STREPTOKINASE
DESCRIPTION:
Streptase(R), Streptokinase, is a sterile, purified preparation of a bacterial
protein elaborated by group C beta-hemolytic streptococci. It is supplied as a
lyophilized white powder containing 25 mg cross-linked gelatin polypeptides, 25
mg sodium L-glutamate, sodium hydroxide to adjust pH, and 100 mg Albumin (Human)
per vial or infusion bottle as stabilizers. The preparation contains no
preservatives and is intended for intravenous and intracoronary administration.
ACTIONS/CLINICAL PHARMACOLOGY:
Streptase, Streptokinase, acts with plasminogen to produce an "activator
complex" that converts plasminogen to the proteolytic enzyme plasmin. The t1/2
of the activator complex is about 23 minutes; the complex is inactivated, in
part, by antistreptococcal antibodies. The mechanism by which dissociated
streptokinase is eliminated is clearance by sites in the liver; however, no
metabolites of streptokinase have been identified. Plasmin degrades fibrin clots
as well as fibrinogen and other plasma proteins. Plasmin is inactivated by
circulating inhibitors, such as alpha-2-plasmin inhibitor or alpha- 2-
macroglobulin. These inhibitors are rapidly consumed at high doses of
streptokinase.
Intravenous infusion of Streptokinase is followed by increased fibrinolytic
activity, which decreases plasma fibrinogen levels for 24 to 36 hours. The
decrease in plasma fibrinogen is associated with decreases in plasma and blood
viscosity and red blood cell aggregation. The hyperfibrinolytic effect
disappears within a few hours after discontinuation, but a prolonged thrombin
time may persist for up to 24 hours due to the decrease in plasma levels of
fibrinogen and an increase in the amount of circulating fibrin(ogen) degradation
products (FDP). Depending upon the dosage and duration of infusion of
Streptokinase, the thrombin time will decrease to less than two times the normal
control value within 4 hours, and return to normal by 24 hours.
Intravenous administration has been shown to reduce blood pressure and total
peripheral resistance with a corresponding reduction in cardiac afterload. These
expected responses were not studied with the intracoronary administration of
Streptase, Streptokinase. The quantitative benefit has not been evaluated.
Variable amounts of circulating antistreptokinase antibody are present in
individuals as a result of recent streptococcal infections. The recommended
dosage schedule usually obviates the need for antibody titration.
Two very large, randomized, placebo-controlled studies (REF. 1, 2) involving
almost 30,000 patients have demonstrated that a 60-minute intravenous infusion
of 1,500,000 IU of Streptokinase significantly reduces mortality following a
myocardial infarction. One of these studies also evaluated concomitant oral
administration of low dose aspirin (160 mg/d over one month).
In the GISSI study the reduction in mortality was time dependent. There was a
47% reduction in mortality among patients treated within one hour of the onset
of chest pain, a 23% reduction among patients treated within three hours, and a
17% reduction among patients treated between three and six hours. There was also
a reduction in mortality in patients treated between six and twelve hours from
the onset of symptoms, but the reduction was not statistically significant.
In the ISIS-2 study the reduction in mortality was also time dependent. If
Streptokinase and aspirin were administered within the first hour after symptom
onset, the reduction in mortality was 44%. The reduction in the odds of death in
patients treated within four hours was 53% for the combination of Streptokinase
and aspirin, and 35% for Streptokinase alone. However, the reduction was still
significant when treatment was started 5-24 hours after symptom onset: 33% for
the combined therapy and 17% for Streptokinase alone. Overall, in the 0-24 hour
time period there was a 42% reduction in the odds of death with combined
treatment (Streptokinase and aspirin) versus placebo (2p<0.00001) and a 25%
reduction in the odds of death with Streptokinase alone versus placebo
(2p<0.00001).
One of eight smaller studies using a similar dosing schedule showed a
statistically significant reduction in mortality. When all of these studies were
pooled, the overall decrease in mortality was approximately 23%. Results from
pooling several studies using different dosages with long term infusion
corroborate these observations.
In addition, studies measuring left ventricular ejection fraction (LVEF) at
discharge showed the mean LVEFs were 3-6 percentage points higher in the
Streptokinase group than in the control group. This difference was statistically
significant in some of the studies ((REF. 3, 4). Furthermore, some studies
reported greater improvement in LVEF among patients treated within three hours
than in patients treated later.
