Streptokinase

Streptokinase acts with plasminogen to produce an activator complex that converts plasminogen to plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins. Unlike other plasminogen activators, Streptokinase is not an enzyme and does not directly convert plasminogen to plasmin. Instead, Streptokinase forms a 1:1 stoichiometric complex with plasminogen. Formation of this complex induces a conformational change in plasminogen that exposes its active site. This conformationally altered plasminogen then converts additional plasminogen molecules to plasmin.

Pharmacokinetics: Plasma Streptokinase concentrations reach a peak at 2 to 3 min after intravenous administration and peak fibrinolytic activity occurs at approximately 30 min depending on the dose. Streptokinase is cleared from the plasma in two phases. The first phase has an average half life of 18 min, and is caused by the presence of antistreptokinase antibody which combines with Streptokinase to produce a complex that is cleared rapidly from the circulation. The second phase is slower, with a half life of approximately 80 min, and reflects the rate at which Streptokinase combines with plasminogen. Hence, the clearance rate will vary according to the availability of plasminogen and the dosage regimen used.

Acute evolving transmural MI: Administer as soon as possible after symptom onset. The greatest benefit in mortality reduction was observed when Streptokinase was administered within 4 hours, but statistically significant benefit has been reported up to 24 hours.

• IV infusion- Administer a total dose of 1500000 IU within 60 minutes.
• Intracoronary infusion- Administer 20000 IU by bolus followed by 2000 IU/min for 60 minutes for a total dose of 140000 IU.

PE, DVT, arterial thrombosis, or embolism: Institute treatment as soon as possible after thrombotic event onset, preferably within 7 days. Any delay in instituting lytic therapy to evaluate the effect of heparin therapy decreases the potential for optimal efficacy. Because 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 250000 IU Streptokinase infused into a peripheral vein over 30 minutes was appropriate in over 90% of patients. If the thrombin time, or any other parameter of lysis after 4 hours of therapy is not significantly different from the normal control level, discontinue Streptokinase because excessive resistance is present.

AV cannulae occlusion: Before using, try to clear the cannula by syringe technique, using heparinized saline solution. If adequate flow is not re-established, use Streptokinase. Allow the effect of any pretreatment anticoagulants to diminish. Slowly instill 250000 IU in 2 mL solution into each occluded limb of the cannula. Clamp off cannula limb(s) for 2 hours. Observe closely for adverse effects. After treatment, aspirate contents of infused cannula limb(s), flush with saline, and reconnect cannula.

Pediatric use: Controlled clinical studies have not been conducted in children to determine safety and efficacy. The evidence of clinical benefits and risks is solely based on anecdotal reports in patients ranging in age from less than 1 month to 16 years. The largest number of patient reports has pertained to the use of Streptokinase in arterial occlusions. For arterial occlusions, the most frequently used loading dose was 1000 IU/kg; fewer numbers of patients received 3000 IU/kg. Loading dose durations typically have ranged from 5 to 30 minutes. Continuous infusion doses were frequently 1000 IU/kg/h; fewer were at 1500 IU/kg/h. Infusions were maintained for 12 hours or less in approximately half of the published cases; a smaller proportion were between 12 and 24 hours. Reported adverse events associated with the use of Streptokinase in the pediatric population are similar in nature to those associated with its use in adults. Rates of all bleeding complications have been variable and as high as 50% at catheter sites in some studies. Occasionally, bleeding has required transfusion. Careful monitoring of patient status is necessary.

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:

Antiplatelet therapy: 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.

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 1gG 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 fetal harm when administered to a pregnant woman or can affect reproduction capacity. Use these drugs during pregnancy only if clearly needed. No information is available on 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 Gaillain-Barre syndrome.

Anticoagulant 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, Ml, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.

PE: 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.

Slowly add 5 mL NaCl injection or 5% dextrose injection to the Streptokinase vial, directing the diluent at the side of the vacuum-packed vial rather than into the drug powder.

Roll and tilt the vial gently to reconstitute. Avoid shaking (shaking may cause foaming). If necessary, total volume may be increased to a maximum of 500 mL in glass or 50 mL in plastic containers; adjust the infusion pump rate accordingly. To facilitate setting the infusion pump rate, a total volume of 45 mL, or a multiple thereof, is recommended.

Withdraw the entire reconstituted contents of the vial; slowly and carefully dilute further to a total volume as recommended. Avoid shaking and agitation on dilution.

When diluting the 1500000 IU infusion bottle (50 mL), slowly add 5 mL NaCl injection or 5% dextrose injection, directing it at the side of the bottle rather than into the drug powder. Roll and tilt the bottle gently to reconstitute. Avoid shaking as it may cause foaming. Add an additional 40 mL of diluent to the bottle, avoiding shaking and agitation (total volume=45 mL). Administer by infusion pump at the rate indicated.

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration (the human albumin may impart a slightly yellow color to the solution).

The reconstituted solution can be filtered through a 0.8 mcm or larger pore size filter.

Because Streptokinase contains no preservatives, reconstitute immediately before use. The solution may be used for direct IV administration within 8 hours following reconstitution if stored at 2° to 8°C (36° to 46°F).

Do not add other medication to the container.

Discard unused reconstituted drug.

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.