Thrombolytic Agents (Systemic)

This monograph includes information on the following:

1) Alteplase, Recombinant
2) Anistreplase
3) Streptokinase
4) Urokinase

VA CLASSIFICATION
Primary: BL115

Commonly used brand name(s): Abbokinase4; Abbokinase Open-Cath4; Activase1; Activase rt-PA1; Cathflo Activase1; Eminase2; Streptase3.

Other commonly used names for —Anistreplase
are anisoylated plasminogen-streptokinase activator complex and APSAC .

Other commonly used names for —Alteplase, Recombinant
, are tissue-type plasminogen activator (recombinant), t-PA, and rt-PA .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Thrombolytic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
The selection of thrombolytic therapy must be evaluated individually for each patient based on confirmation of thrombotic disease and assessment of patient condition and history. Some of the indications for thrombolytic therapy are identical to those for heparin or coumarin- or indanedione-derivative anticoagulants. However, the goals of thrombolytic therapy and anticoagulant therapy are different. Thrombolytic agents are used primarily to lyse obstructive thrombi and restore blood flow in a recently occluded blood vessel, whereas anticoagulants are used primarily to prevent thrombus formation and extension of existing thrombi. {127}4 The potential benefit of thrombolytic therapy must be weighed against the risk of bleeding {127}3 {127}2 because the risk of hemorrhage may be greater with thrombolytic agents than with heparin or coumarin- or indanedione-derivative anticoagulants.

Note: During its inspections of the facilities involved in the manufacture and production of urokinase, the Food and Drug Administration (FDA) identified numerous significant deviations from the Current Good Manufacturing Practice regulations; the FDA recommended that urokinase be reserved for only those situations in which a physician has determined that the use of urokinase is critical to the care of a specific patient in a specific situation {127}1.


Accepted

Thrombosis, coronary arterial, acute (treatment)—Alteplase {127}0 {167}9 {167}8 {167}7 {167}6 {167}5 {167}4 {167}3 {167}2 {167}1 {167}0 {167}9 {167}8 {167}7 {167}6 {167}5 {167}4 {167}3, anistreplase {167}2 {167}1 {167}0 {45}9 {45}8 {45}7 {45}6 {45}5 {45}4 {45}3 {45}2 {45}1 {45}0 {168}9 {168}8 {168}7 {168}6 {168}5 {168}4 {168}3 {168}2 {168}1 {168}0, streptokinase {168}9, and urokinase are indicated to lyse acute coronary arterial thrombi associated with evolving transmural myocardial infarction. Alteplase {168}8 {168}7 and anistreplase {168}6 {168}5 are indicated for use via intravenous infusion; streptokinase {168}4 {168}3 is indicated for use via intravenous and intracoronary infusion; and urokinase {168}2 {168}1 {168}0 is indicated for use only via intracoronary infusion. Various studies with intracoronary arterial injection have reported recanalization rates of 72 to 96%. In patients who received urokinase by intracoronary infusion within 6 hours following the onset of symptoms of a transmural myocardial infarction, 60% of the occluded coronary vessels were opened {169}9. However, it has not been established that the administration of urokinase during an evolving transmural myocardial infarction results in a preservation of myocardial tissue or a reduction in mortality {169}8 {169}7. Additionally, intracoronary arterial administration requires prior identification of the site of the thrombus by coronary angiography. Intravenous infusion does not require coronary angiography and is the preferred route of administration because therapy can be instituted more rapidly and can be initiated in locations that lack facilities for cardiac catheterization.
—Thrombolytic therapy, via intravenous or intracoronary routes of administration, may relieve chest pain {169}6, reduce the incidence {169}5 of congestive heart failure {169}4 {169}3 {169}2 {169}1 {169}0 {168}9 {168}8 {168}7, improve left ventricular function {168}6 {168}5 {168}4 {168}3 {168}2 {168}1 {168}0 {168}9 {168}8 {168}7 {168}6 {168}5 {168}4, limit cardiac damage (i.e., infarct size) {168}3 {168}2 {168}1 {168}0 {167}9 {167}8 {167}7 {167}6 {167}5, and decrease the risk of early death {167}4 {167}3 {167}2 {167}1 {167}0 {169}9 {169}8 {169}7 {169}6 {169}5 {169}4 if coronary arterial blood flow is restored before irreversible cardiac damage occurs. The reperfusion rate is dependent on the interval between the onset of symptoms and the initiation of therapy {169}3 {169}2 {169}1 {169}0. Higher reperfusion rates are achieved when thrombolytic therapy is started within 4 hours after symptoms of ischemia first appear {169}9 {169}8 {169}7 {169}6 {169}5 {169}4. However, reductions in mortality can be achieved if thrombolytic therapy is started up to 24 to 36 hours after the onset of symptoms {169}3 {169}2 {169}1 {169}0 {167}9.
—Thrombolytic therapy is not a substitute for other measures that may be required to treat acute myocardial infarction {167}8 or prevent reinfarction. Restoration of coronary arterial blood flow via thrombolysis does not correct underlying conditions that may promote thrombus formation {167}7 {167}6 {167}5. Recurrent ischemia, with or without reocclusion or overt reinfarction, may occur following initially successful thrombolysis {167}4 {167}3 {167}2 {167}1 {167}0 {167}9 {167}8 {167}7 {167}6 {167}5 {167}4 {167}3 {167}2 {167}1 {167}0 {02}9 {02}8 {02}7 {02}6 {02}5 {02}4. The risk of reocclusion may depend on the extent of residual stenosis in the affected vessel {02}3 {02}2 {02}1 {02}0 {167}9 {167}8 {167}7. Following successful thrombolytic therapy, long-term anticoagulation, platelet aggregation inhibitor therapy, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass graft (CABG) surgery may be required to provide long-lasting protection against reocclusion {167}6 {167}5 {167}4 {167}3 {167}2 {167}1 {167}0. However, initial thrombolytic therapy may permit a revascularization procedure to be performed on a delayed or elective, rather than on an emergency, basis {169}9 {169}8.

Stroke, acute ischemic (treatment)— Alteplase1 is indicated for the management of acute ischemic stroke in adults; it is used to improve neurologic recovery and reduce the incidence of disability. However, the safety and efficacy of alteplase therapy in patients with minor neurologic deficit, or with rapidly improving symptoms prior to the initiation of treatment, have not been evaluated. {169}7

Thromboembolism, pulmonary, acute (treatment)— Alteplase1 {169}6 {169}5 {169}4 {169}3, streptokinase {169}2, and urokinase {169}1 {169}0 {02}9 are indicated {02}8, and may be the therapy of choice in selected patients, for the lysis of acute, massive pulmonary emboli producing obstruction or significant filling defects involving two or more lobar pulmonary arteries or an equivalent degree of obstruction in other pulmonary vessels. These agents are also indicated for lysing pulmonary emboli accompanied by unstable hemodynamics, i.e., failure to maintain blood pressure without supportive measures {02}7 {02}6 {02}5. Heparin is recommended for the treatment of subacute or small emboli; however, some clinicians recommend thrombolytic therapy for comparatively small emboli in patients with limited cardiopulmonary reserve caused by significant cardiac or pulmonary disease. Prior to administration of a thrombolytic agent, the diagnosis should be confirmed by objective means such as pulmonary angiography via an upper extremity vein (preferred) or ventilation-perfusion lung scanning. {02}4 {02}3 {02}2

Thrombosis, deep venous (treatment)—Streptokinase {02}1 and [urokinase {02}0]1 are indicated for the lysis of acute, extensive, deep venous thrombi in the popliteal or more proximal vessels. Thrombolytic therapy may be the treatment of choice for deep venous thrombosis in selected patients. [These agents are also used for the lysis of acute, extensive thrombi in the axillary subclavian veins and vena cavae {113}9 in selected patients.] However, anticoagulants are recommended for treatment of calf-vein thrombi. Prior to administration of a thrombolytic agent, the diagnosis should be confirmed, preferably by ascending venography or by Doppler ultrasound {113}8.

Thromboembolism, arterial, acute (treatment) and
Thrombosis, arterial, acute (treatment)—Streptokinase {113}7 and [urokinase] are indicated for use via intravenous infusion for the lysis of acute arterial thrombi or emboli. [These agents are also administered locally (via a catheter positioned adjacent to or inserted into the substance of the thrombus as shown by arteriogram) to lyse arterial thrombi or emboli.] Studies have shown that thrombolytic therapy alone may be ineffective for treating chronic arterial occlusion. Angioplasty or distal bypass may be required following initial thrombolytic therapy in order to salvage the affected limb.
—Streptokinase has been used in the treatment (lysis) of arterial occlusions in pediatric patients from younger than 1 month of age up to 16 years of age; however, the evidence of clinical benefits and risks in these patients is based solely on anecdotal reports. Adverse events associated with the use of streptokinase in the pediatric population are similar in nature to those associated with its use in adults, including bleeding at catheter sites.1 {113}6

Cannula, arteriovenous, clearance—Streptokinase {113}5 and [urokinase]1 are indicated to clear totally or partially occluded arteriovenous cannulae, as an alternative to surgical revision, when acceptable flow cannot be achieved by conventional mechanical measures.

Catheter, intravenous, clearance—  Alteplase and urokinase are indicated to restore patency to intravenous catheters, including central venous catheters, obstructed by clotted blood or fibrin deposits {113}4 {113}3 {113}2{113}1.

—[Thrombolytic agents are also used to treat renal artery thrombosis, retinal blood vessel occlusions, hemolytic uremic syndrome, and impending renal cortical necrosis. However, controlled studies are {113}0 required to establish the safety and {167}9 effectiveness of such therapy in these conditions.]1

Unaccepted
Thrombolytic agents should not be used to treat superficial thrombophlebitis.

Alteplase has not been sufficiently studied, and is currently not recommended, for treatment of deep venous thrombosis or arterial thrombosis not associated with evolving acute myocardial infarction {167}8 or for clearing occluded arteriovenous cannulae or obstructed intravenous catheters {167}7.

Alteplase {167}6 and streptokinase are not recommended for treatment of arterial emboli originating in the left side of the heart (e.g., mitral stenosis accompanied by atrial fibrillation) because of the risk of cerebral embolism {167}5.

Streptokinase is not indicated for restoration of patency of intravenous catheters. {167}4

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Alteplase: Glycoprotein enzyme (serine protease) containing 527 amino acids; produced by recombinant DNA technology utilizing the complementary DNA (cDNA) for natural human tissue-type plasminogen activator obtained from a human melanoma cell line {167}3.
    Anistreplase: P-anisoylated derivative of a fibrinolytic enzyme (protein) complex consisting of human plasma-derived lys-plasminogen and bacterially derived streptokinase {167}2.
    Streptokinase: Co-enzyme (protein) obtained from cultures of group C, beta-hemolytic streptococci {167}1.
    Urokinase: Enzyme (protein) obtained from cultures of primary human neonatal kidney cells {167}0.
Molecular weight—
    Alteplase: About 68,000 daltons {169}9 {169}8
    Anistreplase: About 131,000 daltons {169}7 {169}6
    Streptokinase: About 46,000 daltons {169}5
    Urokinase: About 33,000 daltons {169}4

Mechanism of action/Effect:

Thrombolytic agents activate the endogenous fibrinolytic system by cleaving the arginine 560–valine 561 bond in plasminogen to produce {169}3 {169}2 plasmin, an enzyme that degrades fibrin clots {169}1 {169}0 {167}9 {167}8 {167}7, fibrinogen, and other plasma proteins {167}6 {167}5 {167}4, including the procoagulant factors V and VIII {167}3 {167}2 {167}1. Alteplase and urokinase cleave the peptide bond directly {167}0. Anistreplase and streptokinase act indirectly; they combine with plasminogen {02}9 {02}8 to form streptokinase-plasminogen complexes that are converted to streptokinase-plasmin complexes. These activator complexes, rather than streptokinase itself, convert residual plasminogen to plasmin. These complexes are inactivated, in part, by antistreptococcal antibodies {02}7.

Conversion of plasminogen to plasmin occurs within the thrombus {02}6 {02}5 or embolus as well as on its surface and in circulating blood. Thrombolytic agents lyse fibrin deposits wherever they exist and can be reached by the plasmin generated; therefore, thrombolytic agents also promote lysis of fibrin deposits responsible for hemostasis. {02}4 {02}3

Alteplase is more clot-selective than the other thrombolytic agents, binding more readily to the fibrin-plasminogen complex within a clot than to circulating (free) plasminogen {02}2. However, limited systemic fibrinolysis does occur with usual therapeutic doses {02}1 {02}0 {167}9 {167}8 {167}7 {167}6 {167}5.


Other actions/effects:

Fibrinogenolysis and fibrinolysis induced by thrombolytic agents increase the concentration {167}4 of fibrinogen-degradation and fibrin-degradation products (FDP/fdp) in the blood {167}3 {167}2 {167}1 {167}0. The FDP/fdp exert an anticoagulant effect, probably by impairing fibrin polymerization and possibly by decreasing thrombin generation and/or interfering with platelet function. Alteplase usually reduces the circulating fibrinogen concentration and increases FDP/fdp concentrations to a lesser extent than does streptokinase, but to about the same extent that urokinase does {168}9 {168}8. However, studies have not shown a significantly lower incidence of bleeding with alteplase than has been reported with the other thrombolytic agents {168}7 {168}6, probably because factors other than the concentrations of fibrinogen and/or FDP/fdp also significantly influence the risk of bleeding (see Side/Adverse Effects ) {168}5. Specifically, the risk of bleeding complications associated with thrombolytic therapy may be more dependent on the presence of vascular injury than on the extent of systemic fibrinolysis induced by a specific agent {168}4 {168}3.

