PRODUCT MONOGRAPH

INCLUDING PATIENT MEDICATION INFORMATION

Pr
ACTIVASE® rt-PA
alteplase for injection
Lyophilized powder for injection - 50 mg and 100 mg
Fibrinolytic Agent

ACUTE MYOCARDIAL INFARCTION INDICATION ONLY

Hoffmann-La Roche Limited Date of Initial Authorization:

7070 Mississauga Road DEC 31, 1996
Mississauga, Ontario
Date of Revision:
L5N 5M8 October 7, 2021

www.rochecanada.com

Submission Control Number: 251948

ACTIVASE® is a registered trade mark of Genentech, Inc., used under license

© Copyright 1996 - 2021 Hoffmann-La Roche Limited

PRACTIVASE® rt-PA (alteplase for injection) Page 1 of 45

RECENT MAJOR LABEL CHANGES

3 Dosage and Administration, 3.3 Reconstitution April 19, 2021

3 Dosage and Administration, 3.4 Administration April 19, 2021

Sections or subsections that are not applicable at the time of authorization are not listed.

TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES ............................................................................................ 2

Sections or subsections that are not applicable at the time of authorization are not listed. ... 2
TABLE OF CONTENTS .............................................................................................................. 2
PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4
1 INDICATIONS ............................................................................................................... 4
1.1 Pediatrics.................................................................................................................. 4
1.2 Geriatrics .................................................................................................................. 4
2 CONTRAINDICATIONS ................................................................................................. 4
4 DOSAGE AND ADMINISTRATION ................................................................................. 5
4.1 Dosing Considerations ............................................................................................. 5
4.2 Recommended Dose and Dosage Adjustment ........................................................ 5
4.3 Reconstitution .......................................................................................................... 7
4.4 Administration ....................................................................................................... 11
5 OVERDOSAGE............................................................................................................ 13
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................... 14
7 WARNINGS AND PRECAUTIONS ................................................................................ 14
7.1 Special Populations ................................................................................................ 17
7.1.1 Pregnant Women ............................................................................................. 17
7.1.2 Breast-feeding .................................................................................................. 17
7.1.3 Pediatrics.......................................................................................................... 17
7.1.4 Geriatrics .......................................................................................................... 17
8 ADVERSE REACTIONS ................................................................................................ 18
8.1 Adverse Reaction Overview ................................................................................... 18

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 8.2 Clinical Trial Adverse Reactions ............................................................................. 18
8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 19
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other
Quantitative Data............................................................................................................. 20
8.5 Post-Market Adverse Reactions............................................................................. 20
9 DRUG INTERACTIONS ................................................................................................ 20
9.1 Serious Drug Interactions ...................................................................................... 20
9.2 Drug Interactions Overview ................................................................................... 20
9.3 Drug-Behavioural Interactions ............................................................................... 20
9.4 Drug-Drug Interactions .......................................................................................... 20
10 CLINICAL PHARMACOLOGY ....................................................................................... 20
10.1 Mechanism of Action ....................................................................................... 20
10.2 Pharmacodynamics .......................................................................................... 22
10.3 Pharmacokinetics ............................................................................................. 22
11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 22
12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 23
PART II: SCIENTIFIC INFORMATION ....................................................................................... 23
13 PHARMACEUTICAL INFORMATION ............................................................................ 23
14 CLINICAL TRIALS ........................................................................................................ 26
14.1 Trial Design and Study Demographics ............................................................. 26
14.2 Study Results .................................................................................................... 27
15 MICROBIOLOGY ........................................................................................................ 29
16 NON-CLINICAL TOXICOLOGY ..................................................................................... 29
PATIENT MEDICATION INFORMATION .................................................................................. 31

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PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

ACTIVASE rt-PA (alteplase for injection) is indicated for intravenous use in adults for:

1) the lysis of suspected occlusive coronary artery thrombi associated with evolving transmural
myocardial infarction; and

2) the reduction of mortality associated with acute myocardial infarction (AMI), the improvement of
ventricular function following AMI and the reduction in the incidence of congestive heart failure.

Treatment should be initiated as soon as possible after the onset of acute myocardial symptoms.
Greater benefit appears to be associated with earlier treatment of ACTIVASE rt-PA, following the onset
of symptoms.

ACTIVASE rt-PA is effective in patients in whom therapy is initiated within six (6) hours of onset of
symptoms for the accelerated infusion regimen or up to twelve (12) hours after onset of symptoms for
the 3-hour infusion regimen. The GUSTO study was designed to enrol patients within a 6-hour period
following the onset of myocardial infarct symptoms. The data available from this trial are insufficient to
support a recommendation for use of the accelerated infusion regimen in patients presenting more
than six (6) hours after the onset of symptoms.

For information on use in acute ischemic stroke (AIS), please consult the product monograph for the
AIS indication.

1.1 Pediatrics
• Safety and effectiveness of ACTIVASE rt-PA in children has not been established. Therefore,
treatment of such patients is not recommended.

1.2 Geriatrics
• The risks of therapy may be increased in the elderly (see ADVERSE REACTIONS, ACTIONS AND
CLINICAL PHARMACOLOGY).

2 CONTRAINDICATIONS

ACTIVASE rt-PA (alteplase for injection) should not be administered to patients with known
hypersensitivity to the active substance alteplase or to any ingredient in the formulation or
components of the container. For a complete listing, see the Dosage Forms, Composition and Packaging
section of the product monograph.

ACTIVASE rt-PA (alteplase for injection) therapy is contraindicated in the following situations because
of an increased risk of bleeding:

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• Active internal bleeding
• History of stroke
• Patients receiving other intravenous thrombolytic agents
• Recent (within two months) intracranial, or intraspinal surgery or trauma
• Intracranial neoplasm, arteriovenous malformation, or aneurysm
• Known bleeding diathesis
• Severe uncontrolled hypertension (systolic BP > 180 mm Hg and/or diastolic BP > 110 mm Hg)
• Recent traumatic cardiopulmonary resuscitation
• Recent severe trauma

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

ACTIVASE rt-PA (alteplase for injection) is intended for intravenous use only. It should be given via a
dedicated intravenous line with an infusion pump. Extravasation of ACTIVASE rt-PA infusion can cause
ecchymosis and/or inflammation. Management consists of terminating the infusion at the IV site and
application of local therapy.
Administer ACTIVASE rt-PA as soon as possible after the onset of symptoms.

Anticoagulation During and After Treatment with ACTIVASE rt-PA

To date, heparin has been administered concomitantly in more than 90% of patients given ACTIVASE
rt-PA. Adjunctive intravenous heparin administration is recommended to obtain a therapeutic partial
thromboplastin time (PTT). The infusion of heparin should be initiated prior to the termination of the
infusion of ACTIVASE rt-PA.

4.2 Recommended Dose and Dosage Adjustment

There are two dose regimens for ACTIVASE rt-PA for use in the management of AMI. The comparative
efficacy of these two regimens has not been evaluated.

90-MINUTE ACCELERATED INFUSION

The recommended total dose is based upon patient weight, not to exceed 100 mg. For patients
weighing >67 kg, the recommended dose is 100 mg, administered as a 15 mg intravenous bolus,
followed by 50 mg infused over 30 minutes and then 35 mg infused over the next 60 minutes.

For patients weighing < 67 kg, the recommended dose is 15 mg administered as an intravenous bolus,
followed by 0.75 mg/kg to a maximum of 50 mg, infused over the next 30 minutes, and then 0.50
mg/kg to a maximum of 35 mg infused over the next 60 minutes.

This 90-minute infusion regimen is recommended for use up to 6 hours after onset of AMI symptoms.