Results from a randomized controlled trial in over 11,000 patients show that,
following treatment with IV Streptokinase, there is a reduction in the number of
patients with clinical congestive heart failure during the 14-21 day in-
hospital period. Clinical congestive heart failure occurred in 12.8% of
Streptokinase- treated patients compared with 15% of the control patients
(p=0.001) (REF. 1).
The rate of reocclusion of the infarct-related vessel has been reported to be
approximately 15-20%. The rate of reocclusion depends on dosage, additional
anticoagulant therapy and residual stenosis. When the reinfarctions were
evaluated in studies involving 8800 Streptokinase-treated patients, the overall
rate was 3.8% (range 2-15%). In over 8500 control patients, the rate of
reinfarction was 2.4%. However, the ISIS-2 study showed that an increase in
reinfarction was avoided when Streptokinase was combined with low dose aspirin.
The rate of reinfarction in the combination group was 1.8% vs 1.9% in the group
given aspirin alone.
Streptase, Streptokinase, administered by the intracoronary route has resulted
in thrombolysis usually within one hour, and ensuing reperfusion results in
improvement of cardiac function and reduction of mortality (REF. 5, 6). LVEF was
increased in patients treated with Streptokinase when compared to patients
treated with conventional therapy. When the initial LVEF was low, the
Streptokinase-treated patients showed greater improvement than did the controls.
Spontaneous reperfusion is known to occur and has been observed with angiography
at various time points after infarction. Data from one study show that 73% of
Streptokinase-treated patients and 47% of the placebo-allocated patients
reperfused during hospitalization.
Studies with thrombolytic therapy for pulmonary embolism show no significant
difference in lung perfusion scan between the thrombolysis group and the heparin
group at one-year follow-up. However, measurements of pulmonary capillary blood
volumes and diffusing capacities at two weeks and one year after therapy
indicate that a more complete resolution of thrombotic obstruction and
normalization of pulmonary physiology was achieved with thrombolytic therapy,
thus preventing the long term sequelae of pulmonary hypertension and pulmonary
failure (REF. 7).
The long term benefit of Streptase, Streptokinase, therapy for deep vein
thrombosis (DVT) has been evaluated venographically (REF. 8). The combined
results of five randomized studies show no residual thrombotic material in 60-
75% of patients treated with Streptokinase versus only 10% of those treated with
heparin. Thrombolytic therapy also preserves venous valve function in a majority
of cases, thus avoiding the pathologic venous changes that produce the clinical
post-phlebitic syndrome which occurs in 90% of the DVT patients treated with
heparin.
There is a time-related decrease in effectiveness when Streptase, Streptokinase,
is used in the management of peripheral arterial thromboembolism. When
administered three to ten days after onset of obstruction, rates of clearance of
50-75% were reported.
INDICATIONS AND USAGE:
ACUTE EVOLVING TRANSMURAL MYOCARDIAL INFARCTION: Streptase, Streptokinase, is
indicated for use in the management of acute myocardial infarction (AMI) in
adults, for the lysis of intracoronary thrombi, the improvement of ventricular
function, and the reduction of mortality associated with AMI, when administered
by either the intravenous or the intracoronary route, as well as for the
reduction of infarct size and congestive heart failure associated with AMI when
administered by the intravenous route. Earlier administration of Streptokinase
is correlated with greater clinical benefit. (See ACTIONS/CLINICAL
PHARMACOLOGY.)
PULMONARY EMBOLISM: Streptase, Streptokinase, is indicated for the lysis of
objectively diagnosed (angiography or lung scan) pulmonary emboli, involving
obstruction of blood flow to a lobe or multiple segments, with or without
unstable hemodynamics.
DEEP VEIN THROMBOSIS: Streptase, Streptokinase, is indicated for the lysis of
objectively diagnosed (preferably ascending venography), acute, extensive
thrombi of the deep veins such as those involving the popliteal and more
proximal vessels.
ARTERIAL THROMBOSIS OR EMBOLISM: Streptase, Streptokinase, is indicated for the
lysis of acute arterial thrombi and emboli. Streptokinase is not indicated for
arterial emboli originating from the left side of the heart due to the risk of
new embolic phenomena such as cerebral embolism.
OCCLUSION OF ARTERIOVENOUS CANNULAE: Streptase, Streptokinase, is indicated as
an alternative to surgical revision for clearing totally or partially occluded
arteriovenous cannulae when acceptable flow cannot be achieved.
