Contraindications to treatment with Biofactor Heberkinase (recombinant streptokinase), because of the increased risk of haemorrhage under thrombolytic therapy, include:
- existing or recent internal haemorrhage
- all forms of reduced blood coagulability, in particular spontaneous fibrinolysis and extensive clotting disorders
- recent cerebrovascular accident, intracranial or intraspinal surgery
- intracranial neoplasm
- recent head trauma
- arteriovenous malformation or aneurysm
- known neoplasm with risk of haemorrhage
- acute pancreatitis
- uncontrollable hypertension with systolic values over 200 mm Hg and/or diastolic values over 100 mm Hg or hypertensive retinal changes Grades III/IV
- recent implantation of a vessel prosthesis
- simultaneous or recent treatment with oral anticoagulants (INR >1.3)
- severe liver or kidney damage
- endocarditis or pericarditis. Isolated cases of pericarditis, misdiagnosed as acute myocardial infarction and treated with Heberkinase (recombinant streptokinase), have resulted in pericardial effusions including tamponade
- known haemorrhagic diathesis
- recent major operations (6th to 10th post-operative day, depending on the extent of the procedure)
- invasive operations, e.g. recent organ biopsy, long-term (traumatic) closed chest cardiac massage
No incompatibilities have been reported when Biofactor Heberkinase (recombinant streptokinase) is used as recommended. This medicinal product must not be mixed with other medicinal products.
The following adverse reactions are based on clinical trial and post-marketing experience. The following standard categories are used:
| Very common | more than1/10 |
| 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, Heberkinase (recombinant 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 antiHeberkinase (recombinant streptokinase) 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 Heberkinase (recombinant 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 Heberkinase (recombinant 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.
In an Ames Test on Biofactor Heberkinase (recombinant streptokinase), no evidence of mutagenic potential was found. No other preclinical safety studies have been performed on Biofactor Heberkinase (recombinant streptokinase).
Biofactor Heberkinase (recombinant streptokinase) is indicated in adults.
Acute myocardial infarction: within 12 hours of onset with persistent ST-segment elevation or recent left bundle-branch block. Note: No statement on therapy outcome can be made for administration beyond the time window indicated above.
Pharmacotherapeutic group: Heberkinase (recombinant streptokinase) (antithrombotic agents, enzymes)
ATC code: B01A D01
Biofactor Heberkinase (recombinant streptokinase) is a highly purified Heberkinase (recombinant streptokinase) derived from β haemolytic streptococci of Lancefield group C. The activation of the endogenous fibrinolytic system is initiated by the formation of a Heberkinase (recombinant streptokinase)-plasminogen complex.
This complex possesses activator properties and converts plasminogen into the proteolytic and fibrinolytic active plasmin. The more plasminogen that is bound within this activator complex, the less plasminogen is left to be converted into its enzymatically active form. Therefore, high doses of Heberkinase (recombinant streptokinase) are associated with a lower bleeding risk and vice versa.
After intravenous administration and neutralisation of the individual antiHeberkinase (recombinant streptokinase)-antibody titre, Heberkinase (recombinant streptokinase) is immediately available systemically for activation of the fibrinolytic system.
Heberkinase (recombinant streptokinase) has a very short half-life. The first rapid clearance from the plasma is due to the formation of the complex between Heberkinase (recombinant streptokinase) and Heberkinase (recombinant streptokinase) antibody. This complex is biochemically inert and is cleared rapidly from the circulation. Once the antibody has been neutralised, the Heberkinase (recombinant streptokinase) activates the plasminogen as described above.
The elimination kinetics of Heberkinase (recombinant streptokinase) follows a biphasic course. A small proportion of the dose is bound to anti-Heberkinase (recombinant streptokinase) antibodies and metabolised with a half-life of 18 minutes while most of it forms a Heberkinase (recombinant streptokinase)-plasminogen activator complex and is biotransformed with a half-life of about 80 minutes.
Peak fibrinolytic activity is found in the blood about 20 minutes after dosing.
Like other proteins, Heberkinase (recombinant streptokinase) is metabolised proteolytically in the liver and eliminated via the kidneys. Animal data suggest that Heberkinase (recombinant streptokinase) may also be excreted unchanged in the bile.
The following conditions would normally be considered contraindications to Heberkinase (recombinant 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
- 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
AntiHeberkinase (recombinant streptokinase)
Repeat treatment with Heberkinase (recombinant 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 antiHeberkinase (recombinant streptokinase) 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 Heberkinase (recombinant streptokinase) infusion.
Simultaneous treatment with acetylsalicylic acid
Recent evidence indicates that controlled-dose adjuvant acetylsalicyclic therapy in combination with Heberkinase (recombinant streptokinase) is capable of improving the response in the management of acute myocardial infarction.
Heberkinase (recombinant streptokinase) is not indicated for restoration of patency of intravenous catheters.
Not relevant.
Posology
Paediatric population
The safety and efficacy of Biofactor Heberkinase (recombinant streptokinase) have not been sufficiently established in children. Due to low levels of plasminogen in newborns and in children with acquired plasminogen deficiency and due to the potential of Heberkinase (recombinant streptokinase) for allergic/anaphylactic reactions, it is not recommended in neonates, infants and children.
Adults
Systemic administration: A single dose of 1.5 million IU Heberkinase (recombinant streptokinase) should be infused intravenously over one hour.
Local intracoronary administration: A bolus of 20,000 IU Heberkinase (recombinant streptokinase) should be followed by a maintenance infusion of 2,000 IU to 4,000 IU per minute over 30 to 90 minutes depending on the achievement of coronary artery patency.
Method of Administration
Upon reconstitution with physiological saline a clear solution, colourless to yellowish, is obtained.
Note: When thrombolytic therapy is necessary and a high antibody concentration against Heberkinase (recombinant streptokinase) is present or when recent Heberkinase (recombinant streptokinase) therapy has been given (more than 5 days and less than one year previously), homologous fibrinolytics should be used.
Adjuvant treatment
Treatment with aspirin (150 mg daily) for at least 4 weeks is recommended for prophylaxis after Heberkinase (recombinant streptokinase) therapy for acute myocardial infarction. The first dose should be given as soon as possible after the myocardial infarction.
The contents should be dissolved in 4-5 ml of physiological saline or water for injection. The solution should be swirled gently to facilitate quick reconstitution, but care should be taken to avoid foaming.
Biofactor Heberkinase (recombinant streptokinase) may be given by intravenous infusion in 50-200 ml of physiological saline, 5% glucose solution, 5% fructose solution, or Ringer-lactate solution.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