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 Accelerated Regimen: Infusion Chart

Patient Bolus Volume 0.75 mg/kg over 0.50 mg/kg over tPA Total Dose
of tPA (mg) (Bolus +
Weight 30 Minutes 60 Minutes
Maintenance)
added to
(Maximum
empty
15 mg pvc bag Infusion Infusion Volume Infusion Infusion Volume Dose = 100
mg)
(lb) (kg) (15 mL) or Dose Rate to be Dose Rate to be
over 2 glass vial (mg) (mL/hr) Infused (mg) (mL/hr) Infused
(mL)
minutes (Max (mL) (Max (mL)
Dose Dose
= 50 mg) = 35 mg)

90-94 41-42 15 mL 52 mL 31 62 31 mL 21 21 21mL 67

95-97 43-44 15 mL 54 mL 32 64 32 mL 22 22 22mL 69
98-104 45-47 15 mL 57 mL 34 68 34 mL 23 23 23mL 72
105-109 48-49 15 mL 60 mL 36 72 36 mL 24 24 24mL 75
110-114 50-51 15 mL 63 mL 38 75 38 mL 25 25 25mL 78
115-119 52-54 15 mL 65 mL 39 78 39 mL 26 26 26mL 80
120-124 55-56 15 mL 68 mL 41 82 41 mL 27 27 27mL 83
125-129 57-58 15 mL 71 mL 43 86 43 mL 28 28 28mL 86
130-134 59-60 15 mL 73 mL 44 88 44 mL 29 29 29mL 88
135-139 61-63 15 mL 76 mL 46 92 46 mL 30 30 30mL 91
140-144 64-65 15 mL 80 mL 48 96 48 mL 32 32 32mL 95
145-149 66-67 15 mL 83 mL 50 100 50 mL 33 33 33mL 98
>149 >67 15 mL 85 mL 50 100 50 mL 35 35 35mL 100

1 mg = 1 mL

3-HOUR INFUSION
The recommended dose is 100 mg administered as 60 mg in the first hour, of which 6-7 mg is
administered as a bolus over the first 1-2 minutes and the remainder is administered by continuous
infusion, 20 mg by continuous infusion during the second hour, and 20 mg by continuous infusion over
the following one to four hours. For smaller patients (<65 kg), a dose of 1.25 mg/kg may be warranted.
This 3-hour infusion regimen is recommended for use up to 12 hours after onset of AMI symptoms.

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4.3 Reconstitution
The reconstituted solution may be diluted further immediately before administration to yield
concentrations as low as 0.5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection,
USP. Excessive agitation during dilution should be avoided; mixing should be accomplished with gentle
swirling and/or slow inversion. Do not use other infusion solutions e.g. Sterile Water for Injection, USP,
or preservative containing solutions for further dilution.

No other medication should be added to ACTIVASE rt-PA solution. Solutions should be administered
as described above. Unused infusion solution should be immediately discarded.

50 MG VIALS
ACTIVASE rt-PA should be reconstituted by aseptically adding 50 mL Sterile Water for Injection, USP
[SWFI] to the vial of ACTIVASE rt-PA, . It is important that ACTIVASE rt-PA be reconstituted only with
Sterile Water for Injection, USP, without preservatives. Do not use Bacteriostatic Water for Injection.
The reconstituted preparation results in a colourless to pale yellow transparent solution containing
ACTIVASE rt-PA 1.0 mg/mL at a pH of 7.3. The osmolality of this solution is approximately 215
mOsm/kg.
Before further dilution or administration, parenteral drug products should be visually inspected for
particulate matter and discoloration prior to administration whenever solution and container permit.
Because ACTIVASE rt-PA contains no preservatives, it must be used within 8 hours following
reconstitution (when stored at 2-30℃) (see STORAGE AND STABILITY).

Do not use a transfer device but use a large bore needle (e.g. 18 gauge), and the accompanying 50 mL
Sterile Water for Injection, USP, direct the stream of Sterile Water for Injection, USP into the
lyophilized cake. DO NOT USE IF VACUUM IS NOT PRESENT. Slight foaming upon reconstitution is not
unusual; standing undisturbed for several minutes is usually sufficient to allow dissipation of any large
bubbles. Excessive or vigorous shaking should be avoided.

100 MG VIALS
Activase 100 mg Kit Contents

Transfer device

Activase 100 mg vial

(no vacuum)

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 Activase 100 mg vial
stopper parts:

Sterile Water for

Injection (water) vial

Note: Do not use

Bacteriostatic Water
for Injection, USP.

Prescribing Information

Instructions for Use

Activase 100 mg Also Required (not included in kit)

1 Luer syringe for

removing bolus dose, as
needed

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 1 Luer syringe for
removing excess
volume, as needed

2 large bore needles

2 Alcohol swabs

IV infusion set

Activase 100 mg Reconstitution (use aseptic technique)

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 Step 1: Cleaning
• Remove caps from both vials.
• Wipe both stoppers with alcohol swabs.

Step 2: Spiking Water Vial

• Remove cover from one end of transfer device (Note:
Either side of transfer device can be used. Do not wipe
transfer device spikes with alcohol.).
• Insert spike straight through center of water vial
stopper.

Do not invert water vial yet. Inverting too early may

lead to leakage and incorrect dosing.

Step 3: Spiking Activase Vial

• Remove cover from other end of transfer device.
• Hold Activase vial upside down over spike.
• Press Activase vial down to insert spike straight
through center of Activase vial stopper.
Inserting the spike off-center could lead to
stopper collapse.

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 Step 4: Inverting and transferring
• Invert vials so that water vial is on top.
• Allow all water to transfer into Activase vial.
• If the flow does not start immediately or pauses, initiate
the flow by flipping and re-inverting the vials.
• Swirl gently and/or invert slowly to dissolve Activase
powder.
Do not shake vials. Shaking may lead to excessive
foaming and degraded medication.

Step 5: Inspecting
• Separate empty water vial and transfer device from
Activase vial.
• Reconstituted Activase vial (1 mg/mL) should be:
o Colorless to pale yellow and transparent
o Free of particulates
• If needed, let stand undisturbed for a few minutes to
allow large bubbles to dissipate.

4.4 Administration
50 MG VIALS

90-MINUTE ACCELERATED INFUSION

The ACTIVASE rt-PA dose administered by accelerated infusion may be prepared and administered as
follows:

A. The bolus dose may be prepared in one of the following ways:

1) By removing 15 mL from the vial of reconstituted (1 mg/mL) ACTIVASE rt-PA using a syringe and
needle. The syringe should not be primed with air and the needle should be inserted into the
ACTIVASE rt-PA vial stopper.

2) By removing 15 mL from a port (second injection site) on the infusion line after the infusion set
is primed.

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 3) By programming an infusion pump to deliver a 15 mL (1 mg/mL) bolus at the initiation of the
infusion.

B. The remainder of the ACTIVASE rt PA dose may be administered using either a polyvinyl chloride bag
or glass vial and infusion set.

3-HOUR INFUSION
A. The bolus dose may be prepared in one of the following ways:

1) By removing 6-10 mL from the vial of reconstituted (1 mg/mL) ACTIVASE rt-PA using a
syringe and needle. The syringe should not be primed with air and the needle should be
inserted into the ACTIVASE rt-PA vial stopper.

2) By removing 6-10 mL from a port (second injection site) on the infusion line after the
infusion set is primed.

3) By programming an infusion pump to deliver a 6-10 mL (1 mg/mL) bolus at the initiation of

the infusion.

B. The remainder of the ACTIVASE rt-PA dose may be administered using either a polyvinyl
chloride bag or glass vial and infusion set.

100 MG VIALS

Activase 100 mg Administration (use aseptic technique)

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5 OVERDOSAGE

Overdosage could lead to serious bleeding. Should serious bleeding occur in a critical location, the
infusion of ACTIVASE rt-PA (alteplase for injection) and any other concomitant anticoagulant should be
discontinued immediately. If necessary, blood loss and reversal of the bleeding tendency can be
managed with whole blood or packed red cells. In the event of clinically significant fibrinogen

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depletion, fresh frozen plasma or cryoprecipitate can be infused.

