Urokinase Medac (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Medac, GmbH (Germany)

Manufactured By

Green Cross Corporation (Republic of Korea)

ATC Code

B01AD04 (Urokinase)

Active Substance

Urokinase (Rec.INN registered by WHO)

Dosage Forms

	Urokinase Medac	Lyophilisate for preparation of solution for infusion 10 thousand IU: vial 1 pc.
		Lyophilisate for preparation of solution for infusion 50 thousand IU: vial 1 pc.
		Lyophilisate for preparation of solution for infusion 100 thousand IU: vial 1 pc.
		Lyophilisate for preparation of solution for infusion 500 thousand IU: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion as a mass or white powder.

Excipients: human serum albumin, sodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate.

The free space in the vial is filled with nitrogen to create an inert atmosphere.

Vials (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion as a mass or white powder.

Excipients: human serum albumin, sodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate.

The free space in the vial is filled with nitrogen to create an inert atmosphere.

Vials (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion as a mass or white powder.

Excipients: human serum albumin, sodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate.

The free space in the vial is filled with nitrogen to create an inert atmosphere.

Vials (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion as a mass or white powder.

Excipients: human serum albumin, sodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate.

The free space in the vial is filled with nitrogen to create an inert atmosphere.

Vials (1) – cardboard packs.

Clinical-Pharmacological Group

Thrombolytic – tissue plasminogen activator

Pharmacotherapeutic Group

Fibrinolytic agent

Pharmacological Action

Urokinase is a proteolytic enzyme with the amino acid serine as the active center (synonym: serine protease). As a direct plasminogen activator, the enzyme is able to penetrate the thrombus and convert plasminogen into plasmin within it by hydrolyzing the arginine-valine bond. Plasmin breaks down fibrin, resulting in the dissolution of the thrombus (unlike the action of anticoagulants, which only inhibit thrombus formation).

The activity of urokinase leads to a dose-dependent decrease in plasminogen and fibrin levels, and also increases the levels of fibrin and fibrinogen degradation products, which has an anticoagulant effect and enhances the effect of heparin.

Pharmacokinetics

Urokinase is metabolized in the liver. Inactive degradation products are excreted in bile and urine. T_1/2 is about 10-20 min. Clinically, the duration of action depends on the duration of action of activated plasmin. The decrease in plasminogen and fibrinogen levels, as well as the increase in fibrin and fibrinogen degradation products caused by the administration of urokinase, persists for 12-24 hours after the end of the infusion.

Indications

Treatment of acute vascular occlusions caused by thrombosis or embolism

• Deep vein thrombosis;
• Severe pulmonary embolism;
• Peripheral vascular occlusions;
• Blockage of hemodialysis shunts by fibrin clots.

ICD codes

Dosage Regimen

The drug is administered intravenously by drip or bolus.

The required dose is selected individually. Thus, the schemes below should be used as a general guide for dose selection. Depending on the clinical picture, the dose may be increased. As a rule, an increase in thrombin time by 3-5 times relative to the norm is considered optimal for achieving an adequate effect. Standard blood coagulation parameters should also be monitored to guide dosage selection.

Deep vein thrombosis

• Initial dose 4400 IU/kg body weight, for patients at increased risk – 150,000 IU over 10-20 min;
• Maintenance dose 100,000 IU/h, for patients at increased risk
• 40,000-60,000 IU over 2-3 days. If the desired effect is not achieved after 72 hours, the dose may be increased, in each case individually.

Severe pulmonary embolism

• Initial dose 4400 IU/kg body weight over 10-20 min
• Maintenance dose 4400 IU/kg body weight per hour for 12 hours

If the desired effect is not achieved after 24 hours, the dose may be increased, in each case individually.

Peripheral vascular occlusion

4000 IU/min (240,000 IU/h) is administered by infusion into an intra-arterial catheter for the first 2-4 hours, or until anterograde blood flow (patency) is restored, then 1000-2000 IU/min. The infusion should be stopped after completion of thrombus lysis, if angiography shows no further progress, or after 48 hours from the start of the infusion.

Blockage of hemodialysis shunts by fibrin clots

For use in lysing blockages of thrombosed arteriovenous shunts, the drug is dissolved in 2-3 ml of saline to obtain a solution with a concentration of 5000 to 25000 IU/ml. The solution is injected into both branches of the arteriovenous shunt. If necessary, the administration is repeated after 30-45 minutes. The total time of drug use should not exceed 2 hours.

To prevent re-formation of clots after urokinase use, treatment with heparin and oral anticoagulants in usual doses should be initiated with monitoring of standard coagulogram parameters.

