Streptokinase

Registered South African indications:

• Acute transmural myocardial infarction (≤12 hours) with persistent ST-segment elevation or recent left bundle-branch block
• Deep vein thromboses (≤14 days)
• Acute massive pulmonary embolism
• Acute and subacute thromboses of peripheral arteries
• Chronic occlusive arterial diseases (≤6 weeks)
• Occlusion of central retinal artery or vein (arterial occlusions ≤6-8 hours, venous occlusions ≤10 days)
• Acute myocardial infarction for re-opening of coronary vessels (≤12 hours)
• Acute, subacute and chronic thromboses as well as embolisms of peripheral venous and arterial vessels

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients  
• Pregnancy
• Renal impairment (eGFR <10ml/min/1.73m²)
• Severe hepatic impairment (Child-Pugh Class C)
• 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 200mmHg and/or diastolic values over 100mmHg or hypertensive retinal changes Grades III/IV
• Recent implantation of a vessel prosthesis
• Simultaneous or recent treatment with oral anticoagulants (INR>1.3)
• Endocarditis or pericarditis
• 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
• Use within the past 2 years

Cautions

• Breastfeeding
• Renal impairment (eGFR ≥11-29ml/min/1.73m²)
• Mild to moderate hepatic impairment (Child-Pugh Classes A & B)
• Elderly
• Recent severe gastrointestinal bleeding, e.g. active peptic ulcer
• Risk of severe local haemorrhage, e.g. 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
• Urogenital tract diseases with existing or potential sources of bleeding e.g. 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 fibrillation
• Aortic dissection
• Diabetic retinopathy
• Recent streptococcal infections, such as streptococcal pharyngitis, acute rheumatic fever and acute glomerulonephritis
• Restoration of patency of intravenous catheters

Forms avail. in SA and covered in this monograph: inj

Acute myocardial infarction within 12 hours of onset with persistent ST-segment elevation or recent left bundle-branch block 

• IV: 1 500 000 IU (one and a half million IU), as an infusion over 1hr
• Intracoronary: 20 000 IU (twenty thousand IU), as a bolus; Maintenance: 2000-4000 IU (two to four thousand)/min, as an infusion over 30-90min according to achievement of coronary artery patency

Acute, subacute and chronic thromboses/embolisms of peripheral venous and arterial vessels
Chronic occlusive arterial diseases

• Intracoronary: 1000-2000IU (one thousand to two thousand IU), in intervals of 3-5mins; Max: 120 000 IU(one hundred and twenty thousand IU)/3hrs  

The duration of administration depends on the length and localisation of the vessel occlusion

- Short-term thrombolysis

• IV: Initial: 250 000 IU (two hundred and fifty thousand IU), as an infusion over 30min; Maintenance: 1 500 000 IU (one and a half million IU)/hrover a max of 6hrs

The 6hr infusion can be repeated on the following day, depending on the therapeutic success of lysis. However, repetition of treatment must on no account be conducted >5 days after the first course

- Long-term thrombolysis

• IV: Initial: 250 000 IU (two hundred and fifty thousand IU), as an infusion over 30min; Maintenance: 100 000 IU (one hundred thousand IU)/hr  

The duration of therapy depends on the extension and localisation of the vessel occlusion. In peripheral vessel occlusion the maximum duration is 5 days

A percutaneous transluminal angioplasty can be performed simultaneously, if necessary

For occlusions of central retinal arteries or veins:
In case of thromboses of the central retinal vessels, for systemic intravenous administration, lysis of arterial occlusions should be limited to max. 24hrs, in venous occlusions to max. 72hrs. If continuation of thrombolysis is indicated due to extensive thrombotic occlusions, therapy should be interrupted for one day, followed by administration of a homologous fibrinolytic

Streptokinase is contraindicated if used within the past 2 years

See additional prescribing points

Not established for use in children

Pregnancy 

• Contraindicated
• Streptokinase is contraindicated in pregnancy. There is no evidence of the agent'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

Breastfeeding 

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

Renal Impairment 

• eGFR ≥30-89ml/min/1.73m²: No dose adjustment recommended
• eGFR ≥11-29ml/min/1.73m²: Caution; no dose adjustment recommended
  Use with high caution
  Reserve for use in acute coronary artery disease (CAD) and/or pulmonary embolism (PE)
• eGFR <10ml/min/1.73m²: Contraindicated

Hepatic Impairment 

• Mild to moderate (Child-Pugh Classes A & B): Caution; no dose adjustment recommended
  Use with high caution
  Monitor INR and other coagulation and bleeding profiles
  Reserve for use in acute coronary artery disease (CAD) and/or pulmonary embolism (PE)
• Severe (Child-Pugh Class C): Contraindicated

Elderly

• Caution; no dose adjustment recommended
  Use with high caution
  Reserve for use in acute coronary artery disease (CAD) and/or pulmonary embolism (PE)

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Neurologic symptoms
  - Dizziness
  - Confusion
  - Paralysis
  - Hemiparesis
  - Agitation
  - Seizures
• Cerebral haemorrhage
• Hypoperfusion of the brain
• Headache
• Asthenia