For management of a suspected drug overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table – Dosage Forms, Strengths, Composition and Packaging

Route of Dosage Form/

Non-medicinal Ingredients
Administration Strength/Composition
Intravenous (I.V.) Lyophilized powder for L-arginine, phosphoric acid and polysorbate 80
solution, 50 mg 100 mg

Description
ACTIVASE rt-PA (alteplase for injection) is supplied as a sterile, lyophilized powder in 50 mg vials with
vacuum present and in 100 mg vials with no vacuum present.

Composition
The composition of the lyophilized product is alteplase (medicinal ingredient), L-arginine, phosphoric
acid and polysorbate 80.

Packaging

ACTIVASE rt-PA is available in:

• Boxes each containing one (1) vial of ACTIVASE rt-PA 50 mg and one (1) vial of Sterile Water for
Injection, USP 50 mL, for preparing a sterile solution of ACTIVASE rt-PA.
• Boxes each containing one (1) vial of ACTIVASE rt-PA 100 mg and one (1) vial of Sterile Water
for Injection, USP 100 mL, and one transfer device for preparing a sterile solution of ACTIVASE
rt-PA.

7 WARNINGS AND PRECAUTIONS

General
ACTIVASE rt-PA (alteplase for injection) should be administered in a hospital setting where the
appropriate diagnostic and monitoring techniques are readily available.
Routine management of myocardial infarction should not be deferred after evidence of successful
thrombolysis is seen. Evaluation and management of underlying atherosclerotic heart disease should
be carried out as clinically indicated.
Non compressible arterial puncture must be avoided. Arterial and venous punctures should be
minimized. In the event of serious bleeding, ACTIVASE rt-PA and heparin should be discontinued
immediately. Heparin effects can be reversed by protamine.

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Bleeding
The most common complication encountered during therapy with ACTIVASE rt PA (alteplase for
injection) is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into
two broad categories:
• Internal bleeding involving the gastrointestinal tract, genitourinary tract, respiratory tract,
retroperitoneal or intracranial sites
• Superficial or surface bleeding, observed mainly at invaded or disturbed sites (e.g. venous
cutdowns, arterial punctures, sites of recent surgical intervention)

The concomitant use of heparin anticoagulation contributes to the risk of bleeding.

Fibrin will be lysed during the infusion of ACTIVASE rt-PA and bleeding from recent puncture sites may
occur. Therefore, therapy with ACTIVASE rt-PA, as with other thrombolytic agents, requires careful
attention to all potential bleeding sites (including catheter insertion sites, arterial and venous puncture
sites, cutdown sites and needle puncture sites).

Intramuscular injections and nonessential handling of the patient should be avoided during and
immediately following treatment with ACTIVASE rt-PA. Venipunctures should be performed carefully
and only as required.

Should an arterial puncture be necessary during an infusion of ACTIVASE rt-PA, it is preferable to use an
upper extremity vessel that is accessible to manual compression. Pressure should be applied for at least
30 minutes, a pressure dressing applied and the puncture site checked frequently for evidence of
bleeding.

Should serious bleeding in a critical location (not controllable by local pressure) occur, the infusion of
ACTIVASE rt-PA and any other concomitant anticoagulant should be discontinued immediately and
treatment initiated (See OVERDOSAGE).

In the following conditions, the risks of ACTIVASE rt-PA therapy may be increased and should be
weighed against the anticipated benefits:
• Recent (within 10 days) major surgery, e.g. coronary artery bypass graft, obstetrical delivery,
organ biopsy, previous puncture of non-compressible vessels
• Clinical evidence or history of transient ischemic attacks
• Recent gastrointestinal or genitourinary bleeding (within 10 days)
• Recent trauma (within 10 days)
• Hypertension: systolic BP ≥ 175 mm Hg and/or diastolic BP ≥ 110 mm Hg
• A history or clinical evidence of hypertensive disease in a patient over 70 years old
• Advanced age, e.g. over 75 years old
• Acute pericarditis
• Subacute bacterial endocarditis
• Hemostatic defects including those secondary to severe hepatic or renal disease
• Significant liver dysfunction, e.g. prolonged prothrombin time

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 • Pregnancy
• Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions
• Septic thrombophlebitis or occluded AV cannula at seriously infected site
• Patients currently receiving oral 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.

In a small subgroup of AMI patients who are at low risk for death from cardiac causes (i.e., no previous
myocardial infarction, Killip class I) and who have high blood pressure at the time of presentation, the
risk for stroke may offset the survival benefit produced by thrombolytic therapy.

Thromboembolism
The use of thrombolytics including ACTIVASE can increase the risk of thrombo-embolic events in
patients with left heart thrombus, e.g., mitral stenosis or atrial fibrillation.

Cardiovascular

Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such
as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations,
ventricular tachycardia) are not different from those often seen in the ordinary course of AMI and may
be managed with standard antiarrhythmic measures. It is recommended that antiarrhythmic therapy
for bradycardia and/or ventricular irritability be available when infusions of ACTIVASE rt-PA are
administered.

Cholesterol Embolization
Cholesterol embolization has been reported rarely in patients treated with all types of thrombolytic
agents; the true incidence is unknown. This serious condition, which can be lethal, is also associated
with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or
anticoagulant therapy. Clinical features of cholesterol embolism include livedo reticularis, “purple toe”
syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction,
cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and
rhabdomyolysis.

Use of Antithrombotics
Acetylsalicylic acid (ASA) and heparin may be administered concomitantly with and following infusions
of ACTIVASE rt-PA. Because heparin, ASA or ACTIVASE rt-PA alone may cause bleeding complications,
careful monitoring for bleeding is advised, especially at arterial puncture sites.

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Immune

Hypersensitivity
Anaphylactoid reactions associated with the administration of Activase are rare and can be caused by
hypersensitivity to the active substance alteplase or to any of the excipients. Rare fatal outcome for
hypersensitivity was reported.

Angioedema
Angioedema has been observed in post-market experience in patients treated for acute myocardial
infarction (see DRUG INTERACTIONS and ADVERSE REACTIONS: Hypersensitivity). Onset of angioedema
occurred during and up to 2 hours after infusion of ACTIVASE rt-PA. In many cases, patients were
receiving concomitant Angiotensin-converting enzyme inhibitors. Patients treated with ACTIVASE rt-PA
should be monitored during and for several hours after infusion for signs of hypersensitivity.

If signs of hypersensitivity occur, e.g. anaphylactoid reaction or angioedema develops, promptly

institute appropriate therapy (e.g., antihistamines, intravenous corticosteroids or epinephrine) and
discontinue the ACTIVASE rt-PA infusion.

7.1 Special Populations

7.1.1 Pregnant Women
ACTIVASE has been shown to have an embryocidal effect in rabbits when intravenously administered in
doses of approximately two times (3 mg/kg) the human dose for AMI. No maternal or fetal toxicity was
evident at 0.65 times (1 mg/kg) the human dose in pregnant rats and rabbits dosed during the period of
organogenesis. There are no adequate and well controlled studies in pregnant women. ACTIVASE
should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

7.1.2 Breast-feeding
It is not known whether ACTIVASE rt-PA is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when ACTIVASE rt-PA is administered to a nursing woman.

7.1.3 Pediatrics
Safety and effectiveness of ACTIVASE rt-PA in children has not been established. Therefore, treatment
of such patients is not recommended.

7.1.4 Geriatrics
The risks of therapy may be increased in the elderly (see ADVERSE REACTIONS, ACTIONS AND CLINICAL
PHARMACOLOGY).

Monitoring and Laboratory Tests

During ACTIVASE rt-PA infusion, coagulation tests and/or measures of fibrinolytic activity may be
performed if desired. However, routine measurements of fibrinogen as well as fibrinogen degradation
products are unreliable, and should not be undertaken unless specific precautions are taken to prevent
in vitro artifacts. ACTIVASE rt-PA is a serine protease that when present in blood in pharmacologic
concentrations remains active under in vitro conditions. This can lead to degradation of fibrinogen in a

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blood sample removed for analysis. Collection of blood samples on aprotinin (150-200 units/mL) can to
some extent mitigate this phenomenon.

