastic hanger from the vial label. Hang the Alteplase vial from the resulting loop.

Alteplase is for intravenous administration only. Extravasation of Alteplase infusion can cause ecchymosis or inflammation. If extravasation occurs, terminate the infusion at that IV site and apply local therapy. Do not add any other medication to infusion solutions containing Alteplase.

The interaction of Actilyse 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 Actilyse 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.

Acute Ischemic Stroke: Do not administer Alteplase to treat acute ischemic stroke in the following situations in which the risk of bleeding is greater than the potential benefit [see Warnings and Precautions (5.1)]:

• Current intracranial hemorrhage
• Subarachnoid hemorrhage
• Active internal bleeding
• Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma
• Presence of intracranial conditions that may increase the risk of bleeding (e.g., some neoplasms, arteriovenous malformations, or aneurysms)
• Bleeding diathesis
• Current severe uncontrolled hypertension.

Acute Myocardial Infarction or Pulmonary Embolism: Do not administer Alteplase for treatment of AMI or PE in the following situations in which the risk of bleeding is greater than the potential benefit:

• Active internal bleeding
• History of recent stroke
• Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma
• Presence of intracranial conditions that may increase the risk of bleeding (e.g. some neoplasms, arteriovenous malformations, or aneurysms)
• Bleeding diathesis
• Current severe uncontrolled hypertension.

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 Actilyse.
• Monitor patients during and for several hours after infusion for orolingual angioedema. If angioedema develops, discontinue Actilyse.
• 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 Actilyse 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 Actilyse-treated elderly.
• Acute Myocardial Infarction: In a large trial of accelerated-infusion Actilyse 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 Actilyse 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 Actilyse, 21.5% for SK (IV), and 22.0% for SK (SQ).

Anti-platelet drugs, Fibrinolytics (Thrombolytics)

Store lyophilized Actilyse 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, Actilyse 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.