A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Activase Indications, Dosage, Storage, Stability - Alteplase
Activase Indications, Dosage, Storage, Stability - Alteplase
INDICATIONS
Acute Myocardial Infarction
Activase®, Alteplase, recombinant
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 (see CLINICAL PHARMACOLOGY).
Acute Ischemic Stroke
Activase 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 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, and
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.
DOSAGE AND ADMINISTRATION
Activase®, Alteplase, recombinant
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.
A DOSE OF 150 mg OF ACTIVASE SHOULD
NOT BE USED FOR THE TREATMENT OF ACUTE MYOCARDIAL INFARCTION BECAUSE IT
HAS BEEN ASSOCIATED WITH AN INCREASE IN INTRACRANIAL BLEEDING.
Accelerated Infusion
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 ¾ 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.
a. The bolus dose
may be prepared in one of the following ways:
- 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 syringe should not be primed with air
and the needle should be
inserted away from the puncture
mark made by the transfer
device.
- By removing 15 mL from a proof (second injection
site) on the infusion line after the infusion
set is primed.
- 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®, Alteplase, recombinant
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.
Hang the Activase vial from
the plastic molded capping
attached to the bottom of the vial.
3-Hour Infusion
The recommended dose is 100
mg administered as 60 mg
(34.8 million IU) in the first hour (of which 6 to 10 mg
is administered as a bolus), 20 mg (11.6 million IU) over the second hour,
and 20 mg (11.6 million IU) 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.14
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:
- 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 syringe should not be primed with air
and the needle should be
inserted away from the puncture
mark made by the transfer
device.
- By removing 6 to 10 mL from a proof (second injection
site) on the infusion line after the infusion
set is primed.
- 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.
Hang the Activase vial from
the plastic molded capping
attached to the bottom of the vial.
Acute Ischemic Stroke
The recommended dose is 0.9
mg/kg (maximum of 90 mg) 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.
THE DOSE FOR TREATMENT OF ACUTE ISCHEMIC STROKE SHOULD NOT EXCEED 90
mg.
a. The bolus dose
may be prepared in one of the following ways:
- 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 syringe should
not be primed with air and the
needle should be inserted
away from the puncture
mark made by the transfer
device.
- By removing the appropriate
volume from a proof (second
injection site) on the
infusion line
after the infusion set
is primed.
- 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.
Hang the Activase vial from
the plastic molded capping
attached to the bottom of the vial.
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.
Hang the Activase vial from the
plastic molded capping attached
to the bottom of the vial.
Reconstitution and Dilution
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 2-30C (3686F). 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®, Alteplase.
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®,
Alteplase, recombinant
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®, Alteplase.
Any unused infusion solution
should be discarded.
HOW SUPPLIED
Activase®, Alteplase, recombinant
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
30C (86F), or under refrigeration
(28C/3646F). Protect the lyophilized material during extended
storage from excessive exposure
to light.
Do not use beyond the expiration
date stamped on the vial.
REFERENCES
1.Mueller H, Rao AK, Forman SA, et al. Thrombolysis in
myocardial infarction (TIMI):
comparative studies of coronary
reperfusion and systemic
fibrinogenolysis with two forms of recombinant
tissue type plasminogen
activator. J Am Coll Cardiol. 1987;10:47990.
2.Topol EJ, Morriss DC, Smalling RW, et al. A multicenter,
randomized, placebo controlled trial of a new form
of intravenous recombinant
tissue type plasminogen activator
(Activase®) in acute myocardial
infarction. J Am Coll Cardiol. 1987;9:120513.
3.Seifried E, Tanswell P, Ellbrück D, et al. Pharmacokinetics
and haemostatic status during
consecutive infusions of recombinant
tissue type plasminogen activator
in patients with acute myocardial
infarction. Thromb Haemostas. 1989;61:497501.
4.Tanswell P, Tebbe U, Neuhaus K L, et al. Pharmacokinetics
and fibrin specificity of Alteplase during accelerated infusions in acute
myocardial infarction. J Am Coll
Cardiol. 1992;19:10715.
5.De Wood MA, Spores J, Notske R, et al. Prevalence of
total coronary occlusion during the early hours of transmural
myocardial infarction.
New Engl J Med. 1980;303:897902.
6.Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis
in myocardial infarction (TIMI) trial, Phase I: a comparison between intravenous
tissue plasminogen activator
and intravenous streptokinase.
Circulation. 1987;76(1):14254.
7.Guerci AD, Gerstenblith G, Brinker JA, et al. A randomized
trial of intravenous tissue
plasminogen activator
for acute myocardial
infarction with subsequent randomization
to elective coronary angioplasty.
New Engl J Med. 1987;317:161318.
8.O¹Rourke M, Baron D, Keogh A, et al. Limitation
of myocardial infarction by early infusion
of recombinant tissue
plasminogen activator. Circulation. 1988;77:131115.
9.Wilcox RG, von der Lippe G, Olsson CG, et al. Trial
of tissue plasminogen activator
for mortality reduction
in acute myocardial
infarction: ASSET. Lancet. 1988;2:52530.
10.Hampton JR, The University of Nottingham. Personal
communication.
11.Van de Werf F, Arnold AER, et al. Effect of intravenous
tissue plasminogen activator on infarct
size, left ventricular
function and survival
in patients with acute myocardial
infarction. Br Med J. 1988;297:13749.
12.The National Institute of Neurological Disorders and
Stroke t PA Stroke Study Group. Tissue plasminogen
activator for acute
ischemic stroke. New Engl J Med. 1995;333:15817.
13.Goldhaber SZ, Kessler CM, Heit J, et al. A randomized
controlled trial of recombinant
tissue plasminogen
activator versus urokinase
in the treatment of acute pulmonary
embolism. Lancet. 1988;2:2938.
14.Califf RM, Topol EJ, George BS, et al. Hemorrhagic
complications associated with the use of intravenous
tissue plasminogen
activator in treatment
of acute myocardial infarction.
Am J Med. 1988;85:3539.
15.Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic
events during therapy with recombinant
tissue type plasminogen
activator, heparin, and aspirin for acute
myocardial infarction:
results from the thrombolysis
in myocardial infarction (TIMI), Phase II trial. Ann Int Med. 1991;115(4):25665.
16.National Heart Foundation of Australia Coronary Thrombolysis
Group. Coronary thrombolysis
and myocardial infarction
salvage by tissue plasminogen
activator given up to 4 hours after onset of myocardial
infarction. Lancet. 1988;1:2037.
17.Gore JM, Sloan M, Price TR, et al. and the TIMI Investigators.
Intracerebral hemorrhage, cerebral infarction, and subdural
hematoma after acute
myocardial infarction and thrombolytic
therapy in the thrombolysis
in myocardial infarction
study. Circulation. 1991;83:44859.
18.Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von
Kummer R, et al. for the ECASS Study Group. Intravenous thrombolysis
with recombinant tissue
plasminogen activator for
acute hemispheric stroke. The
European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:101725.
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