Anistreplase has potent proteolytic activity in the systemic circulation. In addition to decreasing plasma concentrations of fibrinogen, the medication lowers plasma concentrations of {168}2 {168}1 {168}0 {02}9 {02}8 {02}7 {02}6 {02}5 {02}4 {02}3 {02}2 {02}1 {02}0 {113}9 plasminogen, {113}8 {113}7 {113}6 {113}5 {113}4 {113}3 {113}2 {113}1 {113}0 procoagulant factors V and VIII {167}9 {167}8, and the fibrinolysis inhibitor alpha-2-antiplasmin {167}7 {167}6 {167}5 {167}4 {167}3 {167}2 {167}1 {167}0 {168}9.

Anistreplase, streptokinase, and urokinase have also been reported to decrease plasma viscosity {168}8 {168}7 {168}6 and erythrocyte aggregation {168}5, probably as a result of reduced fibrinogen concentration.

Streptokinase and the streptokinase component of anistreplase {168}4 {168}3 {168}2 are antigenic and induce the formation of antibodies. Elevation of the antistreptokinase antibody titer usually occurs about 5 {168}1 to 7 {168}0 days following administration, reaches a peak after 2 to 3 weeks {169}9, and may persist for 1 year or longer {169}8 {169}7. The antibodies may cause resistance to subsequent streptokinase or anistreplase therapy {169}6 {169}5 {169}4, and possibly an increased risk of anaphylaxis or other severe allergic reactions {169}3.

Biotransformation:

Alteplase—Hepatic; rapid {169}2 {169}1 {169}0 {02}9 {02}8.

Streptokinase—Hepatic; no metabolites identified {02}7.

Urokinase—Hepatic; rapid {02}6.

Half-life:


Alteplase:

Distribution: Less than 5 minutes {02}5 {02}4 {02}3 {02}2.

Elimination: Approximately 35 minutes {02}1 {02}0 {167}9.



Anistreplase:

The half-life of anistreplase's fibrinolytic activity is 70 to 120 minutes {167}8 {167}7 {167}6 {167}5 {167}4 (average about 90 minutes {167}3 {167}2 {167}1 {167}0 {02}9). The deacylation half-life of the complex is about 105 to 120 minutes {02}8 {02}7. The plasma clearance and duration of fibrinolytic activity of the medication are probably controlled primarily by its deacylation rate {02}6 {02}5.



Streptokinase:

Following intravenous administration of 1.5 million International Units (IU) over a 1-hour period: the half-life of the activator complexes (streptokinase-plasminogen and/or streptokinase-plasmin) is 23 minutes {02}4 {02}3.



Urokinase:

Up to 20 minutes {02}2 {02}1 {02}0 {167}9 {167}8. The half-life may be prolonged in patients with hepatic function impairment {167}7 {167}6.


Time to peak effect:

Reperfusion of the myocardium {167}5 generally occurs 20 minutes {167}4 to 2 hours (average 45 minutes) {167}3 {167}2 {167}1 {167}0 following initiation of intravenous therapy.

Duration of action:

Thrombolysis may continue for approximately 4 hours following administration of alteplase, streptokinase, or urokinase; the hyperfibrinolytic effect disappears within a few hours following discontinuation of administration. Following administration of anistreplase, thrombolysis may continue for approximately 6 hours, {131} and a systemic hyperfibrinolytic state, as demonstrated by euglobulin clot lysis time determinations, may persist for more than 2 days {139}. For all thrombolytic agents, the prothrombin time may rarely be prolonged for 12 to 24 hours following cessation of therapy because of the decreased plasma concentration of fibrinogen, decreased plasma concentration of factor V and possibly other coagulant factors, and/or the anticoagulant effects of FDP/fdp. However, prolonged, high FDP/fdp concentrations may potentiate bleeding for a longer period of time, especially after administration of non–clot-selective thrombolytic agents. {71}

Elimination:
    Alteplase—Renal; approximately 80% of a dose is excreted in the urine, as metabolites, within 18 hours {48}.
    Urokinase—Small quantities are eliminated via the renal and biliary routes {02} {167}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to streptokinase will be allergic to anistreplase also, and vice versa {68} {101}.

Carcinogenicity

Alteplase, anistreplase, and urokinase—Long-term studies to determine whether alteplase, anistreplase, and urokinase have carcinogenic potential have not been done {02} {07} {68} {101} {167}.

Mutagenicity

Alteplase—No mutagenicity was demonstrated in the Ames test or in chromosomal aberration assays in human lymphocytes {76}.

Anistreplase—No mutagenicity was demonstrated in chromosomal aberration assays in human lymphocytes {68} {101}.

Pregnancy/Reproduction
Fertility—
Alteplase: Studies have not been done in animals {76} {77}.

Anistreplase: Studies have not been done in humans {134}.

Studies have not been done in animals {68} {101}.

Urokinase: Studies in mice and rats have not shown that urokinase causes impaired fertility {02} {167}.

Pregnancy—
It has been suggested that administration of a thrombolytic agent during the first 18 weeks of pregnancy may increase the risk of premature separation of the placenta because fetal attachments to the uterus during this time are composed primarily of fibrin. However, this problem has not been reported following administration of streptokinase or urokinase to patients during the first 2 trimesters of pregnancy.


Alteplase and anistreplase

Studies have not been done in humans.

Studies have not been done in animals.

FDA Pregnancy Category C. {07} {68} {76} {77}



Streptokinase

Streptokinase apparently crosses the human placenta minimally if at all. However, antibodies to streptokinase do cross the placenta. Studies in pregnant women (treated mostly during the second and third trimesters) have not shown evidence of abnormalities or induction of fibrinolysis in the fetus. {05} {08}

Studies have not been done in animals.

FDA Pregnancy Category C. {03} {04} {06} {68} {101}



Urokinase

Adequate and well-controlled studies have not been done in humans {02} {167}.

Studies in mice and rats have not shown that urokinase causes fetal harm when administered in doses up to 1000 times the human dose {02} {167}.

FDA Pregnancy Category B {02} {167}.


Postpartum —
Thrombolytic agents should be administered with great caution during the first 10 days postpartum because of the increased risk of hemorrhage.

Breast-feeding

It is not known whether thrombolytic agents are distributed into breast milk {02} {07} {76} {77} {167}. However, problems in humans have not been documented.

Pediatrics

Safety and efficacy have not been established {05} {68} {76} {77} {167} {168} {169} {170}.

Although controlled clinical studies have not been conducted to determine the safety and efficacy of using streptokinase in pediatric patients, a significant number of anectodal reports exist supporting the use of streptokinase in children, particularly for the treatment of arterial occlusions. In patients from younger than 1 month of age up to 16 years of age, the use of streptokinase for the treatment of acute arterial occlusions resulted in bleeding complications in as many as 50% of catheter sites in some studies. Occasionally, bleeding has required blood transfusion. Careful monitoring of the patient is therefore recommended {06}.


Geriatrics


Geriatric patients generally have a poorer prognosis than younger adults following an acute myocardial infarction {21} {22} {23}. Also, they may be more likely than younger adults to have pre-existing conditions that tend to increase the risk of intracranial bleeding or other hemorrhagic complications {22} {23}. Because the risks of thrombolytic therapy, as well as its potential benefits, are increased in older patients {24}, careful patient selection {22} {23} and monitoring {23} are recommended.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, also may interact with this medication.
In addition to the interactions listed below, the possibility should be considered that multiple effects leading to further impairment of blood clotting and/or increased risk of hemorrhage may occur if a thrombolytic agent is administered to a patient receiving any medication having a significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage.

» Anticoagulants, coumarin- or indanedione-derivative{02}{68}{76}{77}{79} or
» Enoxaparin or
» Heparin    (concurrent use with antithrombotic or thrombolytic agents increases the risk of hemorrhage {76} {77}; however, heparin is often administered concurrently with intravenous thrombolytic therapy for the treatment of acute coronary arterial occlusion or with low doses of thrombolytic agents given intra-arterially; in one clinical study, no increased risk of hemorrhage was shown with concurrent use of heparin during intracoronary administration of urokinase {167}; also, thrombolytic therapy may be administered following initial anticoagulant therapy)

    (anticoagulants are recommended to prevent additional thrombus formation following thrombolytic therapy for most indications; however, following intravenous thrombolytic therapy for acute coronary arterial occlusion, the need for anticoagulant administration should be determined on an individual basis; if an anticoagulant is administered under these circumstances, careful monitoring of the patient is recommended {68} {101} because studies have shown that heparin, when administered after intravenous streptokinase for this indication, increases the risk of hemorrhage {03} {04} {05})

    (although an initial dose of heparin is recommended prior to intracoronary use of urokinase, anticoagulants including heparin should not be given concurrently with large doses of intravenous urokinase, when used to treat pulmonary embolism, because of an increased risk of hemorrhage {167})


» Antifibrinolytic agents, such as:
Aminocaproic acid
Aprotinin
Tranexamic acid    (the actions of antifibrinolytic agents and of thrombolytic agents are mutually antagonistic; although antifibrinolytic agents may be effective in treating severe hemorrhage caused by thrombolytic agents, controlled studies to verify their efficacy and safety have not been done {143} {36})


Antihypertensive agents or
Other hypotension-producing medications    (the risk of severe hypotension may be increased {158}, especially when streptokinase is administered rapidly for treatment of coronary arterial occlusion {25})


» Cefamandole or
» Cefoperazone or
» Cefotetan or
» Plicamycin or
» Valproic acid{26}    (these medications may cause hypoprothrombinemia; in addition, plicamycin or valproic acid may inhibit platelet aggregation; concurrent use with a thrombolytic agent may increase the risk of severe hemorrhage and is not recommended)


Corticosteroids, glucocorticoids or
Corticotropin, chronic therapeutic use or
Ethacrynic acid or
Salicylates, nonacetylated    (gastrointestinal ulceration or hemorrhage may occur during therapy with these medications and cause increased risk of severe hemorrhage in patients receiving thrombolytic therapy)


» Nonsteroidal anti-inflammatory drugs (NSAIDs), especially:
Aspirin{02}{68}{77}{167}
Indomethacin{02}{167}
Phenylbutazone{02}{167} or
» Other platelet aggregation inhibitors (see Appendix II ), especially:
Sulfinpyrazone
Ticlopidine{80}    (concurrent use of a platelet aggregation inhibitor and a thrombolytic agent may increase the risk of bleeding {68} {77} {101} and is generally not recommended [except when aspirin therapy for acute myocardial infarction is initiated concurrently with thrombolytic therapy])

    (initiation of aspirin therapy [160 mg per day] before or during intravenous administration of alteplase, anistreplase, or streptokinase for treatment of acute coronary arterial occlusion may reduce significantly the risk of reocclusion, reinfarction, stroke, and death without increasing the risk of adverse effects [as compared to the thrombolytic agent or aspirin alone] {12} {36} {45}; however, larger doses of aspirin have been shown to increase the risk of bleeding in patients receiving thrombolytic agents for other indications; the possibility of hemorrhage should be considered and the patient carefully monitored)

    (the potential occurrence of gastrointestinal ulceration and/or hemorrhage during therapy with NSAIDs [including analgesic or antirheumatic doses of aspirin] or sulfinpyrazone also may cause increased risk to patients receiving thrombolytic therapy)


Thiotepa    (urokinase may increase the efficacy of thiotepa in the treatment of bladder cancer by acting as a plasminogen activator and increasing the amount of thiotepa in tumor tissue)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Coagulation tests and
Tests for systemic fibrinolysis    (the fibrinolytic activity of thrombolytic agents persists in vitro ; unless the patient is extremely resistant to thrombolytic therapy, degradation of fibrinogen in blood samples will lead to unreliable test results {68} {76} [when specific measurements of fibrinogen {11}, rather than a general indication that fibrinolysis is occurring, are required]; the addition of a fibrinolysis inhibitor, e.g., aprotinin {38} {68} {101} [150 to 200 Kallikrein Inhibitor Units per mL of blood {76} {77}], or aminocaproic acid {27} may reduce this effect {07} {28} {101})

With physiology/laboratory test values
Activated partial thromboplastin time (APTT) and{27}{68}{101}{129}
Prothrombin time (PT){27}{68}{101} and
Thrombin time (TT){15}{27}{68}{101}    (values will be increased unless the patient is extremely resistant to thrombolytic therapy)


Alpha 2-antiplasmin activity and{17}{18}{27}{33}{128}{129}{131}
Factor V activity and{18}{131}
Factor VIII activity and{18}{131}
Fibrinogen activity{17}{18}{27}{33}{36}{38}{68}{110}{114}{128}{129}{131}{139}{146}{149}{167} and
Plasminogen activity{17}{18}{27}{33}{36}{68}{128}{129}{131}{146}    (will be decreased unless the patient is extremely resistant to thrombolytic therapy; significant recovery of fibrinogen activity may occur within 18 to 36 hours after discontinuation of thrombolytic therapy {21} {33} {38} {110} {114} {126} {127} {128} {129} {135} {149}, but return of fibrinogen activity to pretreatment values may require up to 48 hours {17} {27} {36} {110} {129} {139} {146} after discontinuation of thrombolytic therapy; recovery of plasminogen activity also may require more than 30 hours {128})


Blood pressure    (may be decreased, especially when a thrombolytic agent is administered rapidly {06} {46} for treatment of acute coronary arterial occlusion {46} {99}; a decrease in blood pressure [not secondary to anaphylaxis or bleeding], which may be severe, has also been reported in about 10% of anistreplase-treated patients {101})