Readministration
There has been little documentation of readministration of ACTIVASE rt-PA. Readministration should be
undertaken with caution. Less than 0.5% of patients receiving single courses of ACTIVASE rt-PA therapy
have experienced transient antibody formation. Nevertheless, if an anaphylactoid reaction occurs, the
infusion should be discontinued immediately and appropriate therapy initiated.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Bleeding: General
The most frequent adverse reaction associated with ACTIVASE rt-PA (alteplase for injection) is bleeding.
13,22,23
The type of bleeding associated with thrombolytic therapy can be divided into two broad
categories:
• Internal bleeding, involving the gastrointestinal tract, genitourinary tract, respiratory tract,
retroperitoneal or intracranial sites
• Superficial or surface bleeding, observed mainly at invaded or disturbed sites (e.g. venous
cutdowns, arterial punctures, sites of recent surgical intervention)

Hypersensitivity
Hypersensitivity reactions, e.g. anaphylactoid reaction, anaphylactic reaction, laryngeal edema,
angioedema, rash urticaria and shock have been reported very rarely (<0.02%). A cause and effect
relationship has not been established. A rare fatal outcome for hypersensitivity has been reported.

8.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed
in the clinical trials may not reflect the rates observed in practice and should not be compared to the
rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful
for identifying drug-related adverse events and for approximating rates.

Reported Incidence of Bleeding During ACTIVASE Treatment

The incidence of all strokes reported for the accelerated (90 minute) infusion regimen in the GUSTO
trial was 1.6%, while the incidence of nonfatal stroke was 0.9%. The incidence of hemorrhagic stroke
was 0.7%, not all of which were fatal. Data from previous trials utilizing a three hour infusion indicates
that the incidence of total stroke in six randomized double-blind placebo controlled trials was 1.2%
(37/3161) in ACTIVASE rt-PA-treated patients (≤100 mg) compared with 0.9% (27/3092) in placebo-
treated patients.

Although the incidence of all strokes, as well as that for hemorrhagic stroke, increased with increasing
age, treatment with accelerated regimen of ACTIVASE rt-PA was still shown to reduce mortality in older
patients. For patients who were over 75 years of age, a predefined subgroup consisting of 12% of

PRACTIVASE® rt-PA (alteplase for injection) Page 18 of 45

patients enrolled, the incidence of stroke was 4.0% for the accelerated regimen of ACTIVASE rt-PA
group, 2.8% for streptokinase (intravenous heparin), and 3.2% for streptokinase (subcutaneous
heparin) (See Table 1). However, combined 30-day mortality or non-fatal stroke was 20.6% for
accelerated regimen of ACTIVASE rt-PA, 21.5% for streptokinase (intravenous heparin) and 22.0% for
streptokinase (subcutaneous heparin) in the GUSTO study.

Table 1
rt-PA SK (IV) SK (SQ)
% % p-value % p-value
stroke 1.6% 1.4% 0.32 1.2% 0.03
intracranial hemorrhage 0.7% 0.6% 0.22 0.5% 0.02
stroke in >75 yrs 4.0% 2.8% 0.09 3.2% 0.27
intracranial hemorrhage >75 yrs 2.0% 1.1% 0.06 1.3% 0.17
p-value is for pairwise comparison to rt-PA.

The following incidence of significant internal bleeding (estimated as ≥ 250 mL blood loss) has been
reported in studies involving over 1300 patients treated at all doses of ACTIVASE rt-PA, administered as
a 3-hour infusion regimen:

• gastrointestinal 5%
• genitourinary 4%

The following incidence of moderate or severe bleeding was reported when ≤100 mg ACTIVASE rt-PA
was administered by accelerated infusion to >10,000 patients [GUSTO study]:

• gastrointestinal 1.5%
• genitourinary 0.5%

The incidence of intracranial bleeding in patients treated with up to 120 mg ACTIVASE rt-PA (3-hour
infusion) has been 0.4%. At doses in excess of 120 mg (120-180 mg) the incidence of intracranial
bleeding increased to 1.3%. The incidence of intracranial bleeding in patients treated with ≤100 mg
ACTIVASE rt-PA (accelerated infusion, weight adjusted) was 0.7%. The maximum total dose of ACTIVASE
rt-PA used in the treatment of acute myocardial infarction should not exceed 100 mg.

Death and permanent disability have been reported in patients who have experienced stroke and other
serious bleeding episodes.

8.3 Less Common Clinical Trial Adverse Reactions

Not applicable.

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8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data
Not applicable.

8.5 Post-Market Adverse Reactions

The following adverse reactions have been reported among patients receiving ACTIVASE in clinical trials
and in post marketing experience. These reactions are frequent sequelae of the underlying disease and
the effect of ACTIVASE on the incidence of these events is unknown.

Patients with myocardial infarction can experience disease-related events such as cardiogenic shock,
arrhythmias, AV block, pulmonary edema, heart failure, cardiac arrest, recurrent ischemia, myocardial
reinfarction, myocardial rupture, mitral regurgitation, pericardial effusion, pericarditis, cardiac
tamponade, venous thrombosis and embolism, and electromechanical dissociation. These events may
lead to death. Other adverse reactions have been reported, principally nausea and/or vomiting,
hypotension, and fever.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

Not applicable.

9.2 Drug Interactions Overview

Not applicable.

9.3 Drug-Behavioural Interactions

Not applicable.

9.4 Drug-Drug Interactions

The interaction of ACTIVASE rt-PA with other drugs has not been studied. In addition to bleeding
associated with anticoagulants such as heparin and warfarin, drugs that alter platelet function (such as
acetylsalicylic acid) may increase the risk of bleeding if administered prior to, during or after ACTIVASE
rt-PA infusion.

Angioedema has been observed after ACTIVASE rt-PA administration in patients receiving concomitant
ACE inhibitor therapy. However, the significance of this observation has not been determined (see
ADVERSE REACTIONS OVERVIEW: Hypersensitivity section).

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

ACTIVASE rt-PA (alteplase for injection) is a serine protease which has the property of fibrin-enhanced
conversion of plasminogen to plasmin. ACTIVASE rt-PA produces minimal conversion of plasminogen in
the absence of fibrin; and when introduced into the systemic circulation, ACTIVASE rt-PA binds to fibrin
in a thrombus and converts the entrapped plasminogen to plasmin. This initiates local fibrinolysis with

PRACTIVASE® rt-PA (alteplase for injection) Page 20 of 45

minimal systemic effects. Following administration of ACTIVASE rt-PA, there is a decrease (20-30%) in
circulating fibrinogen. Decreases in plasminogen and α 2 -antiplasmin are also evident.

An occlusive thrombus is present in the infarct-related coronary artery in approximately 80% of

patients experiencing a transmural myocardial infarction evaluated within four hours of onset of
symptoms.

Detailed Pharmacology

Effect on Coagulation
ACTIVASE rt-PA (alteplase for injection) differs from other plasminogen activators in that it is fibrin
dependent. Relatively selective fibrinolysis with ACTIVASE rt-PA, i.e., localized activation of the
fibrinolytic system, is possibly due to several factors such as the high affinity of tissue plasminogen
activator for fibrin, the fibrin-dependent activation of tissue plasminogen activator, and the
coprecipitation of plasminogen within the fibrin clot. As a result, ACTIVASE rt-PA produces clot
dissolution in vivo with minimal systemic effects.

Two controlled trials in acute myocardial infarction patients have measured circulating plasma
fibrinogen levels after infusion of activators. Results with ACTIVASE rt-PA were compared to those with
a non-selective activator, streptokinase. In the first study, the circulating fibrinogen level (measured by
coagulation rate assay) was approximately 61% of the starting value in ACTIVASE rt-PA treated patients
compared with approximately 12% for those treated with streptokinase. In the second study, post-
treatment levels of fibrinogen (measured by the sodium phosphate precipitation method) were
approximately 75% of baseline with ACTIVASE rt-PA compared with 53% with streptokinase.

