For Acute Ischemic Stroke

Activase® (alteplase) Dosing and Administration 1

Dosing Total Discard Bolus Infusion

Weight Dose Quantity* Dose Dose
The recommended dose of Activase is 0.9 mg/kg (not to exceed (over 1 (over 60
90 mg total dose) infused intravenously over 60 minutes with 10% of (lb) (kg) minute) minutes)
the total dose administered as an initial bolus over 1 minute. Reconstitute 90 40.9 36.8 63.2 3.7 33.1
the Activase powder using the accompanying Sterile Water for Injection,
92 41.8 37.6 62.4 3.8 33.8
USP. Swirl the vial gently to dissolve the powder—do not shake.
For more information on reconstitution of 50-mg and 100-mg 94 42.7 38.4 61.6 3.8 34.6
vials of Activase, see full Prescribing Information below. 96 43.6 39.2 60.8 3.9 35.3
98 44.5 40.1 59.9 4.0 36.1
Administration 100 45.5 41.0 59.0 4.1 36.9
Step 1 After reconstitution to 1 mg/mL, inspect the solution for particulate 102 46.4 41.8 58.2 4.2 37.6
matter and discoloration prior to administration.
INSPECT SOLUTION 104 47.3 42.6 57.4 4.3 38.3
The reconstituted preparation results in a colorless to pale yellow
transparent solution. 106 48.2 43.4 56.6 4.3 39.1
108 49.1 44.2 55.8 4.4 39.8
Step 2 Keyhole port DO NOT prime To ensure proper dosing, discard excess by removing from
110 50.0 45.0 55.0 4.5 40.5
syringe the vial any quantity of drug in excess of that specified for
DISCARD Syringe the patient’s treatment. 112 50.9 45.8 54.2 4.6 41.2
EXCESS (no air)
• Slightly tilt the vial and insert the needle into the
No 114 51.8 46.6 53.4 4.7 41.9
Air keyhole port of the vial top, away from the puncture
site made by the transfer device 116 52.7 47.4 52.6 4.7 42.7

SE
Alternative option: 118 53.6 48.2 51.8 4.8 43.4
VA
TI g
0m
Activase
AC
10 At this step, you can prepare the infusion set and remove 120 54.6 49.1 50.9 4.9 44.2
vial excess from the injection port.
122 55.5 50.0 50.0 5.0 45.0
Step 3 Keyhole port The bolus dose is 10% of the 0.9-mg/kg dose. Prepare 124 56.4 50.8 49.2 5.1 45.7
DO NOT prime it one of the following ways, using a syringe and needle:
PREPARE syringe 126 57.3 51.6 48.4 5.2 46.4
1. Remove the dose from the Y-site injection port on the
BOLUS infusion line after the infusion set is primed; 128 58.2 52.4 47.6 5.2 47.2
No
Air
OR 130 59.1 53.2 46.8 5.3 47.9
2. Remove the dose from the vial before the vial is attached 132 60.0 54.0 46.0 5.4 48.6
E
AS
AC
TI

10
V
0m
g to the infusion set. Be sure to insert the needle into the 134 60.9 54.8 45.2 5.5 49.3
keyhole port of the vial top, away from the puncture site
1 Injection OR 2 Activase made by the transfer device. 136 61.8 55.6 44.4 5.6 50.0
port vial
138 62.7 56.4 43.6 5.6 50.8
Step 4 Infusion set 100-mg vials 140 63.6 57.2 42.8 5.7 51.5
• Insert the spike end of an infusion set through the center
PREPARE of the stopper of the vial of reconstituted Activase, using 142 64.5 58.1 41.9 5.8 52.3
INFUSION 100 mg

the same puncture site made by the transfer device

ACTIVASE

144 65.5 59.0 41.0 5.9 53.1

SET 100 mg
ASE
ACTIV

• Peel the clear plastic hanger from the vial label. Hang
146 66.4 59.8 40.2 6.0 53.8
the Activase vial from the resulting loop
50-mg vials 148 67.3 60.6 39.4 6.1 54.5
Center
• Administer using either a polyvinyl chloride bag or glass 150 68.2 61.4 38.6 6.1 55.3
vial and infusion set
Activase vial 152 69.1 62.2 37.8 6.2 56.0
Step 5 Prime infusion set tubing with Activase solution. 154 70.0 63.0 37.0 6.3 56.7
PRIME INFUSION SET 156 70.9 63.8 36.2 6.4 57.4
100 mg
ACTIVASE

100 mg
ACTIVA
SE

158 71.8 64.6 35.4 6.5 58.1

160 72.7 65.4 34.6 6.5 58.9
Step 6 Administer initial IV bolus over 1 minute. 162 73.6 66.2 33.8 6.6 59.6
ADMINISTER BOLUS Administer IV bolus directly through the IV port or program
164 74.5 67.1 32.9 6.7 60.4
the infusion pump to deliver the bolus dose.
166 75.5 68.0 32.0 6.8 61.2
168 76.4 68.8 31.2 6.9 61.9
Step 7 Immediately following the bolus dose, infuse the remaining
90% of the 0.9-mg/kg dose over 60 minutes. 170 77.3 69.6 30.4 7.0 62.6
ADMINISTER REMAINDER
172 78.2 70.4 29.6 7.0 63.4
174 79.1 71.2 28.8 7.1 64.1
176 80.0 72.0 28.0 7.2 64.8
Step 8 To ensure the full dose is delivered:
178 80.9 72.8 27.2 7.3 65.5
100 mg

CLEAR IV TUBING • Spike a small bag (eg, 50 mL) of 0.9% Sodium Chloride,
ACTIVASE

