1. Name Of The Medicinal Product
Streptase Injection 250,000 and 750,000 IU
Powder for solution for infusion.
2. Qualitative And Quantitative Composition
Each vial of Streptase Injection 250,000 IU contains purified streptokinase as the active ingredient. Each vial contains 134 to 176 mg of dried substance equivalent to 250,000 International Units streptokinase (50,000 IU streptokinase per mL when the contents of the vial are reconstituted with 5mL physiological saline).
Each vial of Streptase Injection 750,000 IU contains purified streptokinase as the active ingredient. Each vial contains 139 to 182 mg of dried substance equivalent to 750,000 International Units streptokinase. (150,000 IU streptokinase per mL when the contents of the vial are reconstituted with 5mL physiological saline).
Stabilised pure streptokinase is derived from the culture filtrate of beta-haemolytic streptococci of Lancefield group C. It is presented as a white powder and contains stabilisers.
For full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for solution for infusion.
White powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Intravascular dissolution of thrombi and emboli:
- massive deep vein thrombosis with risk of gangrene
- acute massive pulmonary embolism
- acute, subacute and chronic (not older than 6 weeks) occlusive arterial diseases with limb threatening ischaemia
- central retinal artery or vein occlusion (arterial occlusions not older than 8 hours, venous occlusion not older than 10 days)
Note: No statement on therapy outcome can be made for administration beyond the time windows indicated above.
4.2 Posology And Method Of Administration
The administration of Streptase may be by systemic intravenous infusion or by local intra-arterial catheter-directed infusion during arteriography.
For instructions regarding reconstitution and further dilution, see section 6.6.
Upon reconstitution with physiological saline, a colourless to yellowish, clear solution is obtained.
Note: 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 (see sections 4.4 and 4.8).
Adults
Deep vein thrombosis
Streptase should be administered by intravenous infusion into a peripheral vein using the following standard dose regimen: an initial dose of 250,000 IU Streptase infused over 30 minutes, followed by a maintenance dose of 100,000 IU per hour for 72 hours.
Pulmonary embolism
Streptase should be administered by intravenous infusion into a peripheral vein using preferably a short infusion of 1,500,000 IU Streptase over 1-2 hours.
Alternatively, the standard dose regimen can be used: an initial dose of 250,000 IU Streptase infused over 30 minutes, followed by a maintenance dose of 100,000 IU per hour for 24 hours.
Occlusive peripheral arterial diseases
Streptase should be administered by local intra-arterial catheter-directed infusion using one of the following dose regimens:
• Stepwise infusion: 1,000 to 2,500 IU Streptase in intervals of 3 to 5 minutes for a maximum duration of 10 hours and a total maximum dose of 250,000 IU.
• Prolonged continuous low-dose infusion (using an infusion pump): 5,000 to 10,000 IU Streptase per hour for a maximum of 5 days.
A percutaneous transluminal angioplasty can be performed simultaneously, if necessary.
Alternatively, in case of difficult arterial access or multiple occlusions, the standard intravenous dose regimen can be used: an initial dose of 250,000 IU Streptase infused over 30 minutes, followed by a maintenance dose of 100,000 IU per hour for a maximum of 5 days.
Occlusion of central retinal vessels
Streptase should be administered by intravenous infusion into a peripheral vein using the standard dose regimen: an initial dose of 250,000 IU Streptase infused over 30 minutes, followed by a maintenance dose of 100,000 IU per hour for 12 hours.
Paediatric patients
The safety and efficacy of Streptase 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 streptokinase for allergic/anaphylactic reactions, its use is not recommended in neonates, infants and children.
Control of therapy
Before commencing thrombolytic therapy, it is desirable to obtain a thrombin time (TT), activated partial thromboplastin time (aPTT), haematocrit and platelet count to obtain the haemostatic status of the patient.
If heparin has been given, it should be discontinued and the TT or aPTT should be less than twice the normal control value before thrombolytic therapy is started. In patients previously treated with coumarin derivatives, the INR (International Normalised Ratio) should be below 1.3 before starting therapy with streptokinase.
