Hoechst Marion Roussel
Action and Clinical Pharmacology:
Streptokinase acts with plasminogen (or plasmin) to produce an “activator complex” that converts residual plasminogen into the proteolytic enzyme, plasmin. Plasmin is capable of hydrolysing fibrin into polypeptides; it also hydrolyses fibrinogen and other plasma proteins. Since plasminogen is present in the thrombus/embolus, activation by streptokinase occurs within the thrombus/embolus as well as on its surface.:
The activity of streptokinase is expressed in International Units (IU) and is a measure of its ability to cause lysis of a fibrin clot via the plasmin system in vitro. The effect on coagulation after i.v. administration may persist for 12 to 24 hours after discontinuation due to a decrease in plasma levels of fibrinogen and an increase in the amount of circulating fibrin (ogen) degradation products (FDP). Studies with radioactive streptokinase indicate 2 disappearance rates: a fast half-life of approximately 18 minutes due to the action of antibodies, and a slow half-life, operative in the absence of antibodies, of approximately 83 minutes. Effective blood level and disappearance rate are dependent upon availability of substrates and, thus, are only relative indices of the pharmacologic effects of the drug. The efficacy of streptokinase in the lysis of venous thrombi and massive pulmonary emboli has been established in clinical studies by angiographic evaluations, before and after treatment.
Two large, randomized, multicentre, placebo-controlled studies involving almost 30 000 patients have demonstrated that a 60-minute i.v. infusion of 1 500 000 IU of streptokinase significantly reduces mortality rates following a myocardial infarction. Concomitant oral administration of low-dose ASA (160 mg/day) over a period of 1 month was shown to significantly enhance this beneficial effect.
Indications And Clinical Uses:
Acute Myocardial Infarction: For use in the management of suspected acute myocardial infarction, for the lysis of acute thrombi obstructing coronary arteries associated with evolving transmural myocardial infarction, for the improvement of ventricular function, and for the reduction of infarct size and mortality associated with acute myocardial infarction, when administered by the i.v. or intracoronary route, as well as for the reduction of congestive heart failure associated with AMI when administered by the i.v. route. In the high risk group with anterior myocardial infarction, 1 year mortality was significantly reduced in those patients who reperfused in response to streptokinase.
Thrombolysis following i.v. streptokinase is usually achieved within less than 1 hour. Early administration is correlated with greater clinical benefit.
Pulmonary Embolism: In adults for the lysis of acute massive pulmonary emboli, defined as obstruction or significant filling defects involving 2 or more lobar pulmonary arteries or an equivalent amount of emboli in other vessels. It is also indicated for embolization accompanied by unstable hemodynamics i.e., failure to maintain blood pressure without supportive measures. The diagnosis should be confirmed by objective means, preferably by pulmonary arteriography via an upper extremity vein, or noninvasive procedures such as lung scanning.
Deep Vein Thrombosis: For lysis of acute, extensive thrombi of the deep veins in adults such as those involving the popliteal and more proximal vessels. Diagnosis should be confirmed by ascending venography or other equally objective methods.
Studies have demonstrated a better salvage of valvular function and prevention of postphlebitic syndrome by the combined usage of streptokinase and heparin than by heparin alone.
Arterial Thrombosis and Embolism: For the lysis of acute arterial thrombi and for the lysis of arterial emboli. However, the use of streptokinase in arterial emboli originating from the left side of the heart (e.g., in mitral stenosis accompanied by atrial fibrillation) should be avoided due to the danger of new embolic phenomena including those to cerebral vessels.
Arteriovenous Cannula Occlusion: For clearing of totally or partially occluded arteriovenous cannulae as an alternative to surgical intervention when acceptable flow cannot otherwise be achieved.
Because thrombolytic therapy increases the risk of bleeding, streptokinase is contraindicated in the following conditions: active or recent internal bleeding; recent (within 2 months) cerebrovascular accident, intracranial or intraspinal surgery (see Warnings); intracranial neoplasm; uncontrollable hypertension with systolic values above 200 mm Hg and/or diastolic values above 100 mm Hg, or hypertensive retinal changes Grades III/IV; all forms of reduced blood coagulability in particular spontaneous fibrinolysis and extensive clotting disorders; recent head trauma; known neoplasm with risk of hemorrhage; acute pancreatitis.