Preparation of the drug solution

Before use, the drug should be dissolved in water for injections according to the scheme below

Vial 10000 IU Use 2 ml of solvent

Vial 50000 IU Use 2 ml of solvent

Vial 100000 IU Use 2 ml of solvent

Vial 500000 IU Use 10 ml of solvent

After that, it can be diluted to the required concentration with 0.9% sodium chloride solution, or 5% or 10% glucose solution. The solution should be used immediately after preparation.

Adverse Reactions

Hemorrhages

The most frequent and severe side effect of urokinase use is hemorrhage, as urokinase therapy leads to more severe disturbances in the hemostatic system compared to anticoagulant therapy with heparin and coumarin derivatives. If bleeding occurs in a patient who has been administered Urokinase, such bleeding may be difficult to control. Urokinase is used to produce plasmin in quantities sufficient to lyse intravascular fibrin stores; however, its use also leads to the lysis of fibrin stores intended, among other things, to ensure hemostasis (at needle puncture sites, incisions, etc.), as a result of which bleeding may occur at such sites. Bleeding often occurs at sites of skin and subcutaneous fat damage. During urokinase therapy, the likelihood of bruising and hematomas is high, especially after intramuscular injections. Urokinase treatment should be avoided in patients in cases where it can be dispensed with. To minimize the possibility of bleeding before and during urokinase treatment, invasive procedures on arteries should be avoided; if arterial puncture is absolutely necessary, it should be performed by a specialist with appropriate experience in such procedures, preferably using radial or brachial, rather than femoral arteries. A pressure bandage should be applied to the puncture site for at least 30 minutes, and such a site should be checked frequently for signs of bleeding. Invasive procedures on veins should be performed carefully and as infrequently as possible. If bleeding from the site of an invasive procedure is minor, urokinase therapy may be continued with careful monitoring of the patient, while appropriate local measures, such as applying a pressure bandage, should be taken immediately.

Serious spontaneous bleeding, including fatal cerebral hemorrhage, has been observed during urokinase therapy. Less serious spontaneous bleeding was observed approximately twice as often as with heparin therapy. In patients with pre-existing hemostasis disorders, the risk of spontaneous bleeding is highest. If such bleeding occurs, the administration of urokinase should be stopped immediately. Plasma substitutes, except for dextrans, may be used to correct the circulating blood volume deficit; in case of significant blood loss, erythrocyte mass is preferable. If very rapid restoration of fibrinolytic status is necessary, the administration of antifibrinolytics such as epsilon-aminocaproic acid may be recommended (see Overdose section).

Hypersensitivity reactions

Unlike streptokinase, no antigenic properties of urokinase have been reported; in-vitro tests and intradermal tests in humans have not revealed signs of urokinase-induced antibody formation. However, rare moderate allergic reactions, including bronchospasm and urticaria, have been reported. In addition, rare cases of anaphylactic reactions have been reported.

Fever

Cases of fever and chills have sometimes been reported in patients treated with urokinase, although a direct causal relationship with the drug has not been established. In the event of such reactions, symptomatic treatment is usually sufficient to relieve discomfort; acetylsalicylic acid should not be used for this purpose.

Other side effects

Cases of embolism due to thrombus disintegration have been rarely reported. A moderate decrease in hematocrit, not accompanied by clinically detected bleeding, has been reported in approximately 20% of patients receiving urokinase. Other side effects encountered with urokinase use: dyspnea, hypoxemia, acidosis, back pain, nausea and/or vomiting, purpura, headache, lethargy; there are reports of these symptoms occurring separately or together, but a causal relationship with urokinase use has not been established.

Contraindications

• Hypersensitivity to any components of the drug;
• Signs of bleeding;
• Increased risk of bleeding associated with severe thrombocytopenia; recent gastrointestinal (GI) bleeding; neoplasms (including brain tumors, metastases); intracranial aneurysm, cerebral thrombosis (including in history), arteriovenous malformation, dissecting aneurysm; active pulmonary tuberculosis, bronchiectasis with a tendency to hemoptysis; esophageal varices; erosive-ulcerative lesions of the GI tract; liver cirrhosis; severe renal impairment (e.g., due to urolithiasis, pyelonephritis, glomerulonephritis); recent childbirth (first 4 weeks after delivery), abortion, threatened miscarriage, suspected placenta previa; recent surgery, until the main wound has healed; puncture of blood vessels in cases where visual control and/or application of a compressive bandage to the vessel is impossible (< 4 weeks ago); recent biopsy of internal organs, lumbar puncture, intramuscular injections, translumbar aortography (< 4 weeks), prolonged indirect cardiac massage (< 10 days); recent trauma, thoracic surgery or neurosurgery (< 2 months);
• Hypocoagulation (especially against the background of severe hepatic and/or renal failure);
• Hematoma, acute pulmonary edema, bleeding tumor, diabetic hemorrhagic retinopathy;
• Subacute bacterial endocarditis, mitral stenosis, atrial fibrillation;
• Acute cerebrovascular accidents (e.g., intracranial bleeding, hemorrhagic and/or ischemic stroke, transient ischemic attacks that occurred within the last two months; arterial occlusions in the carotid artery and vertebrobasilar system);
• Severe uncontrolled arterial hypertension (systolic pressure >200 mm Hg, diastolic >100 mm Hg); hypertensive fundus stage III or IV;
• Acute pancreatitis, pericarditis, bacterial endocarditis, sepsis;
• Pregnancy (I trimester);
• Children’s age (under 18 years).