Fibrinogen-degradation and fibrin-degradation products (FDP/fdp) concentrations    (will be increased unless the patient is extremely resistant to thrombolytic therapy {27} {151}; return to pretreatment values may require up to 48 hours after discontinuation of thrombolytic therapy {129})


Hematocrit values{132} and
Hemoglobin concentrations{118}{132}    (moderate reduction not related to clinical bleeding has been reported in 20% of patients receiving thrombolytic therapy)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:

For all thrombolytic agents:
» Aneurysm{02}{68}{76}{167} , dissecting{91}{99} and/or intracranial, confirmed or suspected or
» Arteriovenous malformation or{02}{68}{76}{167}
» Bleeding, active{01}{02}{06}{68}{76}{77}{79}{83}{91}{99}{138}{167} or
» Brain tumor, primary, or neoplasm metastatic to the central nervous system (CNS) from other primary sites{02}{06}{138}{167} or
» Cerebrovascular accident, or history of{01}{02}{06}{68}{76}{77}{79}{87}{91}{97}{98}{99}{167} or
» Neurosurgery, intracranial or intraspinal{79}{97}{167} , within past 2 months or
» Surgery, thoracic, recent or
» Trauma to the CNS, recent{76}{77}{91}{167}    (increased risk of uncontrollable hemorrhage)


» Hypertension, severe, uncontrolled{02}{06}{68}{76}{167} , i.e., ³ 200 mm Hg systolic and/or ³ 120 mm Hg diastolic{79}{83}{97}    (increased risk of cerebral hemorrhage)


For alteplase used to treat acute ischemic stroke (in addition to medical problems listed above) {07}:
» Bleeding diathesis, such as
Heparin therapy within 48 hours preceding the onset of stroke along with an elevated APTT at presentation
Oral anticoagulant therapy with a PT > 15 seconds
Platelet count < 100,000 per mm 3 or
» Hemorrhage, intracranial, evidence of on pretreatment evaluation, or history of or
» Hemorrhage, subarachnoid, suspected or
» Hypertension, severe, uncontrolled, i.e., > 185 mm Hg systolic or > 110 mm Hg diastolic or
» Seizure at the onset of stroke or
» Stroke, recent    (increased risk of bleeding, which could result in significant disability or death)


For anistreplase and streptokinase (in addition to medical problems listed above):
» Anaphylaxis or other severe allergic reaction to streptokinase or anistreplase, history of{68}    (increased risk of anaphylaxis)


Risk-benefit should be considered when the following medical problems exist

For all thrombolytic agents:
Allergic reaction, mild, to the thrombolytic agent considered for use, history of
Any condition in which the risk of bleeding or hemorrhage is present or would be difficult to control because of its location{02}{06}{68}{76}{77}{167} , such as:
Cardiopulmonary resuscitation with possibility of internal injury, recent{02}{06}{68}{77}{87}{99}{167}
Cerebrovascular disease{06}{68}{76}{77}{167}
» Childbirth within past 10 days{02}{06}{68}{76}{77}{167}
» Coagulation defects, uncontrolled, or other hemostatic defects, including those secondary to severe hepatic or renal disease{02}{06}{68}{76}{77}{79}{91}{99}{167}
» Endocarditis, bacterial, subacute{02}{06}{68}{76}{77}{79}{83}{138}{167}
» Gastrointestinal bleeding, severe, within past 10 days{02}{06}{68}{76}{77}{167}
Gastrointestinal lesion or ulcer, active or history of{79}{91}{98}
Genitourinary bleeding within past 10 days{68}{76}{77}
Hemorrhagic retinopathy, diabetic,{02}{79}{83}{87}{99}{167} or other hemorrhagic ophthalmic conditions{06}{07}{68}{76}{77}
Hepatic function impairment, severe{76}{77}{83}{91}{99}
Hypertension, moderate, not optimally controlled, i.e., 180 to 200 mm Hg systolic and/or 110 to 120 mm Hg diastolic{01}{06}{68}{76}{77}{87}{91}
Invasive procedure, such as lumbar puncture, paracentesis, or thoracentesis, recent
Knitted dacron graft{29}{89}
» Neurosurgical procedure more than 2 months previously
» Organ biopsy within past 10 days{02}{06}{76}{87}{167}
Pregnancy{02}{06}{68}{76}{77}{79}{83}{87}{91}{99}{167}
» Puncture of noncompressible blood vessel within past 10 days{02}{68}{76}{79}{167}
» Surgery, major, other than neurosurgery or thoracic surgery, within past 10 days{01}{02}{68}{76}{77}{87}{138}{167}
Trauma, minor, recent, other than to the CNS{76}{97}
» Trauma, severe, recent, other than to the CNS
Tuberculosis, active, with cavitation of recent onset
Infection at or near site of thrombus, obstructed intravenous catheter, or occluded arteriovenous cannula{06}{68}{76}{77}    (risk of spreading the infection into and via the circulation)


» Mitral stenosis with atrial fibrillation or other indications of probable left heart thrombus{02}{06}{68}{76}{77}{167}    (risk of new embolic phenomena including those to cerebral vessels)


Pericarditis, acute    (risk of hemopericardium, which may lead to cardiac tamponade {65} {68} {76} {77})


For alteplase used to treat acute ischemic stroke (in addition to medical problems listed above) {07}:
» Infarct signs, major, on cranial computed tomographic scan, e.g., substantial edema, mass effect, or midline shift or
» Neurologic deficit, severe, i.e., National Institutes of Health Stroke Scale score > 22 at presentation    (increased risk of intracranial hemorrhage)


For anistreplase and streptokinase (in addition to medical problems listed above):
» Anistreplase or streptokinase therapy{01}{85} within past 5 days to 1 year{06}{10}{68}{84}{87}{91} or
» Streptococcal infection, recent{06}{10}    (antistreptococcal antibodies are likely to be present in the circulation; these antibodies may cause a temporary resistance to the therapeutic effects of anistreplase or streptokinase and/or an increased risk of severe allergic reactions to the medication; although resistance may be overcome by increasing the dosage, use of an alternate thrombolytic agent [alteplase or urokinase] is advisable if thrombolytic therapy is needed within 1 year after anistreplase or streptokinase therapy {85} or streptococcal infection)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


Prior to initiation of therapy

Note: Initiation of therapy for acute coronary arterial occlusion must not be delayed until the results of the tests recommended below are available. However, blood may be drawn prior to initiation of therapy so that appropriate tests can be performed to determine the hemostatic status of the patient, especially if a potential bleeding problem exists or is suspected, and/or to establish baseline values. {66}{167}

» Coagulation tests{02}{06}{167} , such as:
Activated partial thromboplastin time (APTT)
Fibrin/fibrinogen degradation product (FDP/fdp) titer
Fibrinogen concentration
Prothrombin time (PT)
Thrombin time (TT) and
» Hematocrit values{167} and
» Hemoglobin concentrations and
» Platelet count{167}    (recommended prior to initiation of therapy to determine the hemostatic status of the patient and/or to establish baseline values so that the presence of fibrinolysis can be confirmed during therapy; heparin therapy should be discontinued before thrombolytic therapy is instituted unless the heparin is being given in conjunction with urokinase for intracoronary administration {02} {167}; also the APTT or TT should be less than 2 times the control value before thrombolytic therapy is instituted)


» Electrocardiogram (ECG){11}{141}    (recommended when acute coronary arterial thrombosis is suspected, to confirm diagnosis and to aid in selecting patients in whom thrombolytic therapy is likely to be most beneficial)


During and/or following therapy
Coagulation tests, such as APTT, PT, or TT and/or
Tests of fibrinolytic activity, such as fibrinogen concentration, FDP/fdp titer, reptilase clotting time,{18}{27} and/or whole blood euglobulin lysis time    (recommended 3 to 4 hours following initiation of intravenous therapy for indications other than acute coronary arterial thrombosis; these tests may be repeated every 12 hours for the duration of therapy, if necessary, to determine that a fibrinolytic state exists; however, such tests do not reliably predict either efficacy of medication or risk of bleeding {02} {167} and are not currently recommended for determining maintenance dosage; a TT value equal to or greater than 1.5 times the control value in seconds, or a decrease of fibrinogen concentration to 50% or less of the control value [with alteplase or anistreplase, a reduction to 75% of the control value may be sufficient] {31} {75}, indicates that fibrinolysis is occurring)


Note: Confirmation of fibrinolysis does not require that all of the tests listed above be used for each patient. The selection of a particular test for monitoring thrombolytic therapy depends upon physician preference and available laboratory facilities.
Because heparin also prolongs APTT, PT, and TT, the results of these determinations may be misleading if heparin has been or is being administered; tests that more directly measure fibrinolytic activity may be more reliable. {18} {27} {30}


Computed tomography and/or
Impedance plethysmography and/or
Quantitative Doppler effect determination and/or
Visualization of affected vessel via angiography{02}{167} or venography    (may be useful in assessing restoration of blood flow; also, may aid in determining optimum duration of therapy; however, repeated venograms are not recommended)


Coronary angiography and/or
Myocardial scanning, radionuclide    (may be useful for monitoring effectiveness of therapy for coronary arterial thrombosis in evolving transmural myocardial infarction; coronary angiography and myocardial scanning also may be useful for assessing the patency of the coronary vasculature and for determining whether further treatment to prevent reocclusion is needed; however, coronary angiography increases the risk of adverse effects, including severe bleeding, when performed within several days after thrombolytic therapy; it is recommended that the procedure be performed only when necessary [as determined by signs and symptoms of persistent ischemia], preferably after a delay of 7 to 10 days following thrombolytic therapy {66})


Creatine kinase activity or other cardiac enzyme determination{91}    (may be useful for monitoring effectiveness of therapy for acute coronary arterial thrombosis)


» Electrocardiogram (ECG){91}    (monitoring during and following administration for treatment of acute coronary arterial thrombosis is recommended to detect reperfusion atrial or ventricular arrhythmias; also, may be useful as a means of determining effectiveness of treatment because reversal of some abnormalities may occur with recanalization)


Hematocrit values{32}    (monitoring recommended to detect possible blood loss during and following thrombolytic therapy)


» Mental status and
» Neurologic status    (monitoring recommended because altered sensorium or neurologic changes may be indicative of intracranial bleeding {23} {91})


Stool tests for occult blood loss and
Urine tests for hematuria{91}    (recommended periodically during therapy)


» Vital signs, such as blood pressure, pulse, respiratory rate, and temperature    (continuous monitoring recommended during therapy for acute coronary arterial occlusion to detect adverse effects such as bradycardia, hypotension, and allergic reactions {10}; a reduction in the infusion rate is usually sufficient to correct hypotension)

    (monitoring recommended at least every 4 hours during therapy for other indications; however, a lower extremity should not be used for blood pressure determinations when there is a risk of dislodging deep vein thrombi that may be present {02} {167})




Side/Adverse Effects

Note: Rarely, thrombolysis causes clot fragmentation with migration of the fragments resulting in additional embolic complications {152}. Patients should be monitored for new embolic phenomena.
Bleeding, the most common side effect encountered during thrombolytic therapy {76} {77} {86} {89} {91} {96} {99}, occurs most frequently at invaded sites (e.g., sites of arterial punctures, venous cutdowns, recent surgery) {02} {07} {17} {33} {37} {38} {39} {41} {47} {49} {59} {68} {101} {103} {110} {123} {132} {133} {134} {139} {167} because thrombolytic agents promote lysis of the fibrin deposits that are needed to maintain hemostasis at these sites {15} {36} {77}. The risk of bleeding at invaded sites is not reduced by administration of a relatively clot-selective agent such as alteplase. Studies comparing alteplase with streptokinase have shown a similar incidence of internal bleeding with both agents. However, most patients in these studies also received heparin or other potentially hemorrhagic medications concurrently with and/or immediately following the thrombolytic agent. {47} {49} {55} {59} Therefore, the frequency of hemorrhage attributable solely to the thrombolytic agent has not been determined {47} {55}. In some patients, bleeding may be severe enough to result in anemia {33} {101} or shock {34}.
Chest pain or cardiac arrhythmias may occur during or following thrombolytic therapy for acute coronary arterial thrombosis. These are not direct effects of the medication. Chest pain may indicate treatment failure or reocclusion. Cardiac arrhythmias may be associated with the myocardial infarction itself, or may be induced by sudden reperfusion {167}. Specific arrhythmias that have been reported include sinus bradycardia {06} {07} {15} {33} {37} {47} {48} {60} {68} {76} {77} {101} {110}, accelerated idioventricular rhythm {07} {15} {47} {48} {60} {68} {76} {77} {101}, ventricular premature depolarizations {07} {38} {48} {68} {76} {77} {101}, ventricular tachycardia {06} {07} {15} {33} {38} {47} {57} {60} {68} {76} {77} {101} {106}, second- and third-degree atrioventricular block {47} {48} {57}, atrial fibrillation {47} {48}, and (especially in patients with coronary instrumentation {60}) ventricular fibrillation {33} {50} {57} {60}. Hypotension may occur in association with reperfusion bradyarrhythmias {47} {60}.
Nausea and vomiting have also been reported during thrombolytic therapy. However, a causal relationship to the medication has not been established because these symptoms occur frequently during acute myocardial infarction. {07} {68} {76} {77} {101}
The lys-plasminogen used in manufacturing anistreplase is obtained from human plasma. To reduce the risk of the patient's contracting viral infections that may be transmitted via human blood-derived products, the material is tested for viral antigens or particles and heat-treated to inactivate viral particles. Hepatitis has not been reported to date. {68} {101}
The human neonatal kidney cells used in the manufacture of urokinase were obtained from populations at high risk for a variety of infectious diseases, and the screening and testing measures instituted were not consistently or reliably performed {167}. In addition, the kidney cells were harvested, stored, and handled in a manner which may have permitted contamination with infectious agents {171}. Available lots of urokinase, as of March 1999, have received testing for hepatitis C virus (HCV) and have been subjected to a viral inactivation process, which has been shown to substantially inactivate HCV as well as human immunodeficiency virus (HIV) in other biological products. However, these procedures have not been fully validated. {167} The Food and Drug Administration (FDA) is not aware of any cases of infectious disease that may be directly attributed to the use of urokinase; however, the likelihood that such cases would have been recognized and reported to the FDA is estimated to be very low. Therefore, the actual risk to patients of developing an infectious disease as a result of the administration of urokinase is unknown. The FDA recommended that the use of urokinase be reserved only for those situations in which a physician has determined that the use of urokinase is critical to the care of a specific patient in a specific situation {171}.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Bleeding or oozing from cuts, invaded or disturbed sites, wounds, or gums{02}{17}{33}{34}{37}{38}{39}{41}{79}{98}{101}{110}{112}{123}{132}{139} {167}
    
decreased blood pressure, not secondary to bleeding or to streptokinase-induced anaphylaxis{06}{18}{33}{37}{38}{39}{41}{68}{79}{98}{101}{114}{115}{132}{133}{134}{139} —may be severe, especially when a thrombolytic agent is given rapidly{46} and/or when other medications having hypotensive actions, such as vasodilators or morphine, are used concurrently{25}{110}