Cardiovascular Disorders 

• Hypotension
• Tachycardia
• Bradycardia
• Crystal cholesterol embolism
• Heart rate and rhythm disorders
• Angina pectoris
• Recurrent ischaemia
• Cardiac failure
• Reinfarction
• Cardiogenic shock
• Pericarditis
• Pulmonary oedema
• Cardiac arrest (leading to respiratory arrest)
• Mitral insufficiency
• Pericardial effusion
• Cardiac tamponade
• Myocardial rupture
• Pulmonary or peripheral embolism
• Distal embolisation
• Haemorrhage into pericardium

Respiratory Disorders 

• Non-cardiogenic pulmonary oedema
• Epistaxis

Gastrointestinal Disorders 

• Nausea and vomiting
• Diarrhoea
• Epigastric pain
• Gastrointestinal bleeding
• Retroperitoneal bleeding
• Splenic rupture

Hepatobiliary Disorders

• Hepatic haemorrhages
• Increased serum transaminases
• Increased bilirubin

Genitourinary Disorders

• Genitourinary bleeding  

Musculoskeletal Disorders

• Bleeding into joints
• Back pain
• Musculoskeletal pain

Immune, Blood and Lymphatic System Disorders 

• Haemorrhage at the injection site
• Ecchymoses
• Severe haemorrhages
• Development of antistreptokinase antibodies
• Allergic anaphylactic reactions
  - Rash
  - Flushing
  - Itching
  - Urticaria
  - Angioneurotic oedema
  - Dyspnoea
  - Bronchospasm
  - Hypotension
• Delayed allergic reactions
  - Serum sickness
  - Arthritis
  - Vasculitis
  - Nephritis
  - Neuroallergic symptoms (polyneuropathy, e.g. Guillain Barré syndrome)
  - Severe allergic reactions up to shock including respiratory arrest
• Fever
• Chills

Sensory Disorders 

• Iritis
• Uveitis
• Iridocyclitis
• Retinal haemorrhages

• Anticoagulants
• Heparin
• Agents that inhibit platelet formation or function
• Platelet aggregation inhibitors
• Dextrans

None routine. Specific cases may require

• Thrombin time (TT)
• Partial thromboplastin time (aPTT)
• INR

Control of therapy

• Systemic intravenous administration
  - In case of short-term lysis over six hours heparin should be administered during or following infusion when the thrombin time (TT) or partial thromboplastin time (aPTT) have reached less than twice or 1,5 times the normal control value, respectively. The TT and aPTT should be prolonged to 2-4 fold and 1,5-2,5 fold the normal value, respectively, in order to ensure sufficient protection against re-thrombosis
  - If the infusion is not repeated the heparin therapy is instituted simultaneously with the administration of oral anticoagulants (see follow-up treatment)
  - The long-term lysis is controlled with the thrombin time (TT). A 2-4 fold prolongation of the TT which is considered as sufficient anticoagulant protection has to be aimed at. Therefore, a simultaneous administration of heparin may become necessary. If the TT after the 16th hour is still prolonged to more than 4 fold the normal control value, the maintenance dose of streptokinase has to be doubled for several hours until the TT recedes
• Local intracoronary, intra-arterial and intravenous administration
  - As is usual with angiographies heparin is administered - If necessary - prior to the angiography as a safeguard against catheter-induced thromboses. The success of therapy can be determined by the angiography. With a sufficient blood flow of more than 15 minutes, the therapy can be considered successful and then terminated
• Follow-up treatment
  - After every course of streptokinase therapy, follow-up treatment with anticoagulants or platelet aggregation inhibitors can be instituted as prevention of re-thromboses
  With heparin therapy, in particular, an increased risk of haemorrhage must be considered. The heparin therapy is controlled individually with the TT or a PTT. A 2-4 fold prolongation of the TT and 1,5-2,5 fold prolongation of the aPTT is aimed at. For long term prophylaxis oral anticoagulants, as, for example, coumarin derivatives or platelet aggregation inhibitors can be applied

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
• When thrombolytic therapy is necessary and a high antibody concentration against streptokinase is present or when recent streptokinase therapy has been given (more than 5 days and less than one year previously), homologous fibrinolytics should be used
• 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 heparinisation, 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 must be less than 1.3 before starting the streptokinase infusion

Simultaneous treatment with acetylsalicylic acid

• Recent evidence indicates that controlled-dose adjuvant acetylsalicylic therapy in combination with streptokinase is capable of improving the response in the management of acute myocardial infarction
• Treatment with aspirin (150mg daily) for at least 4 weeks is recommended for prophylaxis after streptokinase therapy for acute myocardial infarction. The first dose should be given as soon as possible after the myocardial infarction

Reconstitution directions

• The contents should be dissolved in 4-5ml 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
• Streptokinase may be given by intravenous infusion in 50-200ml of physiological saline, 5% glucose solution, 5% fructose solution, or Ringer-lactate solution
• Upon reconstitution, with physiological saline, a clear solution, colourless to yellowish, is obtained

Streptokinase is a highly purified streptokinase derived from β haemolytic streptococci of Lancefield group C. It activates the endogenous fibrinolytic system by the formation of a 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 streptokinase are associated with lower bleeding risk and vice versa. After IV administration and neutralisation of the individual antistreptokinase-antibody titre, streptokinase is immediately available systemically for activation of the fibrinolytic system.

Injection (per vial) 750 000 iu

• Streptase 750 000 iu (Actor Pharma) originator

Injection (per vial) 1 500 000 iu

• Fibreaker (Actor Pharma)
• Streptase 1500 000 iu (Actor Pharma) originator