USP, with end of the Activase infusion set when the 180 81.8 73.6 26.4 7.4 66.2
Activase vial is empty. The infusion should continue
at the same rate 182 82.7 74.4 25.6 7.4 67.0
184 83.6 75.2 24.8 7.5 67.7
No medication should be added to infusion solutions that contain Activase. 186 84.5 76.1 23.9 7.6 68.5
For additional information regarding dosing and administration, please see the Activase full Prescribing Information below.
188 85.5 77.0 23.0 7.7 69.3
Indication carefully and only as required. Fatal cases shown to treat adequately underlying 190 86.4 77.8 22.2 7.8 70.0
of hemorrhage associated with traumatic deep vein thrombosis in patients with PE.
Activase (alteplase) is indicated for the
intubation in patients administered Activase Consider the possible risk of re-embolization 192 87.3 78.6 21.4 7.9 70.7
treatment of acute ischemic stroke. Exclude have been reported. Heparin, aspirin, or due to the lysis of underlying deep venous 194 88.2 79.4 20.6 7.9 71.5
intracranial hemorrhage as the primary Activase may cause bleeding complications; thrombi in this setting.
cause of stroke signs and symptoms prior therefore carefully monitor for bleeding. 196 89.1 80.2 19.8 8.0 72.2
to initiation of treatment. Initiate treatment Cholesterol Embolization
If serious bleeding occurs, terminate the Cholesterol embolism, sometimes fatal, 198 90.0 81.0 19.0 8.1 72.9
as soon as possible but within 3 hours
Activase infusion and treat appropriately. has been reported rarely in patients
after symptom onset. 200 90.9 81.8 18.2 8.2 73.6
Hypersensitivity treated with thrombolytic agents.
Important Safety Information Hypersensitivity, including urticarial / Coagulation Tests May be 202 91.8 82.6 17.4 8.3 74.3
Contraindications anaphylactic reactions have been reported. Unreliable during Activase Therapy
Rare fatal outcome for hypersensitivity was 204 92.7 83.4 16.6 8.3 75.1
Do not administer Activase to treat Coagulation tests and/or measures
reported. Angioedema has been observed of fibrinolytic activity may be unreliable 206 93.6 84.2 15.8 8.4 75.8
acute ischemic stroke in the following during and up to 2 hours after Activase
situations in which the risk of bleeding is during Activase therapy. 208 94.5 85.1 14.9 8.5 76.6
infusion in patients treated for acute ischemic
greater than the potential benefit: current stroke and acute myocardial infarction. In Adverse Reactions
intracranial hemorrhage (ICH); subarachnoid
210 95.5 86.0 14.0 8.6 77.4
many cases, patients received concomitant The most frequent adverse reaction
hemorrhage; active internal bleeding; recent angiotensin converting enzyme inhibitors. associated with Activase AIS therapy 212 96.4 86.8 13.2 8.7 78.1
(within 3 months) intracranial or intraspinal Monitor patients during and for several hours is bleeding.
surgery or serious head trauma; presence 214 97.3 87.6 12.4 8.8 78.8
after infusion for hypersensitivity. If signs of
of intracranial conditions that may increase hypersensitivity occur, e.g. anaphylactoid 216 98.2 88.4 11.6 8.8 79.6
Please see the full Prescribing
the risk of bleeding (e.g., some neoplasms, reaction or angioedema develops, Information below. 218 99.1 89.2 10.8 8.9 80.3
arteriovenous malformations, or aneurysms); discontinue Activase and promptly institute
bleeding diathesis; and current severe appropriate therapy (e.g., antihistamines, ≥220 ≥100.0 90.0 10.0 9.0 81.0
uncontrolled hypertension. intravenous corticosteroids, epinephrine). *Calculations based on 100-mg vial of Activase.
Warnings and Precautions Thromboembolism Reference: 1. Activase [prescribing information]. South San Francisco, CA: Genentech, Inc; 2018.
Bleeding The use of thrombolytics can increase the
Activase can cause significant, and risk of thrombo-embolic events in patients
sometimes fatal internal or external bleeding. with high likelihood of left heart thrombus,
Avoid intramuscular injections and trauma such as patients with mitral stenosis or
to the patient. Perform venipunctures atrial fibrillation. Activase has not been © 2018 Genentech USA, Inc.  All rights reserved. ACI/121614/0041(3)a
HIGHLIGHTS OF PRESCRIBING INFORMATION Acute Ischemic Stroke
These highlights do not include all the information needed to use • Current intracranial hemorrhage. (4.1)
ACTIVASE safely and effectively. See full prescribing information for • Subarachnoid hemorrhage. (4.1)
ACTIVASE. Acute Myocardial Infarction or Pulmonary Embolism
• History of recent stroke. (4.2)
Activase (alteplase) for injection, for intravenous use
Initial U.S. Approval: 1987 -----------------------WARNINGS AND PRECAUTIONS------------------------
------------------- RECENT MAJOR CHANGES ------------------ • Increases the risk of bleeding. Avoid intramuscular injections. Monitor for
bleeding. If serious bleeding occurs, discontinue Activase. (5.1)
Warnings and Precautions (5.3) 02/2018 • Monitor patients during and for several hours after infusion for
hypersensitivity. If signs of hypersensitivity develop, discontinue Activase.
---------------------------INDICATIONS AND USAGE--------------------------- (5.2)
Activase is a tissue plasminogen activator (tPA) indicated for the treatment of • Consider the risk of reembolization from the lysis of underlying deep
• Acute Ischemic Stroke (AIS). (1.1) venous thrombi in patients with pulmonary embolism. (5.3)
• Acute Myocardial Infarction (AMI) to reduce mortality and incidence of • Cholesterol embolism has been reported rarely in patients treated with
heart failure. (1.2) thrombolytic agents. (5.4)
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) ------------------------------ADVERSE REACTIONS------------------------------
• Acute Massive Pulmonary Embolism (PE) for lysis. (1.3) The most frequently occurring adverse reaction ( > 5%) is bleeding. (6)

------------------------DOSAGE AND ADMINISTRATION--------------------- To report SUSPECTED ADVERSE REACTIONS, contact Genentech at

• Acute Ischemic Stroke: The recommended dose is 0.9 mg/kg (not to 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
exceed 90 mg total dose) infused intravenously over 60 minutes with 10% -------------------------------DRUG INTERACTIONS-----------------------------
of the total dose administered as an initial bolus over 1 minute. (2.1)
• Anticoagulants and drugs that inhibit platelet function increase the risk of
• Acute Myocardial Infarction: The recommended total dose is based on
bleeding when administered with Activase therapy. (7)
patient weight, not to exceed 100 mg. (2.2)
• Concomitant angiotensin-converting enzyme inhibitors may increase the
• Acute Massive Pulmonary Embolism: The recommended dose is 100 mg
risk of angioedema. (7)
administered by IV infusion over 2 hours. (2.3)
• Do not add other medications to infusions containing Activase. (2.5) ----------------------USE IN SPECIFIC POPULATIONS------------------------
See 17 for PATIENT COUNSELING INFORMATION.
---------------------DOSAGE FORMS AND STRENGTHS---------------------
• Lyophilized powder: 50 mg and 100 mg with Sterile Water for Injection Revised: 02/2018
USP for reconstitution at 1 mg per 1 mL. (3)

