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UROKINASE MEDAC 250 000 I.U. POWDER FOR SOLUTION FOR INJECTION OR INFUSION

Active substance(s): UROKINASE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Urokinase medac 250,000 I.U.
Powder for solution for injection or infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 250,000 I.U. of human urokinase extracted from human
urine.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Powder for solution for injection or infusion

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Intravascular lysis of blood clots in the following conditions:
• extensive acute proximal deep vein thrombosis
• acute massive pulmonary embolism
• acute occlusive peripheral arterial disease with limb threatening ischemia
• thrombosed arteriovenous haemodialysis shunts
• thrombosed central venous catheters

4.2

Posology and method of administration
Urokinase medac should only be used by physicians experienced in the management
of thrombotic diseases in hospitals where adequate diagnostic and monitoring
techniques are available.

Depending on the indication, the route of administration of Urokinase medac is by
systemic intravenous infusion, by local intra-arterial catheter-directed infusion during
arteriography, or by local instillation.
It must not be given by subcutaneous or intramuscular injection.
For instructions regarding reconstitution and further dilution, see section 6.6.
Adults
The dosage may be adjusted individually depending on the clinical condition. The
following dose regimens should be used as a guideline.
Deep vein thrombosis
Urokinase medac should be administered by intravenous infusion into a peripheral
vein using an initial dose of 4,400 I.U./kg bodyweight infused over 10 – 20 min,
followed by a maintenance dose of 100,000 I.U. per hour for 2 – 3 days.
Pulmonary embolism
Urokinase medac should be administered by intravenous infusion into a peripheral
vein using an initial dose of 4,400 I.U./kg bodyweight infused over 10 – 20 min,
followed by a maintenance dose of 4,400 I.U./kg bodyweight per hour for 12 hours.
Occlusive peripheral arterial disease
Urokinase medac should be administered by local intra-arterial catheter-directed
graded infusion using an initial dose of 4,000 I.U./min (i.e. 240,000 I.U. per hour) for
2 – 4 hours or until restoration of antegrade flow, followed by a dose of 1,000 –
2,000 I.U./min until complete lysis or a maximum of 48 hours.
Thrombosed arteriovenous haemodialysis shunts
Urokinase medac should be administered by local forced periodic infusion (pulse
spray) into both branches of the shunt at a concentration of 5,000 to 25,000 I.U./ml up
to a total dose of 250,000 I.U. If necessary, the application can be repeated every 30 –
45 minutes up to a maximum of 2 hours.
Thrombosed central venous catheters
Urokinase medac should be dissolved in physiological saline at a concentration of
5,000 I.U./ml. A volume sufficient to completely fill the lumen of the occluded
catheter should be instilled and either locked for a duration of 20 to 60 minutes or
pushed with aliquots of saline before the lysate is aspirated. The procedure may be
repeated if necessary.

Special populations
• Elderly patients: Available data are limited in patients over 65 years and it is
not known whether they respond differently from younger subjects.
Urokinase medac should be used with caution in elderly patients (see
section 4.4).
• Patients with renal or hepatic impairment: A dose reduction may be required
in patients with impaired renal and/or hepatic function. In these cases, the
fibrinogen level should not fall below 100 mg/dl.
Paediatric patients
There is very limited experience with urokinase in children with thromboembolic
occlusive vascular disease and urokinase should not be used in this indication.

Urokinase medac may be used in children of all ages for the treatment of thrombosed
central venous catheters using the same lock procedure as in adults.
Therapeutic monitoring
Before starting thrombolytic therapy, haemostasis tests should be performed
including haematocrit, platelet count, thrombin time (TT) and activated partial
thromboplastin time (aPTT).
If heparin has been given, it should be discontinued and the aPTT should be less than
twice the normal control value before urokinase therapy is initiated.
For systemic administration, a 3 to 5 fold prolongation of the TT measured 4 hours
after initiation of therapy is generally considered sufficient. However, results of
coagulation tests and fibrinolytic activity do not reliably predict either efficacy or risk
of bleeding.
Follow-up treatment
In order to prevent recurrent thrombosis subsequent administration of anticoagulants
should be instituted provided the aPTT is less than twice the normal control value.

4.3

Contraindications
• Hypersensitivity to the active substance or to any of the excipients
• Active clinically relevant bleeding
• Aneurysm and arteriovenous malformation
• Intracranial neoplasm or other neoplasm with risk of haemorrhage
• Decreased blood coagulation (haemorrhagic diathesis, concomitant
therapy with anticoagulants, spontaneous fibrinolysis) and severe
thrombocytopenia
• Severe uncontrolled arterial hypertension (systolic > 200 mmHg, diastolic
> 100 mmHg; grade III or IV hypertensive retinopathy)
• Acute pancreatitis, pericarditis, bacterial endocarditis, sepsis
• Recent cerebrovascular accident (e.g. within 2 months)
• Recent trauma including cardiopulmonary resuscitation, thoracic surgery
or neurosurgery (e.g. within 2 months)
• Recent major surgery until primary wound healing, recent organ biopsy,
lumbar puncture, translumbal aortography (e.g. within 10 days)