Systemic administration
During the infusion, decreases in the plasminogen and fibrinogen level and an increase in the level of fibrin degradation products (FDP) (the latter two serving to prolong the clotting times of coagulation tests) will generally confirm the existence of a thrombolytic state. Therefore therapy can be monitored by performing the TT or aPTT approximately 4 hours after initiation of therapy.
A 2 to 4 fold prolongation of the TT is considered as a sufficient anticoagulation protection that should be aimed for. If the TT or any other parameter of lysis after 4 hours of therapy is less than approximately 1.5 times the normal control value, Streptase should be discontinued as excessive resistance to streptokinase is present.
Local 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 a follow-up treatment with anticoagulants or platelet aggregation inhibitors can be instituted as a prevention of rethromboses. With heparin therapy, in particular, an increased risk of haemorrhage must be considered.
4.3 Contraindications
Streptase must not be used in case of severe allergic reactions to the product.
Because of the increased risk of haemorrhage under thrombolytic therapy Streptase must not be given in the following situations:
• existing or recent internal haemorrhages
• all forms of reduced blood coagulability, in particular spontaneous fibrinolysis and extensive clotting disorders
• recent cerebrovascular insults, 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 above 200 mm Hg and/or diastolic values above 100 mm Hg or hypertensive retinal changes grades III/IV
• recent implantation of a vessel prosthesis
• simultaneous treatment with oral anticoagulants (INR>1.3)
• severe liver or kidney damage
• endocarditits or pericarditis. Isolated cases of pericarditis, misdiagnosed as acute myocardial infarction and treated with Streptase, have resulted in pericardial effusions including tamponade
• known haemorrhagic diathesis
• recent major operations (6th to 10th postoperative day, depending on the severity of surgical intervention)
• invasive operations, e.g. recent organ biopsy, long-term (traumatic) closed-chest cardiac massage
4.4 Special Warnings And Precautions For Use
Individual benefit/risk assessment
The risk of therapy in case of life-threatening thromboembolic events, in particular that of haemorrhages, must be weighed against the anticipated benefit in cases such as:
• recent severe gastrointestinal bleeding, e.g. active peptic ulcer
• risk of severe local haemorrhage, e.g. in case of aortography by lumber route
• recent trauma and cardiopulmonary resuscitation
• invasive operations, e.g. recent intubation
• puncture of non-compressible vessels, intramuscular injections
• recent delivery, abortion
• diseases of the urinogenital tract with existing or potential sources of bleeding (implanted bladder catheter)
• known septic thrombotic disease
• severe atherosclerotic vessel degeneration, cerebrovascular diseases
• cavernous pulmonary diseases, e.g. open tuberculosis
• mitral valve defects or atrial fibrillation
Antistreptokinase antibodies
Because of the increased likelihood of resistance due to antistreptokinase antibodies, repeat treatment with Streptase or streptokinase containing products may not be effective if administered more than 5 days, particularly between 5 days and 12 months after initial treatment.
Likewise, 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 reaching as far as 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 the administration of 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.
Arterial puncture
Should an arterial puncture be necessary during intravenous therapy, upper extremity vessels are preferable. After the puncture, pressure should be applied for at least 30 minutes by a compression bandage and the puncture site should be checked frequently for evidence of bleeding.
Streptase is not indicated for restoration of patency of intravenous catheters.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
There is an increased risk of haemorrhage in patients who are receiving or have recently been treated with anticoagulants e.g. heparin or drugs which inhibit platelet formation or function e.g. platelet aggregation inhibitors, dextrans.
The effects of drugs which act upon platelet formation or function should be allowed to subside, before starting long-term lysis of deep vein thromboses and arterial occlusions with Streptase (see section 4.2).
4.6 Pregnancy And Lactation
Streptase 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 Streptase is given within the first 18 weeks of pregnancy. Use only when there is no safer alternative.
It is not known whether streptokinase is excreted in breast milk. Breast milk should be discarded during the first 24 hours following thrombolytic therapy.
4.7 Effects On Ability To Drive And Use Machines
Not applicable.