Incidence more frequent with anistreplase and streptokinase {06}; less frequent with urokinase {86}
    
Fever

Note: Elevations of body temperature by about 1.5 °F occur in up to 33%, and body temperature as high as 104 °F has been reported in about 3.5%, of patients receiving streptokinase. Approximately 2 to 3% of patients receiving urokinase develop a febrile reaction to the medication. {79} Fever has also been reported with alteplase {77}, but a causal relationship has not been established.


Incidence less frequent or rare
    
Allergic reaction (flushing or redness of skin; mild headache; mild muscle pain; nausea; skin rash, hives, or itching; troubled breathing or wheezing)—less frequent with streptokinase and rare with alteplase or urokinase{02}{72}{85}{98}
{167}    
bleeding into subcutaneous tissues (bruising)
    
cholesterol embolism —with alteplase, anistreplase, and streptokinase{06}{81}{82}{137}
    
internal bleeding (abdominal pain or swelling{92}; back pain or backaches{06}{78}; bloody urine; bloody or black, tarry stools; constipation caused by hemorrhage-induced paralytic ileus or intestinal obstruction; coughing up blood; dizziness; headaches, sudden, severe, and/or continuing; joint pain, stiffness, or swelling; muscle pain or stiffness, severe or continuing; nosebleeds; unexpected or unusually heavy bleeding from vagina; vomiting of blood or material that looks like coffee grounds)
    
stroke, hemorrhagic or thromboembolic{01}{13}{95}{98}{100} (confusion; double vision; impairment of speech; weakness in arms or legs)—more frequent with alteplase{01}{95}{100}

Note: Individual symptoms of internal bleeding depend on the site of bleeding and have not necessarily been reported with all of the thrombolytic agents; internal bleeding has been reported following intracoronary arterial administration as well as following intravenous administration; with alteplase, the incidences of gastrointestinal, genitourinary, and retroperitoneal bleeding are 5%, 4%, and < 1%, respectively; the incidence of intracranial hemorrhage (ICH) in patients with acute myocardial infarction treated with alteplase is 0.4% with total doses of 100 mg {07} {64} or 1 to 1.4 mg per kg of body weight (mg/kg) and 1.3% with a total dose of 150 mg {07}; the incidence of ICH in patients treated with alteplase for acute ischemic stroke was found to be 15.4% in trials {07}.


Incidence rare
—for anistreplase, streptokinase, and urokinase    
Allergic reaction, severe, or anaphylaxis (changes in facial skin color; fast or irregular breathing; large, hive-like swellings on eyelids, face, mouth, lips, or tongue; puffiness or swelling of the eyelids or around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; skin rash, hives, and/or itching)—also may include anaphylactic shock with sudden, severe decrease in blood pressure{06}

Note: An anaphylactic reaction has been reported in a patient following a second course of streptokinase given 1 month after the first course for clearance of an occluded arteriovenous shunt. Therefore, the probability {74} of systemic absorption of streptokinase following use for this purpose must be considered.




Those not indicating need for medical attention
Incidence rare
    
Skin lesions —with streptokinase{90}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Thrombolytic Agents (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Allergic reaction to the thrombolytic agent considered for use, history of, especially a severe allergic reaction to anistreplase or streptokinase





Use in the elderly—May have conditions which increase the risk of hemorrhage
Other medications, especially anticoagulants, antifibrinolytic agents, enoxaparin, heparin, hypoprothrombinemia-inducing cephalosporins, nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors, plicamycin, and valproic acid
Other medical problems, especially conditions leading to an increased risk of uncontrollable or cerebral hemorrhage. For anistreplase and streptokinase, prior treatment with either agent (within the past 12 months) or history of anaphylaxis or severe allergic reaction to either agent

Proper use of this medication

» Proper dosing

Precautions after receiving this medication
» Importance of compliance with strict bed rest or other measures to minimize bleeding


Side/adverse effects
Signs of potential side effects, especially bleeding or oozing from cuts, invaded or disturbed sites, wounds, or gums; decreased blood pressure, not secondary to bleeding or streptokinase-induced anaphylaxis; fever; allergic reaction; bleeding into subcutaneous tissues; cholesterol embolism; internal bleeding; hemorrhagic or thromboembolic stroke; and severe allergic reaction or anaphylaxis


General Dosing Information
The activity and doses of alteplase are expressed in milligrams {45}, the activity and doses of anistreplase are expressed in units, and the activity and doses of streptokinase and urokinase are expressed in International Units (IU). However, in some countries, individual products may be labeled in other units. Different tests and standards are used to determine activity of each thrombolytic agent.

Thrombolytic therapy for indications other than acute coronary arterial thrombosis and catheter clearance {127} should be performed only in a hospital with the facilities and trained personnel necessary for performance of the recommended diagnostic and monitoring techniques.

Thrombolytic therapy should be instituted as soon as possible following the onset of clinical symptoms {42} {68} {76} {101} {112} because resistance to lysis increases with the age of the thrombus. For coronary arterial thrombosis or occlusion in evolving transmural myocardial infarction, rapid initiation of treatment is critical {07} {49} {55} {60} {63} {99} {167}. However, patients receiving treatment within 6 to 12 hours following the onset of symptoms also may benefit from thrombolytic therapy {95} {97} {98} {99}. In patients who experience intermittent symptoms resulting from alternating coronary artery occlusion and spontaneous recanalization, thrombolytic therapy may limit the extent of myocardial damage even if given late. In addition, late thrombolytic therapy may limit myocardial damage by providing collateral flow in the event of subsequent coronary artery occlusion. {98} For other indications, treatment should preferably be started within:    • Pulmonary embolism—5 to 7 days.
   • Deep venous thrombosis—3 to 4 days, although treatment started later may be somewhat successful.
   • Arterial thrombosis or thromboembolism (noncoronary)—3 days, although treatment started later may be successful.


Factors that may affect the success of thrombolytic therapy include the age, size, and location of the thrombus, and the extent of pretreatment perfusion, with most failures occurring when no blood is flowing past the thrombus (grade 0 flow as defined in the Thrombolysis in Myocardial Infarction [TIMI] trials) {33} {139} {148}. Factors that decrease the efficiency or activation potential of the fibrinolytic system include extremes in body temperature, elevated concentration of endogenous inhibitors, the presence of abnormal proteins or dysfunctional components of the fibrinolytic system, and the presence of high titers of antistreptokinase antibodies {11}.

Prior to initiation of intravenous thrombolytic therapy for indications other than acute coronary arterial thrombosis, heparin (if being given) should be discontinued and the patient"s thrombin time (TT) or activated partial thromboplastin time (APTT) should be less than twice the control value.

Thrombolytic agents should be administered via a constant infusion pump. A separate intravenous line, which should be established prior to initiation of thrombolytic therapy to reduce the need for venipuncture during treatment {66}, should be used for administration of other medications, if required.

To minimize the risk of bleeding during thrombolytic therapy, the patient should be kept on strict bed rest and pressure dressings applied to recently invaded sites. Nonessential handling or moving of the patient, invasive procedures (biopsy, etc.), and intramuscular injections must be avoided. Only essential procedures or diagnostic tests should be performed. Cutdowns should be performed only if unavoidable. Venipunctures should be performed as carefully and infrequently as possible, preferably only in arm vessels, using a 23-gauge (or smaller) needle. If an arterial puncture is necessary, an upper extremity distal vessel should be used. Manual pressure should be applied for 30 minutes after the arterial puncture, followed by application of a pressure dressing. The puncture site should be checked frequently for signs of bleeding. {02} {06} {76} {77} Profuse bleeding may persist for a prolonged period of time {68} {101}.

Therapy should be discontinued immediately if bleeding not controllable by local pressure occurs. Some clinicians recommend that thrombolytic therapy be discontinued permanently if such bleeding occurs. However, other clinicians suggest that reinstitution of therapy using one half the original maintenance dose may be considered if the results of blood coagulation tests performed shortly after the bleeding episode show values higher than the normal therapeutic range. These clinicians further suggest that therapy not be reinstituted until the results of blood coagulation tests have returned to within the normal therapeutic range, and, if bleeding recurs, that therapy be discontinued permanently.

Anticoagulation with heparin (preferably by continuous intravenous infusion) followed, if necessary, by a coumarin or indanedione derivative is recommended following thrombolytic therapy for deep venous thrombosis or pulmonary embolism to prevent further thrombus formation. It is usually recommended that heparin be administered only after the patient"s TT or APTT returns to less than twice the normal control value. This usually occurs within 2 to 4 hours after cessation of thrombolytic therapy. {53} {167} However, heparin therapy may be instituted earlier, depending on clinical circumstances. A loading dose of heparin is generally not recommended, but may be required in some circumstances, especially if the TT or APTT has fallen to substantially less than twice the control value. Administration of a coumarin- or indanedione-derivative anticoagulant, if necessary, should be started at least 5 days prior to discontinuation of heparin. {83} {167}

Angioplasty, coronary bypass surgery, or another revascularization procedure may be necessary to provide long-lasting protection against reocclusion, especially if extensive stenosis (> 80%) persists in the affected artery. Performance of these procedures within several days after thrombolytic therapy increases the risk of adverse effects, including hemorrhage, and should therefore be delayed if possible. {36} If such a procedure cannot be postponed, replacement of fibrinogen to 50% of normal activity by administration of cryoprecipitate may reduce the risk of bleeding complications {36}. If systemic fibrinolysis induced by the thrombolytic agent has not yet ceased, administration of an antifibrinolytic agent (e.g., aminocaproic acid, tranexamic acid) will be necessary to prevent immediate lysis of the infused fibrinogen {36}, but the risks of administering an antifibrinolytic agent to a patient undergoing a revascularization procedure must be carefully considered {11} {156}.

For treatment of acute coronary arterial thrombosis
A suitable antiarrhythmic agent may be administered prior to or concurrently with the thrombolytic agent to prevent reperfusion arrhythmias.

It has been shown that aspirin, administered in conjunction with streptokinase for treatment of coronary arterial thrombosis, significantly decreases the occurrence of reocclusion, reinfarction, stroke, and death, as compared to aspirin or streptokinase administered alone {12} {45} {88} {91} {94} {96} {99} {105}. Although the benefit of aspirin administered with alteplase or anistreplase has not been studied, it is widely held that the combination of aspirin and any thrombolytic agent is likely to have benefit similar to that of aspirin and streptokinase {91}. It is therefore recommended that at least 160 mg of aspirin be administered as soon as possible after myocardial infarction is suspected {13} {88} {94} {96} {105}. It is also recommended that the aspirin be chewed so that it reaches the bloodstream rapidly {94} {105}.

Heparin (in dosage sufficient to prolong the APTT to 1.5 to 2 times the control value) has been administered in conjunction with thrombolytic therapy for acute coronary arterial occlusion {07} {49} {52} {53} {54} {55} {56} {57} {58} {167}. However, recent studies have found that the addition of heparin to a regimen of aspirin and thrombolysis does not significantly improve survival, but does increase the risk of major bleeding and cerebral hemorrhage {87} {88}. In addition, there are little data to show that heparin contributes to sustained coronary artery patency when administered with aspirin and streptokinase {105} or with aspirin and anistreplase {88}. When administered with aspirin and alteplase, intravenous heparin seems to improve coronary artery patency slightly {84} {88} {96} {105}, but the benefit must be weighed against the risk of hemorrhage associated with the use of intravenous heparin {88}.

For arteriovenous cannula occlusion clearance
First, the cannula should be cleared by careful syringe technique, using heparinized saline solution. If this procedure is unsuccessful, a thrombolytic agent may be used after the effects of prior anticoagulation have been allowed to diminish. After the thrombolytic agent has been instilled in the cannula, the affected cannula limb(s) should be clamped for 2 hours and the patient closely observed for possible adverse effects. After treatment, the contents of the affected cannula limb(s) should be aspirated, and the cannula flushed with saline solution and reconnected. {06}

For intravenous catheter obstruction clearance
The manufacturer's product information for urokinase should be consulted for a complete description of the recommended procedure.