With caution: moderate arterial hypertension, moderate thrombocytopenia, suspected left ventricular heart thrombosis, hepatic and/or renal failure, elderly age (over 70 years), suspected internal organ damage.

Use in Pregnancy and Lactation

There are insufficient data on the use of the drug in pregnant women. Experimental animal studies have not revealed evidence of adverse effects on reproductive function, but are insufficient due to the low doses used in the tests.

Low molecular weight fragments of urokinase and active plasmin cross the placenta.

During pregnancy, urokinase should be used only for vital indications due to the danger to the fetus.

The possibility of bleeding, premature labor contractions, and placental abruption cannot be ruled out. Urokinase should not be used during the first 4 weeks after delivery.

There is no information on the ability of urokinase to pass into breast milk, but it is considered unlikely that significant amounts of the drug could reach the child through breast milk. Urokinase can be used during breastfeeding.

Use in Hepatic Impairment

With caution hepatic insufficiency.

Use in Renal Impairment

With caution renal insufficiency.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

With caution: elderly age (over 70 years).

Special Precautions

For the preparation of urokinase solution, no drugs other than those indicated in the “Dosage and Administration” section should be used.

Urokinase should not be mixed in one solution with other medicinal products. The drug solution should be used immediately after preparation. In case of bleeding, follow the recommendations given in the “Adverse Reactions” section.

The use of dextrans to restore circulating blood volume should be avoided, as they cause platelet disaggregation (see “Adverse Reactions” section). Attention

• In elderly patients (especially after 75 years) Urokinase can be used only in cases where the expected benefit from effective thrombolysis outweighs the potential risk of cerebral bleeding;
• In patients with atrial fibrillation or in other clinical situations where there is a risk of cerebral embolism, urokinase therapy may be dangerous due to the risk of bleeding into the area of cerebral infarction.

Precautions

Urokinase treatment should be carried out exclusively by a physician experienced in the treatment of thrombotic pathologies, in clinics where monitoring of thrombin time and other necessary clinical and laboratory parameters is possible. Before starting urokinase treatment, the general clinical status of the patient should be carefully assessed, his medical history, including medications used during previous or concomitant treatment, and past surgical interventions should be thoroughly studied. The interrelationship of fibrinolysis, blood coagulation, and platelet aggregation, which may be important in terms of the synergistic action of urokinase with other antiplatelet drugs and anticoagulants, should be taken into account.

During urokinase therapy, intramuscular injections and the use of rigid catheters should be avoided.

Note: Urokinase is a highly purified enzyme derived from human urine. Drugs made from products of human origin are potentially capable of transmitting infectious agents. Special procedures are used to exclude the transmission of infections, which significantly reduce the risk of such transmission, but do not completely exclude its possibility.

The safety and efficacy of urokinase use in children have not been established.

Effect on the Ability to Drive Vehicles and Mechanisms

During urokinase therapy, patients should not drive a car or operate machinery due to the increased risk of bleeding even with minimal trauma.

Overdose

Overdose may lead to hemorrhage (see section Adverse Reactions). The urokinase-induced transformation of plasminogen into plasmin can be competitively inhibited by the application of aprotinin and synthetic fibrinolysis inhibitors, such as epsilon-aminocaproic acid or tranexamic acid. These fibrinolysis inhibitors, however, do not potentiate the anticoagulant effect of fibrinogen/fibrin hydrolysis products in the circulating blood.

Drug Interactions

Urokinase is pharmaceutically incompatible in the same solution with other medicines.

No agents other than those specified in the “Dosage and Administration” section should be used for the preparation of the urokinase solution.

Anticoagulants

Oral anticoagulants, as well as heparin, may increase the risk of bleeding and therefore should not be used concomitantly with urokinase.

Drugs Affecting Platelet Function

To reduce the risk of bleeding, concomitant use of urokinase with drugs affecting platelet function (e.g., acetylsalicylic acid, dipyridamole, indomethacin, phenylbutazone, sulfinpyrazone) should be avoided.

Radiocontrast Agents

May impede fibrinolysis. The effect of urokinase is reduced when used with ?-aminocaproic acid, tranexamic acid.

Storage Conditions

Store in a light-protected place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.