Streptokinase should not be administered to patients having experienced severe allergic reaction to the product.
Warnings in Clinical States:
Bleeding: The aim of streptokinase therapy is the production of sufficient amounts of plasmin for the lysis of intravascular deposits of fibrin; however, fibrin deposits which provide hemostasis, for example at sites of needle punctures, are also lysed and bleeding from such sites may occur.
Following i.v. high-dose brief-duration streptokinase therapy (1 500 000 IU over 60 minutes), in acute myocardial infarction, severe bleeding complications requiring transfusion are extremely rare (0.3 to 0.5%), and combined therapy with low-dose ASA (160 mg/day over a period of 1 month) does not appear to increase the risk of major bleeding. The addition of ASA to streptokinase may cause a slight increase in the risk of minor bleeding (3.1% without ASA vs 3.9% with ASA).
I.M. injections and nonessential handling of the patient must be avoided during treatment with streptokinase. Venipunctures should be performed carefully and as infrequently as possible.
Should an arterial puncture be necessary, upper extremity vessels are preferable. Pressure should be applied for at least 30 minutes, a pressure dressing applied and the puncture site checked frequently for evidence of bleeding. When internal bleeding occurs, it may be more difficult to manage than that which occurs with conventional anticoagulant therapy.
In the following conditions, the risks of therapy may be increased and should be weighed against the anticipated benefits: recent (within 10 days) major surgery; recent delivery, abortion; recent organ biopsy, previous puncture of noncompressible vessels, i.m. injections or intubation; recent (within 10 days) serious gastrointestinal bleeding; recent (within 10 days) trauma including cardiopulmonary resuscitation; high likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation; subacute bacterial endocarditis or pericarditis; isolated cases of a pericarditis, misdiagnosed as acute myocardial infarction and treated with streptokinase, have resulted in pericardial effusions including tamponade; hemostatic defects including those secondary to severe hepatic or renal disease; pregnancy; cerebrovascular disease; pulmonary diseases with cavitation (e.g., open tuberculosis) or severe bronchitis; acute pancreatitis or severe diabetes mellitus; diseases of the urogenital tract with potential sources of bleeding; diabetic hemorrhagic retinopathy; septic thrombophlebitis or occluded AV cannula at seriously infected site; suspicion of severe artherosclerotic degeneration; any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.
Should serious spontaneous bleeding (not controllable by local pressure) occur, the infusion of streptokinase should be terminated immediately and treatment instituted as described under Adverse Effects.
Arrhythmias: Rapid lysis of coronary thrombi may cause reperfusion atrial or ventricular dysrhythmia requiring immediate treatment. Careful monitoring for arrhythmia should be maintained during and immediately following administration of streptokinase.
Hypotension: Hypotension, sometimes severe, not secondary to bleeding or anaphylaxis has been observed during i.v. streptokinase infusion in 1 to 10% of patients. Patients should be monitored closely and should symptomatic or alarming hypotension occur, appropriate treatment should be administered. This treatment may include a decrease in the i.v. streptokinase infusion rate. Smaller hypotensive effects are common and have not required treatment.
General: Streptokinase should be used in hospitals where the recommended diagnostic and monitoring techniques are available.
Noncardiogenic pulmonary edema has been reported rarely in patients treated with streptokinase. The risk of this appears greatest in patients who have large myocardial infarctions and are undergoing thrombolytic therapy by the intracoronary route.
Rarely, polyneuropathy has been temporally related to the use of streptokinase.
Should pulmonary embolism or recurrent pulmonary embolism occur during streptokinase therapy, the originally planned course of treatment should be completed in an attempt to lyse these emboli. While pulmonary embolism may occasionally occur during streptokinase treatment, the incidence is no greater than when patients are treated with heparin alone.
Repeated Administration: Because of the increased likelihood of resistance due to antistreptokinase antibodies, streptokinase may not be effective if administered more than 5 days after prior streptokinase administration or streptokinase-containing products, particularly between 5 days and 12 months.