4.4

Special warnings and precautions for use
In the following conditions, the risk of bleeding may be increased and should be
weighed against the anticipated benefits:
• Recent severe gastrointestinal bleeding
• Recent surgery other than thoracic or neurosurgery, recent obstetrical
delivery, puncture of non-compressible vessels









Moderate coagulation defects including those due to severe hepatic or renal
diseases
Cavernous pulmonary diseases
Genitourinary tract diseases with existing or potential sources of bleeding
(e.g. implanted bladder catheter)
High likelihood of a left heart thrombus (e.g. mitral stenosis with atrial
fibrillation) with possible risk of cerebral embolism
Known septic thrombotic disease
Severe cerebrovascular disease
Elderly patients (especially those over 75 years)

Concomitant administration of urokinase with other thrombolytic agents,
anticoagulants, or agents inhibiting platelet function may further increase the risk of
serious bleeding (see section 4.5).
When bleeding occurs in patients receiving urokinase, it may be difficult to control.
Although urokinase is intended to produce sufficient amounts of plasmin to lyse
intravascular deposits of fibrin, other fibrin deposits including those which provide
haemostasis (at sites of needle puncture, catheter insertion, cut, etc.) are also subject
to lysis, and bleeding from such sites may result. Oozing of blood from sites of
percutaneous trauma occurs frequently.
The possibility of bruising or haematoma formation, especially after intramuscular
injections, is high during urokinase therapy. Intramuscular injections and unnecessary
handling of the patient should be avoided. Venipunctures and invasive venous
procedures should be performed as infrequently as possible and with care to minimize
bleeding. If bleeding from an invasive site is not serious, urokinase therapy may be
continued while closely observing the patient; local measures such as application of
pressure should be initiated immediately.
Arterial invasive procedures must be avoided before and during urokinase treatment
to minimise bleeding. If an arterial puncture is absolutely essential, it should be
performed by a physician experienced in the procedure, using a radial or brachial
rather than a femoral artery. Direct pressure should be applied at the puncture site for
at least 30 minutes, a pressure dressing applied, and the site checked frequently for
evidence of bleeding.
If severe bleeding occurs following systemic treatment with urokinase, infusion
should be stopped immediately and measures to manage the bleeding implemented.
Plasma volume expanders other than dextrans may be used to replace blood volume
deficits; if blood loss has been extensive, administration of packed red blood cells is
preferred to whole blood. If very rapid reversal of the fibrinolytic state is required,
administration of an antifibrinolytic agent such as epsilon-aminocaproic acid may be
considered (see section 4.9).
Urokinase medac is a highly purified enzyme produced from human urine. It also
contains human serum albumin. Products manufactured from human source materials
have the potential to transmit infectious agents. Procedures to control such risks
strongly reduce but cannot completely eliminate the risk of transmitting infectious
agents.

4.5

Interaction with other medicinal products and other forms of interaction
Anticoagulants

Oral anticoagulants or heparin may increase the risk of haemorrhage and
should not be used concomitantly with urokinase.
Active substances affecting platelet function
Due to increased risk of haemorrhage, concomitant use of urokinase and
active substances that affect platelet function (e.g., acetylsalicylic acid, other
non-steroidal anti-inflammatory agents, dipyridamole, dextrans) should be
avoided.
Contrast agents
Contrast agents may delay fibrinolysis.

4.6

Pregnancy and lactation
There are no adequate data from the use of urokinase in pregnant women.
Animal studies are insufficient with respect to effects on pregnancy,
embryonal/fetal development, parturition or postnatal development. The
potential risk for humans is unknown. However, low-molecular urokinase
fragments and active plasmin cross the placenta.
Urokinase should not be used during pregnancy or in the immediate postpartum period unless clearly necessary.
It is unknown whether urokinase is excreted into human breast milk. Breastfeeding should be avoided during treatment with urokinase.

4.7

Effects on ability to drive and use machines
Not relevant.

4.8

Undesirable effects

Haemorrhage
The most frequent and severe adverse effect of urokinase therapy is haemorrhage. The
haemostatic status of the patient may be more profoundly altered with urokinase
therapy than with heparin or coumarin-derivative anticoagulant therapy.
Severe spontaneous bleeding, including fatalities resulting from cerebral
haemorrhage, has occurred during urokinase therapy. Less severe spontaneous
bleeding has occurred approximately twice as frequently as that occurring during
heparin therapy. Patients with pre-existing haemostatic defects have the greatest risk
of spontaneous bleeding.