------------------------------CONTRAINDICATIONS-----------------------------
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)
_______________________________________________________________________________________________________________________________________

FULL PRESCRIBING INFORMATION: CONTENTS* 6 ADVERSE REACTIONS

6.1 Clinical Trials Experience
1 INDICATIONS AND USAGE 6.2 Post-Marketing Experience
1.1 Acute Ischemic Stroke 7 DRUG INTERACTIONS
1.2 Acute Myocardial Infarction 8 USE IN SPECIFIC POPULATIONS
1.3 Pulmonary Embolism 8.1 Pregnancy
2 DOSAGE AND ADMINISTRATION 8.2 Lactation
2.1 Acute Ischemic Stroke 8.4 Pediatric Use
2.2 Acute Myocardial Infarction 8.5 Geriatric Use
2.3 Pulmonary Embolism 11 DESCRIPTION
2.4 Preparation for Administration 12 CLINICAL PHARMACOLOGY
2.5 Administration 12.1 Mechanism of Action
3 DOSAGE FORMS AND STRENGTHS 12.2 Pharmacodynamics
4 CONTRAINDICATIONS 12.3 Pharmacokinetics
4.1 Acute Ischemic Stroke 13 NONCLINICAL TOXICOLOGY
4.2 Acute Myocardial Infarction or Pulmonary Embolism 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5 WARNINGS AND PRECAUTIONS 14 CLINICAL STUDIES
5.1 Bleeding 14.1 Acute Ischemic Stroke (AIS)
5.2 Hypersensitivity 14.2 Acute Myocardial Infarction (AMI)
5.3 Thromboembolism 14.3 Acute Massive Pulmonary Embolism (PE)
5.4 Cholesterol Embolization 16 HOW SUPPLIED/STORAGE AND HANDLING
5.5 Coagulation Tests May Be Unreliable during Activase 16.1 How Supplied
Therapy 16.2 Stability and Storage
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the Full Prescribing Information are
not listed.
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
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.
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.
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 DOSAGE AND ADMINISTRATION
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)].
Accelerated Infusion
The recommended accelerated infusion dose consists of an IV bolus [see Dosage and Administration
(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

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
Reconstitution
Use only the accompanying Sterile Water for Injection (SWFI), USP without preservatives. Do not
use Bacteriostatic Water for Injection, USP.
Reconstitute using aseptic technique. Do not add other medication to solutions containing Activase.
Reconstitute Activase no more than 8 hours before use, as it contains no antibacterial preservatives
[see How Supplied/Storage and Handling (16.2)].
Slight foaming is not unusual; let stand undisturbed for several minutes to allow large bubbles to
dissipate. Inspect parenteral drug products for particulate matter and discoloration prior to
administration whenever solution and container permit.
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.
Avoid excessive agitation during dilution; mix by gently swirling and/or slow inversion.
50 mg Vials
DO NOT USE IF VACUUM IS NOT PRESENT.
Using a large bore needle (e.g., 18 gauge) and a syringe, reconstitute by adding the contents of the
accompanying 50 mL vial of SWFI to the 50 mg vial of Activase, directing the SWFI stream into
the lyophilized cake.
100 mg Vials
THE 100 mg VIALS DO NOT CONTAIN VACUUM.
Using the transfer device provided, reconstitute by adding the contents of the accompanying
100 mL vial of SWFI to the 100 mg vial of Activase.
1. Use aseptic technique.
2. Remove the protective flip-caps from one vial of Activase and one vial of SWFI.
3. Open the package containing the transfer device by peeling the paper label off the package.
4. Remove the protective cap from one end of the transfer device and keeping the vial of SWFI
upright, insert the piercing pin vertically into the center of the stopper of the vial of SWFI.
5. Remove the protective cap from the other end of the transfer device. DO NOT INVERT THE
VIAL OF SWFI.
6. Hold the vial of Activase upside down, position it so that the center of the stopper is directly
over the exposed piercing pin of the transfer device, and push the vial of Activase down so
that the piercing pin is inserted through the center of the Activase vial stopper.
7. Invert the two vials so that the vial of Activase is on the bottom (upright) and the vial of SWFI
is upside-down, allowing the SWFI to flow down through the transfer device. Allow the entire
contents of the vial of SWFI to flow into the Activase vial (approximately 0.5 cc of SWFI will
remain in the diluent vial).
8. Remove the transfer device and the empty SWFI vial from the Activase vial and discard.
9. Swirl gently to dissolve the Activase powder. DO NOT SHAKE.
Preparation of Bolus Dose
• Prepare the bolus dose in one of the following ways: Remove the appropriate volume from
the vial of reconstituted (1 mg/mL) Activase using a syringe and needle. If this method is used
with the 50 mg vials, the syringe should not be primed with air and the needle should be inserted
into the Activase vial stopper. If the 100 mg vial is used, the needle should be inserted away
from the puncture mark made by the transfer device.
• Remove the appropriate volume from a port (second injection site) on the infusion line after the
infusion set is primed.
• Program an infusion pump to deliver the appropriate volume as a bolus at the initiation of the
infusion
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.
3 DOSAGE FORMS AND STRENGTHS
• 50 mg lyophilized powder per single use vial with 50 mL SWFI USP for reconstitution
• 100 mg lyophilized powder per single use vial with 100 mL SWFI USP for reconstitution
4 CONTRAINDICATIONS
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 WARNINGS AND PRECAUTIONS
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 ADVERSE REACTIONS
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)]
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.
Bleeding
Acute Ischemic Stroke (AIS)
In clinical studies in patients with AIS (Studies 1 and 2) the incidence of intracranial hemorrhage,
especially symptomatic intracranial hemorrhage, was higher in Activase-treated patients than in
placebo patients. A dose-finding study of Activase suggested that doses greater than 0.9 mg/kg may
be associated with an increased incidence of intracranial hemorrhage.
The incidence of all-cause 90-day mortality, intracranial hemorrhage, and new ischemic stroke
following Activase treatment compared to placebo are presented in Table 3 as a combined safety
analysis (n=624) for Studies 1 and 2. These data indicate a significant increase in intracranial
hemorrhage following Activase treatment, particularly symptomatic intracranial hemorrhage within
36 hours. There was no increase in the incidences of 90-day mortality or severe disability in
Activase-treated patients compared to placebo.
Table 3
Combined Safety Outcomes for Studies 1 and 2

