INDICATIONS AND USAGE
Acute Myocardial Infarction
Activase® (Alteplase) is indicated for use in the management of acute
myocardial infarction in adults for the improvement of ventricular function
following AMI, the reduction of the incidence of congestive heart failure, and
the reduction of mortality associated with AMI. Treatment should be initiated
as soon as possible after the onset of AMI symptoms.
Acute Ischemic Stroke
Activase® (Alteplase) is indicated for the management of acute ischemic stroke
in adults for improving neurological recovery and reducing the incidence of
disability. Treatment should only be initiated within 3 hours after the onset
of stroke symptoms, and after exclusion of intracranial hemorrhage by a
cranial computerized tomography (CT) scan or other diagnostic imaging method
sensitive for the presence of hemorrhage (see CONTRAINDICATIONS).
Pulmonary Embolism
Activase® (Alteplase) is indicated in the management of acute massive
pulmonary embolism (PE) in adults:
--For the lysis of acute pulmonary emboli, defined as obstruction of
blood flow to a lobe or multiple segments of the lungs.
--For the lysis of pulmonary emboli accompanied by unstable hemodynamics,
e.g., failure to maintain blood pressure without supportive measures.
The diagnosis should be confirmed by objective means, such as pulmonary
angiography or noninvasive procedures such as lung scanning.
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CONTRAINDICATIONS
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Acute Myocardial Infarction or Pulmonary Embolism
Activase therapy in patients with acute myocardial infarction or pulmonary
embolism is contraindicated in the following situations because of an
increased risk of bleeding:
- Active internal bleeding
- History of cerebrovascular accident
- Recent intracranial or intraspinal surgery or trauma (see package
insert for WARNINGS)
- Intracranial neoplasm, arteriovenous malformation, or aneurysm
- Known bleeding diathesis
- Severe uncontrolled hypertension
Acute Ischemic Stroke
Activase therapy in patients with acute ischemic stroke is contraindicated in
the following situations because of an increased risk of bleeding, which could
result in significant disability or death:
- Evidence of intracranial hemorrhage on pretreatment evaluation
- Suspicion of subarachnoid hemorrhage on pretreatment evaluation
- Recent (within 3 months) intracranial or intraspinal surgery, serious head
trauma, or previous stroke
- History of intracranial hemorrhage
- Uncontrolled hypertension at time of treatment (e.g., > 185 mm Hg systolic or
> 110 mm Hg diastolic)
- Seizure at the onset of stroke
- Active internal bleeding
- Intracranial neoplasm, arteriovenous malformation, or aneurysm
- Known bleeding diathesis including but not limited to:
- Current use of oral anticoagulants (e.g., warfarin sodium) or an International
Normalized Ratio (INR)>1.7 or a prothrombin time (PT) > 15 seconds
- Administration of heparin within 48 hours preceding the onset of stroke and
have an elevated activated partial thromboplastin time (aPTT) at presentation
- Platelet count < 100,000/mm3
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WARNINGS
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Bleeding
The most common complication encountered during Activase therapy is bleeding.
The type of bleeding associated with thrombolytic therapy can be divided into
two broad categories:
>Internal bleeding, involving intracranial and
retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory
tracts.
>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 may contribute to bleeding. Some
of the hemorrhage episodes occurred 1 or more days after the effects of
Activase had dissipated, but while heparin therapy was continuing.
As fibrin is lysed during Activase therapy, bleeding from recent puncture sites
may occur. Therefore, thrombolytic therapy 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 treatment with Activase. Venipunctures should be performed
carefully and only as required.
Should an arterial puncture be necessary during an infusion of Activase, 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 (not controllable by local pressure) occur, the
infusion of Activase and any concomitant heparin should be terminated
immediately.
Each patient being considered for therapy with Activase should be carefully
evaluated and anticipated benefits weighed against potential risks associated
with therapy.
In the following conditions, the risks of Activase therapy for all approved
indications may be increased and should be weighed against the anticipated
benefits:
- Recent major surgery, e.g., coronary artery bypass graft, obstetrical
delivery, organ biopsy, previous puncture of noncompressible vessels
- Cerebrovascular disease
- Recent gastrointestinal or genitourinary bleeding
- Recent trauma
- Hypertension: systolic BP >/=175 mm Hg and/or diastolic BP >/=110 mm Hg
- High likelihood of left heart thrombus, e.g., mitral stenosis with
atrial fibrillation
- 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 (e.g., over 75 years old)
- 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
Cholesterol Embolization
Cholesterol embolism 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 may
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 in Acute Myocardial Infarction
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.