It is not known whether persisting high in vitro neutralization titres affect the efficacy and safety of repeat administration of streptokinase or steptokinase-containing compounds.
Likewise, the effect may be reduced in patients with recent streptococcal infections such as streptococcal pharyngitis, acute rheumatic fever, acute glomerulonephritis secondary to a streptococcal infection.
Pregnancy: Experience in pregnant women has not shown that streptokinase increases the risk of fetal abnormalities if administered during pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, however, streptokinase should be used during pregnancy only if clearly needed.
Thrombolytic therapy should be avoided within the first 18 weeks of the pregnancy because of the risk of placental separation.
Children: Safety and effectiveness in children have not been established.
Lactation: It is not known whether streptokinase is excreted in the breast milk nor whether it has harmful effects on the newborn. In the absence of further information, it is recommended that breast-feeding be discontinued in a woman who is to receive streptokinase.
Drug Interactions :
The potential for an additive hypotensive effect should be borne in mind when streptokinase therapy is combined with antihypertensive agents, such as b-blockers and glyceryl trinitrate.
Until information regarding the interaction between streptokinase and tissue plasminogen activator (tPA) is available, special care should be taken if such a combination is considered.
There is an increased risk of hemorrhage in:
- Patients previously receiving heparin or coumarin derivatives. The effect of heparin can, however, be rapidly neutralized by administering protamine sulfate. In the case of prior treatment with coumarin derivatives, the Quick value must be more than 50% before the beginning of lysis.
- Patients receiving simultaneous treatment with platelet-aggregation inhibitors, e.g., ASA (see below also), phenylbutazone, dipyridamole and nonsteroidal anti-inflammatory drugs (NSAIDs).
- Patients receiving simultaneous or previous treatment with dextrans.
Combination of Streptokinase with ASA for Treatment of Myocardial Infarction: In the treatment of acute myocardial infarction with i.v. streptokinase (1 500 000 IU over 1 hour) combined with enteric-coated ASA (160 mg/day for 1 month), it was shown that the combined treatment results in a further reduction in mortality rate, as well as a decreased risk of reinfarction and stroke in comparison to treatment with each of the drugs alone. The addition of ASA to streptokinase may cause a slight increase in the risk of minor bleeding, but does not appear to increase the incidence of major bleeding. Unless contraindicated, concomitant administration of ASA is recommended (see Dosage).
Anticoagulation Treatment Following Streptokinase: Anticoagulation Following Treatment for Myocardial Infarction: The use of anticoagulants following administration of streptokinase treatment for acute myocardial infarction increases the risk of bleeding, and has not been shown to be of unequivocal clinical benefit. Therefore, their use should be decided upon at the discretion of the treating physician.
Anticoagulation Following I.V. Treatment for Other Indications: To prevent rethrombosis following termination of streptokinase infusion treatment for pulmonary embolism or deep vein thrombosis, continuous i.v. infusion of heparin without a loading dose is recommended (see Patient Monitoring).
Patient Monitoring: I.V. or Intracoronary Artery Infusion for Myocardial Infarction: I.V. administration of streptokinase will cause marked decreases in plasminogen and fibrinogen levels and increases in thrombin time (TT), activated partial thromboplastin time (APTT), and prothrombin time (PT), which usually normalize within 12 to 24 hours. These changes may also occur in some patients with intracoronary administration of the drug.
I.V. Infusion for Other Indications: Before commencing thrombolytic therapy, it is desirable to obtain a thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT), and hematocrit and platelet count to obtain hemostatic status of the patient.
If heparin has been given, it should be discontinued and the TT or APTT should be less than twice the normal control value before thrombolytic therapy is started.
During the infusion, decreases in the plasminogen and fibrinogen levels and an increase in the level of FDP (the latter two serving to prolong the clotting times of coagulation tests) will generally confirm the existence of a lytic state. Therefore, therapy can be monitored by performing the TT, or APTT or PT, approximately 4 hours after initiation of therapy.
