STREPTOKINASE Powder for solution for infusion Ref.[8580] Active ingredients: Streptokinase

The following conditions would normally be considered contraindications to streptokinase therapy, but in certain situations the benefits could outweigh the potential risks:

• recent severe gastrointestinal bleeding, e.g. active peptic ulcer
• risk of severe local haemorrhage, e.g. in case of translumbar aortography
• recent trauma and cardiopulmonary resuscitation
• invasive operations, e.g. recent intubation
• puncture of non-compressible vessels, intramuscular injections, large arteries
• recent abortion or delivery
• pregnancy (see section 4.6)
• diseases of the urogenital tract with existing or potential sources of bleeding (implanted bladder catheter)
• known septic thrombotic disease
• severe arteriosclerotic vessel degeneration, cerebrovascular diseases
• cavernous pulmonary diseases, e.g. open tuberculosis or severe bronchitis
• mitral valve defects or atrial fibrilation
• aortic dissection
• diabetic retinopathy increase risk of local bleeding

Antistreptokinase

Repeat treatment with streptokinase administered more than 5 days and less than 12 months after initial treatment may not be effective. This is because of the increased likelihood of resistance due to antistreptokinase antibodies.

Also, the therapeutic effect may be reduced in patients with recent streptococcal infections such as streptococcal pharyngitis, acute rheumatic fever and acute glomerulonephritis.

Infusion rate and corticosteroid prophylaxis

At the beginning of therapy, a fall in blood pressure, tachycardia or bradycardia (in individual cases going as far a shock) are commonly observed. Therefore, at the beginning of therapy the infusion should be performed slowly.

Corticosteroids can be administered prophylactically to reduce the likelihood of infusion-related allergic reactions.

Pre-treatment with heparin or coumarin derivatives

If the patient is under active heparinization, it should be neutralised by administering protamine sulphate before the start of the thrombolytic therapy. The thrombin time should not be more than twice the normal control value before thrombolytic therapy is started. In patients previously treated with coumarin derivatives, the INR (International Normalized Ratio) must be less than 1.3 before starting the streptokinase infusion.

Simultaneous treatment with acetylsalicylic acid

Recent evidence indicates that controlled-dose adjuvant acetylsalicyclic therapy in combination with streptokinase is capable of improving the response in the management of acute myocardial infarction. See also section 4.2.

Streptokinase is not indicated for restoration of patency of intravenous catheters.

There is an increased risk of haemorrhage in patients who are receiving or who have recently been treated with anticoagulants, e.g. heparin or drugs which inhibit platelet formation or function, e.g. platelet aggregation inhibitors, dextrans.

Biofactor Streptokinase is contraindicated in pregnancy. There is no evidence of the drug’s safety in pregnancy, nor is there evidence from animal work that it is free from hazard. Bleeding and anaphylactic reactions might cause abortion and foetal death, especially when streptokinase is given within the first 18 weeks of pregnancy. Use only when there is no safer alternative.

It is unknown whether streptokinase is excreted in human milk. Breast milk should be discarded during the first 24 hours following thrombolytic therapy.

Not relevant.

The following adverse reactions are based on clinical trial and post-marketing experience. The following standard categories are used:

Very common more than 1/10
Common more than 1/100; less than 1/10
Uncommon more than 1/1000; less than 1/100
Rare more than 1/10,000; less than 1/1000
Very Rare less than 1/10,000 (including isolated cases)

Blood and lymphatic system disorders

Common: haemorrhage at the injection site, ecchymoses, gastrointestinal bleeding, genitourinary bleeding, epistaxis

Uncommon: cerebral haemorrhages with their complications and possible fatal outcome, retinal haemorrhages, severe haemorrhages (also with fatal outcome), liver haemorrhages, retroperitoneal bleeding, bleeding into joints, splenic rupture. Blood transfusions are rarely required.

Very rare: haemorrhage into the pericardium including myocardial rupture during thrombolytic treatment of acute myocardial infarction

In serious haemorrhagic complications, streptokinase therapy should be discontinued and a proteinase inhibitor, e.g. aprotinin, should be given as follows. Initially 500 000 KIU (Kallikrein Inactivator Unit) up to one million KIU by slow intravenous injection or infusion. If necessary this should be followed by 200,000 KIU every four hours by intravenous drip until the bleeding stops. In addition, combination with synthetic antifibrinolytics is recommended. If necessary, clotting factors can be substituted. Additional administration of synthetic antifibrinolytics has been reported to be efficient in single cases of bleeding episodes.

Immune system disorders

Very Common: development of antistreptokinase antibodies (see also 4.4)

Common: allergic anaphylactic reactions, e.g. rash, flushing, itching, urticaria, angioneurotic oedema, dyspnoea, bronchospasm, hypotension

Very Rare: delayed allergic reactions, e.g. serum sickness, arthritis, vasculitis, nephritis, neuroallergic symptoms (polyneuropathy, e.g. Guillain Barré syndrome), severe allergic reactions up to shock including respiratory arrest.

Allergic reactions can largely be avoided by giving the infusion slowly. Moderate or mild allergic reactions can be managed with concomitant antihistamine and/or corticosteroid therapy. If a severe allergic reaction occurs the infusion of streptokinase should be discontinued immediately and the patient given the appropriate treatment. The current medical standards for shock treatment should be observed. Lysis therapy should be continued with homologous fibrinolytics, such as Urokinase or tPA.

Nervous system disorders

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

Eye disorders

Very rare: iritis/uveitis/iridocyclitis

Cardiac and vascular disorders

Common: at the start of therapy, hypotension, tachycardia, bradycardia

Very rare: crystal cholesterol embolism

During fibrinolytic therapy with streptokinase in patients with myocardial infarction, the following events have been reported as complications of myocardial infarction and/or symptoms of reperfusion:

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 peripheral embolism

These cardiovascular complications can be life-threatening and may lead to death.

During local lysis of peripheral arteries, distal embolization cannot be excluded.

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, vomiting

General disorders and administration site conditions

Common: headache, back pain, musculoskeletal pain, chills, fever, asthenia, malaise

Testing

Common: Transient elevations of serum transaminases and bilirubin

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

No incompatibilities have been reported when Biofactor Streptokinase is used as recommended. This medicinal product must not be mixed with other medicinal products.