Moderate decreases in haematocrit not accompanied by clinically detectable bleeding
have been reported in approximately 20 % of patients receiving urokinase.
Hypersensitivity reactions
In contrast to streptokinase, urokinase is reportedly non-antigenic. However, mild
allergic reactions including bronchospasm and rash have been reported rarely. In
addition, very rare cases of fatal anaphylaxis have been reported.
Infusion Reactions
Fever and chills, including shaking chills (rigors), have been reported occasionally in
patients receiving urokinase. Symptomatic treatment is usually sufficient to alleviate
discomfort caused by urokinase-induced fever; however, acetylsalicylic acid should
not be used.
Other infusion reactions reported with urokinase therapy include dyspnoea, cyanosis,
hypoxemia, acidosis, back pain, and nausea and/or vomiting; these reactions generally
occurred within one hour of beginning urokinase infusion.
The following frequency convention was used as a basis for the evaluation of
undesirable effects:
Very common
Common:
Uncommon:
Rare:
Very rare

≥ 1/10
≥ 1/100 to < 1/10
≥ 1/1,000 to < 1/100
≥ 1/10,000 to < 1/1,000
< 1/10,000

Immune system disorders
Rare
Hypersensitivity reactions including dyspnoea, hypotension,
flushing, urticaria, rash
Very rare
Anaphylactic reactions
Vascular disorders
Very common

Common

Uncommon

Haemorrhage from puncture sites, wounds
Haematoma
Epistaxis, gingival bleeding
Haematuria (microscopic)
Intracranial haemorrhage
Gastrointestinal haemorrhage, retroperitoneal haemorrhage
Urogenital haemorrhage
Muscle haemorrhage
Embolism, including cholesterol embolism
Intrahepatic haemorrhage

General disorders and administration site conditions
Common
Fever, chills
Investigations
Very common
haemorrhage

Decrease in haematocrit without clinically detectable
Transient increase in transaminases

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 at: www.mhra.gov.uk/yellowcard.
4.9

Overdose
Haemorrhage that occurs during treatment with urokinase may be controlled
with local pressure and treatment continued. If severe bleeding occurs,
treatment with urokinase must be stopped and inhibitors such as aprotinin,
epsilon-aminocaproic acid, p-aminoethylbenzoic acid or tranexamic acid can
be given. In serious cases, human fibrinogen, factor XII, packed red cells or
whole blood should be given as appropriate. For correction of volume
deficiency, dextrans should be avoided.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
ATC code: B01A D04, antithrombotic agent.
Urokinase medac is a highly purified form of naturally occurring human urokinase
extracted from urine. Urokinase exists in two distinct molecular entities, a high
molecular weight (approximately 54,000 daltons) and a low molecular weight
(approximately 33,000 daltons). Urokinase medac contains more than 85 % of the
HMW form.
Urokinase is a thrombolytic agent which converts plasminogen into plasmin
(fibrinolysin) a proteolytic enzyme that degrades fibrin as well as fibrinogen and
other plasma proteins. The activity of urokinase leads to a dose-dependent decrease in
plasminogen and fibrinogen levels and to increased presence of fibrin and fibrogen
degradation products, which have an anticoagulant effect and potentiate the effect of
heparin. These effects persist for 12 – 24 hours after the end of urokinase infusion.

5.2

Pharmacokinetic properties
Urokinase is eliminated rapidly from the circulation by the liver with a halflife of 10 to 20 minutes. The inactive degradation products are excreted via
the bile and primarily via the kidneys.
Elimination is delayed in patients with liver disease and impaired kidney
function.

5.3

Preclinical safety data
There is no preclinical safety data of additional value to the prescribing
physician.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate,
human albumin.

6.2

Incompatibilities
No information is available regarding loss of activity in PVC containers or
plastic bags/syringes.

6.3

Shelf life
32 months
Use reconstituted material immediately.
After reconstitution and dilution, chemical and physical stability has been
demonstrated for 72 hours at room temperature. From a microbiological point
of view, the product should be used immediately after reconstitution and
dilution. If not used immediately, in-use storage times and conditions prior to
use are the responsibility of the user and would normally not be longer than 24
hours at 2 °C to 8 °C.

6.4

Special precautions for storage
Do not store above 25 ºC.
Keep the vial in the outer container to protect from light.

6.5

Nature and contents of container
All presentations are contained in borosilicate clear type 1 glass vials closed
with chlorobutyl rubber stoppers and sealed with an aluminium flip-off cap.

6.6

Special precautions for disposal
The powder for solution for infusion should be dissolved in water for injection
and further diluted with 0.9 % sodium chloride solution or glucose 5 % or
glucose 10 % solution.
The powder is to be reconstituted as follows:
For a 250,000 I.U. vial use 5 ml of water for injection.
After reconstitution the solution must be clear and colourless.

7

MARKETING AUTHORISATION HOLDER

medac
Gesellschaft für klinische
Spezialpräparate mbH
Theaterstr.6
22880 Wedel
Germany
Phone: +49 (0)4103 8006-0
Fax: +49 (0)4103 8006-100

8

MARKETING AUTHORISATION NUMBER(S)
PL 11587/0068

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
17/03/2010

10

DATE OF REVISION OF THE TEXT
29/04/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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