Professional Information

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. ^{01} The potential benefit of thrombolytic therapy must be weighed against the risk of bleeding ^{02} ^{167} 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 ^{171}.

Accepted

Thrombosis, coronary arterial, acute (treatment)—Alteplase ^{07} ^{47} ^{48} ^{49} ^{50} ^{51} ^{52} ^{53} ^{54} ^{55} ^{56} ^{57} ^{58} ^{59} ^{61} ^{62} ^{76} ^{77}, anistreplase ^{18} ^{33} ^{41} ^{42} ^{68} ^{69} ^{101} ^{106} ^{110} ^{111} ^{112} ^{113} ^{114} ^{116} ^{117} ^{118} ^{119} ^{123} ^{136} ^{139} ^{146} ^{148} ^{149}, streptokinase ^{06}, and urokinase are indicated to lyse acute coronary arterial thrombi associated with evolving transmural myocardial infarction. Alteplase ^{76} ^{77} and anistreplase ^{68} ^{170} are indicated for use via intravenous infusion; streptokinase ^{05} ^{06} is indicated for use via intravenous and intracoronary infusion; and urokinase ^{167} ^{168} ^{169} 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 ^{167}. 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 ^{167} ^{169}. 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 ^{48}, reduce the incidence ^{11} of congestive heart failure ^{06} ^{07} ^{41} ^{48} ^{61} ^{76} ^{77} ^{101}, improve left ventricular function ^{06} ^{07} ^{48} ^{61} ^{76} ^{77} ^{101} ^{112} ^{114} ^{120} ^{123} ^{142} ^{149}, limit cardiac damage (i.e., infarct size) ^{76} ^{101} ^{114} ^{121} ^{122} ^{124} ^{140} ^{142} ^{149}, and decrease the risk of early death ^{03} ^{04} ^{05} ^{11} ^{21} ^{41} ^{67} ^{76} ^{101} ^{106} ^{130} 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 ^{33} ^{112} ^{139} ^{148}. Higher reperfusion rates are achieved when thrombolytic therapy is started within 4 hours after symptoms of ischemia first appear ^{07} ^{33} ^{61} ^{112} ^{139} ^{148}. However, reductions in mortality can be achieved if thrombolytic therapy is started up to 24 to 36 hours after the onset of symptoms ^{53} ^{95} ^{97} ^{98} ^{99}.
—Thrombolytic therapy is not a substitute for other measures that may be required to treat acute myocardial infarction ^{101} or prevent reinfarction. Restoration of coronary arterial blood flow via thrombolysis does not correct underlying conditions that may promote thrombus formation ^{50} ^{55} ^{56}. Recurrent ischemia, with or without reocclusion or overt reinfarction, may occur following initially successful thrombolysis ^{17} ^{33} ^{38} ^{48} ^{49} ^{50} ^{51} ^{52} ^{55} ^{56} ^{57} ^{58} ^{62} ^{101} ^{112} ^{116} ^{118} ^{136} ^{139} ^{146} ^{148}. The risk of reocclusion may depend on the extent of residual stenosis in the affected vessel ^{03} ^{04} ^{48} ^{49} ^{50} ^{56} ^{63}. 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 ^{15} ^{47} ^{50} ^{55} ^{56} ^{61} ^{112}. However, initial thrombolytic therapy may permit a revascularization procedure to be performed on a delayed or elective, rather than on an emergency, basis ^{50} ^{55}.

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. ^{07}

Thromboembolism, pulmonary, acute (treatment)— Alteplase¹ ^{19} ^{20} ^{66} ^{76}, streptokinase ^{06}, and urokinase ^{02} ^{86} ^{167} are indicated ^{79}, 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} ^{76} ^{167}. 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} ^{76} ^{167}

Thrombosis, deep venous (treatment)—Streptokinase ^{06} and [urokinase ^{86}]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 ^{117} 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 ^{53}.

Thromboembolism, arterial, acute (treatment) and
Thrombosis, arterial, acute (treatment)—Streptokinase ^{06} 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 ^{06}

Cannula, arteriovenous, clearance—Streptokinase ^{06} 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 ^{02} ^{138} ^{168}^{173}.

—[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 ^{43} required to establish the safety and ^{73} 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 ^{47} or for clearing occluded arteriovenous cannulae or obstructed intravenous catheters ^{66}.

Alteplase ^{125} 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 ^{06}.

