STK Powder for Injection

Streptokinase forms a complex with plasminogen which then converts plasminogen to plasmin. Plasmin breaks down clots as well as fibrinogen and other plasma proteins.

Streptokinase can be reconstituted using 5 ml sodium chloride injection or 5% Dextrose Injection directing the diluent at the side of the vacuum packed vial rather than into drug powder

Acute Myocardial Infarction:

IV infusion:

• Vial size (IU): 15,00,000
• Total solution volume: 45 ml
• Infusion rate: Infuse 45 ml within 60 mins

Intracoronary infusion:

• Vial size (IU): 2,50,000
• Total solution volume: 125 ml
• 20,000 IU bolus, Infusion rate: Loading dose of 10 ml
• 2,000 IU/min. for 60 minutes, Infusion rate: 60 ml/hour

Pulmonary Embolism, Deep Vein Thrombosis, Arterial Thrombosis or Embolism:

• 2,50,000 IU loading dose over 30 min, Vial size (IU): 15,00,000, Total solution volume 90 ml, Infusion rate: Infuse 30 ml/hour for 30 min
• 1,00,000 IU/hour for maintenance dose, Infusion rate: Infuse 6 ml/hour

There is an increased risk of haemorrhage in patients simultaneously or previously receiving anticoagulants (such as Heparin or Coumarin derivatives) or drugs which inhibit platelet formation or function (e.g., Platelet aggregation inhibitors, Dextrans, Phenylbutazone, Dipyridamole, Non-steroidal anti-inflammatory drugs). The effect of Heparin can be neutralized rapidly by administration of Protamine Sulphate. The Thrombin time (TT) should not be more than twice the normal control value before thrombolytic therapy is started. In the case of prior treatment with coumarin derivatives, the International Normalized Ratio (INR) must be less than 1.3 before starting STK infusion.

Combination of STK with Aspirin for treatment of Myocardial infarction: Study showed a significant benefit to patients treated with these two agents after acute myocardial infarction. Mortality (both short and longer term) was reduced in these patients to a greater extent than in those treated with either agent alone.

Unless contraindicated, the concomitant use of Acetylsalicylic acid (ASA, Aspirin), starting prior to STK infusion and continued for one month thereafter may be instituted at the discretion of the physician. The benefit of combination therapy should therefore be weighed against the risk of increased haemorrhage.

Anticoagulation treatment following STK: Following high dose (1.5 million IU), short term treatment with STK, for acute myocardial infarction, the use of subsequent anticoagulant treatment has not yet been shown to be of unequivocal benefit. Therefore, in this situation, the use of anticoagulants should be decided by the physician.

As thrombolytic therapy increases the risk of bleeding, Streptokinase, administered either systemically or locally, is contraindicated in the following situations:

Existing or recent haemorrhage and haemorrhagic diathesis (with the exception of consumption coagulopathy) Potential for internal bleeding (e.g., peptic ulcer, ulcerative colitis, diverticulitis or visceral tumours) All forms of reduced blood coagulability, in particular spontaneous fibrinolysis and extensive clotting disorders.

Recent (within 2 months) cerebrovascular accident, recent (within 10 days) facial or head trauma, intracranial or intraspinal surgery, known intracranial neoplasm and all known neoplasms with risk of haemorrhage 

Invasive operations, e.g., recent organ biopsy, invasive diagnostic procedure, recent implantation of a vessel prosthesis, long-term traumatic closed-chest massage or other recent surgery (until the 6th to 10th post operative day, depending on the severity of surgical intervention)

Arteriovenous malformation or aneurysm: Haemorrhagic diathesis including thrombocytopenia or pronounced hepatic or renal dysfunction 

Severe uncontrolled hypertension (systolic BP > 200 mm Hg, diastolic BP > 100 mm Hg), or hypertensive retinal changes grades III/IV), hypertonic fundus 

Severe liver or kidney damage: Simultaneous treatment with oral anticoagulants (International Normalized Ratio (INR) >1.3) 

Endocarditis or pericarditis (Immediately after streptococcal infections which have produced a high antiStreptokinase titre (acute rheumatic fever, acute glomerulo-nephritis, etc.). More than 5 days and less than 12 months since previous Streptokinase therapy.

The following adverse reactions are based on experience from clinical trials and on post marketing experience of STK. 