Streptokinase is not indicated for restoration of patency of intravenous catheters. Under postmarketing surveillance, an increased number of serious adverse events have been reported. Most have involved the use of high doses of streptokinase in small volumes (250,000 IU in 2 mL). Uses of lower doses of streptokinase in infusions over several hours, generally into partially occluded catheters, or local instillation into the catheter lumen and subsequent aspiration, have been described in the medical literature. {172}

Excessive pressure should be avoided when instilling a thrombolytic agent into the catheter in order to avoid rupture of the catheter or expulsion of the clot into the circulation {113}.

To prevent air from entering an open central venous catheter, the patient should be instructed to exhale and hold his or her breath any time the catheter is not connected to intravenous tubing or to a syringe {02} {113} {168}.

Intravenous catheters may be obstructed by substances not responsive to thrombolysis (i.e., substances other than clotted blood or fibrin). The possibility that such a precipitate may be forced into the circulation must be considered.

For treatment of adverse effects
Recommended treatment includes

   • For minor bleeding—Applying local measures, such as pressure at the site of bleeding {06} {68}. Although efficacy has not been proved, topical application of an antifibrinolytic agent such as aminocaproic acid may help to stop stubborn minor bleeding. Thrombolytic therapy need not be discontinued unless such measures are unsuccessful and it is determined that the risk to the patient outweighs the benefit of continuing treatment. {66}
   • For uncontrollable or internal bleeding—Discontinuing thrombolytic therapy {06} {77} {91}. If necessary, replacement of lost blood and reversal of the bleeding tendency can be accomplished by administration of fresh whole blood {02} {38} {77} {91} {167}, packed red blood cells {77} {167}, cryoprecipitate {02} {77} {91} {167} or fresh frozen plasma {02} {38} {77} {167}, platelets {11} {91} {156}, and/or desmopressin {11} {91} {156}. Plasma volume expanders may be administered; however, dextrans should not be used {02} {167}, because of their platelet aggregation–inhibiting activity. Heparin, if being given, should be discontinued and consideration given to administration of the heparin antagonist protamine {68} {76} {77} {101}. Also, an antifibrinolytic agent, such as aminocaproic acid {02} {06} {167} (5 grams initially or over a period of 1 hour, followed by 1 gram per hour for approximately 4 to 8 hours or until the desired response has been obtained), or tranexamic acid may be administered intravenously (preferably by continuous infusion) or orally. However, the efficacy of aminocaproic acid {91} or other antifibrinolytic agents in the treatment of thrombolytic agent–induced hemorrhage has not been documented by controlled studies in humans {02} {167}. Also, the risk of reocclusion or other thrombotic complications must be considered {11} {156}.
   • For bradycardia—If necessary, atropine may be administered {37}.
   • For reperfusion arrhythmias—Administering a suitable antiarrhythmic agent, such as lidocaine or procainamide. Electrical cardioversion may be needed for ventricular tachycardia or fibrillation. {38} {39} {91}
   • For mild hypersensitivity reaction—Administering antihistamines and, if necessary, glucocorticoids {06} {79} {99}.
   • For severe hypersensitivity or anaphylactic reaction—Discontinuing thrombolytic therapy {06} and administering epinephrine. Antihistamines and/or glucocorticoids also may be administered as required {06}.
   • For sudden hypotension—If sudden hypotension occurs during rapid, high-dose administration, reducing the infusion rate. If sudden hypotension occurs in other circumstances or does not respond to a reduction in the infusion rate, placing the patient in the Trendelenburg position {79} and/or administering volume expanders (other than dextrans), atropine {37}, and/or a vasopressor, e.g., dopamine {114}, as clinical circumstances permit.
   • For fever—Administering acetaminophen if treatment is required. Administration of multiple antipyretic doses of aspirin is not recommended.

ALTEPLASE, RECOMBINANT

Summary of Differences


Indications:
Indicated in the treatment of acute coronary arterial thrombosis, acute ischemic stroke, acute pulmonary thromboembolism, and in the clearance of central intravenous catheters.{173}



Pharmacology/pharmacokinetics:


Mechanism of action/effect—
Acts directly to convert plasminogen to plasmin.

May be more clot-selective than anistreplase, streptokinase, or urokinase.



Half-life—
Biphasic; about 4 minutes for distribution phase and 35 minutes for elimination phase.




Side/adverse effects:
Incidence of stroke and cerebral hemorrhage greater than with other thrombolytic agents {53}. Incidence and severity of allergic reactions lower than with anistreplase or streptokinase {72} {85} {98}.



Additional Dosing Information
Alteplase is not antigenic (as are anistreplase and streptokinase) and does not promote antibody formation. Therefore, a second course of alteplase therapy can be administered, if reocclusion occurs, without resistance having developed to the effects of alteplase and without risk of precipitating an anaphylactic reaction. {66} In one study, a second course of alteplase therapy was shown to be effective, without producing significant bleeding complications, in patients exhibiting signs and symptoms of reocclusion following initial thrombolytic therapy for treatment of acute myocardial infarction {84}. However, it must still be considered that a second course of therapy, if initiated before systemic effects of the first dose have subsided, may increase the risk of severe hemorrhage {63}.

A large multi-center study has shown that alteplase, administered in an accelerated or front-loaded dosing regimen within 6 hours {64} {137} of the onset of symptoms of myocardial infarction, may achieve earlier and more complete patency of the infarct-affected artery {10} {105} than does streptokinase in combination with intravenous or subcutaneous heparin, or a combination of alteplase, streptokinase, and intravenous heparin. Twenty-four-hour and 30-day mortality was also lower with the accelerated or front-loaded alteplase regimen than with these combinations {01} {64}.

For treatment of acute ischemic stroke
The treatment of acute ischemic stroke with alteplase should be limited to facilities that can provide appropriate evaluation and management of intracranial hemorrhage {07}.

Treatment should be initiated only within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage by a cranial computed tomographic scan or other diagnostic imaging method sensitive to the presence of hemorrhage {07}.

In patients who have not recently been treated with oral anticoagulants or heparin, alteplase may be given prior to the availability of coagulation study results. However, treatment should be stopped if either a pre-treatment prothrombin time > 15 seconds or an elevated APTT is identified. {07}

Blood pressure should be monitored frequently and controlled with appropriate medication during and following alteplase administration {07}.

The safety and efficacy of concomitant administration of heparin and aspirin during the first 24 hours after symptom onset have not been investigated {07}.


Parenteral Dosage Forms

ALTEPLASE, RECOMBINANT, FOR INJECTION

Usual adult dose
Intravenous catheter clearance{173}
After the intravenous tubing has been disconnected and catheter occlusion confirmed, the catheter should be filled with a solution containing 1 mg per mL of alteplase. The solution should be administered as follows:Initial Dose



• For patients weighing 30 kg or more—Intravenous, 2 mg in 2 mL.


• For patients weighing at least 10 kg and less than 30 kg—Intravenous, 110% of internal lumen volume of the catheter, not to exceed 2 mg in 2 mL.
Second dose



• If catheter function is not restored at 120 minutes after dose 1, a second dose may be administered.
.
{173}
Note: There is no efficacy or safety information on dosing in excess of 2 mg per dose for this indication. Studies have not been performed with administration of total doses greater than 4 mg (two 2 mg doses).{173}


Thrombosis, coronary arterial, acute {07} {76} {77} {91} {99}


Standard regimen:
For patients weighing less than 65 kg—Intravenous, 1.25 mg per kg of body weight administered over a period of three hours, as follows:

• First hour—60% of the total dose. Initially, 6 to 10% of the total dose is given by direct intravenous injection within the first one or two minutes. The next 50 to 54% of the total dose is given via intravenous infusion during the remainder of the hour.


• Second hour—20% of the total dose, via intravenous infusion.


• Third hour—20% of the total dose, via intravenous infusion.


For patients weighing 65 kg or more—Intravenous, 100 mg, administered over a period of three hours, as follows:

• First hour—60 mg. Initially, 6 to 10 mg is given by direct intravenous injection within the first one or two minutes. The next 50 to 54 mg is given via intravenous infusion during the remainder of the hour.


• Second hour—20 mg, via intravenous infusion.


• Third hour—20 mg, via intravenous infusion.




Accelerated regimen:
For patients weighing less than 67 kg—Intravenous, initially 15 mg followed by an infusion of 0.75 mg per kg of body weight, up to 50 mg, administered over a period of thirty minutes. The infusion should continue for an additional sixty minutes at a dose of 0.5 mg per kg of body weight, up to 35 mg. {01} {76}

For patients weighing 67 kg or more—Intravenous, initially 15 mg by direct intravenous injection, followed by 50 mg infused over the next thirty minutes, and then 35 mg infused over the next sixty minutes {07} {76}.

Note: It is recommended that intravenous heparin be administered in conjunction with accelerated-dose alteplase at an initial dose of 5000 USP Heparin Units, followed by 1000 USP Heparin Units per hour (1200 USP Heparin Units per hour for patients weighing more than 80 kg), with the dose adjusted to raise the activated partial thromboplastin time to between sixty and eighty-five seconds {01}.



Stroke, acute ischemic 1
Intravenous, 0.9 mg per kg of body weight (up to a maximum of 90 mg) infused over sixty minutes, with 10% of the total dose administered by direct intravenous injection over the first minute {07} {76}.

Thromboembolism, pulmonary, acute1
Intravenous infusion, 100 mg, administered over a period of two hours {19} {76} {83} {92}.
Note: It is recommended that heparin be used in conjunction with alteplase for treatment of acute pulmonary embolism. Heparin should be administered only if the patient's activated partial thromboplastin time or thrombin time value is no higher than twice the control value, near the end of or immediately following the alteplase infusion. {19} {76} {83}




Usual pediatric dose
Safety and efficacy have not been established {76}.

Size(s) usually available:
U.S.—


50 mg (Rx) [Activase{76} (vials contain a vacuum) (l-arginine 1.7 grams) ( phosphoric acid 0.5 gram) (polysorbate 80 £ 4 mg)]


100 mg (Rx) [Activase{76} (vials do not contain a vacuum) (l-arginine 3.5 grams) (phosphoric acid 1 gram) (polysorbate 80 £ 11 mg)]


2.2 mg vial [Cathflo Activase (vials contain 2.2 mg which includes a 10% overfill supplying a 2 mg dose) (77 mg of L-arginine, 0.2 mg polysorbate 80, phosphoric acid){173}]

Canada—


50 mg (Rx) [Activase rt-PA{77} (vials contain a vacuum) (l-arginine) ( phosphoric acid) (polysorbate 80)]


100 mg (Rx) [Activase rt-PA{77} (vials do not contain a vacuum) (l-arginine ) (phosphoric acid) ( polysorbate 80)]

Packaging and storage:
Store between 2 and 30 °C (36 and 86 °F), unless otherwise specified by manufacturer {76} {77}. Protect from excessive exposure to light {77}.

Store Cathflo Activase between 2 and 8°C (36 and 46°F). May be used within 8 hours of reconstitution when stored between 2 and 30 °C (36 and 86 °F). Protect from excessive exposure to light.{173}

Preparation of dosage form:
Alteplase should be reconstituted using Sterile Water for Injection, USP (diluent may or may not be provided). Bacteriostatic water for injection must not be used. A large-bore (18-gauge) needle or the transfer device (for use with the 100-mg vials) should be used to direct the stream of diluent directly into the lyophilized material.

If a vacuum is not present in the 50-mg vial, it should not be used.

When reconstituting the 100-mg vials using the transfer device, the vial of sterile water for injection, with the transfer device inserted, is held upright while the vial of alteplase is held upside down and pushed down onto the piercing pin of the transfer device. The vials are then inverted to allow the sterile water for injection to flow into the alteplase vial. The resulting colorless to pale yellow, transparent solution will contain 1 mg of alteplase per mL. This solution may be used without further dilution or it may be diluted to a concentration of 0.5 mg per mL using an equal volume of 0.9% sodium chloride injection or 5% dextrose injection. Other infusion solutions or preservative-containing solutions should not be used when further diluting the reconstituted solution. The solution may be mixed with gentle swirling and/or slow inversion; excessive agitation should be avoided. Slight foaming may occur during reconstitution; however, large bubbles dissipate when the solution is left undisturbed for a few minutes. {07} {76}{77}

When reconstituting alteplase 2 mg for intracatheter installation, aseptically withdraw 2.2 ml of sterile water for injection USP and inject into the cathflow activase vial directing the diluent stream into the powder. Let the vial stand undisturbed until all large bubbles have dissipated. Do not shake. Mix by swirling until the contents are completely dissolved. Complete dissolution results in a pale yellow transparent solution containing 1 mg per ml and should occur within 3 minutes.{173}

Stability:
The reconstituted solution should be used within 8 hours when stored between 2 and 30 °C (36 and 86 °F) {45}. It should be discarded if not used within this time. However, because alteplase for injection contains no preservatives, it should not be reconstituted until immediately prior to use. Any unused solution must be discarded. {76}

Incompatibilities:
Do not add any other medication to the container of alteplase solution or administer other medications through the same intravenous line {76} {77}.


ANISTREPLASE

Summary of Differences


Indications:
Indicated in the treatment of acute coronary arterial thrombosis.



Pharmacology/pharmacokinetics:
Mechanism of action/effect—Acts indirectly to promote conversion of plasminogen to plasmin.

Other actions/effects—Antigenic; promotes antibody formation.