CONTRAINDICATIONS:
Because thrombolytic therapy increases the risk of bleeding, Streptase,
Streptokinase, is contraindicated in the following situations:
-- active internal bleeding
-- recent (within 2 months) cerebrovascular accident, intracranial or
intraspinal surgery (see WARNINGS)
-- intracranial neoplasm
-- severe uncontrolled hypertension
Streptokinase should not be administered to patients having experienced severe
allergic reaction to the product.
WARNINGS:
BLEEDING: Following intravenous high-dose brief- duration Streptokinase therapy
in acute myocardial infarction, severe bleeding complications requiring
transfusion are extremely rare (0.3-0.5%), and combined therapy with low dose
aspirin does not appear to increase the risk of major bleeding. The addition of
aspirin to Streptokinase may cause a slight increase in the risk of minor
bleeding (3.1% without aspirin vs. 3.9% with) (REF. 2).
Streptokinase will cause lysis of hemostatic fibrin deposits such as those
occurring at sites of needle punctures, particularly when infused over several
hours, and bleeding may occur from such sites. In order to minimize the risk of
bleeding during treatment with Streptokinase, venipunctures and physical
handling of the patient should be performed carefully and as infrequently as
possible, and intramuscular injections must be avoided.
Should an arterial puncture be necessary during intravenous therapy, upper
extremity vessels are preferable. Pressure should be applied for at least 30
minutes, a pressure dressing applied, and the puncture site checked frequently
for evidence of bleeding.
In the following conditions the risks of therapy may be increased and should be
weighed against the anticipated benefits.
-- Recent (within 10 days) major surgery, obstetrical delivery, organ biopsy,
previous puncture of noncompressible vessels
-- Recent (within 10 days) serious gastrointestinal bleeding
-- Recent (within 10 days) trauma including cardiopulmonary resuscitation
-- Hypertension: systolic BP >180 mm Hg and/or diastolic BP >110 mm Hg
-- High likelihood of left heart thrombus, e.g., mitral stenosis with atrial
fibrillation
-- Subacute bacterial endocarditis
-- Hemostatic defects including those secondary to severe hepatic or renal
disease
-- Pregnancy
-- Age >75 years
-- Cerebrovascular disease
-- Diabetic hemorrhagic retinopathy
-- Septic thrombophlebitis or occluded AV cannula at seriously infected site
-- Any other condition in which bleeding constitutes a significant hazard or
would be particularly difficult to manage because of its location.
Should serious spontaneous bleeding (not controllable by local pressure) occur,
the infusion of Streptase, Streptokinase, should be terminated immediately and
treatment instituted as described under ADVERSE REACTIONS.
Bleeding into the pericardium, sometimes associated with myocardial rupture, has
been seen in individual cases and has resulted in fatalities.
ARRHYTHMIAS: Rapid lysis of coronary thrombi has been shown to cause reperfusion
atrial or ventricular dysrhythmias requiring immediate treatment. Careful
monitoring for arrhythmia is recommended during and immediately following
administration of Streptase, Streptokinase, for acute myocardial infarction.
Occasionally, tachycardia and bradycardia have been observed.
HYPOTENSION: Hypotension, sometimes severe, not secondary to bleeding or
anaphylaxis has been observed during intravenous Streptase, Streptokinase,
infusion in 1% to 10% of patients. Patients should be monitored closely and,
should symptomatic or alarming hypotension occur, appropriate treatment should
be administered. This treatment may include a decrease in the intravenous
Streptokinase infusion rate. Smaller hypotensive effects are common and have not
required treatment.
CHOLESTEROL EMBOLISM: 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.
OTHER: Non-cardiogenic pulmonary edema has been reported rarely in patients
treated with Streptase, Streptokinase. The risk of this appears greatest in
patients who have large myocardial infarctions and are undergoing thrombolytic
therapy by the intracoronary route.
Rarely, polyneuropathy has been temporally related to the use of Streptase,
Streptokinase, with some cases described as Guillain Barre Syndrome.
Should pulmonary embolism or recurrent pulmonary embolism occur during
Streptase, Streptokinase, therapy, the originally planned course of treatment
should be completed in an attempt to lyse the embolus. While pulmonary embolism
may occasionally occur during Streptokinase treatment, the incidence is no
greater than when patients are treated with heparin alone. In addition to
pulmonary embolism, embolization to other sites during Streptase treatment, has
been observed.
