UROKINASE MEDAC 1,000,000 IU

The format of this leaflet was determined by the Ministry of Health and its content

was checked and approved in July 2010.

UROKINASE MEDAC 10,000 I.U, 50,000 I.U,

100,000 I.U, 250,000 I.U, 500,000 I.U

Information for Health Professionals

1.

Name of the medicinal product

Urokinase medac 10,000 I.U.

Urokinase medac 50,000 I.U.

Urokinase medac 100,000 I.U.

Urokinase medac 250,000 I.U.

Urokinase medac 500,000 I.U.

Powder for solution for injection or infusion

2.

Qualitative and quantitative composition

1 vial of Urokinase medac 10,000 I.U. with 24 mg of powder for solution for injection

or infusion contains 10,000 IU of urokinase.

1 vial of Urokinase medac 50,000 I.U. with 38 mg of powder for solution for injection

or infusion contains 50,000 IU of urokinase.

1 vial of Urokinase medac 100,000 I.U. with 39 mg of powder for solution for injection

or infusion contains 100,000 IU of urokinase.

1 vial of Urokinase medac 250,000 I.U. with 63 mg of powder for solution for injection

or infusion contains 250,000 IU of urokinase.

1 vial of Urokinase medac 500,000 I.U. with 125 mg of powder for solution for injection

or infusion contains 500,000 IU of urokinase.

For a complete list of excipients, see section 6.1.

3.

Pharmaceutical form

Powder for solution for injection/infusion

4.

Clinical particulars

4.1

Therapeutic indications

Peripheral arterial thrombosis

Acute and subacute deep vein thrombosis

Acute

diagnostically

confirmed

pulmonary

embolism,

particular

when

associated with unstable haemodynamic status

Thrombosed arteriovenous shunt

4.2

Posology and method of administration

Dosage:

Dosages are determined in accordance with the respective indication.

Peripheral arterial thrombosis

Systemic lysis:

For the treatment of arterial occlusion, the recommended initial dose of urokinase is

250,000 ‑ 600,000 IU given intravenously over 10 ‑ 20 minutes, with 80,000 ‑ 150,000

IU urokinase/h as a maintenance dose.

Simultaneous administration of heparin is generally required to ensure adequate

protection against recurrent thrombosis. The start time and duration of the heparin

infusion will depend on the aPTT, which should be extended to 1.5 to 2.5 times the

normal aPTT. A dose of 500 ‑ 1,000 IU of unfractionated heparin/h i.v. is generally

sufficient.

Local lysis:

The thrombus is first infiltrated with urokinase solution. The dose should not exceed

100,000 ‑ 120,000 IU/hour for a patient weighing 70 kg. Local lysis is performed until

a successful outcome has been achieved (up to a maximum of 48 hours).

Deep vein thrombosis

The initial dose of urokinase is 250,000 ‑ 600,000 IU urokinase given intravenously

over 10 ‑ 20 minutes. The maintenance dose is 40,000 ‑ 100,000 IU/h.

Simultaneous administration of heparin is generally required to ensure adequate

protection against recurrent thrombosis. The start time and duration of the heparin

infusion will depend on the aPTT, which should be extended to 1.5 to 2.5 times the

normal aPTT. A dose of 500 ‑ 1,000 IU of unfractionated heparin/h i.v. is generally

sufficient.

Pulmonary embolism

The initial dose is 2,000 or 4,400 IU of urokinase/kg body weight given intravenously

over 10 ‑ 20 minutes. The maintenance dose is 2,000 IU of urokinase/kg body

weight/h over 24 hours with simultaneous administration of heparin, or 4,400 IU of

urokinase/kg of body weight/h over 12 hours without heparin. The start time and

duration of the heparin infusion will depend on the aPTT.

Subsequent administration of heparin is generally required to ensure adequate

protection against recurrent thrombosis. The start and duration of the heparin infusion

will depend on the aPTT, which should be extended to 1.5 to 2.5 times the normal

aPTT. A dose of 500 ‑ 1,000 IU of unfractionated heparin/h i.v. is generally sufficient.

Thrombosed arteriovenous shunt

Urokinase solution with a concentration of 5,000 ‑ 25,000 IU/ml is instilled into both

tube sets in the shunt.

Method of administration

For injection, infusion and local instillation after dissolution as instructed.

The contents of one vial of Urokinase medac 10,000 I.U. are dissolved in 2 ml of

water for injections.

The contents of one vial of Urokinase medac 50,000 I.U. are dissolved in 2 ml of

water for injections.

The contents of one vial of Urokinase medac 100,000 I.U. are dissolved in 2 ml of

water for injections.

