Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions in the form of a mass or white powder.
1 f.
urokinase 500,000 IU
Excipients: human serum albumin, sodium dodecahydrate hydrophosphate, sodium dihydrogen phosphate dihydrate.
The free space in the vial is filled with nitrogen to create an inert atmosphere.
Vials (1) - packs of cardboard.
Lyophilizate for the preparation of a solution for infusions in the form of a mass or white powder.
1 f.
urokinase 10,000 IU
Excipients: human serum albumin, sodium dodecahydrate hydrophosphate, sodium dihydrogen phosphate dihydrate.
The free space in the vial is filled with nitrogen to create an inert atmosphere.
Vials (1) - packs of cardboard.
Lyophilizate for the preparation of a solution for infusions in the form of a mass or white powder.
1 f.
urokinase 100,000 IU
Excipients: human serum albumin, sodium dodecahydrate hydrophosphate, sodium dihydrogen phosphate dihydrate.
The free space in the vial is filled with nitrogen to create an inert atmosphere.
Vials (1) - packs of cardboard.
Lyophilizate for the preparation of a solution for infusions in the form of a mass or powder of white color.
1 f.
urokinase 50,000 IU
Excipients: human serum albumin, sodium dodecahydrate hydrophosphate, sodium dihydrogen phosphate dihydrate.
The free space in the vial is filled with nitrogen to create an inert atmosphere.
Vials (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2012.
PHARMACHOLOGIC EFFECT
Urokinase is a proteolytic enzyme with an amino acid serine as an active center (synonym: serine protease). As a direct plasminogen activator, the enzyme is able to penetrate the thrombus and convert plasminogen into plasmin through hydrolysis of the arginine-valine bond. Plasmin destroys fibrin, resulting in the dissolution of thrombus (as opposed to the action of anticoagulants, which only inhibit the formation of a thrombus).
Urokinase activity 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 with bile and urine. T 1/2 is about 10-20 minutes. Clinically, the duration of action depends on the duration of the activated plasmin. Reduction of levels of plasminogen and fibrinogen, as well as an increase in the content of degradation products of fibrin and fibrinogen, caused by the introduction 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;
- Occlusion of peripheral vessels;
- blocking by fibrin clots of shunts during hemodialysis.
DOSING MODE
The drug is applied iv / drip or jet.
The required dose is selected individually. Therefore, the following diagrams 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 3-5 times relative to the norm is considered optimal to achieve an adequate effect. Also, standard blood coagulability parameters should be monitored in order to select the dosage based on them.
Deep vein thrombosis
- Initial dose of 4400 IU / kg of body weight, for patients with increased risk - 150,000 MEv for 10-20 minutes;
- Maintenance dose of 100,000 IU / h, for patients at increased risk
- 40000-60000 MEv for 2-3 days. If the desired effect can not be achieved after 72 hours, the dose may be increased, in each case individually.
Severe pulmonary embolism
- Initial dose of 4400 IU / kg of body weight for 10-20 min
- Maintenance dose of 4400 IU / kg body weight per hour for 12 hours
If the desired effect can not be achieved after 24 hours, the dose may be increased, in each case individually.
Occlusion of peripheral vessels
4000 IU / min (240,000 IU / h) is infused into the intraarterial catheter in the first 2-4 hours, or until the anterograde flow of blood (permeability) is restored, then 1000-2000 IU / min. Infusion should be discontinued after the completion of the thrombus lysis, if the arteriography shows no further progress, or after 48 hours after the start of the infusion.
Blocking fibrin clots of hemodialysis shunts
For the purpose of lysis of blockages of thrombosed arteriovenous shunts, the preparation is dissolved in 2-3 ml of physiological solution to obtain a solution with a concentration of 5000 to 25000 IU / ml. The solution is introduced into both branches of the arteriovenous shunt. If necessary, the administration is repeated after 30-45 minutes. The total time of application should not exceed 2 hours.
To prevent the re-formation of clots after the application of urokinase, treatment with heparin and oral anticoagulants in usual doses with the control of standard coagulogram parameters should be started.
Preparation of the drug solution
Before use, the preparation should be dissolved in water for injection in accordance with the diagram below:
Vial 10000 ME Use 2 ml of a solvent
Bottle 50000 ME Use 2 ml of solvent
Vial 100000 ME Use 2 ml of a solvent
Vial 500000 ME Use 10 ml of a solvent
After that, it can be diluted to the required concentration of 0.9% solution of sodium chloride, or 5% or 10% glucose solution. The solution should be used immediately after preparation.