PRECAUTIONS:
GENERAL: There have been rare cases where Streptase, Streptokinase, has been
administered for suspected AMI subsequently diagnosed as pancreatitis.
Fatalities have occurred under these circumstances.
REPEATED ADMINISTRATION - Because of the increased likelihood of resistance due
to antistreptokinase antibody, Streptase, Streptokinase, may not be effective if
administered between five days and twelve months of prior Streptokinase or
Anistreplase administration, or streptococcal infections, such as streptococcal
pharyngitis, acute rheumatic fever, or acute glomerulonephritis secondary to a
streptococcal infection.
LABORATORY TESTS:
INTRAVENOUS OR INTRACORONARY INFUSION FOR MYOCARDIAL INFARCTION--Intravenous
administration of Streptase, Streptokinase, will cause marked decreases in
plasminogen and fibrinogen and increases in thrombin time (TT), activated
partial thromboplastin time (APTT), and prothrombin time (PT), which usually
normalize within 12-24 hours. These changes may also occur in some patients with
intracoronary administration of Streptokinase.
INTRAVENOUS INFUSION FOR OTHER INDICATIONS- -Before commencing thrombolytic
therapy, it is desirable to obtain an activated partial thromboplastin time
(APTT), a prothrombin time (PT), a thrombin time (TT), or fibrinogen levels, and
a hematocrit and platelet count. If heparin has been given, it should be
discontinued and the TT or APTT should be less than twice the normal control
value before thrombolytic therapy is started.
During the infusion, decreases in plasminogen and fibrinogen levels and an
increase in the level of FDP (the latter two causing a prolongation in the
clotting times of coagulation tests) will generally confirm the existence of a
lytic state. Therefore, lytic therapy can be confirmed by performing the TT,
APTT, PT, or fibrinogen levels approximately 4 hours after initiation of
therapy. If heparin is to be (re)instituted following the Streptase,
Streptokinase, infusion, the TT or APTT should be less than twice the normal
control value (see manufacturer's prescribing information for proper use of
heparin).
DRUG INTERACTIONS: The interaction of Streptase, Streptokinase, with other drugs
has not been well studied.
USE OF ANTICOAGULANTS AND ANTIPLATELET AGENTS- -Streptase, Streptokinase, alone
or in combination with antiplatelet agents and anticoagulants, may cause
bleeding complications. Therefore, careful monitoring is advised. In the
treatment of acute MI, aspirin, when not otherwise contraindicated, should be
administered with Streptokinase (See Below).
ANTICOAGULATION AND ANTIPLATELETS AFTER TREATMENT FOR MYOCARDIAL INFARCTION--In
the treatment of acute myocardial infarction, the use of aspirin has been shown
to reduce the incidence of reinfarction and stroke. The addition of aspirin to
Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs.
3.1%), but does not appear to increase the incidence of major bleeding (see
ADVERSE REACTIONS) (REF. 2). The use of anticoagulants following administration
of Streptokinase increases the risk of bleeding, but has not yet been shown to
be of unequivocal clinical benefit. Therefore, whereas the use of aspirin is
recommended unless otherwise contraindicated, the use of anticoagulants should
be decided by the treating physician.
ANTICOAGULATION AFTER IV TREATMENT FOR OTHER INDICATIONS--Continuous intravenous
infusion of heparin, without a loading dose, has been recommended following
termination of Streptase, Streptokinase, infusion for treatment of pulmonary
embolism or deep vein thrombosis to prevent rethrombosis. The effect of
Streptokinase on thrombin time (TT) and activated partial thromboplastin time
(APTT) will usually diminish within 3 to 4 hours after Streptokinase therapy,
and heparin therapy without a loading dose can be initiated when the TT or the
APTT is less than twice the normal control value.
PREGNANCY:
PREGNANCY CATEGORY C -- Animal reproduction studies have not been conducted with
Streptase, Streptokinase. It is also not known whether Streptokinase can cause
fetal harm when administered to a pregnant woman or can affect reproduction
capacity. Streptokinase should be given to a pregnant woman only if clearly
needed.