Streptokinase is not indicated for restoration of patency of intravenous catheters. ^{172}

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 ^{76}.
    Anistreplase: P-anisoylated derivative of a fibrinolytic enzyme (protein) complex consisting of human plasma-derived lys-plasminogen and bacterially derived streptokinase ^{68}.
    Streptokinase: Co-enzyme (protein) obtained from cultures of group C, beta-hemolytic streptococci ^{06}.
    Urokinase: Enzyme (protein) obtained from cultures of primary human neonatal kidney cells ^{167}.
Molecular weight—
    Alteplase: About 68,000 daltons ^{48} ^{60}
    Anistreplase: About 131,000 daltons ^{68} ^{96}
    Streptokinase: About 46,000 daltons ^{09}
    Urokinase: About 33,000 daltons ^{127}

Mechanism of action/Effect:

Thrombolytic agents activate the endogenous fibrinolytic system by cleaving the arginine ₅₆₀–valine ₅₆₁ bond in plasminogen to produce ^{13} ^{14} plasmin, an enzyme that degrades fibrin clots ^{02} ^{79} ^{99} ^{138} ^{167}, fibrinogen, and other plasma proteins ^{02} ^{06} ^{167}, including the procoagulant factors V and VIII ^{99} ^{107} ^{151}. Alteplase and urokinase cleave the peptide bond directly ^{96}. Anistreplase and streptokinase act indirectly; they combine with plasminogen ^{96} ^{101} 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 ^{06}.

Conversion of plasminogen to plasmin occurs within the thrombus ^{76} ^{77} 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. ^{15} ^{36}

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 ^{91}. However, limited systemic fibrinolysis does occur with usual therapeutic doses ^{47} ^{49} ^{55} ^{60} ^{66} ^{76} ^{96}.

Other actions/effects:

Fibrinogenolysis and fibrinolysis induced by thrombolytic agents increase the concentration ^{11} of fibrinogen-degradation and fibrin-degradation products (FDP/fdp) in the blood ^{18} ^{27} ^{131} ^{167}. 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 ^{07} ^{53}. However, studies have not shown a significantly lower incidence of bleeding with alteplase than has been reported with the other thrombolytic agents ^{51} ^{52}, probably because factors other than the concentrations of fibrinogen and/or FDP/fdp also significantly influence the risk of bleeding (see Side/Adverse Effects ) ^{66}. 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 ^{15} ^{16}.

Anistreplase has potent proteolytic activity in the systemic circulation. In addition to decreasing plasma concentrations of fibrinogen, the medication lowers plasma concentrations of ^{17} ^{18} ^{27} ^{33} ^{36} ^{38} ^{110} ^{114} ^{128} ^{129} ^{131} ^{139} ^{146} ^{149} plasminogen, ^{17} ^{18} ^{27} ^{33} ^{36} ^{128} ^{129} ^{131} ^{146} procoagulant factors V and VIII ^{18} ^{131}, and the fibrinolysis inhibitor alpha-2-antiplasmin ^{17} ^{18} ^{27} ^{33} ^{36} ^{128} ^{129} ^{131} ^{146}.

Anistreplase, streptokinase, and urokinase have also been reported to decrease plasma viscosity ^{06} ^{145} ^{151} and erythrocyte aggregation ^{06}, probably as a result of reduced fibrinogen concentration.

Streptokinase and the streptokinase component of anistreplase ^{17} ^{18} ^{101} are antigenic and induce the formation of antibodies. Elevation of the antistreptokinase antibody titer usually occurs about 5 ^{101} to 7 ^{17} days following administration, reaches a peak after 2 to 3 weeks ^{18}, and may persist for 1 year or longer ^{85} ^{99}. The antibodies may cause resistance to subsequent streptokinase or anistreplase therapy ^{18} ^{101} ^{131}, and possibly an increased risk of anaphylaxis or other severe allergic reactions ^{101}.

Biotransformation:

Alteplase—Hepatic; rapid ^{01} ^{03} ^{61} ^{76} ^{77}.

Streptokinase—Hepatic; no metabolites identified ^{06}.

Urokinase—Hepatic; rapid ^{02}.

Half-life:

Alteplase:

Distribution: Less than 5 minutes ^{59} ^{76} ^{96} ^{99}.

Elimination: Approximately 35 minutes ^{59} ^{91} ^{96}.

Anistreplase:

The half-life of anistreplase's fibrinolytic activity is 70 to 120 minutes ^{33} ^{68} ^{91} ^{101} ^{107} (average about 90 minutes ^{18} ^{21} ^{41} ^{101} ^{107}). The deacylation half-life of the complex is about 105 to 120 minutes ^{101} ^{108}. The plasma clearance and duration of fibrinolytic activity of the medication are probably controlled primarily by its deacylation rate ^{108} ^{151}.

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 ^{06} ^{99}.

Urokinase:

Up to 20 minutes ^{02} ^{91} ^{96} ^{99} ^{167}. The half-life may be prolonged in patients with hepatic function impairment ^{127} ^{167}.

Time to peak effect:

Reperfusion of the myocardium ^{11} generally occurs 20 minutes ^{66} to 2 hours (average 45 minutes) ^{33} ^{66} ^{101} ^{139} 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

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