In a dose response trial conducted by the National Heart, Lung and Blood Institute (NHLBI), comparing
three different doses of ACTIVASE rt-PA in AMI patients, baseline plasma fibrinogen levels (measured
by the precipitation method 1-2 hours after infusion) were 96%, 90% and 77% for doses of 80 mg, 100
mg, and 150 mg respectively.

In general, it is believed that fibrinogen levels in excess of about 100 mg per decilitre may be important
in controlling most occurrences of bleeding. In two multicentre trials of ACTIVASE rt-PA in AMI patients
in which degradation of circulating fibrinogen was measured, the incidence of fibrinogen levels below
100 mg% (mg/dL ~ measured with precipitation techniques) was less than 5%. In two multicentre trials
of ACTIVASE rt-PA in AMI patients, the incidence of fibrinogen levels below 100 mg% (measured with
clotting rate techniques) was less than 25%. In contrast, a multicentre trial comparing ACTIVASE rt-PA
to streptokinase found the incidence of fibrinogen levels below 100 mg% in the streptokinase group
(measured with clotting rate techniques) to be 95%.

Another measure of systemic fibrinolytic activation is the elevation of fibrinogen-fibrin degradation

products (FDP’s). In a study in AMI patients comparing ACTIVASE rt-PA to streptokinase, FDP’s
increased to 0.75 mg/mL in the streptokinase group but to only 0.10 mg/mL in the ACTIVASE rt-PA
group.

Myocardial Infarction Studies

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In angiographically controlled studies, intravenous ACTIVASE rt-PA has been demonstrated to induce
prompt and significant improvement in perfusion of the obstructed coronary vessel. In a study
sponsored by the National Heart, Lung and Blood Institute designed to compare the intravenous
thrombolytic effects of ACTIVASE rt-PA and streptokinase, The Thrombolysis in Myocardial Infarction
(TIMI) trial which involved 316 patients at 13 centres, ACTIVASE rt-PA produced reperfusion in 66% of
patients, compared with 36% for streptokinase treated patients studied angiographically 90 minutes
after the commencement of thrombolytic therapy. In a subsequent non-comparative phase of the
same study which involved 139 patients, ACTIVASE rt-PA produced reperfusion in 73% of patients who
received at least 70 - 100 mg over 90 minutes. A second randomized study, The European Cooperative
Trial, demonstrated similar efficacy of intravenous ACTIVASE rt-PA.

The recanalization rate for a 70 mg dose is equivalent to that for a 100 mg dose at 90 minutes, but the
100 mg dose elicits thrombolysis more rapidly. The following table summarizes the results of the TIMI
open label dose response study:

PERCENT VESSELS OPEN

Dose in first 90 minutes
Time after onset of
infusion 70 mg 100 mg

30 min. 24% 42%

60 min. 57% 68%
90 min. 71% 76%
No. of patients 83 62

10.2 Pharmacodynamics

10.3 Pharmacokinetics
Elimination
ACTIVASE rt-PA is cleared rapidly from circulating 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 acute myocardial infarction (AMI). The plasma clearance of ACTIVASE rt-PA is
approximately 500 mL/min. The clearance is mediated primarily by the liver.

11 STORAGE, STABILITY AND DISPOSAL

Lyophilized ACTIVASE rt-PA is stable up to the expiration date stamped on the vial when stored at
controlled temperatures between 2℃ and 30℃. Protect the lyophilized material during extended
storage from excessive exposure to light.

Unused reconstituted ACTIVASE rt-PA (in the vial) may be stored at 2-30℃ for up to 8 hours. After that
time, any unused portion of the reconstituted material should be discarded. During the period of
reconstitution and infusion, protection from light is not necessary.

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12 SPECIAL HANDLING INSTRUCTIONS

Not applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance
Proper name: alteplase for injection
Chemical name: alteplase
Molecular formula and molecular mass:
The theoretical mass of rt-PA is 65,000 Daltons.
The amino acid sequence is as shown in Figure 1 & Figure 2
Figure 1: The linear sequence of rt- PA. Amino acid residues are identified by the single letter code.
Disulfide bonds are denoted by solid lines connecting cysteine residues.

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There are 17 disulfide bonds in rt-PA found between cysteine residues (see Figure 1).

FIGURE 2
rt-PA (527 res.)
SYQVICRDEKTQMIYQQHQSWLRPVLRSNRVEYCWCNSGRAQCHSVPVKSCSEPRCFNG
GTCQQALYFSDFVCQCPEGFAGKCCEIDTRATCYEDQGISYRGTWSTAESGAECTNWNSS
ALAQKPYSGRRPDAIRLGLGNHNYCRNPDRDSKPWCYVFKAGKYSSEFCSTPACSEGNSDC
YFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQALGLGKHNYCRNPDGDAK

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PWCHVLKNRRLTWEYCDVPSCSTCGLRQYSQPQFRIKGGLFADIASHPWQAAIFAKHRRS
PGERFLCGGILISSCWILSAAHCFQERFPPHHLTVILGRTYRVVPGEEEQKFEVEKYIVHKEFD
DDTYDNDIALLQLKSDSSRCAQESSVVRTVCLPPADLQLPDWTECELSGYGKHEALSPFYSE
RLKEAHVRLYPSSRCTSQHLLNRTVTDNMLCAGDTRSGGPQANLHDACQGDSGGPLVCLN
DGRMTLVGIISWGLGCGQKDVPGVYTKVTNYLDWIRDNMRP

The purified glycoprotein contains 527 amino acids with an approximate molecular weight of 65,000
daltons.
The relative molecular mass is between 55 and 66 kD as measured by sodium dodecyl sulfate-
polyacrylamide gel electrophoresis (SDS-PAGE). ACTIVASE rt-PA is expressed as a 59kD protein. The
addition of carboyhydrate moieties brings the apparent molecular weight as determined by SDS PAGE
to closer to 65 kD.
Physicochemical properties:
The isoelectric focusing (IEF) pattern of rt-PA has multiple bands between pH 5.8 and 8.4. The isoelectric
point (pI) for rt-PA exhibits heterogeneity due to deamidation, proteolysis, and sialic acid.

Product Characteristics:
ACTIVASE rt-PA (alteplase for injection) is a tissue plasminogen activator produced by recombinant
DNA technology. It is a sterile, purified fibrinolytic glycoprotein of 527 amino acids. It is synthesized
using the complementary DNA (cDNA) for natural human tissue-type plasminogen activator. The
manufacturing process involves the secretion of the serine protease alteplase into the culture medium
by an established mammalian cell line into which the cDNA for tissue plasminogen activator has been
genetically inserted.

ACTIVASE rt-PA, a sterile, white to off-white, lyophilized powder, is intended for intravenous
administration after reconstitution with Sterile Water for Injection, USP.

The composition of the lyophilized product is alteplase (medicinal ingredient), L-arginine, phosphoric
acid and polysorbate 80.

Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment.

Biological potency is determined by an in vitro clot lysis assay and is expressed in International Units
(58 x 104 I.U./mg ACTIVASE rt-PA).

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14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

Acute Myocardial Infarction Patients Studies
Two ACTIVASE rt-PA dose regimens have been studied in patients experiencing AMI: accelerated
infusion, and 3-hour infusion. The comparative efficacy of these two regimens has not been evaluated.

There is no difference in the dominant initial plasma half-life between the 3-hour and accelerated
regimens for acute myocardial infarction (AMI).