PEDIATRIC USE: Controlled clinical studies have not been conducted in children
to determine safety and efficacy in the pediatric population. The evidence of
clinical benefits and risks is solely based on anecdotal reports in patients
ranging in age from <1 month to 16 years. The largest number of patient reports
have pertained to the use of streptokinase in arterial occlusions. For arterial
occulsions the most frequently used loading dose was 1000 IU/kg; fewer numbers
of patients received 3000 IU/kg. Loading dose durations have typically ranged
from 5 minutes to 30 minutes. Continuous infusion doses were frequently 1000
IU/kg/hr; fewer were at 1500 IU/kg/hr. Infusions were maintained for 12 hours
in approximately half of the published cases; a smaller proportion were between
12 hours and 24 hours. Reported adverse events associated with the use of
streptokinase in the pediatric population are similar in nature to those
associated with its use in adults. Rates of all bleeding complications have been
variable, and as high as 50% at catheter sites in some studies. Occasionally
bleeding has required transfusion. Careful monitoring of patient status is
necessary.
DRUG INTERACTIONS:
The interaction of Streptase, Streptokinase, with other drugs has not been well
studied.
USE OF ANTICOAGULANTS AND ANTIPLATELET AGENTS- -Streptase, Streptokinase, alone
or in combination with antiplatelet agents and anticoagulants, may cause
bleeding complications. Therefore, careful monitoring is advised. In the
treatment of acute MI, aspirin, when not otherwise contraindicated, should be
administered with Streptokinase (see Below).
ANTICOAGULATION AND ANTIPLATELETS AFTER TREATMENT FOR MYOCARDIAL INFARCTION--In
the treatment of acute myocardial infarction, the use of aspirin has been shown
to reduce the incidence of reinfarction and stroke. The addition of aspirin to
Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs.
3.1%), but does not appear to increase the incidence of major bleeding (see
ADVERSE REACTIONS) (REF. 2). The use of anticoagulants following administration
of Streptokinase increases the risk of bleeding, but has not yet been shown to
be of unequivocal clinical benefit. Therefore, whereas the use of aspirin is
recommended unless otherwise contraindicated, the use of anticoagulants should
be decided by the treating physician.
ANTICOAGULATION AFTER IV TREATMENT FOR OTHER INDICATIONS--Continuous intravenous
infusion of heparin, without a loading dose, has been recommended following
termination of Streptase, Streptokinase, infusion for treatment of pulmonary
embolism or deep vein thrombosis to prevent rethrombosis. The effect of
Streptokinase on thrombin time (TT) and activated partial thromboplastin time
(APTT) will usually diminish within 3 to 4 hours after Streptokinase therapy,
and heparin therapy without a loading dose can be initiated when the TT or the
APTT is less than twice the normal control value.
(See also PRECAUTIONS section.)
ADVERSE REACTIONS:
The following adverse reactions have been associated with intravenous therapy
and may also occur with intracoronary artery infusion:
BLEEDING: The reported incidence of bleeding (major or minor) has varied widely
depending on the indication, dose, route and duration of administration, and
concomitant therapy.
Minor bleeding can be anticipated mainly at invaded or disturbed sites. If such
bleeding occurs, local measures should be taken to control the bleeding.
Severe internal bleeding involving gastrointestinal (including hepatic
bleeding), genitourinary, retroperitoneal, or intracerebral sites has occurred
and has resulted in fatalities. In the treatment of acute myocardial infarction
with intravenous Streptokinase, the GISSI and ISIS-2 studies reported a rate of
major bleeding (requiring transfusion) of 0.3-0.5%. However, rates as high as
16% have been reported in studies which required administration of
anticoagulants and invasive procedures. Major bleed rates are difficult to
determine for other dosages and patient populations because of the different
dosing and intervals of infusions. The rates reported appear to be within the
ranges reported for intravenous administration in acute myocardial infarction.
Should uncontrollable bleeding occur, Streptokinase infusion should be
terminated immediately, rather than slowing the rate of administration of or
reducing the dose of Streptokinase. If necessary, bleeding can be reversed and
blood loss effectively managed with appropriate replacement therapy. Although
the use of aminocaproic acid in humans as an antidote for Streptokinase has not
been documented, it may be considered in an emergency situation.
