These Highlights Do Not Include All The Information Needed To Use Activase Safely And Effectively. See Full Prescribing Information For Activase.

Limitation of Use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose AMI puts them at low risk for death or heart failure.

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.

Alteplase is a tissue plasminogen activator produced by recombinant DNA technology. It is a sterile, purified glycoprotein of 527 amino acids. It is synthesized using the complementary DNA (cDNA) for natural human tissue-type plasminogen activator obtained from a human melanoma cell line. Biological potency is determined by an in vitro clot lysis assay and is expressed in International Units (IU).

Activase (alteplase) is a sterile, white to off-white, lyophilized powder for intravenous administration after reconstitution with Sterile Water for Injection, USP.

The reconstituted preparation results in a colorless to pale yellow transparent solution containing Activase 1 mg/mL at approximately pH 7.3. The osmolality of this solution is approximately 215 mOsm/kg.

Activase is supplied as a sterile, lyophilized powder in 50 mg single-dose vials containing vacuum and in 100 mg single-dose 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.

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

General

• Active internal bleeding. (4.1, 4.2)
• Recent intracranial or intraspinal surgery or serious head trauma. (4.1, 4.2)
• Intracranial conditions that may increase the risk of bleeding. (4.1, 4.2)
• Bleeding diathesis. (4.1, 4.2)
• Current severe uncontrolled hypertension. (4.1, 4.2)

Acute Ischemic Stroke

• Current intracranial hemorrhage. (4.1)
• Subarachnoid hemorrhage. (4.1)

Acute Myocardial Infarction or Pulmonary Embolism

• History of recent stroke. (4.2)

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.

The following adverse reactions are discussed in greater detail in the other sections of the label:

• Bleeding [see Contraindications (4), Warnings and Precautions (5.1)]
• Hypersensitivity [see Warnings and Precautions (5.2)]
• Thromboembolism [see Warnings and Precautions (5.3)]
• Cholesterol Embolization [see Warnings and Precautions (5.4)]

The interaction of Activase 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 Activase therapy.

In the post-marketing setting, there have been reports of angioedema in patients (primarily patients with AIS) receiving concomitant angiotensin-converting enzyme inhibitors. [see Warnings and Precautions (5.2)].

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).

Activase®

(alteplase) for injection

for intravenous use

100 mg (58 million IU)

Read before preparing Activase®

See also enclosed, full prescribing information

Instructions for Use should accompany reconstituted Activase to patient bedside.

Prescribing Information

Instructions for Use

Also Required

(not included in kit)

1 Luer syringe for removing bolus dose, as needed

1 Luer syringe for removing excess volume, as needed

2 large bore needles

2 Alcohol swabs

IV infusion set

Administration Notes

• Activase is for intravenous administration only.
• Do not add any other medication to infusion solutions containing Activase.
• Extravasation of Activase infusion can cause ecchymosis or inflammation. If extravasation occurs, terminate the infusion at that IV site and apply local therapy.
• See full prescribing information for alternative dilution instructions.

Storage & Stability

• Store lyophilized Activase at controlled room temperature not to exceed 30°C (86°F), or under refrigeration at 2° to 8° C (36° to 46° F). Protect the lyophilized material during extended storage from excessive exposure to light.
• Activase contains no antibacterial preservatives and must be used within 8 hours following reconstitution (when stored at 2-30°C).

Manufactured by:

Genentech, Inc.

A Member of the Roche Group

1 DNA Way

South San Francisco, CA 94080-4990

U.S. License No. 1048

Activase® (alteplase) is a registered trademark of Genentech, Inc.

©2025 Genentech, Inc. All rights reserved.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised: February/2025

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

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.

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.

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.

Activase is a tissue plasminogen activator (tPA) indicated for the treatment of:

• Acute Ischemic Stroke (AIS). (1.1)
• Acute Myocardial Infarction (AMI) to reduce mortality and incidence of heart failure. (1.2)
  
  Limitation of Use in AMI: the risk of stroke may be greater than the benefit in patients at low risk of death from cardiac causes. (1.2)
• Acute Massive Pulmonary Embolism (PE) for lysis. (1.3)

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.

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.

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)].

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.

Store lyophilized Activase at controlled room temperature not to exceed 30°C (86°F), or under refrigeration at 2° to 8°C (36° to 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.