The contents of one vial of Urokinase medac 250,000 I.U. are dissolved in 5 ml of

water for injections.

The contents of one vial of Urokinase medac 500,000 I.U. are dissolved in 10 ml of

water for injections.

For drip infusions, the contents of one vial can be dissolved in water for injections

and then diluted to a final volume of 50 ml in e.g. a 5% or 10% glucose solution or

physiological saline.

Duration of administration:

The duration of administration depends on the respective indication.

Peripheral arterial thrombosis

The duration of treatment with urokinase depends on the clinical findings and on the

results of diagnostic procedures. The average duration of treatment is 4 ‑ 5 days.

Deep vein thrombosis

The duration of treatment, which depends on an objectively confirmed successful

therapeutic outcome, is generally 7 ‑ 14 days.

Pulmonary embolism

The treatment duration is 24 hours when following the low‑dose urokinase/heparin

dosing regimen and 12 hours when following the high‑dose urokinase regimen.

Thrombosed arteriovenous shunt

The application of urokinase can if necessary be repeated every 30 minutes.

However, the duration of treatment should not exceed 2 hours.

4.3

Contraindications

Urokinase medac must not be used:

in the event of hypersensitivity (allergy) to the active substance urokinase or to

any of the excipients of Urokinase medac,

in the event of any form of reduced blood coagulation, in particular spontaneous

fibrinolysis, haemorrhagic diathesis and during concomitant treatment with oral

anticoagulants,

in the event of acute cerebrovascular events (e.g. cerebral insult, TIA), in

particular intracranial haemorrhage,

event

intracranial

neoplasms,

aneurysms

arteriovenous

malformation of the cerebral arteries,

in the event of dissecting aneurysms,

in the event of manifest, clinically relevant bleeding,

in the event of increased susceptibility to bleeding as a result of:

gastrointestinal

disorders,

such

malignant

tumours,

gastric

duodenal ulcers, acute ulcerative colitis,

genitourinary tract disorders, such as malignant tumours, urolithiasis,

pulmonary disorders such as cavitary tuberculosis or bronchiectasis,

severe hepatic disorders, such as cirrhosis of the liver, oesophageal

varices,

severe renal disorders;

within three months of severe bleeding (such as gastrointestinal or intracranial

haemorrhage), after severe trauma or a major surgical intervention (such as

coronary bypass surgery, intracranial or intraspinal surgeries or traumas),

in the first four weeks after giving birth,

in the event of abortion,

in the event of imminent abortion,

in the event of suspected placenta praevia,

following the puncture of a non‑compressible vessel,

within 10 days of an organ biopsy, lumbar puncture, external cardiac massage

over an extended period or recent intramuscular injection,

in the event of severe arterial hypertension refractory to treatment (systolic

pressure

over

mmHg,

diastolic

over

mmHg,

grade

hypertensive retinopathy),

in the event of haemorrhagic retinopathy or other diseases of the eye involving

susceptibility to bleeding,

in the event of acute pancreatitis, pericarditis, bacterial endocarditis,

in the event of sepsis.

4.4

Special warnings and special precautions for use

Urokinase may only be used with extreme caution:

in cerebrovascular diseases other than those mentioned in section 4.3 or

where there is a known history of cerebrovascular events in the more distant

past,

in arterial hypertension,

in the event of thrombi in the left heart (e.g. accompanying mitral valve stenosis

with atrial fibrillation),

in the event of septic thrombophlebitis or an infected arteriovenous fistula with

thrombotic occlusion,

in any circumstances in which a possible source of bleeding is difficult to

access,

in the event of a reduced platelet count and/or changes in laboratory parameters

indicative of impaired haemostasis (such as prolonged thrombin time, aPTT,

Quick etc.).

Intramuscular injections and the use of rigid catheters are to be avoided during

treatment with urokinase.

After cardiac massage administered during cardiopulmonary resuscitation there is an

increased risk of complications associated with bleeding.

If bleeding occurs, the procedures described in section 4.9 should be followed.

When using medicinal products made from human proteins, the transmission of

infectious diseases ‑ including those of a previously unknown nature ‑ cannot be

ruled out entirely. However, due to the required inactivation procedure (heating in

solution for 10 hours at + 60 °C), this risk is extremely small.

Patients on a high dosage are monitored, as under any fibrinolytic therapy, by

determining their fibrinogen and aPTT, and thrombin time if applicable.

By contrast, at dosages below 40,000 IU/hour, there is generally hardly any change

in laboratory parameters; fibrinolytic activity is shown in this case by a reduced

euglobulin lysis time and an increase in fibrin degradation products.

