Thromboflux

Biofactor Thromboflux 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.

Posology

Paediatric population

The safety and efficacy of Biofactor Thromboflux 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 Thromboflux for allergic/anaphylactic reactions, it is not recommended in neonates, infants and children.

Adults

Systemic administration: A single dose of 1.5 million IU Thromboflux should be infused intravenously over one hour.

Local intracoronary administration: A bolus of 20,000 IU Thromboflux 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 Thromboflux is present or when recent Thromboflux 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 Thromboflux therapy for acute myocardial infarction. The first dose should be given as soon as possible after the myocardial infarction.

Contraindications to treatment with Biofactor Thromboflux, 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 Thromboflux, have resulted in pericardial effusions including tamponade

- known haemorrhagic diathesis

- recent major operations (6^th to 10^th post-operative day, depending on the extent of the procedure)

- invasive operations, e.g. recent organ biopsy, long-term (traumatic) closed chest cardiac massage

The following conditions would normally be considered contraindications to Thromboflux 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

AntiThromboflux

Repeat treatment with Thromboflux 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 antiThromboflux 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 Thromboflux infusion.

Simultaneous treatment with acetylsalicylic acid

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

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

Not relevant.

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

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, Thromboflux 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 antiThromboflux 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 Thromboflux 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 Thromboflux 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.

Pharmacotherapeutic group: Thromboflux (antithrombotic agents, enzymes)

ATC code: B01A D01

Biofactor Thromboflux is a highly purified Thromboflux derived from β haemolytic streptococci of Lancefield group C. The activation of the endogenous fibrinolytic system is initiated by the formation of a Thromboflux-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 Thromboflux are associated with a lower bleeding risk and vice versa.

After intravenous administration and neutralisation of the individual antiThromboflux-antibody titre, Thromboflux is immediately available systemically for activation of the fibrinolytic system.

Thromboflux has a very short half-life. The first rapid clearance from the plasma is due to the formation of the complex between Thromboflux and Thromboflux antibody. This complex is biochemically inert and is cleared rapidly from the circulation. Once the antibody has been neutralised, the Thromboflux activates the plasminogen as described above.

The elimination kinetics of Thromboflux follows a biphasic course. A small proportion of the dose is bound to anti-Thromboflux antibodies and metabolised with a half-life of 18 minutes while most of it forms a Thromboflux-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, Thromboflux is metabolised proteolytically in the liver and eliminated via the kidneys. Animal data suggest that Thromboflux may also be excreted unchanged in the bile.

In an Ames Test on Biofactor Thromboflux, no evidence of mutagenic potential was found. No other preclinical safety studies have been performed on Biofactor Thromboflux.

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

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 Thromboflux 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.