Half-life—70 to 120 minutes (average about 90 minutes). The deacylation half-life of the complex is about 105 to 120 minutes.



Precautions:
Medical considerations/contraindications—Caution is required in patients who have had a severe hypersensitivity reaction to prior anistreplase or streptokinase therapy or a prior course of anistreplase or streptokinase therapy within the past 12 months.



Side/adverse effects:
Incidence of mild hypersensitivity and febrile reactions greater than with alteplase or urokinase.

May cause severe hypersensitivity reactions including anaphylaxis.



Additional Dosing Information
It is recommended that equipment and medications (such as epinephrine, glucocorticoids, and antihistamines) for treating anaphylaxis be immediately available whenever anistreplase is administered. Some investigators have administered a glucocorticoid (e.g., 100 mg of hydrocortisone {42} {103} or methylprednisolone, intravenously) {38} {40} {41} and/or an antihistamine (e.g., 50 mg of diphenhydramine, intravenously) {17} {42} prior to anistreplase administration, to decrease the risk of severe hypersensitivity and febrile reactions. However, the prophylactic efficacy of these medications has not been established. {155} {166}

Resistance to anistreplase therapy may occur because of the presence of high titers of antibodies following a prior course of anistreplase or streptokinase therapy {71} {85}. A significant titer of these antibodies generally occurs 5 to 7 days following administration of anistreplase or streptokinase and may persist for 1 year (up to 4 years in some patients) {85}. Alteplase or urokinase may be administered if thrombolytic therapy is indicated during this time {71} {94} {99}. A recent streptococcal infection also may result in high titers of antibodies and resistance to anistreplase.


Parenteral Dosage Forms

ANISTREPLASE FOR INJECTION

Usual adult dose
Thrombosis, coronary arterial, acute
Intravenous, 30 units, administered over two to five minutes {68} {69} {91} {101}.


Usual pediatric dose
Safety and efficacy have not been established {68} {101}.

Size(s) usually available:
U.S.—


30 Units per single-dose vial (Rx) [Eminase{68} ( human albumin 30 mg) (dimethylsulfoxide < 3 mg ) (epsilon-aminocaproic acid 1.3 mg) (glycerol < 2 mg) (l-lysine 46 mg ) (mannitol 100 mg) ( p-amidinophenyl-p'-anisate 150 mcg) (sodium hydroxide < 0.2 mg)]

Canada—


30 Units per single-dose vial (Rx) [Eminase{170} ( human albumin 30 mg) (dimethylsulfoxide < 3 mg ) (epsilon-aminocaproic acid 1.3 mg) (glycerol < 2 mg) (l-lysine 46 mg ) (mannitol 100 mg) ( p-amidinophenyl-p'-anisate 150 mcg) (sodium hydroxide < 0.2 mg)]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) {68} {101}, unless otherwise specified by manufacturer.

Preparation of dosage form:
Five mL of sterile water for injection should be slowly added to the vial containing anistreplase for injection; the stream of water should be directed against the side of the vial. The vial should then be gently rolled (not shaken), to mix the powder with the liquid. Other measures to minimize foaming should also be used. {68} {101}

Stability:
The reconstituted solution is to be administered within 30 minutes after reconstitution {68} {101}.

The medication contains no preservative. Each vial is intended to provide a single dose only; any unused solution should be discarded. {68} {101}

Incompatibilities:
Do not add any other medication to the container of anistreplase solution or administer other medications through the same intravenous line {68} {101}.


STREPTOKINASE

Summary of Differences


Indications:
Indicated in the treatment of acute coronary arterial thrombosis, acute pulmonary thromboembolism, deep venous thrombosis, and acute arterial thromboembolism and thrombosis. Also indicated to clear totally or partially occluded arteriovenous cannulae.

Not indicated for restoration of patency of intravenous catheters.{172}



Pharmacology/pharmacokinetics:
Mechanism of action/effect—Acts indirectly to promote conversion of plasminogen to plasmin.

Other actions/effects—Antigenic; promotes antibody formation.

Half-life—Following rapid, high-dose administration: 23 minutes (as active activator complex activity).



Precautions:
Medical considerations/contraindications—Caution required in patients who have had a severe hypersensitivity reaction to prior streptokinase therapy or a prior course of streptokinase therapy within the past 12 months.



Side/adverse effects:
Incidence of mild hypersensitivity and febrile reactions greater than with urokinase or alteplase.

May cause severe hypersensitivity reactions including anaphylaxis or, rarely, skin lesions.



Additional Dosing Information
It is recommended that equipment and medications (such as epinephrine, glucocorticoids, and antihistamines) for treating anaphylaxis be immediately available whenever streptokinase is administered. Some investigators have administered a glucocorticoid (e.g., 100 mg of hydrocortisone or methylprednisolone {38} {40} {41}, intravenously) and/or an antihistamine (e.g., 50 mg of diphenhydramine, intravenously) {17} {42} prior to streptokinase administration, to decrease the risk of severe hypersensitivity and febrile reactions. However, the prophylactic efficacy of these medications has not been established. {44}

Resistance to streptokinase therapy {70} {71} may occur because of the presence of high titers of {11} antibodies to streptokinase following a prior course of streptokinase or anistreplase therapy {71} {85}. A significant titer of these antibodies generally occurs 5 to 7 days following administration of anistreplase or streptokinase and may persist for 1 year (up to 4 years in some patients) {85}. Alteplase or urokinase may be administered if thrombolytic therapy is indicated during this time {71} {94} {99}. A recent streptococcal infection also may result in high titers of antibodies and resistance to streptokinase.

For intravenous administration of streptokinase (for indications other than acute coronary arterial thrombosis), a loading dose of 250,000 International Units (IU) is recommended to overcome mild resistance caused by exposure (without recent active infection) to streptococci. Since this loading dose successfully overcomes resistance in 85 to 90% of patients, many clinicians state that a previously recommended resistance test is now considered unnecessary. However, if a thrombin time (TT) determination or other test of fibrinolysis performed after 4 hours of therapy indicates minimal or no fibrinolytic activity, and no clinical improvement is apparent, the possibility of excessive resistance to streptokinase should be considered. Streptokinase should be discontinued and an alternate thrombolytic agent (alteplase or urokinase, but not anistreplase) administered instead.

A previously recommended regimen of variable maintenance dosage with frequent laboratory monitoring has not been shown to increase the efficacy or safety of streptokinase therapy. Therefore, this regimen is not currently recommended and has been replaced by a fixed maintenance dosage schedule.

The dosage and duration of intravenous therapy vary with the condition being treated. For the individual patient, tests to determine restoration of blood flow, such as angiography or venography of the affected blood vessel, computed tomography, impedance plethysmography, or quantitative Doppler effect, may be useful in determining the optimum duration of administration.


Parenteral Dosage Forms

STREPTOKINASE FOR INJECTION

Usual adult dose
Thrombosis, coronary arterial, acute
Intravenous, 1,500,000 IU, administered within one hour {03} {04} {05} {06} {91} {99}.

Intra-arterial (via a coronary artery catheter placed via the Judkins or Sones technique), 20,000 IU initially, followed by 2000 IU per minute for one hour {06} {45}.

Note: Recanalization may occur in less than one hour; however, treatment should be continued following recanalization, to ensure complete lysis of all thrombotic material.


Thromboembolism, pulmonary, acute
Intravenous, 250,000 IU as an initial loading dose over thirty minutes, followed by 100,000 IU per hour as a continuous infusion for twenty-four hours (seventy-two hours if concurrent deep venous thrombosis) {06}

Thrombosis, deep venous
Intravenous, 250,000 IU as an initial loading dose over thirty minutes, followed by 100,000 IU per hour as a continuous infusion for seventy-two hours {06}

Thromboembolism or thrombosis, arterial, acute
Intravenous, 250,000 IU as an initial loading dose over thirty minutes, followed by 100,000 IU per hour as a continuous infusion for twenty-four to seventy-two hours {06}

Cannula, arteriovenous, clearance
100,000 to 250,000 IU {06}, instilled slowly into each occluded cannula limb.


Usual pediatric dose
Thromboembolism or thrombosis, arterial, acute
Intravenous, 1000 IU (up to 3000 IU) per kg of body weight initially over five to thirty minutes, followed by 1000 IU (up to 1500 IU) per kg of body weight per hour for twelve to twenty-four hours {06}.

Note: Controlled clinical studies have not been conducted to determine the safety and efficacy of using streptokinase in pediatric patients. The evidence of clinical benefits and risks is based solely on anecdotal reports in patients from younger than 1 month of age up to 16 years of age {06}.



Size(s) usually available:
U.S.—


250,000 IU (Rx) [Streptase{06} ( albumin human 100 mg) (cross-linked gelatin polypeptides 25 mg) (sodium hydroxide) (sodium l-glutamate 25 mg)]


750,000 IU (Rx) [Streptase{06} ( albumin human 100 mg) (cross-linked gelatin polypeptides 25 mg) (sodium hydroxide) (sodium l-glutamate 25 mg)]


1,500,000 IU (Rx) [Streptase{06} ( albumin human 100 mg) (cross-linked gelatin polypeptides 25 mg) (sodium hydroxide) (sodium l-glutamate 25 mg)]

Canada—


250,000 IU (Rx) [Streptase{05} ( albumin human 100 mg) (cross-linked gelatin polypeptides 25 mg) (sodium hydroxide) (sodium l-glutamate 25 mg)]


750,000 IU (Rx) [Streptase{05} ( albumin human 100 mg) (cross-linked gelatin polypeptides 25 mg) (sodium hydroxide) (sodium l-glutamate 25 mg)]


1,500,000 IU (Rx) [Streptase{05} ( albumin human 100 mg) (cross-linked gelatin polypeptides 25 mg) (sodium hydroxide) (sodium l-glutamate 25 mg)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) {06}, unless otherwise specified by manufacturer.

Preparation of dosage form:
For intracoronary artery or intravenous administration—Manufacturer's prescribing information should be consulted for recommendations for reconstituting and further diluting the individual product.

For arteriovenous cannula obstruction clearance—Two mL of sodium chloride injection or 5% dextrose injection should be added to each 250,000-IU vial of streptokinase {06}.

Stability:
Streptokinase for injection should be reconstituted immediately prior to use.

If not administered shortly following reconstitution, the solution should be stored at 2 to 8 °C (36 to 46 °F) {125}. If not used within 8 hours after reconstitution, the solution should be discarded {06}.

One manufacturer states that slight flocculation (described as thin translucent fibers) may occur after reconstitution. Shaking the solution during reconstitution may increase flocculation or cause foaming and should be avoided. The solution may be administered if slight flocculation is present but should be discarded if flocculation is extensive. {06}

Incompatibilities:
Do not add any other medication to the container of streptokinase solution or administer other medications through the same intravenous line {06}.


UROKINASE

Summary of Differences


Indications:
Indicated in the treatment of acute coronary arterial thrombosis, acute pulmonary embolism, and to restore patency to intravenous catheters.

During its inspections of the facilities involved in the manufacture and production of urokinase, the Food and Drug Administration (FDA) identified numerous significant deviations from the Current Good Manufacturing Practice regulations; the FDA recommended that urokinase be reserved for only those situations in which a physician has determined that the use of urokinase is critical to the care of a specific patient in a specific situation {171}.



Pharmacology/pharmacokinetics:
Mechanism of action/effect—Acts directly to convert plasminogen to plasmin.

Half-life—Up to 20 minutes; may be prolonged in patients with hepatic function impairment.



Side/adverse effects:
Incidence and severity of allergic or febrile reactions lower than with anistreplase or streptokinase.



Additional Dosing Information
The dosage and duration of urokinase therapy may vary with the condition being treated. For the individual patient, tests to determine restoration of blood flow, such as angiography or venography of the affected blood vessel, computed tomography, impedance plethysmography, or quantitative Doppler effect, may be useful in determining the optimum duration of administration.

For lysis of coronary artery thrombi
Prior to intracoronary arterial administration of urokinase, it is recommended that 2500 to 10,000 USP Heparin Units be administered via direct intravenous injection. Prior heparin administration should be considered when calculating heparin dosage. {02} {167}


Parenteral Dosage Forms

UROKINASE FOR INJECTION

Usual adult dose
Thrombosis, coronary arterial, acute
Intra-arterial (via a coronary artery catheter), 6000 IU (4 mL of a solution containing approximately 1500 IU per mL) per minute {02} {167}.
Note: The average total dose of urokinase required for lysis of coronary artery thrombi is 500,000 IU {02} {167}.
Urokinase administration should be continued until the artery is maximally opened, usually fifteen to thirty minutes after initial opening {02} {167}. The medication has been administered for periods of up to two hours.
Periodic coronary angiography, at approximately fifteen-minute intervals, is recommended during the infusion with urokinase {167}.



Thromboembolism, pulmonary, acute
Intravenous, 4400 IU per kg of body weight initially over a ten-minute period, followed by 4400 IU per kg of body weight per hour {02} {113} {167} for approximately twelve hours {127}.
Note: Manufacturer's product information should be consulted for recommendations concerning the rate of infusion, based on recommended dilution volume of the product {167}.
Heparin should be discontinued during the intravenous administration of urokinase {167}.



Catheter, intravenous, clearance
After the intravenous tubing has been disconnected and catheter occlusion confirmed, the catheter should be filled with a solution containing 5000 IU per mL of urokinase {45} {168}.


Usual pediatric dose
Safety and efficacy have not been established {168} {169}.