To prevent rethrombosis following the streptokinase infusion, continuous i.v. heparin infusion without a loading dose is recommended. The effect of streptokinase on thrombin time (TT) and activated partical thromboplastin time (APTT) will usually diminish within 3 to 4 hours after streptokinase therapy. A thrombin time value should be obtained during this period, and heparin therapy without a loading dose can be initiated when TT or APTT is less than twice the normal control value. (See manufacturer’s prescribing information for proper use of heparin.) This should be followed by conventional oral anticoagulation therapy.
The following adverse reactions have been frequently associated with i.v. therapy but may also occur with intracoronary artery infusion of streptokinase.
Bleeding: The reported incidence of bleeding (major or minor) has varied widely depending on the indication, dose, route and duration of administration and concomitant therapy.
Minor bleeding occurs often with thrombolytic therapy mainly at invaded or disturbed sites. When lytic therapy is continued while local measures are used to control minor bleeding, do not reduce the dose as this will increase the conversion of plasminogen to plasmin which may increase bleeding.
Severe internal bleeding including gastrointestinal and liver hemorrhages, genitourinary, retroperitoneal or rare cases of intracerebral hemorrhages with their complications (also with fatal outcome), may occur, splenic rupture or retroperitoneal hemorrhages have been observed.
Intracerebral bleeding in connection with the treatment of myocardial infarction has been reported with an incidence of 0.1 to 0.3%. Several fatalities due to cerebral and other serious internal hemorrhage have occurred during thrombolytic therapy.
In the treatment of acute myocardial infarction with i.v. streptokinase, the GISSI and ISIS-2 studies reported a rate of major bleeding (requiring transfusion) of 0.3 to 0.5%. In the TIMI study, which required both invasive techniques and administration of anticoagulants, a frequency of 15.6% for major bleeding (intracranial, or decrease in hemoglobin >5 g/dL, or decrease in hematocrit >15%) was reported.
During thrombolitic treatment of acute myocardial infarction, hemorrhages into the pericardium including myocardial rupture can occur in individual cases.
Should uncontrollable bleeding occur, streptokinase infusion should be terminated immediately; slowing the rate of administration may increase the bleeding. If necessary, bleeding can be reversed and blood loss effectively managed with appropriate replacement therapy (see Overdose, Symptoms and Treatment).
Allergic Reactions: If a severe allergic reaction or anaphylactic shock occurs, the infusion should be discontinued immediately.
Immediate Reactions: Reactions attributed to possible anaphylaxis have been observed rarely in patients treated with streptokinase. These ranged in severity from minor breathing difficulty, dyspnea to bronchospasm, periorbital swelling or angioneurotic edema. Other, milder allergic effects such as rash, urticaria, itching, flushing, nausea, headache and musculoskeletal pain have also been observed. Anaphylactoid shock is very rare, having been reported in 0 to 0.1% of patients.
An anaphylactic reaction has been reported in a patient following a second course of streptokinase within 1 month for clearance of an occluded arteriovenous shunt. Therefore, the possibility of systemic absorption of streptokinase following its use for this purpose must be considered.
Mild or moderate reactions may be managed with concomitant antihistamine and/or corticosteroid therapy. Severe allergic reactions require immediate discontinuation of streptokinase with adrenergics, antihistamines, or corticosteroids administered i.v. as required.
Late Reactions: In individual cases serum sickness, arthritis, vasculitis, nephritis and neuroallergic symptoms (polyneuropathy, e.g., Guillain Barré syndrome) have been reported in temporal coincidence with streptokinase administration.
Embolisms: The risk of pulmonary embolism in patients with deep vein thrombosis is not higher during treatment with streptokinase than during treatment with heparin alone. If acute or recurrent pulmonary embolism occurs during streptokinase treatment, the course of streptokinase therapy should be continued as originally planned, so as to lyse the emboli.
During local lysis of peripheral arteries, distal embolization cannot be excluded.
A few cases of cholesterol embolism have been described in temporal coincidence with thrombolytic therapy, particularly in patients undergoing angiography.
Fever: Although streptokinase is nonpyrogenic in standard animal tests, approximately one-third of patients treated with streptokinase have shown increases in body temperature >0.83°C. Chills may also occur under therapy.
Symptomatic treatment is usually sufficient to alleviate discomfort.
