Streptokinase is indicated for:

Systemic administration:

• Acute transmural myocardial infarction (within 12 hours of onset) with persistent ST-segment elevation or recent left bundle-branch block
• Deep vein thrombosis (within 14 days of onset)
• Acute massive pulmonary embolism
• Acute and subacute thrombosis of peripheral arteries
• Chronic occlusive arterial disease (within 6 weeks)
• Occlusion of the central retinal artery or vein (arterial occlusion within 6–8 hours, venous occlusion within 10 days)

Local administration:

• Acute myocardial infarction for reopening coronary vessels (within 12 hours of onset)
• Acute, subacute, and chronic thrombosis and embolism of peripheral venous and arterial vessels

Streptokinase interacts with plasminogen to form an activator complex that converts plasminogen into plasmin. Plasmin then breaks down fibrin clots, as well as fibrinogen and other plasma proteins. Unlike other plasminogen activators, Streptokinase itself is not an enzyme and does not directly convert plasminogen to plasmin. Instead, it forms a 1:1 complex with plasminogen, inducing a conformational change that exposes the active site. This activated complex subsequently converts additional plasminogen into plasmin.

Pharmacokinetics: Plasma levels of Streptokinase peak within 2–3 minutes after intravenous administration, with maximum fibrinolytic activity occurring around 30 minutes, depending on the dose. Streptokinase is cleared from plasma in two phases. The first phase has an average half-life of about 18 minutes and is due to the rapid clearance of complexes formed with antistreptokinase antibodies. The second phase is slower, with a half-life of approximately 80 minutes, reflecting the rate at which Streptokinase binds with plasminogen. Therefore, clearance depends on plasminogen availability and the dosing regimen used.

Acute evolving transmural MI: Administer as early as possible after symptom onset. The greatest reduction in mortality is seen when Streptokinase is given within 4 hours, though benefits have been reported up to 24 hours.

• IV infusion: A total dose of 1,500,000 IU should be administered over 60 minutes.
• Intracoronary infusion: Give 20,000 IU as a bolus, followed by 2,000 IU/min for 60 minutes (total dose 140,000 IU).

PE, DVT, arterial thrombosis, or embolism: Start treatment as soon as possible, preferably within 7 days of onset. Delay in thrombolytic therapy reduces effectiveness. A loading dose is required to neutralize existing antibodies to Streptokinase. Administer 250,000 IU over 30 minutes via peripheral vein. If after 4 hours, clot lysis parameters (e.g., thrombin time) do not change significantly, discontinue therapy due to resistance.

AV cannula occlusion: Attempt to clear the cannula using a syringe and heparinized saline first. If unsuccessful, administer Streptokinase. Allow the effects of prior anticoagulants to subside. Instill 250,000 IU in 2 mL into each blocked limb, clamp for 2 hours, then aspirate, flush with saline, and reconnect. Monitor for adverse effects.

Pediatric use: Safety and efficacy in children have not been established through controlled studies. Available evidence is based on limited reports (age <1 month to 16 years). For arterial occlusion, loading dose commonly used is 1000 IU/kg (occasionally 3000 IU/kg) over 5–30 minutes. Continuous infusion is typically 1000 IU/kg/hour (sometimes 1500 IU/kg/hour) for up to 12 hours, occasionally up to 24 hours. Adverse effects are similar to those in adults, with bleeding rates varying and sometimes reaching up to 50% at catheter sites. Careful monitoring is essential.

Potentially Hazardous Interactions: Early administration of heparin or hirudin therapy may increase the risk of hemorrhage. Systemic fibrinogenolysis, which inevitably occurs during streptokinase therapy, impairs coagulation both by causing fibrinogen depletion and through the anti-thrombin effects of fibrin degradation products. This may help protect recanalized vessels from reocclusion and may explain the lack of additional benefit from heparin. Conversely, early heparin or hirudin therapy may increase the risk of hemorrhage.

Radiological Contrast Agents: Some radiological contrast agents, such as diatrizoate and iohexol (but not ioxaglate), are inhibitors of fibrinolysis by streptokinase, and this may be clinically important.

Potentially Useful Interactions:  Low-dose aspirin enhances survival in myocardial infarct patients receiving streptokinase, without increasing the risk of major hemorrhage. Data are presently inadequate to assess the interaction of streptokinase with more powerful inhibitors of platelet function.