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 acute myocardial
infarction 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 are administered.
Use in Acute Ischemic Stroke
In addition to the previously listed conditions, the risks of Activase therapy
to treat acute ischemic stroke may be increased in the following conditions and
should be weighed against the anticipated benefits:
>Patients with severe neurological deficit (e.g., NIHSS > 22)
at presentation. There is an increased risk of intracranial hemorrhage in these
patients.
>Patients with major early infarct signs on a computerized
cranial tomography (CT) scan (e.g., substantial edema, mass effect, or midline
shift).
In patients without recent use of oral anticoagulants or heparin, Activase
treatment can be initiated prior to the availability of coagulation study
results. However, infusion should be discontinued if either a pretreatment
International Normalized Ratio (INR) > 1.7 or a prothrombin time (PT) > 15
seconds or an elevated activated partial thromboplastin time (aPTT) is
identified.
Treatment should be limited to facilities that can provide appropriate
evaluation and management of ICH.
In acute ischemic stroke, neither the incidence of intracranial hemorrhage nor
the benefits of therapy are known in patients treated with Activase more than 3
hours after the onset of symptoms. Therefore, treatment of patients with
acute ischemic stroke more than 3 hours after symptom onset is not recommended.
Due to the increased risk for misdiagnosis of acute ischemic stroke, special
diligence is required in making this diagnosis in patients whose blood glucose
values are < 50 mg/dL or > 400 mg/dL. The safety and efficacy of treatment with
Activase in patients with minor neurological deficit or with rapidly improving
symptoms prior to the start of Activase administration has not been evaluated.
Therefore, treatment of patients with minor neurological deficit or with
rapidly improving symptoms is not recommended.
Use in Pulmonary Embolism
It should be recognized that the treatment of pulmonary embolism with Activase
has not been shown to constitute adequate clinical treatment of underlying deep
vein thrombosis. Furthermore, the possible risk of reembolization due to the
lysis of underlying deep venous thrombi should be considered.
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DOSAGE AND ADMINISTRATION
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Activase® (Alteplase) is for intravenous administration only. Extravasation of
Activase infusion can cause ecchymosis and/or inflammation. Management consists
of terminating the infusion at that IV site and application of local therapy.
Acute Myocardial Infarction
Administer Activase as soon as possible after the onset of symptoms.
There are two Activase dose regimens for use in the management of acute
myocardial infarction; controlled studies to compare clinical outcomes with
these regimens have not been conducted.
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Accelerated Infusion
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The recommended total dose is based upon patient weight, not to exceed 100 mg.
For patients weighing > 67 kg, the recommended dose administered is 100 mg as a
15 mg intravenous bolus, followed by 50 mg infused over the next 30 minutes,
and then 35 mg infused over the next 60 minutes.
For patients weighing </= 67 kg, the recommended dose is administered as a 15
mg intravenous bolus, followed by 0.75 mg/kg infused over the next 30 minutes
not to exceed 50 mg, and then 0.50 mg/kg over the next 60 minutes not to exceed
35 mg.
The safety and efficacy of this accelerated infusion of Alteplase regimen has
only been investigated with concomitant administration of heparin and aspirin
as described in CLINICAL PHARMACOLOGY (see package insert).
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 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.
2. By removing 15 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 15 mL (1 mg/mL) bolus at the initiation of the
infusion.
b. The remainder of the Activase dose may be administered as follows:
50 mg vials -- administer using
either a polyvinyl chloride bag or glass vial and infusion set.
100 mg vial -- 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.
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3-Hour Infusion
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The recommended dose is 100 mg administered as 60 mg in the first hour (of
which 6 to 10 mg is 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, as described above, may be used.
Although the value of the use of anticoagulants during and following
administration of Activase has not been fully studied, heparin has been
administered concomitantly for 24 hours or longer in more than 90% of patients.
Aspirin and/or dipyridamole have been given to patients receiving Alteplase
during and/or following heparin treatment.
a. The bolus dose may be prepared in one of the following ways:
1. By removing 6 to 10 mL 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.
2. By removing 6 to 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 to 10 mL (1
mg/mL) bolus at the initiation of the infusion.
b. The remainder of the Activase dose may be administered as follows:
50 mg vials -- administer using either a
polyvinyl chloride bag or glass vial and infusion set.