Other: Transient elevations of serum transaminases as well as of bilirubin may occur.
At the beginning of the therapy, a fall in blood pressure, tachycardia or bradycardia (in individual cases reaching as far as shock) are observed occasionally.
In individual cases, under thrombolytic therapy of acute myocardial infarction, rhythm disturbances, persistent angina pectoris as well as cardiac failure reaching as far as cardiac and respiratory arrest may occur. It could be demonstrated, however, that myocardial infarction cardiac arrest due to ventricular fibrillation is more rare in streptokinase treated patients than in patients treated conventionally.
In a few instances, after intracoronary thrombolytic therapy in patients with extensive myocardial infarction, noncardiogenic pulmonary edema has been observed.
Individual cases of cerebral convulsion were reported under thrombolytic therapy, and in temporal coincidence with cardiovascular hypoxia and cerebral hemorrhage.
Headache and muscle pain,gastrointestinal complaints, back pain as well as asthenia and malaise may occur under therapy.
Hemorrhagic myocardial infarction has been reported.
Symptoms And Treatment Of Overdose:
Minor bleeding complications with streptokinase are usually overcome by increasing the dosage. Should serious uncontrollable bleeding occur as a result of overdosage, the infusion of streptokinase and any other concomitant anticoagulant should be discontinued immediately. If necessary, blood loss and reversal of the bleeding tendency can be effectively managed with whole blood (fresh blood preferable), packed red cells and cryoprecipitate or fresh frozen plasma. Although the use of aminocaproic acid (or aprotinin) in humans as an antidote for streptokinase has not been documented, it may be considered in an emergency situation.
Dosage And Administration:
Streptokinase should be administered by volumetric infusion pump. Do not use drop-counting infusion methods since streptokinase may alter droplet size.
Acute Myocardial Infarction: Streptokinase treatment of coronary thrombosis should be instituted as soon as possible after the onset of symptoms of acute myocardial infarction. The greatest benefit in mortality reduction was observed when streptokinase was administered within 4 hours. The clinical benefit in terms of reduction of mortality could not conclusively be proven in controlled clinical trials in patients being treated beyond 12 hours after the onset of symptoms.
I.V. Administration: With the above regimen, 1 500 000 IU within 60 minutes, no coagulation tests are necessary to monitor streptokinase therapy. Unless contraindicated, the concomitant use of ASA at a dose of 160 mg/day orally, starting prior to streptokinase infusion and continued for 1 month is recommended.
Intracoronary Administration: Streptokinase treatment of coronary thrombosis should be undertaken only in medical centres where coronary arteriography is an established routine and appropriate after-treatment available. Streptokinase is administered selectively into the thrombosed coronary artery via coronary catheter positioned by the Judkins or Sones technique.
Deep Vein Thrombosis, Pulmonary or Arterial Embolism or Arterial Thrombosis: Streptokinase treatment should be instituted as soon as possible after onset of thrombotic event, preferably within 7 days. Any delay in instituting lytic therapy to evaluate the effect of heparin therapy decreases the potential for optimal efficacy, although slight enhancement of clot lysis has been shown with initiation of thrombolytic therapy up to 14 days after the onset of symptoms of deep vein thrombosis.
Since human exposure to streptococci is common, antibodies to streptokinase are prevalent. Thus, a loading dose of streptokinase sufficient to neutralize these antibodies is required. A dose of 250 000 IU infused into a peripheral vein over 30 minutes has been found appropriate in over 90% of patients. If the thrombin time or any other parameter of fibrinolysis after 4 hours of treatment is not significantly different from the normal control level, discontinue streptokinase because excessive resistance to streptokinase is present. Furthermore, if the thrombin time after 16 hours is still prolonged to more than 4-fold the control level, the streptokinase dosage should be doubled for several hours until the thrombin time recedes.
A continuous i.v. infusion of heparin, without a loading dose, is recommended to prevent rethrombosis following termination of streptokinase infusion. (see Precautions, Patient Monitoring).
Arteriovenous Cannula Occlusion: Before Treatment: Before using streptokinase, an attempt should be made to clear the cannula by careful syringe technique, using heparinized saline solution. If adequate flow is not re-established, streptokinase may be employed. Allow the effect of any pretreatment anticoagulants to diminish.