There is an increased risk of intracranial haemorrhage in elderly patients. Therefore,

the risk‑benefit ratio should be analysed with extreme care in these patients.

The experience in children is limited.

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.

4.5

Interaction with other medicinal products and other forms of

interaction

There is an increased risk of bleeding from the prior or concomitant administration of

any of the following:

anticoagulants such as heparin or coumarin derivatives,

drugs that affect platelet formation or function, such as:

acetylsalicylic acid,

allopurinol,

clofibric acid derivatives,

clopidogrel,

indomethazine,

dipyridamole,

phenylbutazone,

ticlopidine,

tetracycline,

valproic acid,

thiouracils,

sulfonamides,

cytostatic agents,

dextrans,

non‑steroidal anti‑inflammatory drugs.

The following substances inhibit the fibrinolytic action of urokinase:

antifibrinolytics such as aprotinin, p‑aminobenzoic acid, epsilon aminocaproic

acid and tranexamic acid.

4.6

Pregnancy and lactation

Pregnancy:

To date, there are no adequate data for use of urokinase during pregnancy. Low‑

molecular urokinase fragments and active plasmin cross the placenta. Although

animal studies showed no evidence of reproductive toxicity, maternal exposure was

inadequate (see section 5.3). Throughout pregnancy, because of the risk to the foetus,

urokinase must only be administered if vitally indicated and following particularly

careful consideration of the risk. The occurrence of bleeding and premature labour, as

well as passive immunisation of the foetus by maternal antibodies against urokinase,

cannot be ruled out.

The use of urokinase is absolutely contraindicated in the first four weeks after

giving birth, in the event of abortion or imminent abortion, or if placenta praevia is

suspected.

Lactation:

There are no data available regarding the passage of urokinase into breast milk.

Urokinase should only be administered during lactation if it is absolutely necessary

for the health of the mother. In this case, breast feeding should be interrupted for the

duration of the therapy.

4.7

Effects on ability to drive and use machines

Urokinase medac has negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

The following frequency convention was used as a basis for the evaluation of

undesirable effects:

Very common:

> 1/10

Common:

> 1/100 to < 1/10

Uncommon:

> 1/1,000 to < 1/100

Rare:

> 1/10,000 to < 1/1,000

Very rare:

< 1/10,000

Not known (cannot be estimated from the available data)

Blood and lymphatic system

Very common:

Drop in haematocrit without clinically identifiable

haemorrhage

Nervous system

Common:

Intracranial haemorrhage

Uncommon:

Life‑threatening intracranial haemorrhage

Eyes

Very rare:

Vitreous haemorrhage

Vascular

Common:

Embolism

Gastrointestinal tract

Common:

Gastrointestinal haemorrhage, retroperitoneal haemorrhage

Uncommon:

Life‑threatening gastrointestinal haemorrhage, life‑

threatening retroperitoneal haemorrhage

Hepatobiliary

Very common:

Transient elevated transaminases

Uncommon:

Life‑threatening intrahepatic haemorrhage

Kidneys and urinary tract

Very common:

Microscopic haematuria

Common:

Genitourinary haemorrhage

Uncommon:

Life‑threatening genitourinary haemorrhage

Skin and allergic reactions

Very rare:

Allergic reactions with flushing, urticaria, dyspnoea and

hypotension

General

Very common:

(Oozing) haemorrhage from puncture sites, wounds,

appearance or increase in size of haematomas or bruises,

nosebleeds and bleeding gums.

Common:

Fever

Uncommon:

Life‑threatening haemorrhage into parenchymatous organs

or muscle

4.9

Overdose

In the event of bleeding that can be controlled by compression, the therapy can be

continued under close monitoring.

In the event of complications due to bleeding which cannot be controlled using the

above measures and which require treatment, the urokinase therapy must be stopped

and aprotinin or another antifibrinolytic drug must be administered if necessary. The

dose of aprotinin is initially 500,000 – 1,000,000 KIU/h i.v., then 50,000 – 100,000

KIU/h until haemostasis is achieved. (Be aware of the possibility of anaphylaxis!)

In the case of severe and life‑threatening haemorrhage due to severe hyperfibrinolysis,

the urokinase treatment must be discontinued immediately. Antifibrinolytic therapy

should

complemented

with

substitution

fibrinogen

concentrate

appropriate blood products. This treatment should be given in consultation with a

specialist in transfusion medicine experienced in haemostaseology.

5.

Pharmacological properties

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: fibrinolytic

ATC code: B01AD04

Urokinase is a serine protease that occurs in different molecular forms. A distinction is

made between a high‑molecular weight and a low‑molecular weight form.