General disorders:

• Common: Headache and back pain, muscle pain (including myalgia), chills and/or fever as well as asthenia/malaise.

Haemorrhage and bleeding:

• Common: Haemorrhages at invaded or disturbed sites, including the injection site, and ecchymoses. Gastrointestinal or genitourinary bleedings (including aggravation of menstrual bleeding), epistaxis. 
• Uncommon: Intracranial haemorrhages with their complications and possible fatal outcome, retinal haemorrhages, severe haemorrhages (also with fatal outcome) including liver haemorrhages, retroperitoneal bleedings, splenic rupture. Blood transfusions are rarely required.

Immune system disorders:

• Very common: Development of antiSTK antibodies 
• Common: Allergic-anaphylactic reactions such as rash, flushing, itching, urticaria, angioneurotic oedema, minor breathing difficulty, periorbital swelling, bronchospasm or hypotension.

Nervous system disorders:

• Rare: Neurologic symptoms (e.g., dizziness, confusion, paralysis, hemiparesis, agitation or convulsion) in the context of cerebral haemorrhages or cardiovascular disorders with hypoperfusion of the brain.

Cardiac complication and vascular disorders:

• Very common: Hypotension, heart rate and rhythm disorders, angina pectoris. 
• Common: Recurrent ischaemia, heart failure, reinfarction, cardiogenic shock, pericarditis, pulmonary oedema. 
• Uncommon: Cardiac arrest (leading to respiratory arrest), mitral insufficiency, pericardial effusion, cardiac tamponade, myocardial rupture, pulmonary or distal embolism.

Respiratory disorders:

• Very rare: Non-cardiogenic pulmonary oedema after intracoronary thrombolytic therapy in patients with extensive myocardial infarction.

Gastrointestinal disorders:

• Common: Nausea, diarrhoea, epigastric pain and vomiting.

Pregnancy category C. 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 women who are to receive Streptokinase.

Because of the increased likelihood of resistance, due to antiSTK antibodies, retreatment with STK or STK-containing products may not be effective if administered between five days and twelve months of prior STK administration or Streptococcal infections, such as Streptococcal pharyngitis, acute rheumatic fever or acute glomerulonephritis secondary to a Streptococcal infection.

In principle, no thrombolytic treatment should be commenced before the 10th postoperative day. However, in cases of pulmonary embolism, the indication for earlier treatment may be very strong and after careful consideration of all the risks, STK may be given before the tenth postoperative day. The danger of bleeding from the operative area must, of course, be taken into account.
The danger of haemorrhage is increased by simultaneous or previous treatment with anticoagulants (e.g., Heparin) or substances which inhibit platelet formation or function. If the patient is under active heparinisation, it should be neutralised by the administration of protamine sulphate before the start of thrombolytic therapy. 

Repeated Administration: After administration of STK, the titre of antiSTK antibodies begins to rise after approximately one week, reaching a peak at 2 to 3 weeks and remains elevated for 8 to 12 months. Because of the increased likelihood of resistance, STK may not be effective if given during this period.

Pediatric use: Safety & effectiveness in children have not been established.

If uncontrollable bleeding occurs as a result of overdosage, STK infusion should be ceased immediately. Bleeding can be reversed and blood loss managed effectively with appropriate replacement therapy. Administration of aminocaproic acid or aprotinin may be useful.

Fibrinolytics (Thrombolytics)

The protein nature and lyophilized form of STK, require careful reconstitution and dilution. The following reconstitution and dilution procedures are recommended for vials & infusion bottles: 

• Slowly add 5 mL Sodium Chloride Injection or 5% Dextrose Injection to the STK 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 50 mL in plastic containers and the infusion pump rate should be adjusted. 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 1 500 000 IU infusion bottle (50 mL), slowly add 5 mL Sodium Chloride 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). Now administer by infusion pump.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. (Human albumin may impart a slightly yellow color to the solution) 
• As STK contains no preservatives, it should be reconstituted immediately before use. The solution may be used for direct intravenous administration within eight hours following reconstitution if stored at 2-8° C
• Do not add other medication to the container of STK.
• Unused reconstituted drug should be discarded.

STK vial should be stored at 2 to 25° 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 STK 1500000 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. Keep out of the reach of children.