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BIOFACTOR STREPTOKINASE 250 000

Active substance(s): STREPTOKINASE / STREPTOKINASE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Biofactor Streptokinase 250 000

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Biofactor Streptokinase 250 000 and 750 000 are presented as a powder for
solution in vials containing 250 000 and 750 000 International Units (IU) of
purified streptokinase as the active ingredient. For a full list of excipients, see
section 6.1.
Highly purified streptokinase is extracted from the culture filtrate of certain
strains of the streptococcus group C. It is presented as a white to slightly yellow
powder and contains stabilisers.

3

PHARMACEUTICAL FORM
Powder for solution for infusion.
White to slightly yellow powder.

4

CLINICAL PARTICULARS

4.1 Therapeutic indications
Biofactor Streptokinase is indicated in adults.
Biofactor Streptokinase is a fibrinolytic agent which may be used for the
intravascular dissolution of thrombi and emboli in:
- acute massive pulmonary embolism
- acute, sub-acute or chronic (not older than 6 weeks) occlusion of peripheral
arteries
- extensive deep vein thrombosis
- central retinal venous or arterial thrombosis (arterial occlusions not older
than 8 hours, venous occlusions 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
Posology
Adults
Deep vein thrombosis

An initial dose of 250 000 IU streptokinase should be infused into a peripheral vein over
30 minutes. A maintenance infusion of 100 000 IU/hour for 72 hours should follow.
Pulmonary embolism
Infuse 1 500 000 IU streptokinase into a peripheral vein preferably over a short time of
1-2 hours.
As an alternative, an initial dose of 250 000 IU streptokinase should be infused into a
peripheral vein over 30 minutes. A maintenance infusion of 100 000 IU/hour for 24
hours should follow.
Occlusive peripheral arterial diseases
Administer streptokinase with a local intra-arterial catheter-directed infusion using one
of the following regimes:
- Gradual infusion: 1000 to 2500 IU streptokinase at an interval of 3 to 5 minutes for a
maximum of 10 hours and a total maximum dose of 250 000 IU
- Prolonged continuous low-dose infusion (using an infusion pump): 5000 to 10,000
IU streptokinase per hour for up to 5 days maximum.
A percutaneous transluminal angioplasty can be performed simultaneously, if necessary.
As an alternative for difficult arterial access or multiple occlusions, an initial dose of 250
000 IU streptokinase should be infused over 30 minutes. A maintenance infusion of 100
000 IU/hour for a maximum of 5 days should follow.
Central retinal vessel occlusion
An initial dose of 250 000 IU streptokinase should be infused into a peripheral vein over
30 minutes. A maintenance infusion of 100 000 IU/hour for 12 hours should follow.
Paediatric population
The safety and efficacy of Biofactor 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 streptokinase for allergic/anaphylactic
reactions, it 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 the
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.
Method of Administration
The administration of streptokinase may be by systemic intravenous infusion or by local
intra-arterial catheter-directed infusion.
For instructions on reconstitution of the medicinal product before administration, see
section 6.6.
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
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).
Systemic Administration
During the infusion, decreases in the plasminogen and fibrinogen levels and an increase
in the level of fibrin degradation product (FDP) (the latter two serving to prolong the
clotting time 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 should be aimed for and is considered a sufficient
anticoagulation protection. If the thrombin time or any other parameter of lysis after 4
hours of therapy is less than approximately 1.5 times the normal control value,
discontinue Biofactor Streptokinase 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 stopped.
Follow-up treatment
After every course of streptokinase therapy, follow-up treatment with anticoagulants or
platelet aggregation inhibitors can be instituted as prevention of rethromboses. With
heparin therapy, in particularly, an increased risk of haemorrhage must be considered.

4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Contraindications to treatment with Biofactor 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 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

4.4 Special warnings and precautions for use
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
- 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.
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. The puncture site should be
checked frequently for evidence of bleeding.
Streptokinase 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 who
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 streptokinase (see section 4.2).
4.6 Fertility, pregnancy and lactation
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.
4.7 Effects on ability to drive and use machines
Not relevant.
4.8 Undesirable effects
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 than1/10,000 (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.
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.
4.9 Overdose
Long-term overdosage of streptokinase may induce the risk of rethrombosis by
prolonged decrease of plasminogen. See also section 4.8 and 5.1.

5

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Streptokinase (antithrombotic agents, enzymes)
ATC code: B01A D01
Biofactor Streptokinase 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 antistreptokinaseantibody titre, 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 the plasminogen as described
above.

5.2 Pharmacokinetic properties
The elimination kinetics of streptokinase follows a biphasic course. A small
proportion of the dose is bound to anti-streptokinase antibodies and metabolised
with a half-life of 18 minutes while most of it forms a streptokinase-plaminogen
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, streptokinase is metabolised proteolytically in the liver and
eliminated via the kidneys. Animal data suggest that streptokinase may also be
excreted unchanged in the bile.
5.3 Preclinical safety data
In an Ames Test on Biofactor Streptokinase, no evidence of mutagenic potential
was found. No other preclinical safety studies have been performed on Biofactor
Streptokinase.

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PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Human albumin, Aminoacetic acid (glycine), Mannitol

6.2 Incompatibilities
No incompatibilities have been reported when Biofactor Streptokinase is used as
recommended. This medicinal product must not be mixed with other medicinal
products.
6.3 Shelf-life
The shelf-life of unopened vials of Biofactor Streptokinase 250 000 and 750 000
is 2 years.
6.4 Special precautions for storage
Do not store above +25°C and do not freeze.
Do not store the reconstituted solution for more than 24 hours in a refrigerator at
+2°C to +8°C.
6.5 Nature and contents of container
Biofactor Streptokinase 250 000 and 750 000 is supplied in 10 ml glass vials with
rubber closures and aluminium seal with plastic flip-top caps.
Biofactor Streptokinase 250 000 and 750 000 is available in packages containing
one vial.
6.6 Special precautions for disposal and other handling
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.

Physiological saline, 5% glucose solution, 5% fructose solution, or Ringer-lactate
solution can be used as a diluent for administration with an infusion pump.
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.

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MARKETING AUTHORISATION HOLDER
Biofactor GmbH
Rudolf-Huch-Str. 14, D-38667 Bad Harzburg, Germany
Fax: +49 5322 30 17 Email: info@biofactor.de

8

MARKETING AUTHORISATION NUMBER(S)
PL 29723/0002

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DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
25/06/1998 / 15/05/2009

10

DATE OF REVISION OF THE TEXT
01/07/2015

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Source: Medicines and Healthcare Products Regulatory Agency

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