Absolute Contraindications:

• Bleeding diathesis or active internal bleeding
• Recent trauma (e.g., head injury, resuscitation)
• Severe uncontrollable hypertension
• Stroke or recent cerebrovascular accident
• Intracranial or intraspinal surgery
• Known intracranial neoplasm
• Severe uncontrollable hypertension
• Uncontrollable clotting disorders
• Known allergy to streptokinase

Relative Contraindications:

• All forms of reduced blood coagulability, in particular spontaneous fibrinolysis
• Local lesions with risk of bleeding
• Recent surgery
• Recent abortion or delivery
• Diseases of the urogenital tract with existing or potential sources of bleeding
• Recent streptococcal infections which have produced high antistreptokinase titers
• Streptokinase therapy more than 5 days and less than 12 months previously
• Subacute bacterial endocarditis
• Pericarditis
• Severe hypertension or hypertensive retinal changes grades III/IV
• Disorders of cerebral blood flow or recent cerebral hemorrhage
• Pulmonary diseases with cavitation or severe bronchitis
• Acute pancreatitis
• Advanced age with suspicion of arteriosclerotic degeneration
• Septic thromboembolic disease

Potentially Life-Threatening Effects: The unwanted effects of streptokinase therapy fall into two categories: those resulting from bleeding and those resulting from allergy. Hypotension and arrhythmias may occur in patients with myocardial infarction.

Bleeding: Major, life-threatening hemorrhage occurs in 0.2-0.3% of patients. Less severe bleeding has been reported in about 10% of patients. In the event of serious hemorrhage, streptokinase therapy should be stopped. Antifibrinolytic therapy (tranexamic acid, aminocaproic acid, or aprotinin) should be considered if there is evidence of persistent fibrinolytic activity in the blood. Transfusions of blood (preferably fresh), cryoprecipitate, or fresh frozen plasma may be necessary. There may also be an excess incidence of cerebral hemorrhage (perhaps 2 per 1000) in patients treated with systemic thrombolytic agents, but there does not appear to be an increase in total strokes—perhaps because of a reduction in ischemic strokes.

Allergic Reactions: The incidence of allergic reactions appears to have fallen with the introduction of more highly purified forms of streptokinase. The incidence of anaphylactic shock is 0.1%. Severe allergic reactions, including death, have been reported in patients with no history of previous exposure to streptokinase. Less severe allergic phenomena, such as chills, rigors, nausea, vomiting, and high fever, have been reported in between 2 and 20% of patients. The immunological basis of allergic reactions to streptokinase is not entirely clear. Investigation of patients who have suffered allergic reactions have demonstrated low titers of antistreptokinase IgG and IgG1. There was no evidence of any other IgG subclass nor of specific antistreptokinase IgE. There is also evidence of cell-mediated immunity with at least five antigenic epitopes on the streptokinase molecule which are recognized by human CD4+ T-cell receptor αβ+ T cells. Allergic reactions usually respond well to withdrawal of therapy, intravenous hydrocortisone and antihistamines. Although some authorities recommend the use of prophylactic intravenous hydrocortisone, there is no good evidence that this is of value.

Acute Overdosage: In view of the mode of use of this drug, overdosage is very unlikely and has not been reported. It would lead to hemorrhage.

It is not known whether Streptokinase can cause harm to the fetus or affect reproductive capacity when administered during pregnancy. Therefore, it should be used during pregnancy only if clearly necessary. There is no available information regarding the presence of Streptokinase in breast milk.

High Risk Patients: Carefully evaluate each patient being considered for therapy and weigh anticipated benefits against potential risks associated with therapy.

In the following conditions, the risk of therapy may be increased and should be weighed against the anticipated benefits:

• Recent (within 10 days) major surgery (eg, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels)
• Recent (within 10 days) serious gastrointestinal bleeding
• Recent (within 10 days) trauma including cardiopulmonary resuscitation
• Hypertension (systolic BP more than 180 mm Hg and/or diastolic BP more than 110 mm Hg)
• Likelihood of left heart thrombus (eg, mitral stenosis with atrial fibrillation)
• Subacute bacterial endocarditis
• Cerebrovascular disease
• Hemostatic defects including secondary to severe hepatic or renal disease
• Pregnancy
• Age over 75 years
• Diabetic hemorrhagic retinopathy
• Septic thrombophlebitis or occluded AV cannula at a seriously infected site
• Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location

Arrhythmias: Rapid lysis of coronary thrombi has been shown to cause reperfusion atrial or ventricular dysrhythmias requiring immediate treatment. Carefully monitor for arrhythmias during and immediately following administration of streptokinase for AMI. Occasionally, tachycardia and bradycardia have been observed.