GUSTO Trial – 90 Minute Accelerated Infusion

90-Minute Accelerated Infusion in Patients with Acute Myocardial Infarction Accelerated infusion of
ACTIVASE rt-PA was studied in an international, multi-centre trial (GUSTO) where 41,021 patients with
acute myocardial infarction were randomized to four thrombolytic regimens: accelerated infusion of
ACTIVASE rt-PA (< 100 mg over 90 minutes) plus intravenous heparin; streptokinase (1.5 x 106 units
over 60 minutes) plus intravenous heparin; streptokinase (1.5 x 106 units over 60 minutes) plus
subcutaneous heparin; or combined ACTIVASE rt-PA (1.0 mg/kg over 60 minutes) plus streptokinase
(1.0 x 106 units over 60 minutes). Acetylsalicylic acid (ASA) was administered daily. The results are
shown in Table 2.

The 30-day mortality for the accelerated infusion of ACTIVASE rt-PA was 1% lower (14% relative risk
reduction) than for streptokinase (intravenous or subcutaneous heparin). In addition, the combined
incidence of 30-day mortality or non-fatal stroke for accelerated ACTIVASE rt-PA was 1% lower (12%
relative risk reduction) than for streptokinase (intravenous heparin) and 0.8% lower (10% relative risk
reduction) than for streptokinase (subcutaneous heparin). One-year follow-up data suggest a sustained
mortality benefit. Subgroup analysis of patients by age, infarct location, and time from symptom onset
to thrombolytic treatment showed consistently lower 30-day mortality for the group receiving the
accelerated infusion of ACTIVASE rt-PA. 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 group
receiving the accelerated infusion of ACTIVASE rt-PA, 2.8% for streptokinase (intravenous heparin), and
3.2% for streptokinase (subcutaneous heparin); the incidence of combined 30-day mortality or nonfatal
stroke was 20.6% for accelerated infusion of ACTIVASE rt-PA, 21.5% for streptokinase (intravenous
heparin), and 22.0% for streptokinase (subcutaneous heparin).

3-Hour Infusion in Patients with Acute Myocardial Infarction

In patients studied with coronary angiography prior to and following infusion of ACTIVASE rt-PA, the
use of ACTIVASE rt-PA resulted in reperfusion of documented obstructed vessels within 90 minutes
after the commencement of thrombolytic therapy in approximately 70% of patients. In two studies
involving 145 patients, ACTIVASE rt-PA produced reperfusion in 73% of patients who received 70-100
mg (40.6 to 58 x 106I.U.) over 90 minutes. In two double blind randomized controlled trials in patients
with AMI, the patients infused with 80-100 mg of ACTIVASE rt-PA experienced improved ventricular
function and reduced incidence of clinical congestive heart failure compared to those treated with
placebo.

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In a double-blind study involving 5013 patients (ASSET Study) where patients were infused with either
ACTIVASE rt-PA or placebo within 5 hours of onset of symptoms of AMI, improved 30-day survival was
shown in patients receiving ACTIVASE rt-PA compared to placebo. At one month, the overall mortality
rates were 7.2% for the ACTIVASE rt-PA-treated group and 9.8% for the placebo-treated group
(p=0.001). This benefit was maintained at 6 months (10.4% and 13.1% for ACTIVASE rt-PA and
placebo-treated patients respectively, p=0.008).

In the LATE study involving 5711 patients where patients were infused with either alteplase (100 mg
over 3 hours) or placebo within 6-24 hours of onset of AMI symptoms, the 35-day mortality rates were
8.9% for ACTIVASE rt-PA treated patients and 10.3% for placebo-treated patients (p=not significant).
Pre-specified survival analysis according to treatment within 12 hours of symptom onset showed a
significant reduction in mortality for the ACTIVASE rt-PA treated patients, 8.9% versus 12.0% for the
placebo treated patients (p=0.0229).

14.2 Study Results

Table 2 – Results from GUSTO Trial

ACCELERATED
STREPTOKINASE STREPTOKINASE P-
EVENT ACTIVASE RT-PA P-VALUE*
(IV HEPARIN) (SC HEPARIN) VALUE*
(IV HEPARIN)
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 2.4% 2.9% 0.009 2.8% 0.029
Mortality
*Two-tailed p-value is for comparison of accelerated infusion of ACTIVASE rt-PA to the respective
streptokinase control arm.

In-hospital events in the overall patient population, as well as events in patients who survived beyond
30 days are shown in Table 3.

Table 3 In-Hospital Clinical Events/Procedures1

OVERALL 30-DAY SURVIVORS2
SK (POOLED) ACTIVASE SK ACTIVAS
% % (POOLED) % E%
Reinfarction 3.9 4.1 3.4 3.6
Cardiogenic Shock 6.5 ** 5.0 3.2 ** 2.3
* *
CABG 8.3 9.0 8.6 9.2
PTCA (IRA) 3
14.3 14.6 14.8 15.2

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 CHF or Pulmonary Edema 16.7 ** 15.0 14.3 ** 13.1
*
Recurrent Ischemia 20.3 19.7 20.1 19.6
Sustained Hypotension 12.8 ** 10.0 9.4 ** 7.0
* *
2E or 3E Atrio-Ventricular 8.9 ** 7.3 7.6 ** 6.2
Block * *
Ventricular Tachycardia 6.5 * 5.7 4.8 4.4
Ventricular Fibrillation 6.9 * 6.2 5.0 4.6
Asystole 6.0 ** 5.1 1.9 1.7
Atrial Fibrillation/Flutter 9.9 ** 8.7 9.1 ** 8.0
Acute Mitral Regurgitation 1.5 1.3 1.3 1.1
Swan-Ganz Catheter 12.6 ** 11.5 11.5 10.7
Cardioversion 9.8 ** 8.6 7.4 * 6.7
Angiography 55 * 56.5 57.4 * 58.9
1
Events other than death, stroke and bleeding.
2
Patients alive at 30-day timepoint
3
IRA=Infarct-Related Artery
*p<0.05, **p<0.01, ***p<0.001

An angiographic substudy of the GUSTO trial provided data on infarct-related artery patency. Results
are shown in Table 4. Reocclusion rates were similar for all three treatment regimens.

Table 4
Patency Accelerated ACTIVASE rt-PA Streptokinase (IV heparin) Streptokinase (SC heparin)
TIMI 2 or TIMI 3 (N) TIMI 2 or TIMI 3 (N) TIMI 2 or TIMI 3 (N)
3 3 3
90-Minute 81.3% * 54.8% (272) 59.0% 30.7% (261) 53.5% 27.3% (260)
*
180- 76.3% 41.3% (80) 72.4% 38.2% (76) 71.6% 34.7% (95)
Minute
24 Hour 88.9% 39.5% (81) 87.5% 47.2% (72) 82.1% 56.7% (67)
5-7 Day 83.3% 63.9% (72) 90.9% 67.5% (77) 78.7% 58.7% (75)

* p<0.001 compared to streptokinase with IV heparin and SC heparin. No other treatment groups
significantly different.

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15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:
The safety of the pharmacological administration of rt-PA was evaluated by conducting acute and sub-
acute toxicity studies in rats, dogs and monkeys.
Acute Toxicology
1) Rats were monitored for fourteen days after receiving one intravenous bolus injection of rt-PA at
dosages of 0.5, 1.5 and 5.0 mg/kg. Additional acute toxicity studies were conducted in rats and
these studies employed rt-PA at dosages of 1, 3 and 10 mg/kg given as an intravenous bolus
injection. In all studies there were no deaths during the study period, no significant toxic signs
observed, and no rt-PA related macroscopic changes observed at the terminal necropsy.

1) Cynomolgus monkeys were administered rt-PA at doses of 1, 3 and 10 mg/kg infused intravenously
for 60 minutes. All of the animals appeared normal for the entire observation period of 7 days.

There were no significant effects of rt-PA on the electrocardiograms, heart rate, systolic blood
pressure or hematological parameters. Consistent with its pharmacologic activity, rt-PA caused
significant fibrinogenolysis at the doses of 3 and 10 mg/kg. Fibrinogen levels at 2 and 4 hours after
rt-PA infusion were decreased to about 60% of excipient controls with the 3 mg/kg dose and about
18% of controls with the 10 mg/kg dose. Fibrin/fibrinogen degradation products were increased at
2 and 4 hours after rt-PA infusion. The parameters were not significantly different from excipient
controls at 24 hours. rt-PA did not induce any unexpected physiological or pathological changes in
the Cynomolgus monkeys.