Size(s) usually available:
U.S.—


5000 IU (Rx) [Abbokinase Open-Cath{168} (gelatin 5 mg) (mannitol 15 mg) ( monobasic sodium phosphate anhydrous 4.6 mg) (sodium chloride 1.7 mg)]


9000 IU (Rx) [Abbokinase Open-Cath{168} (gelatin 5 mg) (mannitol 15 mg) ( monobasic sodium phosphate anhydrous 4.6 mg) (sodium chloride 1.7 mg)]


250,000 IU (Rx) [Abbokinase{167} ( albumin human 250 mg) (mannitol 25 mg) (sodium chloride 50 mg)]

Canada—


5000 IU (Rx) [Abbokinase Open-Cath{169} (gelatin ) (mannitol) (monobasic sodium phosphate anhydrous) (sodium chloride)]


250,000 IU (Rx) [Abbokinase{169} ( albumin human 250 mg) (mannitol 25 mg) (sodium chloride 50 mg)]

Note: The 250,000-IU size is intended for intravenous and intracoronary infusion only. After initial reconstitution, the solution prepared from one 250,000-IU size contains approximately 50,000 IU of urokinase per mL; however, further dilution is required prior to use {167}.
The 5000-IU and 9000-IU sizes are intended for intravenous catheter clearance only. Premeasured diluent is included. After reconstitution, the solution prepared from either the 5000-IU or 9000-IU size contains 5000 IU of urokinase per mL {167}.


Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) {02} {167} {169}, unless otherwise specified by manufacturer. Store Abbokinase Open-Cath below 25 °C (77 °F). Protect from freezing. {02} {113} {167} {169}

Preparation of dosage form:
For the 250,000-IU size only—Five mL of sterile water for injection without preservatives should be added to each 250,000-IU vial. Bacteriostatic water for injection should not be used. The vial should be rolled and tilted (not shaken) to facilitate reconstitution.

For intravenous administration—Manufacturer's prescribing information should be consulted for recommendations for further diluting the product. Intravenous urokinase should be administered by a constant infusion pump capable of delivering a total volume of 195 mL {167}.

For intracoronary arterial administration—The contents of the three reconstituted 250,000-IU vials should be added to 500 mL of 5% dextrose injection to make a solution containing approximately 1500 IU per mL. {02} {167}

For intravenous catheter clearance (for the 5000-IU and 9000-IU sizes only)—Manufacturer's prescribing information should be consulted for instructions for reconstituting product in vials containing premeasured diluent {168}.

Stability:
Because urokinase for injection contains no preservatives, it should not be reconstituted until immediately prior to use. Also, any unused solution must be discarded. {02} {113} {167} {168} {169}

Translucent filaments may form in the solution during reconstitution but do not affect the potency of the product. Shaking the vial should be avoided. If necessary, the solution may be filtered through a 0.45-micron or smaller cellulose membrane filter. {02} {167}

Incompatibilities:
Do not add any other medication to the container of urokinase solution or administer other medications through the same intravenous line {02} {167}.