Hypotension: Sometimes severe hypotension, not secondary to bleeding or anaphylaxis, may occur during or soon after IV streptokinase (1% to 10%). Closely monitor patients and, if symptomatic or alarming hypotension occurs, administer appropriate treatment. This may include a decrease in the IV streptokinase infusion rate. Smaller hypotensive effects are common and have not required treatment.

Injection Sites: If an arterial puncture is necessary, upper extremity vessels are preferable. Apply pressure for at least 30 minutes. Apply a pressure dressing and check puncture site frequently.

Respiratory: There have been reports of respiratory depression in patients receiving streptokinase. In some cases, it was not possible to determine whether the respiratory depression was associated with streptokinase or was a symptom of the underlying process. If respiratory depression is associated with streptokinase, the occurrence is believed to be rare.

Noncardiogenic Pulmonary Edema: Noncardiogenic pulmonary edema has been reported rarely in patients treated with streptokinase. The risk of this appears greatest in patients who have large MIs undergoing thrombolytic therapy by the intracoronary route.

Polyneuropathy: Rarely polyneuropathy has been temporally related to the use of streptokinase, with some cases described as Guillain-Barre syndrome.

Anticoagulants and Antiplatelets After Treatment for MI: In the treatment of AMI, aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs 3.1%) but does not appear to increase the incidence of major bleeding. In the treatment of AMI, aspirin, when not otherwise contraindicated, should be administered with streptokinase. The use of anticoagulants following streptokinase administration increases the risk of bleeding but has not been shown to be of unequivocal clinical benefit. Therefore, whereas the use of aspirin is recommended unless otherwise contraindicated, the use of anticoagulants should be decided by the treating physician.

Anticoagulation After IV Treatment for Other Indications: Continuous IV infusion of heparin, without a loading dose, has been recommended following termination of streptokinase infusion for treatment of PE or DVT to prevent rethrombosis. The effect of streptokinase on thrombin time (TT) and activated partial thromboplastin time (aPTT) usually will diminish within 3 to 4 hours after streptokinase therapy. Heparin therapy without a loading dose can be initiated when the TT or the aPTT is less than twice the normal control value for streptokinase.

Cholesterol Embolism: Cholesterol embolism has occurred rarely in patients treated with all types of thrombolytic agents; the true incidence is unknown. This serious condition, which can be lethal, is also associated with invasive vascular procedures (eg, cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. Clinical features of cholesterol embolism include livedo reticularis, "purple toe" syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, MI, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.

Pulmonary Embolism: If PE or recurrent PE occur during streptokinase therapy, complete the planned course of treatment in an attempt to lyse the embolus. While PE may occasionally occur during streptokinase treatment, the incidence is no greater than when patients are treated with heparin alone. In addition to PE, embolization to other sites during streptokinase treatment has been observed.

Hypersensitivity Reactions: Anaphylactic and anaphylactoid reactions ranging in severity from minor breathing difficulty to bronchospasm, periorbital swelling, or angioneurotic edema have been observed rarely in patients treated with IV streptokinase. Fever and shivering, occurring in 1% to 4% of patients, are the most commonly reported allergic reactions with IV streptokinase in AMI. Other milder allergic effects, such as urticaria, itching, flushing, nausea, headache, and musculoskeletal pain, have been observed, as have delayed hypersensitivity reactions such as vasculitis and interstitial nephritis.

  Fibrinolytics (Thrombolytics)

Streptokinase is to be stored at 2° to 8°C. Once reconstituted with physiological saline, the physico-chemical stability has been demonstrated for 24 hours at 2° to 8°C. From a microbiological point of view and as S-kinase contains no preservative, the reconstituted product should be used immediately. If it is not administered immediately, storage shall not exceed 24 hours at 2° to 8°C.