100 mg vial -- 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.
Acute Ischemic Stroke
THE TOTAL DOSE FOR TREATMENT OF ACUTE ISCHEMIC STROKE SHOULD NOT EXCEED 90 mg.
The recommended dose is 0.9 mg/kg (not to exceed 90 mg total dose) infused over
60 minutes with 10% of the total dose administered as an initial intravenous
bolus over 1 minute.
The safety and efficacy of this regimen with concomitant administration of
heparin and aspirin during the first 24 hours after symptom onset has not been
investigated.
a. The bolus dose may be prepared in one of the following ways:
1. By removing 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.
2. By removing the appropriate volume from a port (second
injection site) on the infusion line after the infusion set is primed.
3. By programming an infusion pump to deliver the appropriate
volume as a bolus at the initiation of the infusion.
b. The remainder of the Activase dose may be administered as follows:
50 mg vials -- administer using either a
polyvinyl chloride bag or glass vial and infusion set.
100 mg vial -- remove from the vial any
quantity of drug in excess of that specified for patient treatment. 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.
Pulmonary Embolism
The recommended dose is 100 mg administered by intravenous infusion over 2
hours. Heparin therapy should be instituted or reinstituted near the end of or
immediately following the Activase infusion when the partial thromboplastin
time or thrombin time returns to twice normal or less.
The Activase dose may be administered as follows:
50 mg vials -- administer using either a
polyvinyl chloride bag or glass vial and infusion set.
100 mg vial -- 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.
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Reconstitution and Dilution
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Activase should be reconstituted by aseptically adding the appropriate volume
of the accompanying Sterile Water for Injection, USP, to the vial. It is
important that Activase be reconstituted only with Sterile Water for Injection,
USP, without preservatives. Do not use Bacteriostatic Water for Injection, USP.
The reconstituted preparation results in a colorless to pale yellow transparent
solution containing Activase 1 mg/mL at approximately pH 7.3. The osmolality of
this solution is approximately 215 mOsm/kg.
Because Activase contains no antibacterial preservatives, it should be
reconstituted immediately before use. The solution may be used for intravenous
administration within 8 hours following reconstitution when stored between
2°-30°C (36°-86°F). Before further dilution or administration, the product
should be visually inspected for particulate matter and discoloration prior to
administration whenever solution and container permit.
Activase may be administered as reconstituted at 1 mg/mL. As an alternative,
the reconstituted solution may be diluted further 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. Either
polyvinyl chloride bags or glass vials are acceptable. Activase is stable for
up to 8 hours in these solutions at room temperature. Exposure to light has no
effect on the stability of these solutions. 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.
50 mg Vials
Reconstitution should be carried out using a large bore needle (e.g., 18 gauge)
and a syringe, directing 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.
No other medication should be added to infusion solutions containing Activase.
Any unused infusion solution should be discarded.
100 mg Vial
Reconstitution should be carried out using the transfer device provided, adding
the contents of the accompanying 100 mL vial of Sterile Water for Injection,
USP, to the contents of the 100 mg vial of Activase powder. Slight foaming upon
reconstitution is not unusual; standing undisturbed for several minutes is
usually sufficient to allow dissipation of any large bubbles. Please refer to
the accompanying Instructions for Reconstitution and Administration. 100 mg
VIALS DO NOT CONTAIN VACUUM.
100 mg VIAL RECONSTITUTION:
- Use aseptic technique throughout.
- Remove the protective flip-caps from one vial of Activase and one vial
of Sterile Water for Injection, USP (SWFI).
- Open the package containing the transfer device by peeling the paper
label off the package.
- 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.
- Remove the protective cap from the other end of the transfer device.
DO NOT INVERT THE VIAL OF SWFI.
- Holding 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.
- Push the vial of Activase down so that the piercing pin is inserted
through the center of the Activase vial stopper.
- 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). Approximately 2 minutes are required for this
procedure.
- Remove the transfer device and the empty SWFI vial from the Activase
vial. Safely discard both the transfer device and the empty diluent vial
according to institutional procedures.
- Swirl gently to dissolve the Activase powder. DO NOT
SHAKE.
No other medication should be added to infusion solutions containing Activase.
Any unused infusion solution should be discarded.
HOW SUPPLIED
Activase® (Alteplase), 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.
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.
Do not use beyond the expiration date stamped on the vial.
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