SIDE EFFECT
Frequency Side effect
Frequent (> 1/100, <1/10) Hemorrhages: microhematuria, bleeding from puncture sites, bleeding from wounds, hematomas, epistaxis, gum bleeding. Laboratory indicators: a decrease in hematocrit without clinical signs of bleeding
Less often (> 1/1000, <1/100) Hemorrhage: bleeding from the gastrointestinal tract, intracranial hemorrhage. Vascular disorders: embolism. The body as a whole: fever, chills
Rarely (> 1/10000, <1/1000) Hemorrhages: life-threatening hemorrhages (intracranial, retroperitoneal, from the gastrointestinal tract, urogenital, intrahepatic hemorrhages and hemorrhages to other organs), stroke Hypersensitivity: allergic reactions in the form of fever, hives, bronchospasm, blood pressure
Very rarely (<1/10000), including individual reports Hypersensitivity: anaphylactic reactions. Hepatobiliary disorders: a transient increase in the level of transaminases
Hemorrhage
The most frequent and severe side effect in the administration of urokinase is hemorrhage, since urokinase therapy leads to more severe disorders in the hemostatic system compared to anticoagulant therapy with heparin and coumarin derivatives. In the event of bleeding in a patient who has been given urokinase, such bleeding may be difficult to control. Urokinase is used for the production of plasmin in quantities sufficient for lysis of intravascular fibrin stores, however, when it is used, lysis of fibrin stores is also being made, including to provide hemostasis (at puncture sites with needles, incisions, etc.) as a result of which bleeding may occur in such places. Often there is bleeding in the areas of damage to the skin and subcutaneous fat. During therapy with urokinase, the risk of bruising and bruising is high, especially after intramuscular injections. It is necessary to avoid treatment of urokinase patients in cases when it is possible to do without its use. To minimize the possibility of bleeding before and during treatment with urokinase, invasive procedures on the arteries should be avoided; if arterial puncture is absolutely necessary, it should be performed by a specialist who has appropriate experience with such procedures, preferably using the radial or shoulder, rather than the femoral arteries. At the place of the puncture, a tight bandage should be applied for at least 30 minutes, and this place should be checked frequently enough for signs of bleeding. Invasive procedures on the veins should be carried out carefully and as rarely as possible. If bleeding from the site of the invasive procedure is insignificant, urokinase therapy can be continued with careful monitoring of the patient, and appropriate local activities such as the imposition of a tight bandage should be immediately carried out.
Serious spontaneous bleeding, including fatal cerebral hemorrhages, was observed with 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. In the event of such bleeding, the administration of urokinase should be stopped immediately. To eliminate the deficit of the volume of circulating blood, plasma-substituting agents can be used with the exception of dextrans; in the case of intensive blood loss, the appointment of erythrocytic mass is preferred. If very rapid restoration of the fibrinolytic status is required, antifibrinolytic agents, such as epsilon-aminocaproic acid (see Overdose), may be recommended.
Hypersensitivity reactions
Unlike streptokinase, no antigenic properties of urokinase have been reported; in-vitro tests and intradermal tests in humans showed no evidence of urokinase-induced antibody formation. However, there have been reports of rare allergic reactions of moderate severity, including bronchospasm and urticaria. In addition, there have been reports of rare cases of anaphylactic reactions.
Fever
Occasionally, cases of heat and shivering were reported in patients treated with urokinase, although no direct relationship was found with the drug. In cases of such reactions, it is usually sufficient to perform symptomatic treatment in order to eliminate discomfort; thus it is impossible to use acetylsalicylic acid.
Other side effects
Seldom reported cases of embolism due to the disintegration of blood clots. About a moderate decrease in hematocrit, not accompanied by clinically detected bleeding, was reported in approximately 20% of patients receiving urokinase. Other side effects of urokinase: dyspnea, hypoxemia, acidosis, back pain, nausea and / or vomiting, purpura, headache, lethargy; there are reports of the onset of these symptoms individually or in combination, with no causal relationship with urokinase established.
CONTRAINDICATIONS
- hypersensitivity to any components of the drug;
- signs of bleeding;
- increased risk of bleeding associated with severe thrombocytopenia; recent bleeding from the gastrointestinal tract (GIT); neoplasms (including brain tumors, metastases); intracranial aneurysm, cerebral thrombosis (including in anamnesis), arteriovenous malformation, exfoliating aneurysm; pulmonary tuberculosis in active form, bronchiectasis with a tendency to hemoptysis; varicose veins of the esophagus; erosive-ulcerative lesions of the gastrointestinal tract; cirrhosis of the liver; severe impairment of kidney function (eg, due to urolithiasis, pyelonephritis, glomerulonephritis); recent birth (the first 4 weeks after childbirth), abortion, the threat of miscarriage, suspicion of placenta previa; recently transferred surgical intervention, until the healing of the main wound; puncture of blood vessels in cases where visual control and / or application of a pressure bandage to the vessel is not possible (prescription <4 weeks); recent biopsy of internal organs, lumbar puncture, intramuscular injections, translumbral aortography (<4 weeks), prolonged indirect cardiac massage (<10 days); recently suffered trauma, thoracic surgical or neurosurgical operation (<2 months);
- hypocoagulation (especially on 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 disorders of cerebral circulation (for example, intracranial bleeding, hemorrhagic and / or ischemic stroke, transient ischemic attacks that have occurred during the last two months, arterial occlusions in the carotid artery and vertebrobasilar system of blood vessels);
- severe uncontrolled arterial hypertension (systolic pressure> 200 mm Hg, diastolic> 100 mm Hg); hypertonic fundus of III or IV stage;
- Acute pancreatitis, pericarditis, bacterial endocarditis, sepsis;
- Pregnancy (I trimester);
- Children's age (up to 18 years).