Sub-acute Toxicology
2) In rats, dosages of 1, 3 and 10 mg/kg were given daily for 14 days via the tail vein. All results were
considered to be comparable and normal between treated animals and those in the excipient
control group, except for small changes in the hematology determinations including significantly
lower mean erythrocyte, hemoglobin and haematocrit values as compared to control values. These
changes were consistent with a mild anaemia and occurred primarily in females at 3 and 10
mg/kg/day.

3) Dogs were given doses of 0.5, 1.0 and 1.5 mg/kg/day (6-hour intravenous infusion) for 14 days.
There was no evidence of any systemic toxicity related to the test article at any dosage level, or in
any dog in the excipient control group.

4) Beagle dogs were given rt-PA as a six hour i.v. infusion at 1, 2, 3 and 10 mg/kg/day for 14 days.
There were some hematological changes observed which were consistent with mild anaemia
(e.g. decreased hemoglobin, hematocrit and erythrocytes) in the 3 and 10 mg/kg/day groups.
Serum biochemical and urine analyses were comparable to control values. There was little or no

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 change in the levels of fibrinogen and fibrinogen degradation products in plasma samples taken
approximately 18 hours after the infusion was completed. Electrocardiograms were normal in all
dose groups. Gross and microscopic pathology revealed evidence of hemorrhage and fibrosis at the
injection site; this occurred in all dose groups including some dogs in the control group.

In addition, evidence of hemorrhage was observed at sites distant to the injection site, including
various locations in the gastrointestinal tract, in 4 of 6 dogs which received 10 mg/kg/day. Organ
weights were comparable between treated and control animals.

Summary of Acute and Sub-acute Toxicology

Acute and sub-acute toxicity studies in the rat, dog and monkey demonstrated no acute systemic
toxicity. In subacute studies, significant systemic toxicity was observed only in dogs given doses of 10
mg/kg/day for 14 days and consisted of hemorrhagic sites, primarily in the gastrointestinal tract. A mild
anaemia was observed in rats and dogs at dosages of 3 and 10 mg/kg/day for 14 days; this could be due
to the hemorrhage which was detected at the injection site.

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PATIENT MEDICATION INFORMATION

READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

ACTIVASE rt-PA
Alteplase for injection
Read this carefully before you start taking ACTIVASE rt-PA and each time you get a refill. This leaflet is a
summary and will not tell you everything about this drug. Talk to your healthcare professional about
your medical condition and treatment and ask if there is any new information about ACTIVASE rt-PA.

What is ACTIVASE rt-PA used for?

ACTIVASE rt-PA (alteplase for injection) is indicated for intravenous use in adults for:
• the breakdown of suspected occlusive coronary artery clots associated with evolving
transmural myocardial infarction; and
• the reduction of death associated with Acute Myocardial Infarction (AMI), the improvement of
function of the heart following AMI and the reduction in occurrence of congestive heart failure.
How does ACTIVASE rt-PA work?
ACTIVASE rt-PA when introduced into the systemic circulation, will bind to fibrin (protein that impedes
the flow of blood) in blood clots and converts the entrapped plasminogen to plasmin (which
breakdowns fibrin clots).
What are the ingredients in ACTIVASE rt-PA?
Medicinal ingredients: alteplase
Important Non-medicinal ingredients: L-arginine, phosphoric acid and polysorbate 80
ACTIVASE RT-PA comes in the following dosage forms:
• Boxes each containing one (1) vial of ACTIVASE rt-PA 50 mg and one (1) vial of Sterile Water for
Injection, USP 50 mL, for preparing a sterile solution of ACTIVASE rt-PA.
• Boxes each containing one (1) vial of ACTIVASE rt-PA 100 mg and one (1) vial of Sterile Water for
Injection, USP 100 mL, and one transfer device for preparing a sterile solution of ACTIVASE rt-PA

Do not use ACTIVASE rt-PA if:

• Hypersensitivity to alteplase or to any ingredient in the formulation or components of the
container
• Bleeding disorder or history of bleeding
• History of stroke
• Patients receiving other intravenous blood thinners
• Recent major surgery or trauma
• Brain tumour, abnormality of the blood vessels, or aneurysm
• Uncontrolled high blood pressure (i.e., > 180 mm Hg systolic or >110 mm Hg diastolic)

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 • Recent traumatic cardiopulmonary resuscitation

The most common complication encountered during therapy with ACTIVASE rt-PA (alteplase for
injection) is bleeding. Using heparin anticoagulation with ACTIVASE rt-PA contributes to the risk of
bleeding.

To help avoid side effects and ensure proper use, talk to your healthcare professional before you
take ACTIVASE rt-PA. Talk about any health conditions or problems you may have, including if you
are/have/had:
• Recent major surgery or trauma
• Clinical evidence or history of transient ischemic attacks
• Recent gastrointestinal or urinary tract bleeding
• High blood pressure (i.e., ≥ 175 mm Hg systolic and/or ≥ 110 mm Hg diastolic)
• A history or clinical evidence of high blood pressure in a patient over 70 years old
• Over 75 years old
• Problems with the heart or heartbeat
• Severe liver failure
• Pregnancy
• Serious infection or inflammation
• Taking medication that affects blood clotting (i.e., warfarin sodium)
• Use of blood clot dissolving drugs
• Cholesterol embolization

Tell your healthcare professional about all the medicines you take, including any drugs, vitamins,
minerals, natural supplements or alternative medicines.
The following may interact with ACTIVASE rt-PA:
• Anticoagulants such as heparin and warfarin
• Drugs that alter platelet function (such as acetylsalicylic acid)
How to take ACTIVASE rt-PA:
ACTIVASE rt-PA (alteplase for injection) is intended for intravenous use only administered by a trained
Health Care Professional.

Recommended Dose and Dosage Adjustment

There are two dose regimens for ACTIVASE rt-PA for use in the management of AMI.

90-Minute Accelerated Infusion

The recommended total dose is based upon patient weight, not to exceed 100 mg.
• For patients weighing >67 kg, the recommended dose is 100 mg, administered as a 15 mg
intravenous bolus, followed by 50 mg infused over 30 minutes and then 35 mg infused over the next
60 minutes.

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• For patients weighing < 67 kg, the recommended dose is 15 mg administered as an intravenous
bolus, followed by 0.75 mg/kg to a maximum of 50 mg, infused over the next 30 minutes, and then
0.50 mg/kg to a maximum of 35 mg infused over the next 60 minutes.

This 90-minute infusion regimen is recommended for use up to 6 hours after onset of AMI symptoms.

3-Hour Infusion
The recommended dose is 100 mg administered as 60 mg in the first hour, of which 6-7 mg is
administered as a bolus over the first 1-2 minutes and the remainder is administered by continuous
infusion, 20 mg by continuous infusion during the second hour, and 20 mg by continuous infusion over
the following one to four hours.

For smaller patients (<65 kg), a dose of 1.25 mg/kg may be warranted. This 3-hour infusion regimen is
recommended for use up to 12 hours after onset of AMI symptoms.

Refer to Product Monograph Part I – Health Professional Information – DOSAGE AND

ADMINISTRATION section for additional Preparation and Administration information.

Overdose:
Overdosage could lead to serious bleeding.

Should serious bleeding occur in a critical location, the infusion of ACTIVASE rt-PA (alteplase for
injection) and any other concomitant anticoagulant should be discontinued immediately. If necessary,
blood loss and reversal of the bleeding tendency can be managed with whole blood or packed red cells.

In the event of clinically significant fibrinogen depletion, you may be infused with fresh frozen plasma
or cryoprecipitate.