Placebo Activase b
(n= 312) (n=312) p-Value
All-Cause 90-day Mortality 64 (20.5%) 54 (17.3%) 0.36

a
Total ICH 20 (6.4%) 48 (15.4%) <0.01

Symptomatic 4 (1.3%) 25 (8.0%) <0.01

Asymptomatic 16 (5.1%) 23 (7.4%) 0.32

Symptomatic Intracranial Hemorrhage within 2 (0.6%) 20 (6.4%) <0.01

36 hours
New Ischemic Stroke (3-months) 17 (5.4%) 18 (5.8%) 1.00

a
Within trial follow-up period. Symptomatic intracranial hemorrhage was defined as the occurrence
of sudden clinical worsening followed by subsequent verification of intracranial hemorrhage on CT
scan. Asymptomatic intracranial hemorrhage was defined as intracranial hemorrhage detected on a
routine repeat CT scan without preceding clinical worsening.
b
Fisher’s Exact Test.
Bleeding events other than intracranial hemorrhage were noted in the studies of AIS and were
consistent with the general safety profile of Activase. In Studies 1 and 2, the frequency of bleeding
requiring red blood cell transfusions was 6.4% for Activase-treated patients compared to 3.8% for
placebo (p = 0.19).
Although exploratory analyses of Studies 1 and 2 suggest that severe neurological deficit (National
Institutes of Health Stroke Scale [NIHSS > 22]) at presentation was associated with an increased risk
of intracranial hemorrhage, efficacy results suggest a reduced but still favorable clinical outcome for
these patients.
Acute Myocardial Infarction (AMI)
For the 3-hour infusion regimen in the treatment of AMI, the incidence of significant internal
bleeding (estimated as > 250 mL blood loss) has been reported in studies in over 800 patients
(Table 4). These data do not include patients treated with the Activase accelerated infusion.

Table 4
Incidence of Bleeding in 3-Hour Infusion in AMI Patients

Total Dose ≤100 mg

Gastrointestinal 5%
Genitourinary 4%
Ecchymosis 1%
Retroperitoneal <1%
Epistaxis <1%
Gingival <1%

The incidence of intracranial hemorrhage in AMI patients treated with Activase is presented in
Table 5.

Table 5
Incidence of Intracranial Hemorrhage in AMI Patients

Dose Number of Patients Intracranial Hemorrhage (%)

100 mg, 3-hour 3272 0.4
≤ 100 mg, accelerated 10,396 0.7
150 mg 1779 1.3
1-1.4 mg/kg 237 0.4

A dose of 150 mg or greater should not be used in the treatment of AMI because it has been
associated with an increase in intracranial bleeding.
Pulmonary Embolism (PE)
For acute massive pulmonary embolism, bleeding events were consistent with the general safety
profile observed with Activase treatment of AMI patients receiving the 3-hour infusion regimen.
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.
Acute Ischemic Stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke, embolism.
These events may be life threatening and may lead to death.
Acute Myocardial Infarction: Arrhythmias, AV block, cardiogenic shock, heart failure, cardiac
arrest, recurrent ischemia, myocardial reinfarction, myocardial rupture, electromechanical
dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade,
thromboembolism, pulmonary edema. These events may be life threatening and may lead to death.
Nausea and/or vomiting, hypotension and fever have also been reported.
Pulmonary Embolism: Pulmonary reembolization, pulmonary edema, pleural effusion,
thromboembolism, hypotension. These events may be life threatening and may lead to death. Fever
has also been reported.
7 DRUG INTERACTIONS
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)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
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).
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.
Clinical Considerations

Maternal Adverse Reactions

The most common complication of thrombolytic therapy is bleeding. Pregnancy may increase this
risk [see Warnings and Precautions (5.1)].
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.
8.2 Lactation
Risk Summary
There are no data on the presence of alteplase in human milk, the effects on the breastfed infant, or
the effects on milk production.
8.4 Pediatric Use
Safety and effectiveness of Activase in pediatric patients have not been established.
8.5 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 Activase-treated elderly
[see Clinical Studies (14.1)].
Acute Myocardial Infarction
In a large trial of accelerated-infusion Activase 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 enrollment. In these patients, the incidence of stroke was 4.0% for the
Activase 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 Activase, 21.5% for SK (IV), and 22.0% for SK (SQ).
11 DESCRIPTION
Activase 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.
Activase is a sterile, white to off-white, lyophilized powder for intravenous administration after
reconstitution with Sterile Water for Injection, USP.
 Table 6
Quantitative Composition of the Lyophilized Product

100 mg Vial 50 mg Vial

Alteplase 100 mg (58 million IU) 50 mg (29 million IU)
L-Arginine 3.5 g 1.7 g
Phosphoric Acid 1g 0.5 g
Polysorbate 80 10 mg 5 mg
Vacuum No Yes

Biological potency is determined by an in vitro clot lysis assay and is expressed in International
Units (IU).
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.
12 CLINICAL PHARMACOLOGY
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 NONCLINICAL TOXICOLOGY
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 CLINICAL STUDIES
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.
 Table 7
Study 2 Three-Month Efficacy Outcomes
a
Frequency of Favorable Outcome
Absolute b
Placebo Activase Difference Odds Ratio c
Analysis (n=165) (n=168) (95% CI) (95% Cl) p-Value
Generalized Estimating 1.71 0.02
Equations (Multivariate) - - - (1.15, 2.56)

Barthel Index 37.6% 50.0% 12.4% 1.66 0.02

(3.0, 21.9) (1.07, 2.57)

Modified Rankin Scale 26.1% 38.7% 12.6% 1.79 0.02

(3.7, 21.6) (1.12, 2.85)

Glasgow Outcome Scale 31.5% 44.0% 12.5% 1.71 0.02

(3.3, 21.8) (1.09, 2.68)

NIHSS 20.0% 31.0% 11.0% 1.79 0.02

(2.6, 19.3) (1.06, 2.96)

a
Favorable Outcome is defined as recovery with minimal or no disability.
b
Value greater than 1 indicates odds of recovery in favor of Activase treatment.
c
p-Value for Odds Ratio is from Generalized Estimating Equations with logit link.