• Increases the risk of bleeding. Avoid intramuscular injections. Monitor for bleeding. If serious bleeding occurs, discontinue Activase. (5.1)
• Monitor patients during and for several hours after infusion for hypersensitivity. If signs of hypersensitivity develop, discontinue Activase. (5.2)
• Consider the risk of reembolization from the lysis of underlying deep venous thrombi in patients with pulmonary embolism. (5.3)
• Cholesterol embolism has been reported rarely in patients treated with thrombolytic agents. (5.4)

• Acute Ischemic Stroke: The recommended dose is 0.9 mg/kg (not to exceed 90 mg total dose) infused intravenously over 60 minutes with 10% of the total dose administered as an initial bolus over 1 minute. (2.1)
• Acute Myocardial Infarction: The recommended total dose is based on patient weight, not to exceed 100 mg. (2.2)
• Acute Massive Pulmonary Embolism: The recommended dose is 100 mg administered by IV infusion over 2 hours. (2.3)

Do not add other medications to infusions containing Activase. (2.5)

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.

• 50 mg lyophilized powder in single-dose vial with 50 mL SWFI USP for reconstitution
• 100 mg lyophilized powder in single-dose vial with 100 mL SWFI USP for reconstitution

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.

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.

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.

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

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)].

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.

Following Activase administration, patients are at increased risk of bleeding internally or externally. Advise patients to contact a health-care professional if they experience symptoms or signs consistent with bleeding (e.g., unusual bruising, pink or brown urine, red or black or tarry stools, coughing up blood, vomiting blood or blood that looks like coffee grounds), headache, or stroke symptoms.

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.

See the enclosed Instructions for Use for Activase 100 mg enclosed in the carton for reconstitution and administration instructions.

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).

NDC 50242-044-13

Activase^®

(alteplase)

For Injection

50 mg per vial

For Intravenous Use

Single-Dose Vial

Discard Unused Portion

a tissue plasminogen activator

10243242

Genentech

NDC 50242-085-27

Activase^®

(alteplase)

For Injection

100 mg per vial

For Intravenous Use

Single-Dose Vial

Discard Unused Portion

a tissue plasminogen activator

10236862

Genentech

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.

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.

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.

• Activase is for intravenous administration only.
• Do not add any other medication to infusion solutions containing Activase.
• Extravasation of Activase infusion can cause ecchymosis or inflammation. If extravasation occurs, terminate the infusion at that intravenous site and apply local therapy.
• Use within 8 hours following reconstitution (when stored at 2–30°C). Activase contains no antibacterial preservatives.

Limitation of Use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose AMI puts them at low risk for death or heart failure.

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.

Alteplase is a tissue plasminogen activator produced by recombinant DNA technology. It is a sterile, purified glycoprotein of 527 amino acids. It is synthesized using the complementary DNA (cDNA) for natural human tissue-type plasminogen activator obtained from a human melanoma cell line. Biological potency is determined by an in vitro clot lysis assay and is expressed in International Units (IU).

Activase (alteplase) is a sterile, white to off-white, lyophilized powder for intravenous administration after reconstitution with Sterile Water for Injection, USP.

The reconstituted preparation results in a colorless to pale yellow transparent solution containing Activase 1 mg/mL at approximately pH 7.3. The osmolality of this solution is approximately 215 mOsm/kg.

Activase is supplied as a sterile, lyophilized powder in 50 mg single-dose vials containing vacuum and in 100 mg single-dose 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.

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

General

• Active internal bleeding. (4.1, 4.2)
• Recent intracranial or intraspinal surgery or serious head trauma. (4.1, 4.2)
• Intracranial conditions that may increase the risk of bleeding. (4.1, 4.2)
• Bleeding diathesis. (4.1, 4.2)
• Current severe uncontrolled hypertension. (4.1, 4.2)

Acute Ischemic Stroke

• Current intracranial hemorrhage. (4.1)
• Subarachnoid hemorrhage. (4.1)

Acute Myocardial Infarction or Pulmonary Embolism

• History of recent stroke. (4.2)

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.

The following adverse reactions are discussed in greater detail in the other sections of the label:

• Bleeding [see Contraindications (4), Warnings and Precautions (5.1)]
• Hypersensitivity [see Warnings and Precautions (5.2)]
• Thromboembolism [see Warnings and Precautions (5.3)]
• Cholesterol Embolization [see Warnings and Precautions (5.4)]

The interaction of Activase 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 Activase therapy.

In the post-marketing setting, there have been reports of angioedema in patients (primarily patients with AIS) receiving concomitant angiotensin-converting enzyme inhibitors. [see Warnings and Precautions (5.2)].

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).