The mean molecular weight of the high‑molecular weight form (HUK) is about 54,000

Daltons, that of the low molecular weight form (LUK) is given as approximately

33,000 Daltons.

The enzyme is formed primarily in the kidneys and secreted into the urine. Urokinase

can be isolated from human urine or from the supernatants of human kidney cell

cultures or produced in recombinant form.

The activity is determined in international units based on the standard preparations

established by the WHO.

These units are based on the fibrinolytic activity of urokinase.

Prourokinase (SCUPA) is the zymogen of urokinase. It is converted into urokinase

(HUK) by trypsin‑type serine proteases such as plasmin or thrombin.

Urokinase

specific

affinity

plasminogen

molecule

converts

plasminogen directly into plasmin by hydrolysis of the arginine‑valine bond.

Fibrinous thrombi can be broken up by the fibrinolytic effect of the protease plasmin.

The plasmin activity triggered by urokinase results in a dose‑dependent drop in the

level of plasminogen and fibrinogen and to the increased incidence of fibrin and

fibrinogen degradation products (FDP), which in addition to their direct anticoagulant

effect potentiate the effect of heparin. Urokinase remains active for up to 12 ‑ 24

hours after the end of the infusion.

The conversion by urokinase of plasminogen into plasmin can be competitively

inhibited by epsilon aminocaproic acid, tranexamic acid and p‑aminobenzoic acid.

However, these fibrinolysis inhibitors do not cancel out the anticoagulant effect of

circulating fibrinogen/fibrin degradation products.

Aprotinin (like α

antiplasmin in the plasma) has a direct inhibitory effect on plasmin.

Urokinase activity can be inhibited to varying degrees in individual cases by urokinase‑

inhibiting plasma proteins (e.g. in uraemia).

5.2

Pharmacokinetic properties

Urokinase must be administered parenterally.

Urokinase is removed rapidly from circulating blood after intravenous administration.

The elimination half life of urokinase is approximately 10 – 20 minutes.

Inactivation (enzymatic degradation) probably occurs primarily in the liver. The

inactive degradation products are excreted via the bile and primarily via the kidneys.

The clinical efficacy half life depends on the duration of efficacy of the activated

plasmin and is therefore longer.

5.3

Preclinical safety data

Chronic toxicity studies in various animal species and studies investigating mutagenic

potential do not indicate any particular risks for humans. There are no long‑term

studies investigating carcinogenic potential.

Embryotoxicity studies in rats, mice and rabbits at doses corresponding at most to 1.4

times the human dose (based on a therapeutic dose in humans of 105,600 IU/kg/day)

gave no indication of any teratogenic potential. Neither were the fertility of rats and

the perinatal and postnatal development of their offspring impaired at these doses.

6.

Pharmaceutical particulars

6.1.

List of excipients

disodium

phosphate

dodecahydrate,

sodium

dihydrogen

phosphate

dehydrate,

human albumin

6.2

Incompatibilities

None identified to date.

6.3

Shelf life

The Shelf life of Urokinase medac is 3 years.

Shelf life after reconstitution of the preparation ready for use:

Once reconstituted, the solution is to be used immediately.

The solution, made under aseptic conditions, must not be stored for longer than 8

hours at 25

This medicinal product must not be used after the expiry date.

6.4

Special precautions for storage

Do not store above 25

6.5

Nature and contents of container

Urokinase medac 10,000 I.U.:

Original package with 1 vial containing 10,000 IU of urokinase

Urokinase medac 50,000 I.U.:

Original package with 1 vial containing 50,000 IU of urokinase

Urokinase medac 100,000 I.U.:

Original package with 1 vial containing 100,000 IU of urokinase

Urokinase medac 250,000 I.U.:

Original package with 1 vial containing 250,000 IU of urokinase

Urokinase medac 500,000 I.U.:

Original package with 1 vial containing 500,000 IU of urokinase

Original package with 5 x 1 vial containing 500,000 IU of urokinase

Original package with 10 x 1 vial containing 500,000 IU of urokinase

Not all pack sizes may be marketed.

6.6

Instructions for use and handling

None

7.

Manufacturer

medac GmbH, Germany.

8.

Registration Holder

Tzamal Bio‑Pharma, Petah‑Tikva.

9.

Registration numbers:

Urokinase medac 10,000 I.U: 143‑91‑33129

Urokinase medac 50,000 I.U: 143‑92‑33130

Urokinase medac 100,000 I.U: 143‑93‑33131

Urokinase medac 250,000 I.U: 143‑94‑33132

Urokinase medac 500,000 I.U: 143‑95‑33133

Urokinase medac PL PB0916‑4