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.

Accelerated Infusion in AMI Patients

Accelerated infusion of Activase was studied in an international, multi-center trial that randomized
41,021 patients with AMI to four thrombolytic regimens (Study 3). Entry criteria included onset of
chest pain within 6 hours of treatment and ST-segment elevation of ECG. The four treatment
regimens included accelerated infusion of Activase (≤100 mg over 90 minutes) plus intravenous (IV)
heparin (n = 10,396); Streptokinase (1.5 million units over 60 minutes) plus IV heparin (SK [IV],
n =10,410); Streptokinase plus subcutaneous (SQ) heparin (SK [SQ] n= 9841). A fourth regimen
combined Activase and Streptokinase (n =10,374). All patients received 160 mg chewable aspirin
administered as soon as possible, followed by 160-325 mg daily. Bolus IV heparin 5000 U was
initiated as soon as possible, followed by a 1000 U/hour continuous IV infusion for at least 48 hours;
subsequent heparin therapy was at the physician’s discretion. Heparin SQ 12,500 U was
administered 4 hours after initiation of SK therapy, followed by 12,500 U twice daily for 7 days or
until discharge, whichever came first. Many of the patients randomized to receive SQ heparin
received some IV heparin, usually in response to recurrent chest pain and/or the need for a medical
procedure. Some received IV heparin on arrival to the emergency room prior to enrollment and
randomization.
Key results from Study 3 are shown in Table 8. The incidence of 30-day mortality for Activase
accelerated infusion was 1.0% lower than for either Streptokinase plus heparin regimen. The
incidence of combined 30-day mortality or nonfatal stroke for the Activase accelerated infusion was
1.0% lower than for SK (IV) and 0.8% lower than for SK (SQ).

Table 8
Efficacy and Safety Results for Study 3

Accelerated a a
Event Activase SK (IV) p-Value SK (SQ) p-Value
30-Day Mortality 6.3% 7.3% 0.003 7.3% 0.007
30-Day Mortality 7.2% 8.2% 0.006 8.0% 0.036
or Nonfatal Stroke
24-Hour Mortality 2.4% 2.9% 0.009 2.8% 0.029
Any Stroke 1.6% 1.4% 0.32 1.2% 0.03
Intracerebral Hemorrhage 0.7% 0.6% 0.22 0.5% 0.02
a
Two-tailed p-value is for comparison of Accelerated Activase to the respective SK control arm.

Subgroup analysis of patients by age, infarct location, time from symptom onset to thrombolytic
treatment, and treatment in the U.S. or elsewhere showed consistently lower 30-day mortality on
Activase.
For patients who were over 75 years of age, a predefined subgroup consisting of 12% of patients
enrolled, the incidence of stroke was 4.0% for the Activase accelerated infusion group, 2.8% for SK
(IV), and 3.2% for SK (SQ); the incidence of combined 30-day mortality or nonfatal stroke was
20.6% for accelerated infusion of Activase, 21.5% for SK (IV), and 22.0% for SK (SQ).

3-Hour Infusion in AMI Patients

In a double-blind, randomized trial (n = 138) comparing 3-hour infusion of Activase to placebo
(Study 4), patients infused with Activase within 4 hours of onset of symptoms experienced improved
left ventricular function at Day 10 compared to the placebo group, when ejection fraction was
measured by gated blood pool scan (53.2% vs. 46.4%, p =0.018). Relative to baseline (Day 1)
values, the net changes in ejection fraction were + 3.6% and -4.7% for the treated and placebo
groups, respectively (p=0.0001). The treated group had a reduced incidence of clinical heart failure
(14%) compared to the placebo group (33%) (p = 0.009).
In a double-blind, randomized trial (n =5013) comparing 3-hour infusion of Activase to placebo
(Study 5), patients infused with Activase within 5 hours of AMI symptom onset experienced
improved 30-day survival compared to the placebo arm. At 1 month, the overall mortality rates were
7.2% for the Activase group and 9.8% for the placebo group (p = 0.001). At 6 months, the overall
mortality rate for Activase-treated patients was 10.4% compared to the placebo arm (13.1%,
p= 0.008).
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 HOW SUPPLIED/STORAGE AND HANDLING
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.

17 PATIENT COUNSELING INFORMATION

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.

Activase (alteplase)
®

Manufactured by:
Genentech, Inc.
A Member of the Roche Group Activase is a registered trademark of Genentech, Inc.
®

©
1 DNA Way 2018 Genentech, Inc.
South San Francisco, CA
94080-4990
U.S. License No. 1048
HIGHLIGHTS OF PRESCRIBING INFORMATION Acute Ischemic Stroke
These highlights do not include all the information needed to use • Current intracranial hemorrhage. (4.1)
ACTIVASE safely and effectively. See full prescribing information for • Subarachnoid hemorrhage. (4.1)
ACTIVASE. Acute Myocardial Infarction or Pulmonary Embolism
• History of recent stroke. (4.2)
Activase (alteplase) for injection, for intravenous use
Initial U.S. Approval: 1987 -----------------------WARNINGS AND PRECAUTIONS------------------------
------------------- RECENT MAJOR CHANGES ------------------ • Increases the risk of bleeding. Avoid intramuscular injections. Monitor for
bleeding. If serious bleeding occurs, discontinue Activase. (5.1)
Warnings and Precautions (5.3) 02/2018 • Monitor patients during and for several hours after infusion for
hypersensitivity. If signs of hypersensitivity develop, discontinue Activase.
---------------------------INDICATIONS AND USAGE--------------------------- (5.2)
Activase is a tissue plasminogen activator (tPA) indicated for the treatment of • Consider the risk of reembolization from the lysis of underlying deep
• Acute Ischemic Stroke (AIS). (1.1) venous thrombi in patients with pulmonary embolism. (5.3)
• Acute Myocardial Infarction (AMI) to reduce mortality and incidence of • Cholesterol embolism has been reported rarely in patients treated with
heart failure. (1.2) thrombolytic agents. (5.4)
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) ------------------------------ADVERSE REACTIONS------------------------------
• Acute Massive Pulmonary Embolism (PE) for lysis. (1.3) The most frequently occurring adverse reaction ( > 5%) is bleeding. (6)