ALLERGIC REACTIONS: Fever and shivering, occurring in 1-4% of patients (REF. 1,
2), are the most commonly reported allergic reactions with intravenous use of
Streptase, Streptokinase, in acute myocardial infarction. Anaphylactic and
anaphylactoid reactions ranging in severity from minor breathing difficulty to
bronchospasm, periorbital swelling or angioneurotic edema have been observed
rarely. Other milder allergic effects such as urticaria, itching, flushing,
nausea, headache and musculoskeletal pain have also been observed, as have
delayed hypersensitivity reactions such as vasculitis and interstitial
nephritis. Anaphylactic shock is very rare, having been reported in 0-0.1% of
patients (REF. 1, 2, 4).
Mild or moderate allergic reactions may be managed with concomitant
antihistamine and/or corticosteroid therapy. Severe allergic reactions require
immediate discontinuation of Streptase, Streptokinase, with adrenergic,
antihistamine, and/or corticosteroid agents administered intravenously as
required.
RESPIRATORY: There have been reports of respiratory depression in patients
receiving Streptokinase. In some cases, it was not possible to determine whether
the respiratory depression was associated with Streptokinase or was a symptom of
the underlying process. If respiratory depression is associated with
Streptokinase, the occurrence is believed to be rare.
OTHER ADVERSE REACTIONS: Transient elevations of serum transaminases have been
observed. The source of these enzyme rises and their clinical significance is
not fully understood.
There have been reports in the literature of cases of back pain associated with
the use of Streptokinase. In most cases the pain developed during Streptokinase
intravenous infusion and ceased within minutes of discontinuation of the
infusion.
DOSAGE AND ADMINISTRATION:
ACUTE EVOLVING TRANSMURAL MYOCARDIAL INFARCTION: Administer Streptokinase as
soon as possible after onset of symptoms. The greatest benefit in mortality
reduction was observed when Streptokinase was administered within four hours,
but statistically significant benefit has been reported up to 24 hours (see
ACTIONS/CLINICAL PHARMACOLOGY).
ROUTE TOTAL DOSE DOSAGE/DURATION
Intravenous 1,500,000 IU 1,500,000 IU
infusion within 60 min.
Intracoronary 140,000 IU 20,000 IU by
infusion bolus followed by
2,000 IU/min.
for 60 min.
PULMONARY EMBOLISM, DEEP VEIN THROMBOSIS, ARTERIAL THROMBOSIS OR EMBOLISM:
Streptase, Streptokinase, treatment should be instituted as soon as possible
after onset of the thrombotic event, preferably within 7 days. Any delay in
instituting lytic therapy to evaluate the effect of heparin therapy decreases
the potential for optimal efficacy. Since human exposure to streptococci is
common, antibodies to Streptokinase are prevalent. Thus, a loading dose of
Streptokinase sufficient to neutralize these antibodies is required. A dose of
250,000 IU of Streptokinase infused into a peripheral vein over 30 minutes has
been found appropriate in over 90% of patients. Furthermore, if the thrombin
time or any other parameter of lysis after 4 hours of therapy is not
significantly different from the normal control level, discontinue Streptokinase
because excessive resistance is present.
IV INFUSION
INDICATION LOADING DOSE DOSAGE/DURATION
Pulomonary 250,000 IU/30 100,000 IU/hr
Embolism min. for 24 hr (72 hrs if
concurrent DVT is
suspected).
Deep Vein 250,000 IU/30 100,000 IU/hr
Thrombosis min. for 72 hr
Arterial
Thrombosis 250,000 IU/30 100,000 IU/hr
or Embolism min. for 24-72 hr
MAINTENANCE THERAPY : After the initial bolus dose 1 lac units/hr for next 12 hrs. every day for three consecutive days. But there is no improvement than no further dose increase is beneficial or needed.
ARTERIOVENOUS CANNULAE OCCLUSION: Before using Streptase, Streptokinase, an
attempt should be made to clear the cannula by careful syringe technique, using
heparinized saline solution. If adequate flow is not re-established,
Streptokinase may be employed. Allow the effect of any pretreatment
anticoagulants to diminish. Instill 250,000 IU Streptokinase in 2 mL of solution
into each occluded limb of the cannula slowly. Clamp off cannula limb(s) for 2
hours. Observe the patient closely for possible adverse effects. After
treatment, aspirate contents of infused cannula limb(s), flush with saline,
reconnect cannula.
PEDIATRIC PATIENTS: Specific dosage and administration recommendations cannot
be made based on the limited data available. However, published experience
generally used loading and continuous infusion doses administered on a weight-
adjusted basis. See PRECAUTIONS, Pediatric Use.