Activase®

(alteplase) for injection

for intravenous use

100 mg (58 million IU)

Read before preparing Activase®

See also enclosed, full prescribing information

Instructions for Use should accompany reconstituted Activase to patient bedside.

Prescribing Information

Instructions for Use

Also Required

(not included in kit)

1 Luer syringe for removing bolus dose, as needed

1 Luer syringe for removing excess volume, as needed

2 large bore needles

2 Alcohol swabs

IV infusion set

Administration Notes

• Activase is for intravenous administration only.
• Do not add any other medication to infusion solutions containing Activase.
• Extravasation of Activase infusion can cause ecchymosis or inflammation. If extravasation occurs, terminate the infusion at that IV site and apply local therapy.
• See full prescribing information for alternative dilution instructions.

Storage & Stability

• Store lyophilized Activase at controlled room temperature not to exceed 30°C (86°F), or under refrigeration at 2° to 8° C (36° to 46° F). Protect the lyophilized material during extended storage from excessive exposure to light.
• Activase contains no antibacterial preservatives and must be used within 8 hours following reconstitution (when stored at 2-30°C).

Manufactured by:

Genentech, Inc.

A Member of the Roche Group

1 DNA Way

South San Francisco, CA 94080-4990

U.S. License No. 1048

Activase® (alteplase) is a registered trademark of Genentech, Inc.

©2025 Genentech, Inc. All rights reserved.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised: February/2025

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

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.

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.

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.

Activase is a tissue plasminogen activator (tPA) indicated for the treatment of:

• Acute Ischemic Stroke (AIS). (1.1)
• Acute Myocardial Infarction (AMI) to reduce mortality and incidence of heart failure. (1.2)
  
  Limitation of Use in AMI: the risk of stroke may be greater than the benefit in patients at low risk of death from cardiac causes. (1.2)
• Acute Massive Pulmonary Embolism (PE) for lysis. (1.3)

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.

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.

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)].

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.

Store lyophilized Activase at controlled room temperature not to exceed 30°C (86°F), or under refrigeration at 2° to 8°C (36° to 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.

• Increases the risk of bleeding. Avoid intramuscular injections. Monitor for bleeding. If serious bleeding occurs, discontinue Activase. (5.1)
• Monitor patients during and for several hours after infusion for hypersensitivity. If signs of hypersensitivity develop, discontinue Activase. (5.2)
• Consider the risk of reembolization from the lysis of underlying deep venous thrombi in patients with pulmonary embolism. (5.3)
• Cholesterol embolism has been reported rarely in patients treated with thrombolytic agents. (5.4)

• Acute Ischemic Stroke: The recommended dose is 0.9 mg/kg (not to exceed 90 mg total dose) infused intravenously over 60 minutes with 10% of the total dose administered as an initial bolus over 1 minute. (2.1)
• Acute Myocardial Infarction: The recommended total dose is based on patient weight, not to exceed 100 mg. (2.2)
• Acute Massive Pulmonary Embolism: The recommended dose is 100 mg administered by IV infusion over 2 hours. (2.3)

Do not add other medications to infusions containing Activase. (2.5)

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.

• 50 mg lyophilized powder in single-dose vial with 50 mL SWFI USP for reconstitution
• 100 mg lyophilized powder in single-dose vial with 100 mL SWFI USP for reconstitution

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.

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.

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.

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

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)].

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.

Following Activase administration, patients are at increased risk of bleeding internally or externally. Advise patients to contact a health-care professional if they experience symptoms or signs consistent with bleeding (e.g., unusual bruising, pink or brown urine, red or black or tarry stools, coughing up blood, vomiting blood or blood that looks like coffee grounds), headache, or stroke symptoms.

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.

See the enclosed Instructions for Use for Activase 100 mg enclosed in the carton for reconstitution and administration instructions.

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).

NDC 50242-044-13

Activase^®

(alteplase)

For Injection

50 mg per vial

For Intravenous Use

Single-Dose Vial

Discard Unused Portion

a tissue plasminogen activator

10243242

Genentech

NDC 50242-085-27

Activase^®

(alteplase)

For Injection

100 mg per vial

For Intravenous Use

Single-Dose Vial

Discard Unused Portion

a tissue plasminogen activator

10236862

Genentech

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.

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.

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.

• Activase is for intravenous administration only.
• Do not add any other medication to infusion solutions containing Activase.
• Extravasation of Activase infusion can cause ecchymosis or inflammation. If extravasation occurs, terminate the infusion at that intravenous site and apply local therapy.
• Use within 8 hours following reconstitution (when stored at 2–30°C). Activase contains no antibacterial preservatives.