------------------------DOSAGE AND ADMINISTRATION--------------------- To report SUSPECTED ADVERSE REACTIONS, contact Genentech at

• Acute Ischemic Stroke: The recommended dose is 0.9 mg/kg (not to 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
exceed 90 mg total dose) infused intravenously over 60 minutes with 10% -------------------------------DRUG INTERACTIONS-----------------------------
of the total dose administered as an initial bolus over 1 minute. (2.1)
• Anticoagulants and drugs that inhibit platelet function increase the risk of
• Acute Myocardial Infarction: The recommended total dose is based on
bleeding when administered with Activase therapy. (7)
patient weight, not to exceed 100 mg. (2.2)
• Concomitant angiotensin-converting enzyme inhibitors may increase the
• Acute Massive Pulmonary Embolism: The recommended dose is 100 mg
risk of angioedema. (7)
administered by IV infusion over 2 hours. (2.3)
• Do not add other medications to infusions containing Activase. (2.5) ----------------------USE IN SPECIFIC POPULATIONS------------------------
See 17 for PATIENT COUNSELING INFORMATION.
---------------------DOSAGE FORMS AND STRENGTHS---------------------
• Lyophilized powder: 50 mg and 100 mg with Sterile Water for Injection Revised: 02/2018
USP for reconstitution at 1 mg per 1 mL. (3)

------------------------------CONTRAINDICATIONS-----------------------------
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)
_______________________________________________________________________________________________________________________________________

FULL PRESCRIBING INFORMATION: CONTENTS* 6 ADVERSE REACTIONS

6.1 Clinical Trials Experience
1 INDICATIONS AND USAGE 6.2 Post-Marketing Experience
1.1 Acute Ischemic Stroke 7 DRUG INTERACTIONS
1.2 Acute Myocardial Infarction 8 USE IN SPECIFIC POPULATIONS
1.3 Pulmonary Embolism 8.1 Pregnancy
2 DOSAGE AND ADMINISTRATION 8.2 Lactation
2.1 Acute Ischemic Stroke 8.4 Pediatric Use
2.2 Acute Myocardial Infarction 8.5 Geriatric Use
2.3 Pulmonary Embolism 11 DESCRIPTION
2.4 Preparation for Administration 12 CLINICAL PHARMACOLOGY
2.5 Administration 12.1 Mechanism of Action
3 DOSAGE FORMS AND STRENGTHS 12.2 Pharmacodynamics
4 CONTRAINDICATIONS 12.3 Pharmacokinetics
4.1 Acute Ischemic Stroke 13 NONCLINICAL TOXICOLOGY
4.2 Acute Myocardial Infarction or Pulmonary Embolism 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5 WARNINGS AND PRECAUTIONS 14 CLINICAL STUDIES
5.1 Bleeding 14.1 Acute Ischemic Stroke (AIS)
5.2 Hypersensitivity 14.2 Acute Myocardial Infarction (AMI)
5.3 Thromboembolism 14.3 Acute Massive Pulmonary Embolism (PE)
5.4 Cholesterol Embolization 16 HOW SUPPLIED/STORAGE AND HANDLING
5.5 Coagulation Tests May Be Unreliable during Activase 16.1 How Supplied
Therapy 16.2 Stability and Storage
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the Full Prescribing Information are
not listed.
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
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.
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.
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 DOSAGE AND ADMINISTRATION
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)].
Accelerated Infusion
The recommended accelerated infusion dose consists of an IV bolus [see Dosage and Administration
(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

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
Reconstitution
Use only the accompanying Sterile Water for Injection (SWFI), USP without preservatives. Do not
use Bacteriostatic Water for Injection, USP.
Reconstitute using aseptic technique. Do not add other medication to solutions containing Activase.
Reconstitute Activase no more than 8 hours before use, as it contains no antibacterial preservatives
[see How Supplied/Storage and Handling (16.2)].
Slight foaming is not unusual; let stand undisturbed for several minutes to allow large bubbles to
dissipate. Inspect parenteral drug products for particulate matter and discoloration prior to
administration whenever solution and container permit.
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.
Avoid excessive agitation during dilution; mix by gently swirling and/or slow inversion.
50 mg Vials
DO NOT USE IF VACUUM IS NOT PRESENT.
Using a large bore needle (e.g., 18 gauge) and a syringe, reconstitute by adding the contents of the
accompanying 50 mL vial of SWFI to the 50 mg vial of Activase, directing the SWFI stream into
the lyophilized cake.
100 mg Vials
THE 100 mg VIALS DO NOT CONTAIN VACUUM.
Using the transfer device provided, reconstitute by adding the contents of the accompanying
100 mL vial of SWFI to the 100 mg vial of Activase.
1. Use aseptic technique.
2. Remove the protective flip-caps from one vial of Activase and one vial of SWFI.
3. Open the package containing the transfer device by peeling the paper label off the package.
4. Remove the protective cap from one end of the transfer device and keeping the vial of SWFI
upright, insert the piercing pin vertically into the center of the stopper of the vial of SWFI.
5. Remove the protective cap from the other end of the transfer device. DO NOT INVERT THE
VIAL OF SWFI.
6. Hold the vial of Activase upside down, position it so that the center of the stopper is directly
over the exposed piercing pin of the transfer device, and push the vial of Activase down so
that the piercing pin is inserted through the center of the Activase vial stopper.
7. Invert the two vials so that the vial of Activase is on the bottom (upright) and the vial of SWFI
is upside-down, allowing the SWFI to flow down through the transfer device. Allow the entire
contents of the vial of SWFI to flow into the Activase vial (approximately 0.5 cc of SWFI will
remain in the diluent vial).
8. Remove the transfer device and the empty SWFI vial from the Activase vial and discard.
9. Swirl gently to dissolve the Activase powder. DO NOT SHAKE.
Preparation of Bolus Dose
• Prepare the bolus dose in one of the following ways: Remove the appropriate volume from
the vial of reconstituted (1 mg/mL) Activase using a syringe and needle. If this method is used
with the 50 mg vials, the syringe should not be primed with air and the needle should be inserted
into the Activase vial stopper. If the 100 mg vial is used, the needle should be inserted away
from the puncture mark made by the transfer device.
• Remove the appropriate volume from a port (second injection site) on the infusion line after the
infusion set is primed.
• Program an infusion pump to deliver the appropriate volume as a bolus at the initiation of the
infusion
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.
3 DOSAGE FORMS AND STRENGTHS
• 50 mg lyophilized powder per single use vial with 50 mL SWFI USP for reconstitution
• 100 mg lyophilized powder per single use vial with 100 mL SWFI USP for reconstitution
4 CONTRAINDICATIONS
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 WARNINGS AND PRECAUTIONS
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 ADVERSE REACTIONS
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)]
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.
Bleeding
Acute Ischemic Stroke (AIS)
In clinical studies in patients with AIS (Studies 1 and 2) the incidence of intracranial hemorrhage,
especially symptomatic intracranial hemorrhage, was higher in Activase-treated patients than in
placebo patients. A dose-finding study of Activase suggested that doses greater than 0.9 mg/kg may
be associated with an increased incidence of intracranial hemorrhage.
The incidence of all-cause 90-day mortality, intracranial hemorrhage, and new ischemic stroke
following Activase treatment compared to placebo are presented in Table 3 as a combined safety
analysis (n=624) for Studies 1 and 2. These data indicate a significant increase in intracranial
hemorrhage following Activase treatment, particularly symptomatic intracranial hemorrhage within
36 hours. There was no increase in the incidences of 90-day mortality or severe disability in
Activase-treated patients compared to placebo.
Table 3
Combined Safety Outcomes for Studies 1 and 2