Streptokinase Administration: Instill 250 000 IU streptokinase in 2 mL i.v. solution into each occluded limb of the cannula slowly. Clamp off cannula limb(s) for 2 hours. Observe the patient closely for possible adverse effects.
After Treatment: Aspirate contents of infused cannula limb(s), flush with saline, reconnect cannula.
In patients with occlusions of the central retinal vessels a better success rate can be expected if the therapy is started within 6 to 8 hours of arterial occlusions, within 10 days of venous occlusions and within 6 weeks for chronic arterial occlusive diseases (embolic occlusions).
Reconstitution and Dilution: Intracoronary Artery and I.V. Administration: The protein nature and lyophilized form of streptokinase require careful reconstitution and dilution.
The following procedure is recommended: Add 5 mL Sodium Chloride Injection USP or Dextrose 5% Injection USP slowly to the vacuum packed Streptase container, directing the vehicle at the side of the container rather than into the lyophilized streptokinase powder.
Roll and tilt the container gently to reconstitute. Avoid shaking. (Shaking may cause foaming.)
Dilute the entire reconstituted contents of the container with Sodium Chloride Injection USP or Dextrose 5% Injection USP, to a total volume of approximately 45 mL (see Table III). Dilute slowly and carefully; avoid shaking and agitation. (If necessary, total volume may be increased to a maximum of 500 mL with the infusion pump setting in Table III increased accordingly.) To facilitate setting the infusion pump rate, a total volume of approximately 45 mL, or multiples thereof, is suggested.
Solutions of Streptokinase reconstituted and diluted to 500 mL or 50 mL with Sodium Chloride Injection, USP, in glass containers, irrespective of which potency is used (250 000 IU; 750 000 IU; 1 500 000 IU), can be drawn through in-line filters without a reduction in drug potency providing the filter is of 0.80 ľm or greater pore size (if of cellulose construct) or of 0.22 ľm or greater pore size (if of PVC-acrylic polymer construct). Flocculated product should be discarded if filters of the above mentioned construct and/or pore size are not available.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. (The Albumin (Human) may impart a slightly yellow color to the solution.)
Do not add other medication to the container of reconstituted streptokinase.
For Use in Arteriovenous Cannulae: Slowly reconstitute the contents of 250 000 IU/streptokinase vial with 2 mL Sodium Chloride Injection USP or Dextrose 5% Injection USP.
The suggested dilutions and infusion rates provided in Table III represent a practical means of streptokinase administration without compromise of safety and efficacy considerations. Depending on the type of available infusion pump/bags, the solution/volumes/rates cited may be adjusted to correspond with the particular dosage rate to be administered.
Stability and Storage of Reconstituted and Diluted Solutions: Reconstituted Solutions: Streptase reconstituted with 5 mL of saline (Sodium Chloride Injection USP, 0.9%) or dextrose (Dextrose Injection USP, 5%) is stable for 24 hours at room temperature (15 to 30°C) and refrigeration (2 to 4°C). For the recommended total period of use of the product, from reconstitution and dilution to the end of patient administration, see Diluted Solutions.
Diluted Solutions: Stability studies have been carried out on the 3 potencies, reconstituted and diluted with saline (Sodium Chloride Injection USP, 0.9%) or dextrose (Dextrose Injection USP, 5%), to 50 or 500 mL, in glass or plastic containers.
Availability And Storage:
Each 6.5 mL vial of sterile, lyophilized white powder contains: 250 000 IU (green labels), 750 000 IU (blue labels) or 1 500 000 IU (red labels) of purified streptokinase, 25 mg crosslinked gelatin polypeptides, 25 mg sodium L-glutamate, sodium hydroxide to adjust pH and 100 mg albumin (human) as stabilizer. Packages of 10. Streptokinase 1 500 000 IU is also available in infusion bottles of 68 mL, individually packaged.
When stored at room temperature below 25°C, the dried product is stable up to the expiration date indicated on the package.
STREPTASE® Hoechst Marion Roussel Streptokinase Fibrinolytic Agent
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