4.8 Undesirable Effects
The following adverse reactions are based on experience from clinical trials and post-marketing experience. The following standard categories are used:
Very common >1/10
Common >1/100, <1/10
Uncommon >1/1000, <1/100
Rare >1/10,000, <1/1000
Very rare <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 severe haemorrhagic complications, Streptase therapy should be discontinued and a proteinase inhibitor, e.g. aprotinin, administered in the following dosage: Initially 500,000 KIU (Kallikrein Inactivator Unit), if necessary up to 1 million KIU, followed by 50,000 KIU per hour by intravenous drip until the bleeding stops. In addition, combination with synthetic antifibrinolytics is recommended. If necessary, coagulation factors should be administered. 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 section 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
Mild or moderate allergic reactions may be managed with concomitant antihistamine and/or corticosteroid therapy. If a severe allergic/anaphylactic reaction occurs the administration of Streptase must be discontinued immediately and an appropriate treatment should be initiated. 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 commencement of therapy, hypotension, tachycardia, bradycardia
• Very rare: Crystal cholesterol embolism
In the setting of fibrinolytic therapy with Streptase 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 edema 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, muscle pain, chills, fever, asthenia, malaise.
Investigations
• Common: Transient elevations of serum transaminases and bilirubin.
4.9 Overdose
Long term overdosage of streptokinase may induce the risk of re-thrombosis by prolonged decrease of plasminogen. (See sections 4.8 and 5.1).
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmaco-therapeutic group: Streptokinase (antithrombotic agents, enzymes).
ATC code: B01A D01
Streptase is a highly purified streptokinase derived from β haemolytic streptococci of Lancefield group C. The activation of the endogenous fibrinolytic system is initiated 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 a lower bleeding risk and vice versa.
After intravenous administration and neutralisation of the individual antistreptokinase-antibody titer, streptokinase is immediately available systemically for activation of the fibrinolytic system.
Streptokinase has a very short half-life. The first rapid clearance from the plasma is due to the formation of the complex between streptokinase and streptokinase antibody. This complex is biochemically inert and is cleared rapidly from the circulation. Once the antibody has been neutralised, the streptokinase activates plasminogen as described above.
5.2 Pharmacokinetic Properties
Due to the high degree of affinity and rapid reaction between streptokinase and antistreptokinase-antibodies, which may be present in the patient's blood, low quantities of streptokinase are eliminated from blood with a half-life of 18 minutes. The elimination half-life of streptokinase based on activator formation is about 80 minutes.
Peak fibrinolytic activity is found in the blood about 20 minutes after dosing. Activity is detected in the urine 2 hours after dosing.
The major part of streptokinase is degraded to peptides and eliminated by the kidneys. Animal data suggest that streptokinase may also be excreted unchanged into the bile.
5.3 Preclinical Safety Data
Several studies in different species of laboratory animals have shown that multiple human doses have no acute toxic effect.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Human albumin
Sodium-L-hydrogen glutamate monohydrate
Polygeline
6.2 Incompatibilities
Other drugs should not be added to the infusion solution.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Do not store above 25 °C. Do not freeze
Once reconstituted with physiological saline, physico-chemical stability has been demonstrated for 24 hours at +2 to +8 °C. From a microbiological point of view and as Streptase 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.
6.5 Nature And Contents Of Container
The immediate container consists of an injection vial of 6ml, colourless tubular glass (Type I, Ph.Eur.), sealed with chlorobutyl rubber stopper, aluminium seal with plastic flip-off cap.
6.6 Special Precautions For Disposal And Other Handling
To ensure that the contents of the vial are rapidly and completely dissolved, 5ml of physiological saline should be injected into the Streptase-containing vacuum vial and the residual vacuum abolished by briefly loosening the needle from the syringe.
For administration with an infusion pump, physiological saline, Ringer-lactate solution, 5% glucose solution, 5% fructose solution or polygeline can be used as a diluent.
7. Marketing Authorisation Holder
CSL Behring UK Limited
Hayworth House
Market Place
Haywards Heath
West Sussex RH16 1DB
UK
8. Marketing Authorisation Number(S)
250,000 IU: PL 00231/0126
750,000 IU: PL 00231/0127
9. Date Of First Authorisation/Renewal Of The Authorisation
01 January 2002
10. Date Of Revision Of The Text
07 September 2010
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