1.1 Acute Ischemic Stroke

Activase 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 [see Contraindications (4.1)]. Initiate treatment as soon as possible but within 3 hours after symptom onset.

1.2 Acute Myocardial Infarction

Activase is indicated for use in acute myocardial infarction (AMI) for the reduction of mortality and reduction of the incidence of heart failure.

1.3 Pulmonary Embolism

Activase 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.

2.1 Acute Ischemic Stroke

Administer Activase 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 Activase administration for the treatment of acute ischemic stroke, frequently monitor and control blood pressure.

In patients without recent use of oral anticoagulants or heparin, Activase treatment can be initiated prior to the availability of coagulation study results. Discontinue Activase if the pretreatment International Normalized Ratio (INR) is greater than 1.7 or the activated partial thromboplastin time (aPTT) is elevated [see Contraindications (4.1)].

2.2 Acute Myocardial Infarction

Administer Activase 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, described below).

There are two Activase 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 [see Clinical Studies (14.2)].

2.3 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 Activase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less.

2.4 Preparation for Administration

2.5 Administration

Following bolus dose, if indicated [see Dosage and Administration (2.1, 2.2)]:

• 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 [see Dosage and Administration (2.1, 2.2)]. 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 Activase. Peel the clear plastic hanger from the vial label. Hang the Activase vial from the resulting loop.

Activase is for intravenous administration only. Extravasation of Activase 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 Activase.

4.1 Acute Ischemic Stroke

Do not administer Activase 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.

4.2 Acute Myocardial Infarction or Pulmonary Embolism

Do not administer Activase for treatment of AMI or PE in the following situations in which the risk of bleeding is greater than the potential benefit [see Warnings and Precautions (5.1)]:

• 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.

5.1 Bleeding

Activase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Avoid intramuscular injections and trauma to the patient while on Activase. Perform venipunctures carefully and only as required. To minimize bleeding from noncompressible sites, avoid internal jugular and subclavian venous punctures. If an arterial puncture is necessary during Activase infusion, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely.

Because of the higher risk of intracranial hemorrhage in patients treated for acute ischemic stroke, limit treatment to facilities that can provide timely access to appropriate evaluation and management of intracranial hemorrhage.

Fatal cases of hemorrhage associated with traumatic intubation in patients administered Activase have been reported.

Aspirin and heparin have been administered concomitantly with and following infusions of Activase in the management of acute myocardial infarction and pulmonary embolism, but the concomitant administration of heparin and aspirin with and following infusions of Activase for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or Activase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of Activase, while patients are still receiving anticoagulant therapy.

If serious bleeding occurs, terminate the Activase infusion and treat appropriately. In the following conditions, the risks of bleeding with Activase therapy for all approved indications are increased and should be weighed against the anticipated benefits:

• Recent major surgery or procedure, (e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels)
• Cerebrovascular disease
• Recent intracranial hemorrhage
• Recent gastrointestinal or genitourinary bleeding
• Recent trauma
• Hypertension: systolic BP above 175 mm Hg or diastolic BP above 110 mm Hg
• Acute pericarditis
• Subacute bacterial endocarditis
• Hemostatic defects including those secondary to severe hepatic or renal disease
• Significant hepatic dysfunction
• Pregnancy
• Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions
• Septic thrombophlebitis or occluded AV cannula at seriously infected site
• Advanced age [see Use in Specific Populations (8.5)]
• Patients currently receiving 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.

5.2 Hypersensitivity

Hypersensitivity, including urticarial / anaphylactic reactions, have been reported after administration of Activase (e.g., laryngeal edema, rash and shock). Rare fatal outcome for hypersensitivity was reported. Angioedema has been observed during and up to 2 hours after Activase infusion in patients treated for acute ischemic stroke and acute myocardial infarction. In many cases, patients received concomitant angiotensin-converting enzyme inhibitors [see Drug Interactions (7)].

Monitor patients treated with Activase during and for several hours after infusion for hypersensitivity. If signs of hypersensitivity occur, e.g. anaphylactoid reaction or angioedema develops, discontinue the Activase infusion and promptly institute appropriate therapy (e.g., antihistamines, intravenous corticosteroids, epinephrine).

5.3 Thromboembolism

The use of thrombolytics can increase the risk of thrombo-embolic events in patients with high likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation. Activase has not been shown to treat adequately underlying deep vein thrombosis in patients with PE. Consider the possible risk of re-embolization due to the lysis of underlying deep venous thrombi in this setting.

5.4 Cholesterol Embolization

Cholesterol embolism has been reported rarely in patients treated with thrombolytic agents; the true incidence is unknown. Cholesterol embolism may present with livedo reticularis, "purple toe" syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, or rhabdomyolysis and can be fatal. It is associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.