Placebo Activase b
(n= 312) (n=312) p-Value
All-Cause 90-day Mortality 64 (20.5%) 54 (17.3%) 0.36

a
Total ICH 20 (6.4%) 48 (15.4%) <0.01

Symptomatic 4 (1.3%) 25 (8.0%) <0.01

Asymptomatic 16 (5.1%) 23 (7.4%) 0.32

Symptomatic Intracranial Hemorrhage within 2 (0.6%) 20 (6.4%) <0.01

36 hours
New Ischemic Stroke (3-months) 17 (5.4%) 18 (5.8%) 1.00

a
Within trial follow-up period. Symptomatic intracranial hemorrhage was defined as the occurrence
of sudden clinical worsening followed by subsequent verification of intracranial hemorrhage on CT
scan. Asymptomatic intracranial hemorrhage was defined as intracranial hemorrhage detected on a
routine repeat CT scan without preceding clinical worsening.
b
Fisher’s Exact Test.
Bleeding events other than intracranial hemorrhage were noted in the studies of AIS and were
consistent with the general safety profile of Activase. In Studies 1 and 2, the frequency of bleeding
requiring red blood cell transfusions was 6.4% for Activase-treated patients compared to 3.8% for
placebo (p = 0.19).
Although exploratory analyses of Studies 1 and 2 suggest that severe neurological deficit (National
Institutes of Health Stroke Scale [NIHSS > 22]) at presentation was associated with an increased risk
of intracranial hemorrhage, efficacy results suggest a reduced but still favorable clinical outcome for
these patients.
Acute Myocardial Infarction (AMI)
For the 3-hour infusion regimen in the treatment of AMI, the incidence of significant internal
bleeding (estimated as > 250 mL blood loss) has been reported in studies in over 800 patients
(Table 4). These data do not include patients treated with the Activase accelerated infusion.

Table 4
Incidence of Bleeding in 3-Hour Infusion in AMI Patients

Total Dose ≤100 mg

Gastrointestinal 5%
Genitourinary 4%
Ecchymosis 1%
Retroperitoneal <1%
Epistaxis <1%
Gingival <1%

The incidence of intracranial hemorrhage in AMI patients treated with Activase is presented in
Table 5.

Table 5
Incidence of Intracranial Hemorrhage in AMI Patients

Dose Number of Patients Intracranial Hemorrhage (%)

100 mg, 3-hour 3272 0.4
≤ 100 mg, accelerated 10,396 0.7
150 mg 1779 1.3
1-1.4 mg/kg 237 0.4

A dose of 150 mg or greater should not be used in the treatment of AMI because it has been
associated with an increase in intracranial bleeding.
Pulmonary Embolism (PE)
For acute massive pulmonary embolism, bleeding events were consistent with the general safety
profile observed with Activase treatment of AMI patients receiving the 3-hour infusion regimen.
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.
Acute Ischemic Stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke, embolism.
These events may be life threatening and may lead to death.
Acute Myocardial Infarction: Arrhythmias, AV block, cardiogenic shock, heart failure, cardiac
arrest, recurrent ischemia, myocardial reinfarction, myocardial rupture, electromechanical
dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade,
thromboembolism, pulmonary edema. These events may be life threatening and may lead to death.
Nausea and/or vomiting, hypotension and fever have also been reported.
Pulmonary Embolism: Pulmonary reembolization, pulmonary edema, pleural effusion,
thromboembolism, hypotension. These events may be life threatening and may lead to death. Fever
has also been reported.
7 DRUG INTERACTIONS
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)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
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).
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.
Clinical Considerations

Maternal Adverse Reactions

The most common complication of thrombolytic therapy is bleeding. Pregnancy may increase this
risk [see Warnings and Precautions (5.1)].
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.
8.2 Lactation
Risk Summary
There are no data on the presence of alteplase in human milk, the effects on the breastfed infant, or
the effects on milk production.
8.4 Pediatric Use
Safety and effectiveness of Activase in pediatric patients have not been established.
8.5 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 Activase-treated elderly
[see Clinical Studies (14.1)].
Acute Myocardial Infarction
In a large trial of accelerated-infusion Activase 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 enrollment. In these patients, the incidence of stroke was 4.0% for the
Activase 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 Activase, 21.5% for SK (IV), and 22.0% for SK (SQ).
11 DESCRIPTION
Activase 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.
Activase is a sterile, white to off-white, lyophilized powder for intravenous administration after
reconstitution with Sterile Water for Injection, USP.
 Table 6
Quantitative Composition of the Lyophilized Product