RECONSTITUTION AND DILUTION: THE PROTEIN NATURE AND LYOPHILIZED FORM OF
STREPTASE, STREPTOKINASE, REQUIRE CAREFUL RECONSTITUTION AND DILUTION. SLIGHT
FLOCCULATION (DESCRIBED AS THIN TRANSLUCENT FIBERS) OF RECONSTITUTED
STREPTOKINASE OCCURRED OCCASIONALLY DURING CLINICAL TRIALS BUT DID NOT INTERFERE
WITH THE SAFE USE OF THE SOLUTION. THE FOLLOWING RECONSTITUTION AND DILUTION
PROCEDURES ARE RECOMMENDED:
VIALS AND INFUSION BOTTLES
1. Slowly add 5 mL Sodium Chloride Injection, USP or 5% Dextrose Injection,
USP to the Streptase, Streptokinase, vial, directing the diluent at the side
of the vacuum-packed vial rather than into the drug powder.
2. Roll and tilt the vial gently to reconstitute. Avoid shaking. (Shaking may
cause foaming.) (If necessary, total volume may be increased to a maximum of
500 mL in glass or 50 mL in plastic containers, and the infusion pump rate in
Table 1 should be adjusted accordingly.) To facilitate setting the infusion pump
rate, a total volume of 45 mL, or a multiple thereof, is recommended.
3. Withdraw the entire reconstituted contents of the vial; slowly and
carefully dilute further to a total volume as recommended in Table 1. Avoid
shaking and agitation on dilution.
4. When diluting the 1,500,000 IU infusion bottle (50 mL), slowly add 5 mL
Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, directing it
at the side of the bottle rather than into the drug powder. Roll and tilt the
bottle gently to reconstitute. Avoid shaking as it may cause foaming. Add an
additional 40 mL of diluent to the bottle, avoiding shaking and agitation.
(Total volume = 45 mL). Administer by infusion pump at the rate indicated in
Table 1.
5. Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration. (The Albumin (Human) may
impart a slightly yellow color to the solution.)
6. The reconstituted solution can be filtered through a 0.8 Mcgm or larger
pore size filter.
7. Because Streptase, Streptokinase, contains no preservatives, it should be
reconstituted immediately before use. The solution may be used for direct
intravenous administration within eight hours following reconstitution if
stored at 2-8 deg C (36-46 deg F).
8. Do not add other medication to the container of Streptase, Streptokinase.
9. Unused reconstituted drug should be discarded.
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TABLE 1
SUGGESTED DILUTIONS AND INFUSION RATES
TOTAL
VIAL SIZE SOLUTION
DOSAGE (IU) VOLUME INFUSION RATE
1. ACUTE MYOCARDIAL INFARCTION
A. INTRAVENOUS INFUSION 1,500,000 45 mL Infuse 45 mL within 60 min.
B. INTRACORONARY INFUSION 250,000 125 mL
1. 20,000 IU bolus 1.Loading Dose of 10 mL
2. 2,000 IU/minute for 60 minutes 2.Then 60 mL/hour
II. PULMONARY EMBOLISM, DEEP VEIN THROMBOSIS, ARTERIAL THROMBOSIS OR EMBOLISM
INTRAVENOUS INFUSION
A. 1. 250,000 IU loading 1,500,000 90 mL 1.Infuse 30 mL/hour for 30 minutes
dose over 30 minutes
2. 100,000 IU/hour maintenance dose 2. Infuse 6 mL per hour
B. SAME 1,500,000 infusion bottle 45 mL
1. 15 mL/hour for 30 minutes
2. Infuse 3 mL per hour
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FOR USE IN ARTERIOVENOUS CANNULAE: Slowly reconstitute the contents of 250,000
IU Streptase, Streptokinase, vacuum-packed vial with 2 mL Sodium Chloride
Injection, USP or 5% Dextrose Injection, USP.
Dosage and administration
Dosage
Note:
When thrombolytic therapy is necessary and a high antibody concentration against streptokinase is present, or when recent streptokinase therapy has been given (more than 5 days and less than one year previously), homologous fibrinolytics (e.g. urokinase or t-PA) can be used (see also section "Contra-indication" and "Special warnings and special precautions for use".