5.5 Coagulation Tests May Be Unreliable during Activase Therapy

Coagulation tests and measures of fibrinolytic activity may be unreliable during Activase therapy, unless specific precautions are taken to prevent in vitro artifacts. When present in blood at pharmacologic concentrations, Activase remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most frequent adverse reaction associated with Activase in all approved indications is bleeding.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Activase. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions are frequent sequelae of the underlying disease, and the effect of Activase on the incidence of these events is unknown.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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

8.5 Geriatric Use

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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

12.3 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility. Short-term studies, which evaluated tumorigenicity of Activase and effect on tumor metastases in rodents, were negative.

Studies to determine mutagenicity (Ames test) and chromosomal aberration assays in human lymphocytes were negative at all concentrations tested. Cytotoxicity, as reflected by a decrease in mitotic index, was evidenced only after prolonged exposure and only at the highest concentrations tested.

14.1 Acute Ischemic Stroke (AIS)

Two placebo-controlled, double-blind trials (Studies 1 and 2) were conducted in patients with AIS. Both studies enrolled patients with measurable neurological deficit who could complete screening and begin study treatment within 3 hours from symptom onset. A cranial computerized tomography (CT) scan was performed prior to treatment to rule out the presence of intracranial hemorrhage. Blood pressure was actively controlled (185/110 mm Hg or lower) for 24 hours.

Patients were randomized (1:1) to receive either 0.9 mg/kg Activase (maximum of 90 mg) or placebo. Activase was administered as a 10% initial IV bolus over 1 minute followed by continuous IV infusion of the remainder over 60 minutes. Study treatment was initiated prior to the availability of coagulation study results in patients without recent use of oral anticoagulants and/or heparin and was discontinued if the pretreatment prothrombin time (PT) was greater than 15 seconds or the activated partial thromboplastin time (aPTT) was elevated. Patients with prior aspirin use were included. Administration of anticoagulants and antiplatelet agents was prohibited for the first 24 hours following symptom onset.

Study 1 (n=291) evaluated neurological improvement at 24 hours after stroke onset. The primary endpoint, the proportion of patients with a 4 point or greater improvement in the National Institutes of Health Stroke Scale (NIHSS) score or complete recovery (NIHSS score of 0), was not significantly different between treatment groups. A prespecified secondary analysis suggested improved 3-month outcome associated with Activase treatment using the following stroke assessment scales: Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale, and the NIHSS.

Study 2 (n=333) assessed clinical outcome at 3 months. A favorable outcome was defined as minimal or no disability using four stroke assessment scales: Barthel Index (score of 95 or greater), Modified Rankin Scale (score of 1 or less), Glasgow Outcome Scale (score of 1), and NIHSS (score of 1 or less). The results comparing Activase- and placebo-treated patients for the four outcome scales together (Generalized Estimating Equations) and individually are presented in Table 7. In this study, depending upon the scale, the favorable outcome of minimal or no disability occurred in at least 11 per 100 more patients treated with Activase than those receiving placebo. Study results demonstrated consistent functional and neurological improvement within all four stroke scales as indicated by median scores. These results were consistent with the 3-month outcome treatment effects observed in Study 1.

In a prespecified subgroup analysis of patients receiving aspirin prior to onset of stroke symptoms, the favorable outcome for Activase-treated patients was preserved.

14.2 Acute Myocardial Infarction (AMI)

Two Activase dose regimens have been studied in patients experiencing acute myocardial infarction [see Dosage and Administration (2.2)]. The comparative efficacy of these two regimens has not been evaluated.

14.3 Acute Massive Pulmonary Embolism (PE)

Study 6 was a comparative randomized trial (n =45) in which 59% of patients (n =22) treated with Activase (100 mg over 2 hours) experienced moderate or marked lysis of pulmonary emboli when assessed by pulmonary angiography 2 hours after treatment initiation. Activase-treated patients also experienced a significant reduction in pulmonary embolism-induced pulmonary hypertension within 2 hours of treatment (p=0.003). Pulmonary perfusion at 24 hours, as assessed by radionuclide scan, was significantly improved (p= 0.002).

16.1 How Supplied

Activase is supplied as a sterile, lyophilized powder in 50 mg vials containing vacuum and in 100 mg vials without vacuum.

Each 50 mg Activase vial (29 million IU) is packaged with diluent for reconstitution (50 mL Sterile Water for Injection, USP): NDC 50242-044-13.

Each 100 mg Activase vial (58 million IU) is packaged with diluent for reconstitution (100 mL Sterile Water for Injection, USP), and one transfer device: NDC 50242-085-27.

16.2 Stability and Storage

Store lyophilized Activase at controlled room temperature not to exceed 30°C (86°F), or under refrigeration (2-8°C/36-46°F). Protect the lyophilized material during extended storage from excessive exposure to light. If stored between 2-30°C (36-86°F), Activase 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.