100 mg Vial 50 mg Vial

Alteplase 100 mg (58 million IU) 50 mg (29 million IU)
L-Arginine 3.5 g 1.7 g
Phosphoric Acid 1g 0.5 g
Polysorbate 80 10 mg 5 mg
Vacuum No Yes

Biological potency is determined by an in vitro clot lysis assay and is expressed in International
Units (IU).
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.
12 CLINICAL PHARMACOLOGY
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 NONCLINICAL TOXICOLOGY
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 CLINICAL STUDIES
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.
 Table 7
Study 2 Three-Month Efficacy Outcomes
a
Frequency of Favorable Outcome
Absolute b
Placebo Activase Difference Odds Ratio c
Analysis (n=165) (n=168) (95% CI) (95% Cl) p-Value
Generalized Estimating 1.71 0.02
Equations (Multivariate) - - - (1.15, 2.56)

Barthel Index 37.6% 50.0% 12.4% 1.66 0.02

(3.0, 21.9) (1.07, 2.57)

Modified Rankin Scale 26.1% 38.7% 12.6% 1.79 0.02

(3.7, 21.6) (1.12, 2.85)

Glasgow Outcome Scale 31.5% 44.0% 12.5% 1.71 0.02

(3.3, 21.8) (1.09, 2.68)

NIHSS 20.0% 31.0% 11.0% 1.79 0.02

(2.6, 19.3) (1.06, 2.96)

a
Favorable Outcome is defined as recovery with minimal or no disability.
b
Value greater than 1 indicates odds of recovery in favor of Activase treatment.
c
p-Value for Odds Ratio is from Generalized Estimating Equations with logit link.

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.

Accelerated Infusion in AMI Patients

Accelerated infusion of Activase was studied in an international, multi-center trial that randomized
41,021 patients with AMI to four thrombolytic regimens (Study 3). Entry criteria included onset of
chest pain within 6 hours of treatment and ST-segment elevation of ECG. The four treatment
regimens included accelerated infusion of Activase (≤100 mg over 90 minutes) plus intravenous (IV)
heparin (n = 10,396); Streptokinase (1.5 million units over 60 minutes) plus IV heparin (SK [IV],
n =10,410); Streptokinase plus subcutaneous (SQ) heparin (SK [SQ] n= 9841). A fourth regimen
combined Activase and Streptokinase (n =10,374). All patients received 160 mg chewable aspirin
administered as soon as possible, followed by 160-325 mg daily. Bolus IV heparin 5000 U was
initiated as soon as possible, followed by a 1000 U/hour continuous IV infusion for at least 48 hours;
subsequent heparin therapy was at the physician’s discretion. Heparin SQ 12,500 U was
administered 4 hours after initiation of SK therapy, followed by 12,500 U twice daily for 7 days or
until discharge, whichever came first. Many of the patients randomized to receive SQ heparin
received some IV heparin, usually in response to recurrent chest pain and/or the need for a medical
procedure. Some received IV heparin on arrival to the emergency room prior to enrollment and
randomization.
Key results from Study 3 are shown in Table 8. The incidence of 30-day mortality for Activase
accelerated infusion was 1.0% lower than for either Streptokinase plus heparin regimen. The
incidence of combined 30-day mortality or nonfatal stroke for the Activase accelerated infusion was
1.0% lower than for SK (IV) and 0.8% lower than for SK (SQ).

Table 8
Efficacy and Safety Results for Study 3

Accelerated a a
Event Activase SK (IV) p-Value SK (SQ) p-Value
30-Day Mortality 6.3% 7.3% 0.003 7.3% 0.007
30-Day Mortality 7.2% 8.2% 0.006 8.0% 0.036
or Nonfatal Stroke
24-Hour Mortality 2.4% 2.9% 0.009 2.8% 0.029
Any Stroke 1.6% 1.4% 0.32 1.2% 0.03
Intracerebral Hemorrhage 0.7% 0.6% 0.22 0.5% 0.02
a
Two-tailed p-value is for comparison of Accelerated Activase to the respective SK control arm.

Subgroup analysis of patients by age, infarct location, time from symptom onset to thrombolytic
treatment, and treatment in the U.S. or elsewhere showed consistently lower 30-day mortality on
Activase.
For patients who were over 75 years of age, a predefined subgroup consisting of 12% of patients
enrolled, the incidence of stroke was 4.0% for the Activase accelerated infusion group, 2.8% for SK
(IV), and 3.2% for SK (SQ); the incidence of combined 30-day mortality or nonfatal stroke was
20.6% for accelerated infusion of Activase, 21.5% for SK (IV), and 22.0% for SK (SQ).

3-Hour Infusion in AMI Patients

In a double-blind, randomized trial (n = 138) comparing 3-hour infusion of Activase to placebo
(Study 4), patients infused with Activase within 4 hours of onset of symptoms experienced improved
left ventricular function at Day 10 compared to the placebo group, when ejection fraction was
measured by gated blood pool scan (53.2% vs. 46.4%, p =0.018). Relative to baseline (Day 1)
values, the net changes in ejection fraction were + 3.6% and -4.7% for the treated and placebo
groups, respectively (p=0.0001). The treated group had a reduced incidence of clinical heart failure
(14%) compared to the placebo group (33%) (p = 0.009).
In a double-blind, randomized trial (n =5013) comparing 3-hour infusion of Activase to placebo
(Study 5), patients infused with Activase within 5 hours of AMI symptom onset experienced
improved 30-day survival compared to the placebo arm. At 1 month, the overall mortality rates were
7.2% for the Activase group and 9.8% for the placebo group (p = 0.001). At 6 months, the overall
mortality rate for Activase-treated patients was 10.4% compared to the placebo arm (13.1%,
p= 0.008).
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 HOW SUPPLIED/STORAGE AND HANDLING
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.

17 PATIENT COUNSELING INFORMATION

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.

Activase (alteplase)
®

Manufactured by:
Genentech, Inc.
A Member of the Roche Group Activase is a registered trademark of Genentech, Inc.
®

©
1 DNA Way 2018 Genentech, Inc.
South San Francisco, CA
94080-4990
U.S. License No. 1048