Revised: 12/12/2001



References
  1. The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-82.
  1. Urokinase (Abbokinase, Abbott). In: PDR Physician's desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: p. 403-5.
  1. Streptokinase package insert (Kabikinase, SKF—US), Rev 11/87, Rec 12/87.
  1. Streptokinase package insert (Streptase, Hoechst-Roussel—US), Rev 11/87, Rec 12/87.
  1. Streptokinase (Streptase, Hoechst Marion Roussel). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p 1583-5.
  1. Streptokinase (Streptase, Astra). In: PDR Physician's desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 597-9.
  1. Alteplase, recombinant package insert (Activase, Genentech—US), Rev 11/87, Rec 12/87; Rev 6/96, Rec 6/96.
  1. Briggs GG, Freeman RK, Yaffe SJ. A reference guide to fetal and neonatal risk. Drugs in pregnancy and lactation. 3rd ed. Baltimore: Williams & Wilkins, 1990: p. 328.
  1. Panel comment.
  1. The GUSTO angiographic investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993; 329: 1615-22.
  1. Reviewers' consensus on monograph revision of 4/90.
  1. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349-60.
  1. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41299 cases of suspected acute myocardial infarction. Lancet 1992; 339: 753-70.
  1. Fears R. Development of anisoylated plasminogen-streptokinase activator complex from the acyl enzyme concept. Semin Thromb Hemost 1989; 15: 129-39.
  1. Been M, deBono DP, Muir AL, et al. Coronary thrombolysis with intravenous anisoylated plasminogen-streptokinase complex BRL 26921. Br Heart J 1985; 53: 253-9.
  1. Bassand J-P, Machecourt J, Cassagnes J, et al. Multicenter trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: effects on infarct size and left ventricular function. J Am Coll Cardiol 1989; 13: 988-97.
  1. Marder VJ, Rothbard RL, Fitzpatrick PG, Francis CW, Norry EC. Dose-ranging studies of anisoylated plasminogen streptokinase activator complex—studies in healthy volunteers and in patients with acute myocardial infarction. Drugs 1987; 33 (Suppl 3): 124-32.
  1. Monk JP, Heel RC. Anisoylated plasminogen streptokinase activator complex (APSAC)—a review of its mechanism of action, clinical pharmacology and therapeutic use in acute myocardial infarction. Drugs 1987; 34: 25-49.
  1. Alteplase, Recombinant package insert (Activase, Genentech—US), Rev 6/90, Rec 7/90.
  1. Personal communication, Genentech Canada, 7/30/90.
  1. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; 1: 545-9.
  1. Johnston FA, Dunn FG, Hogg KJ, et al. Thrombolytic therapy in acute myocardial infarction in the elderly. Gerontology 1987; 33: 331-9.
  1. Wittry MD, Thornton RA, Chaitman BR. Safe use of thrombolysis in the elderly. Geriatrics 1989; 44: 28-36.
  1. Panel comment.
  1. Reviewers' consensus on monograph revision.
  1. Panel comment, 12/88.
  1. Hoffmann JJML, Bonnier JJRM, de Swart JBRM, et al. Systemic effects of anisoylated plasminogen streptokinase activator complex and streptokinase therapy in acute myocardial infarction—coagulation aspects of the Dutch invasive reperfusion trial. Drugs 1987; 33 (Suppl 3): 242-6.
  1. Reviewers' consensus on monograph revision.
  1. Reviewers' consensus on monograph revision.
  1. Reviewers' consensus on monograph revision.
  1. Panel comment.
  1. Reviewers' consensus on monograph revision.
  1. Anderson JL, Rothbard RL, Hackworthy RA, et al. Multicenter reperfusion trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: controlled comparison with intracoronary streptokinase. J Am Coll Cardiol 1988; 11: 1153-63.
  1. Bossaert LL. Safety and tolerance data from the Belgian multicentre study of anisoylated plasminogen streptokinase activator complex versus heparin in acute myocardial infarction. Drugs 1987; 33 (Suppl 3): 287-92.
  1. Reviewers' consensus on monograph revision.
  1. Marder VJ. Comparison of thrombolytic agents: selected hematologic, vascular and clinical events. Am J Cardiol 1989 Jul 5; 64(2): 2A-7A.
  1. Monnier P, Sigwart U, Vincent A, et al. Anisoylated plasminogen streptokinase activator complex versus streptokinase in acute myocardial infarction—preliminary results of a randomised study. Drugs 1987; 33 (Suppl 3): 175-8.
  1. Kasper W, Meinertz TH, Wollschlager H, et al. Early clinical evaluation of the intravenous treatment of acute myocardial infarction with anisoylated plasminogen activator complex. Drugs 1987; 33 (Suppl 3): 112-6.
  1. Croydon EAP. Preliminary safety and tolerance data obtained in the comparative study of anisoylated plasminogen streptokinase activator complex versus heparin. Drugs 1987; 33 (Suppl 3): 293-6.
  1. Meinertz TH, Kasper W. Randomised multicentre trial of anisoylated plasminogen streptokinase activator complex–interim results. Drugs 1987; 33 (Suppl 3): 223-6.
  1. Meinertz TH, Kasper W, Schumacher M, et al for the APSAC Multicenter Trial Group. The German multicenter trial of anisoylated plasminogen streptokinase activator complex versus heparin for acute myocardial infarction. Am J Cardiol 1988; 62: 347-51.
  1. Marder VJ, Rothbard RL, Fitzpatrick PG, et al. Rapid lysis of coronary artery thrombi with anisoylated plasminogen: streptokinase activator complex. Ann Intern Med 1986; 104: 304-10.
  1. Reviewer comment, 9/89.
  1. Reviewers' consensus on monograph revision.
  1. Manufacturers' comments.
  1. Streptokinase (Streptase, Hoechst-Roussel). In: PDR Physicians' desk reference. 44th ed. 1990. Oradell, NJ: Medical Economics Company, 1990: p. 1048.
  1. Crabbe SJ, Cloninger CC. Tissue plasminogen activator: a new thrombolytic agent. Clin Pharm 1987; 6: 373-86.
  1. Rogers SD, Riemersma LB, Clements SD. Tissue plasminogen activator: an evaluation of clinical efficacy in acute myocardial infarction. Pharmacotherapy 1987; 7: 111-21.
  1. Sherry S. Appraisal of various thrombolytic agents in the treatment of acute myocardial infarction. Am J Med 1987; 83 (Suppl 2A): 31-46.
  1. Sobel BE, Geltman EM, Tiefenbrunn AJ, et al. Improvement of regional myocardial metabolism after coronary thrombolysis induced with tissue-type plasminogen activator or streptokinase. Circulation 1984; 69: 983-90.
  1. The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. N Engl J Med 1985; 312: 932-6.
  1. Verstraete M, Bory M, Collen D, et al. Randomised trial of intravenous recombinant tissue-type plasminogen activator versus intravenous streptokinase in acute myocardial infarction. Lancet 1985; 1: 842-7.
  1. Panel comment, 6/94.
  1. Topol EJ, Bell WR, Weisfeldt ML. Coronary thrombolysis with recombinant tissue-type plasminogen activator. A hematologic and pharmacologic study. Ann Intern Med 1985; 103: 837-43.
  1. Jaffee AS, Sobel BE. Thrombolysis with tissue-type plasminogen activator in acute myocardial infarction. Potentials and pitfalls. JAMA 1986; 255: 237-9.
  1. Walsh DG, Kaplan LR, Burney RE, et al. Use of tissue plasminogen activator in the emergency department for acute myocardial infarction. Ann Emerg Med 1987; 16: 243-7.
  1. Topol EJ, Morris 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: 1205-13.
  1. 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: 142-64.
  1. Mueller HS, 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: 479-90.
  1. Nazari J, Davison R, Kaplan K, et al. Adverse reactions to thrombolytic agents. Implications for coronary reperfusion following myocardial infarction. Med Toxicol 1987; 2: 274-86.
  1. 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. N Engl J Med 1987; 317: 1613-8.
  1. Gold HK, Leinbach RC, Garabedian HD, et al. Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: prevention by a maintenance infusion. Circulation 1986; 73: 347-52.
  1. Videoconference on Alteplase 12/1/87.
  1. Ridker PM, Marder VJ, Hennekens CH. Large-scale trials of thrombolytic therapy for acute myocardial infarction: GISSI-2, ISIS-3, and GUSTO-1. Ann Intern Med 1993; 119: 530-2.
  1. Reviewers' consensus on monograph revision.
  1. Reviewers' consensus on monograph revision.
  1. FDA decision, Feb. 23 1989, that Genentech can state in Activase product labeling that use decreases mortality.
  1. Anistreplase (Eminase, Roberts). In: PDR Physicians' desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 2622-4.
  1. Anderson JL, Becker LC, Sorensen SG, et al. Anistreplase versus alteplase in acute myocardial infarction: comparative effects on left ventricular function, morbidity and 1 day coronary artery patency. J Am Coll Cardiol 1992; 20: 753-66.
  1. Binette MJ, Agnone FA. Failure of APSAC thrombolysis [letter]. Ann Intern Med 1993; 119: 637.
  1. Panel comment, 6/94.
  1. Manufacturer comment.
  1. Reviewer comment, 9/89.
  1. Reviewer comment, 9/89.
  1. Reviewer comment, 6/90.
  1. Alteplase, recombinant (Activase, Genentech). In: PDR Physicians' desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 1057-61.
  1. Alteplase (Activase rt-PA, Roche). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 26-8.
  1. Lear J, Rajapakse R. Low back pain associated with anistreplase. Br Med J 1993; 306: 896.
  1. Woo KS, White HD. Comparative tolerability profiles of thrombolytic agents. A review. Drug Saf 1993; 8: 19-29.
  1. McTavish D, Faulds D, Goa KL. Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders. Drugs 1990; 40: 238-59.
  1. Arora RR, Magun AM, Grossman M, et al. Cholesterol embolization syndrome after intravenous tissue plasminogen activator for acute myocardial infarction. Am Heart J 1993; 126: 225-8.
  1. Gupta BK, Spinowitz BS, Charytan C, et al. Cholesterol crystal embolization–associated renal failure after therapy with recombinant tissue-type plasminogen activator. Am J Kidney Dis 1993; 21: 659-62.
  1. Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 341: 507-11.
  1. Simoons ML, Arnout J, van den Brand M, et al. Retreatment with alteplase for early signs of reocclusion after thrombolysis. Am J Cardiol 1993; 71: 524-8.
  1. Elliott JM, Cross DB, Cederholm-Williams SA, et al. Neutralizing antibodies to streptokinase four years after intravenous thrombolytic therapy. Am J Cardiol 1993; 71: 640-5.
  1. Shibley MH, Clifton GD. Febrile reaction associated with urokinase. Pharmacotherapy 1994; 14: 123-5.
  1. O'Connor CM, Meese R, Carney R, et al. A randomized trial of intravenous heparin in conjunction with anistreplase (anisoylated plasminogen streptokinase activator complex) in acute myocardial infarction: the Duke University clinical cardiology study (DUCCS)1. J Am Coll Cardiol 1994; 23: 11-8.
  1. Ridker PM, Hebert PR, Fuster V, et al. Are both aspirin and heparin justified as adjuncts to thrombolytic therapy for acute myocardial infarction? Lancet 1993; 341: 1574-7.
  1. London NJM, Williams B, Stein A. Systemic thrombolysis causing haemorrhage around a prosthetic abdominal aortic graft. Br Med J 1993; 306: 1530-1.
  1. Smithson JE, Kennedy CTC, Hughes S. A new skin lesion associated with intravenous streptokinase. Br Med J 1993; 306: 973.
  1. Eisenberg MS, Aghababian RV, Bassaert L, et al. Thrombolytic therapy. Ann Emerg Med 1993; 22: 417-27.
  1. Blankenship JC, Indeck M. Spontaneous splenic rupture complicating anticoagulant or thrombolytic therapy. Am J Med 1993; 94: 433-7.
  1. David M, Andrew M. Venous thromboembolic complications in children. J Pediatr 1993; 123: 337-46.
  1. Weston CFM, Penny WJ, Julian DG, et al. Guidelines for the early management of patients with myocardial infarction. Br Med J 1994; 308: 767-71.
  1. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994; 343: 311-22.
  1. Anderson HV, Willerson JT. Thrombolysis in acute myocardial infarction. N Engl J Med 1993; 329: 703-9.
  1. LATE Study Group. Late Assessment of Thrombolytic Efficacy (LATE) study with alteplase 6–24 hours after onset of acute myocardial infarction. Lancet 1993; 342: 759-66.
  1. EMERAS (Estudio Multicéntrico Estreptoquinasa Repúblicas de América del Sur) Collaborative Group. Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. Lancet 1993; 342: 767-72.
  1. Kenyon J, Caldwell M, editors. Thrombolytics improve survival after acute MI. Drugs Ther Perspect 1993; 1: 7-11.
  1. Maggioni AP, Franzosi MG, Santoro E, et al. The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment. N Engl J Med 1992: 327: 1-6.
  1. Anistreplase package insert (Eminase, Beecham—US), Rev 12/89, Rec 1/90.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1997: p. 38-9, 57, 686, 771.
  1. Sobel BE, Collen D. Strokes, statistics and sophistry in trials of thrombolysis for acute myocardial infarction [editorial]. Am J Cardiol 1993; 71: 424-7.
  1. Sobel BE, Collen D. Questions unresolved by the Third International Study of Infarct Survival. Am J Cardiol 1992; 70: 385-9.
  1. Fuster V. Coronary thrombolysis—a perspective for the practicing physician [editorial]. N Engl J Med 1993; 329: 723-5.
  1. Ikram S, Lewis S, Bucknall C, et al. Treatment of acute myocardial infarction with anisoylated plasminogen streptokinase activator complex. Br Med J 1986; 293: 786-9.
  1. Ferres H. Preclinical pharmacological evaluation of anisoylated plasminogen streptokinase activator complex. Drugs 1987; 33 (Suppl 3): 33-50.
  1. Ferres H, Hibbs M, Smith RAG. Deacylation studies in vitro on anisoylated plasminogen streptokinase activator complex. Drugs 1987; 33 (Suppl 3): 80-2.
  1. Nunn B, Esmail A, Fears R, et al. Pharmacokinetic properties of anisoylated plasminogen streptokinase activator complex and other thrombolytic agents in animals and in humans. Drugs 1987; 33 (Suppl 3): 88-92.
  1. Jackson D. Efficacy of anisoylated plasminogen streptokinase activator complex—evidence of vessel patency. Drugs 1987; 33 (Suppl 3): 104-11.
  1. Sharkey SW, Berger CR, Brunette DD, et al. Impact of the electrocardiogram on the delivery of thrombolytic therapy for acute myocardial infarction. Am J Cardiol 1994; 73: 550-3.
  1. Hillis WS, Hornung RS, Hogg KJ, et al. Achievement of coronary artery patency by use of anisoylated plasminogen streptokinase activator complex in acute myocardial infarction. Drugs 1987; 33 (Suppl 3): 117-23.
  1. Urokinase (Abbokinase, Abbott). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: p. 7-9.
  1. Brochier ML, Quilliet L, Kulbertus H, et al. Intravenous anisoylated plasminogen streptokinase activator complex versus intravenous streptokinase in evolving myocardial infarction—preliminary data from a randomised multicentre study. Drugs 1987; 33 (Suppl 3): 140-5.
  1. Timmis AD, Griffin B, Crick JCP, et al. An interim report of a double-blind placebo-controlled recanalisation study of anisoylated plasminogen streptokinase activator complex in acute myocardial infarction. Drugs 1987; 33 (Suppl 3): 146-50.
  1. Bonnier JJRM. Comparison of intravenous anisoylated plasminogen streptokinase activator complex with intracoronary streptokinase in acute myocardial infarction. Drugs 1987; 33 (Suppl 3): 151-3.
  1. Panel comment, 6/94.
  1. Kaspar L, Karnik R, Sehnal E, Zajicek P, Ziegler B, Slany J. Intracoronary streptokinase versus intravenous anisoylated plasminogen streptokinase activator complex in the treatment of acute myocardial infarction. Drugs 1987; 33 (Suppl 3): 179-82.
  1. Hellstern P, Doenecke P, Kohler M, et al. Intravenous bolus application of streptokinase and of anisoylated plasminogen streptokinase activator complex in acute myocardial infarction—clinical and haemostaseological findings. Drugs 1987; 33 (Suppl 3): 183-5.
  1. Been M, Muir AL, de Bono DP. Left ventricular function after anisoylated plasminogen streptokinase activator complex. Drugs 1987; 33 (Suppl 3): 191-7.
  1. Hackworthy RA, Sorensen SG, Menlove, Anderson JL. Electrocardiographic and enzymatic infarct size in a randomised study of intracoronary streptokinase and intravenous anisoylated plasminogen streptokinase activator complex in acute myocardial infarction. Drugs 1987; 33 (Suppl 3): 198-208.
  1. Buchalter MB, Bourke JP, Jennings K, et al. The effect of thrombolytic therapy with anisoylated plasminogen streptokinase activator complex on the indicators of myocardial salvage. Drugs 1987; 33 (Suppl 3): 209-15.
  1. Taeymans Y, Materne P. Assessment of left ventricular function in a randomised study of intravenous anisoylated plasminogen streptokinase activator complex versus heparin in acute myocardial infarction—preliminary results of the European multicentre study (Belgian centres). Drugs 1987; 33 (Suppl 3): 216-20.
  1. Chamberlain DA. Treatment of acute myocardial infarction with anisoylated plasminogen streptokinase activator complex in a district hospital–efficacy data. Drugs 1987; 33 (Suppl 3): 221-2.
  1. Manufacturer comment, 6/94.
  1. Marder VJ, Kinsella PA, Brown MJ. Fibrinogen concentration and coronary artery reperfusion after intravenous anisoylated plasminogen streptokinase activator complex or intracoronary streptokinase therapy. Drugs 1987; 33 (Suppl 3): 237-41.
  1. Manufacturer comment, 6/94.
  1. Monassier J-P, Hanssen M. Haematological effects of anisoylated plasminogen streptokinase activator complex and streptokinase in patients with acute myocardial infarction—interim report of the IRS II study. Drugs 1987; 33 (Suppl 3): 247-52.
  1. Renkin J, Col-De Beys C, Lavenne-Pardonge E, et al. Analysis of coagulation and fibrinolysis after intravenous anisoylated plasminogen streptokinase activator complex or heparin in patients with acute myocardial infarction—a Belgian multicentre study. Drugs 1987; 33 (Suppl 3): 253-60.
  1. Julian DG, Borthwick LS, Reid D, Jennings KP, Wainwright RJ, Rodger JC. Anisoylated plasminogen streptokinase activator complex versus placebo—a preliminary multicentre study of safety and early mortality in acute myocardial infarction. Drugs 1987; 33 (Suppl 3): 261-7.
  1. Samama M, Conard J, Verdy E, et al. Biological study of intravenous anisoylated plasminogen streptokinase activator complex in acute myocardial infarction. Drugs 1987; 33 (Suppl 3): 268-74.
  1. Rothbard RL. Comparative tolerance and complications in a multicentre trial of intracoronary streptokinase and intravenous anisoylated plasminogen streptokinase activator complex in acute myocardial infarction. Drugs 1987; 33 (Suppl 3): 276-8.
  1. Monassier J-P, Hanssen M. Safety and side effects of anisoylated plasminogen streptokinase activator complex and streptokinase in patients with acute myocardial infarction—interim report of the IRS II study. Drugs 1987; 33 (Suppl 3): 282-5.
  1. Manufacturer comment, 6/94.
  1. Panel comment, 6/94.
  1. Johnson ES, Cregeen RJ. An interim report of the efficacy and safety of anisoylated plasminogen streptokinase activator complex (APSAC). Drugs 1987; 33 Suppl 3: 298-311.
  1. Manufacturer comment, 6/94.
  1. Bagnall HA, Gomperts E, Atkinson JB. Continuous infusion of low-dose urokinase in the treatment of central venous catheter thrombosis in infants and children. Pediatrics 1989; 83: 963-6.
  1. Bonnier JJRM, Visser RF, Klomps HC, et al, and the Dutch Invasive Reperfusion Study Group. Comparison of intravenous anisoylated plasminogen streptokinase activator complex and intracoronary streptokinase in acute myocardial infarction. Am J Cardiol 1988; 62: 25-30.
  1. Hackworthy RA, Sorensen SG, Fitzpatrick PG, et al. Effect of reperfusion on electrocardiographic and enzymatic infarct size: results of a randomized multicenter study of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) versus intracoronary streptokinase in acute myocardial infarction. Am Heart J 1988; 116: 903-14.
  1. Reviewers' consensus on monograph revision of 5/94.
  1. Maublant JC, Peycelon P, Cardot JC, et al. Value of myocardial defect size measured by Thallium-201 SPECT: results of a multicenter trial comparing heparin and a new fibrinolytic agent. J Nucl Med 1988; 29: 1486-91.
  1. Trasylol package insert (Aprotinin, Miles—US), Rev 1/94, Rec 2/4/94.
  1. Bucknall C, Darley C, Flax J, et al. Vasculitis complicating treatment with intravenous anisoylated plasminogen streptokinase activator complex in acute myocardial infarction. Br Heart J 1988; 59: 9-11.
  1. Di Minno G, Margaglione M, Cerbone AM, et al. Newer agents for coronary thrombolysis. Perspectives from clinical studies. Pharm Res 1989; 21: 153-61.
  1. Col JJ, Col-De Beys CM, Renkin JP, et al. Pharmacokinetics, thrombolytic efficacy and hemorrhagic risk of different streptokinase regimens in heparin-treated acute myocardial infarction. Am J Cardiol 1989; 63: 1185-92.
  1. Not used.
  1. Anderson JL. Reperfusion, patency and reocclusion with anistreplase (APSAC) in acute myocardial infarction. Am J Cardiol 1989 Jul 5; 64(2): 12A-17A.
  1. Bassand J-P, Machecourt J, Cassagnes J, et al. Multicenter trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: effects on infarct size and left ventricular function. J Am Coll Cardiol 1989; 13: 988-97.
  1. Castaigne AD, Hervé C, Duval-Moulin A-M, et al. Prehospital use of APSAC: results of a placebo-controlled study. Am J Cardiol 1989 Jul 5; 64(2): 30A-33A.
  1. Fears R. Development of anisoylated plasminogen-streptokinase activator complex from the acyl enzyme concept. Semin Thromb Hemost 1989; 15: 129-39.
  1. Stafford PG, Strachan CJL, Rincent R, et al. Multiple microemboli after disintegration of clot during thrombolysis for acute myocardial infarction. Br Med J 1989; 299: 1310-2.
  1. Not used.
  1. Not used.
  1. Reviewers' consensus on monograph revision of 9/89.
  1. Reviewers' consensus on monograph revision.
  1. Not used.
  1. Reviewers' consensus on monograph revision.
  1. Not used.
  1. Not used.
  1. Not used.
  1. Not used.
  1. Reviewers' consensus on monograph revision.
  1. Reviewers' consensus on monograph revision.
  1. Reviewers' consensus on monograph revision.
  1. Reviewers' consensus on monograph revision.
  1. Abbokinase package insert (Abbott—US), Rev 1/99, Rec 4/5/99.
  1. Abbokinase Open-Cath package insert (Abbott—US), Rev 1/99, Rec 4/5/99.
  1. Urokinase (Abbokinase, Abbokinase Open-Cath, Abbott). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 9-11.
  1. Anistreplase (Eminase, Roberts). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 560-2.
  1. Food and Drug Administration. Important drug warning. Food and Drug Administration [online] 1999 Jan 25 [cited 1999 Apr 9]: [3 screens]. Available from: URL: http://www.fda.gov/cber/ltr/abb012599.htm.
  1. Neil G: Important safety information. AstraZeneca, Wayne, PA (press release). December 10,1999 Available at: http://www.fda.gov/medwatch/safety/1999/strept.htm (cited 12/21/99).
  1. Product Information: Cathflo™ Activase®, alteplase. Genentech Inc., San Francisco, CA, (PI revised 09/2001) reviewed 12/2001.
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