Systemic administration
In short-term thrombolysis, adults with peripheral venous and arterial vessels occlusions receive an initial dose of 250,000 IU Streptase within 30 min, followed by a maintenance dose of 1.5 Mio IU per hour over 6 hours.
The 6-hour-Streptase infusion can be repeated on the following day, depending on the therapeutic success of lysis. However, repetition of treatment must on no account be conducted later than 5 days after the first course.
In short-term lysis for the treatment of acute myocardial infarction 1.5 Mio IU Streptase are given within 60 min.
As an alternative to short-term lysis, a long-term lysis for the treatment of peripheral occlusions may be considered. An initial dose of 250,000 IU Streptase is given within 30 min., followed by a maintenance dose of 100,000 IU per hour. The duration of therapy depends on the extension and localisation of the vessel occlusion. In peripheral vessel occlusion the maximum duration is 5 days.
In case of thromboses of the central retinal vessels, lysis of arterial occlusions should be limited to max. 24 hours, in venous occlusions to max. 72 hours. If continuation of thrombolysis is indicated due to extensive thrombotic occlusions, an interval of approx. one day should be observed followed by administration of a homologous thrombolytic
Local administration
In acute myocardial infarction patients are given an intracoronary bolus of 20,000 IU Streptase on average and a maintenance dose of 2000 IU to 4000 IU per min. over 30 to 90 min.
Patients with acute, subacute and chronic peripheral thromboses and embolisms receive 1000 IU to 2000 IU Streptase in intervals of 3 to 5 min. The duration of administration depends on the length and localisation of the vessel occlusion and amounts up to 3 hours at a total dose of max. 120,000 IU Streptase.
A percutaneous transluminal angioplasty (mechanical vessel expansion) can be performed simultaneously, if necessary.
Dosage for neonates, infants and children
Sufficient experience with Streptase therapy in children is not yet available.
Control of therapy
Systemic administration
In case of short-term lysis over 6 hours heparin should be administered during or following Streptase infusion when the thrombin time (TT) or partial thromboplastin time (aPTT) have reached less than twice or 1.5 times the normal control value, respectively, The TT and aPTT should be prolonged to 2 to 4 fold and 1.5 to 2.5 fold the normal value, respectively, in order to ensure sufficient protection against rethrombosis.
If the Streptase infusion is not repeated the heparin therapy is instituted simultaneously with the administration of oral anticoagulants (see follow-up treatment).
The long-term lysis is controlled with the thrombin time. A 2 to 4 fold prolongation of the thrombin time which is considered as a sufficient anticoagulant protection has to be aimed at. Therefore, a simultaneous administration of heparin may become necessary from the 16th four of treatment. If the thrombin time after 16 hours is still prolonged to more than 4 fold the normal control value, the maintenance dose of Streptase has to be doubled for several hours until the thrombin time recedes.
Local administration
As is usual with antiographies (x-ray of the vessels with contrast media), heparin is administered - if necessary - before the angiography as a safeguard against catheter induced thromboses. The success thromboses. The success of therapy can be determined by the angiography, With a sufficient blood flow of more than 15 minutes the therapy is considered successful and can be terminated.
Follow-up treatment
After every course of streptokinase therapy a follow-up treatment with anticoagulants or platelet aggregation inhibitors can be instituted as a prevention of rethromboses. With heparin therapy, in particular, an increased risk of haemorrhage must be considered. The heparin therapy is controlled individually with the thrombin time or aPTT, A2 to 4 fold prolongation of the thrombin time and 1.5 to 2.5 fold prolongation of the aPTT is aimed at.
For long term prophylaxis oral anticoagulants, as - for example - coumarin derivatives or platelet aggregation inhibitors can be applied.
Overdose
Not known
Administration
Streptase is administered intravenously or intra-arterially.
Streptase is presented as a white lyophilisate. Upon reconstituion with physiological saline, a colourless, clear to opalescent solution is obtained.
To ensure that the contents of the vial are rapidly and completely reconstituted, 5 ml of physiological saline should be injected into the vaccum vial, and the residual vacuum abolished by briefly loosening the needle from the syringe.
For administration with an infusion pump, physiological saline, Ringer-lactate solution, 5% glucose or laevulose solution can be used as diluent. For higher dilutions, especially when good stability is required over longer periods, polygelins (Haemaccel) is recommended as diluent.
Duration of administration
The duration of therapy depends on the nature and extension of the vessel occlusion and is different according to the indication.
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