Activase

(Alteplase)

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Activase Prescribing Information

Dosage and Administration (

2.5 Activase 100 mg Instructions for Use

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

Alternative Dilution Instructions

Activase may be administered as reconstituted at 1 mg/mL or further diluted immediately before administration in an equal volume of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to yield a concentration of 0.5 mg/mL, using either polyvinyl chloride bags or glass vials.

)

09/2022

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

Acute Ischemic Stroke (AIS). (
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.
)
Acute Myocardial Infarction (AMI) to reduce mortality and incidence of heart failure. (
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.
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.
)

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 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.
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.
)
Acute Massive Pulmonary Embolism (PE) for lysis. (
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.
)

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 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)]
.
)
Acute Myocardial Infarction
: The recommended total dose is based on patient weight, not to exceed 100 mg. (
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)].
Accelerated Infusion
The recommended accelerated infusion dose consists of an IV bolus
[see Dosage and Administration (2.4, 2.5)]
followed by an IV infusion as set forth in Table 1.
Table 1 Accelerated Infusion Weight-Based Doses for Patients with AMI
Patient weight Intravenous Bolus First 30 min Next 60 min
> 67 kg 15 mg 50 mg 35 mg
≤ 67 kg 15 mg 0.75 mg/kg 0.50 mg/kg
The safety and efficacy of accelerated infusion of Activase have only been investigated with concomitant administration of heparin and aspirin
[see Clinical Studies (14.2)]
.
3-Hour Infusion
For patients weighing ≥ 65 kg, the recommended dose is 100 mg administered as 60 mg in the first hour (6-10 mg administered as a bolus), 20 mg over the second hour, and 20 mg over the third hour. For smaller patients (< 65 kg), a dose of 1.25 mg/kg administered over 3 hours may be used. Weight-based doses are shown in Table 2.
Table 2 3-hour Infusion Weight-Based Doses for Patients with AMI
Patient weight Bolus Rest of 1st hour 2nd hour 3rd hour
≥ 65 kg 6-10 mg 50-54 mg 20 mg 20 mg
< 65 kg 0.075 mg/kg 0.675 mg/kg 0.25 mg/kg 0.25 mg/kg
)
Acute Massive Pulmonary Embolism
: The recommended dose is 100 mg administered by IV infusion over 2 hours. (
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.
)

Table 1 Accelerated Infusion Weight-Based Doses for Patients with AMI
Patient weight	Intravenous Bolus	First 30 min	Next 60 min
> 67 kg	15 mg	50 mg	35 mg
≤ 67 kg	15 mg	0.75 mg/kg	0.50 mg/kg

Table 2 3-hour Infusion Weight-Based Doses for Patients with AMI
Patient weight	Bolus	Rest of 1st hour	2nd hour	3rd hour
≥ 65 kg	6-10 mg	50-54 mg	20 mg	20 mg
< 65 kg	0.075 mg/kg	0.675 mg/kg	0.25 mg/kg	0.25 mg/kg

Do not add other medications to infusions containing Activase. (

2.5 Activase 100 mg Instructions for Use

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

Alternative Dilution Instructions

)

Risk Summary

Published studies and case reports on alteplase use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Alteplase is embryocidal in rabbits when intravenously administered during organogenesis at the clinical exposure for AMI, but no maternal or fetal toxicity was evident at lower exposure in pregnant rats or rabbits

(see

Data

Animal Data

Alteplase is embryocidal in rabbits when administered intravenously during organogenesis in doses (3 mg/kg) approximately equal to the human exposure (based on AUC) at the dose for AMI. No maternal or fetal toxicity was evident at doses (1 mg/kg) approximately 0.3 times the human exposure. In pregnant rats, no maternal or fetal toxicity was evident at doses (1 mg/kg) approximately 0.6 times the human dose for AMI (based on body weight) dosed during the period of organogenesis.

)

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

General

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

Acute Ischemic Stroke

Current intracranial hemorrhage. (
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.
)
Subarachnoid hemorrhage. (
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.
)

Acute Myocardial Infarction or Pulmonary Embolism

History of recent stroke. (
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.
)

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