What are possible side effects from using ACTIVASE rt-PA?

These are not all the possible side effects you may have when taking ACTIVASE rt-PA. If you experience
any side effects not listed here, tell your healthcare professional.

Like all medicines, ACTIVASE rt-PA can have side effects. Below are some of the side effects associated
with ACTIVASE rt-PA:
• Allergic-type reactions, e.g. anaphylactoid reaction, anaphylactic reaction, throat swelling,
angioedema, rash, hives, shock
• Potential bleeding sites as a result of recent invasive procedure (i.e., catheter insertions, puncture,
surgery)
• Nausea and/or vomiting, low blood pressure and fever
• Patients with myocardial infarction can experience disease-related events that may lead to death.

For any unexpected effects while taking ACTIVASE rt-PA contact your doctor or pharmacist.

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In all cases, the health care professional will decide whether the drug should be stopped or not.

These are not all the possible side effects you may have when taking ACTIVASE rt-PA. If you experience
any side effects not listed here, tell your healthcare professional.

Serious side effects and what to do about them

Talk to your healthcare professional Stop taking drug and
Symptom / effect get immediate
Only if severe In all cases
medical help
COMMON
Gastrointestinal bleeding (5%) ✔
Genitourinary bleeding (urinary
✔
tract) (4%)
Intracerebral hemorrhage
✔
(bleeding within the skull) (1.3%)
UNKNOWN
Internal bleeding involving lungs ✔
Thromboembolism ✔
Cholesterol embolism ✔

If you have a troublesome symptom or side effect that is not listed here or becomes bad enough to
interfere with your daily activities, tell your healthcare professional.

Reporting Side Effects

You can report any suspected side effects associated with the use of health products to Health
Canada by:
• Visiting the Web page on Adverse Reaction Reporting (https://www.canada.ca/en/health-
canada/services/drugs-health-products/medeffect-canada.html) for information on how to
report online, by mail or by fax; or
• Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need information about how to manage your side
effects. The Canada Vigilance Program does not provide medical advice.

Storage:

Store between 2°C and 30°C. Protect from excessive exposure to light.

Unused reconstituted ACTIVASE rt-PA (in the vial) may be stored at 2-30°C for up to 8 hours. After that
time, any unused portion of the reconstituted material should be discarded. During the period of
reconstitution and infusion, protection from light is not necessary.

PRACTIVASE® rt-PA (alteplase for injection) Page 34 of 45

If you want more information about ACTIVASE rt-PA:
• Talk to your healthcare professional
• Find the full product monograph that is prepared for healthcare professionals and includes this
Patient Medication Information by visiting the Health Canada website:
(https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-
product-database.html; the manufacturer’s website http://www.rochecanada.com, or by
contacting the sponsor Hoffmann-La Roche Limited at: 1-888-762-4388).

This leaflet was prepared by Hoffmann-La Roche Limited.

Last Revised: October 7, 2021

©
Copyright 1996 – 2021 Hoffmann-La Roche Limited

ACTIVASE® is a registered trade-mark of Genentech Inc., used under license.

PRACTIVASE® rt-PA (alteplase for injection) Page 35 of 45

 Activase®

(alteplase)

for infusion

100 mg (58 million IU)

Read before preparing Activase®

Instructions for Use

See package insert for full prescribing information

PRACTIVASE® rt-PA (alteplase for injection) Page 36 of 45

 Activase® (alteplase)

Kit Contents

Transfer device

Activase vial
(no vacuum)

Activase vial stopper parts:

PRACTIVASE® rt-PA (alteplase for injection) Page 37 of 45

 Sterile Water for Injection (water) vial

Note:
Do not use Bacteriostatic Water for Injection, USP.

Prescribing Information

Instructions for Use

PRACTIVASE® rt-PA (alteplase for injection) Page 38 of 45

 Activase® (alteplase)
Also Required
(not included in kit)
1 Luer Syringe for removing bolus dose, as needed

1 Luer syringe for removing excess volume, as needed

2 large bore needles

2 Alcohol swabs

PRACTIVASE® rt-PA (alteplase for injection) Page 39 of 45

 IV infusion set

PRACTIVASE® rt-PA (alteplase for injection) Page 40 of 45

 Activase® (alteplase) Activase® (alteplase) Activase® (alteplase)

Reconstitution (use aseptic technique)

Step 1: Cleaning Step 2: Spiking Water vial Step 3: Spiking Activase vial

● Remove caps from both vials. ● Remove cover from one end of ● Remove cover from other end of
transfer device (Note: Either side transfer device.
● Wipe both stoppers with alcohol
of transfer device can be used.
swabs. ● Hold Activase vial upside down
Do not wipe transfer device spikes
over spike.
with alcohol).
● Press Activase vial down to insert
● Insert spike straight through center spike straight through center of
of water vial stopper. Activase vial stopper.
Do not invert water vial yet.
Inverting too early may lead

PRACTIVASE® rt-PA (alteplase for injection) Page 41 of 45

 to leakage and incorrect
dosing. Inserting the spike off-center
could lead to stopper collapse.

Activase® (alteplase) Activase® (alteplase) Activase® (alteplase)

Reconstitution (use aseptic technique) Administration Warning

Step 4: Inverting and transferring Step 5: Inspecting

PRACTIVASE® rt-PA (alteplase for injection) Page 42 of 45

 ● Invert vials so that water vial is on ● Separate empty water vial and Review important information
top. transfer device from Activase vial. below before preparing dose.
● Allow all water to transfer into ● Activase should be free of:
Do not push air from the
Activase vial. ○ Discoloration syringe into the vial.
● If the flow does not start ○ Particulates The vial is not under vacuum and
immediately or pauses, initiate the
● If needed, let stand undisturbed for adding air at any time may result
flow by flipping and re-inverting
a few minutes to allow large in leakage and incorrect dosing.
the vials.
bubbles to dissipate.
● Swirl gently and/or invert slowly to Only insert needles into the
dissolve Activase powder. side port.
Insert needle into side port of vial
Do not shake vials. Shaking stopper when withdrawing
may lead to excessive foaming medication to avoid leakage and
and degraded medication. incorrect dosing. Do not insert
needles into center of stopper.

PRACTIVASE® rt-PA (alteplase for injection) Page 43 of 45

 Activase® (alteplase) Activase® (alteplase) Activase® (alteplase)

Administration (use aseptic technique)

Step 6: Preparing bolus Step 7: Removing excess volume Step 8: Spiking and hanging

PRACTIVASE® rt-PA (alteplase for injection) Page 44 of 45

 ● Check if bolus is needed. If yes, ● Check if there is excess volume in ● Insert spike from IV tubing set into
attach needle to empty Luer vial. If yes, attach needle to empty center of vial stopper, through
syringe. Luer syringe. same hole made by transfer
device.
● Insert needle through side port ● Insert needle through side port
and withdraw bolus amount. and withdraw excess volume.
Do not make a new hole in the
vial stopper. Additional holes
Do not push any air from Do not push any air from
in vial stopper may lead to
syringe into vial (may cause syringe into vial (may cause
leakage.
leakage). leakage).
● Peel clear plastic hanger from vial
• Alternatively, the bolus can be left ● Discard any excess volume.
label.
in the vial and administered via an ● Leave infusion dose in vial.
infusion pump or removed from a ● Hang on IV pole and administer
port on the infusion line. per facility protocol.

Administration Notes
• Activase is for intravenous administration only.
• Do not add any other medication to infusion solutions containing Activase.
• Extravasation of Activase infusion can cause ecchymosis or inflammation. If extravasation occurs, terminate the infusion at that
IV site and apply local therapy.
• See full prescribing information for alternative dilution instructions.
Storage & Stability
• Protect the lyophilized Activase vial from excessive exposure to light.
• Activase contains no antibacterial preservatives and must be used within 8 hours following reconstitution (when stored 2–30°C).

PRACTIVASE® rt-PA (alteplase for injection) Page 45 of 45