With caution: moderate arterial hypertension, moderate thrombocytopenia, suspected thrombosis of the left ventricle of the heart, hepatic and / or renal failure, elderly age (over 70 years), suspected damage to internal organs.
PREGNANCY AND LACTATION
There are insufficient data on the use of the drug in pregnant women. Experimental studies in animals showed no evidence of side effects affecting reproductive function, but are inadequate due to low doses used in the tests.
Low molecular weight fragments of urokinase and active plasmin penetrate the placenta.
During pregnancy, urokinase should only be used for vital signs because of the risk to the fetus.
You can not exclude the possibility of bleeding, premature birth pains and separation of the placenta. Urokinase can not be used during the first 4 weeks after childbirth.
There is no information on the ability of urokinase to enter breast milk, but it is unlikely that significant quantities of the drug can enter through breast milk to the baby. Urokinase can be used during breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution: kidney failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution: liver failure.
APPLICATION FOR CHILDREN
Contraindicated in children and adolescents under 18 years.
APPLICATION IN ELDERLY PATIENTS
With caution: the elderly (more than 70 years).
SPECIAL INSTRUCTIONS
To prepare a solution of urokinase, do not use any drugs other than those mentioned in the section "Method of administration and dose".
Do not mix urokinase in one solution with other medicines. The drug solution should be used immediately after preparation. In case of bleeding occur according to the recommendations given in the "Side effect" section.
Do not use dextran to restore the volume of circulating blood. they cause disaggregation of platelets (see section "Side effect"). Attention:
- in elderly patients (especially after 75 years) urokinase can be used only if the expected benefit from effective thrombolysis exceeds the potential risk of cerebral bleeding;
- in patients with atrial fibrillation or in other clinical situations in which there is a risk of cerebral embolism, urokinase therapy may be dangerous because of the risk of bleeding to the area of ​​the cerebral infarction.
Precautions
Treatment with urokinase should be performed exclusively by a doctor who has experience in the treatment of thrombotic pathologies in clinics where it is possible to monitor thrombin time and other necessary clinical and laboratory indicators. Before starting treatment with urokinase, the overall clinical status of the patient should be carefully evaluated, its medical history carefully examined, including medicines used during previous or concomitant treatment, and surgical interventions. It is necessary to take into account the interrelation of fibrinolysis, blood clotting and platelet aggregation, which may be important from the point of view of synergistic action of urokinase with other antiplatelet drugs and anticoagulants.
During therapy with urokinase, intramuscular injections and the use of rigid catheters should be avoided.
Note: Urokinase is a highly purified enzyme derived from human urine. Preparations made from products of human origin are potentially capable of carrying infectious agents. To avoid the transfer of infections, special procedures are used that significantly reduce the risk of such a transfer, but do not completely exclude its possibility.
Safety and effectiveness of urokinase in children have not been established.
Impact on the ability to drive vehicles and manage mechanisms
During therapy with urokinase, patients should not drive the car and use the mechanisms because of the increased risk of bleeding even with minimal injuries.
OVERDOSE
Overdose can lead to hemorrhage (see section Side effect). Urokinase-induced transformation of plasminogen into plasmin can be competitively inhibited by the use of aprotinin and synthetic fibrinolysis inhibitors such as epsilon-aminocaproic or tranexamic acid. Given fibrinolysis inhibitors, however, did not potentiate the anticoagulant effect of fibrinogen / fibrin in the circulation hydrolysis products.
DRUG INTERACTION
Urokinase pharmaceutically compatible in the same solution with other drugs.
For the preparation of urokinase solution should not be used any drugs other than those specified in the "Method of use and dosage."
Anticoagulants
Oral anticoagulants and heparin may increase the risk of bleeding, so they should not be used in combination with urokinase.
Agents affecting platelet function
to reduce the risk of bleeding avoid sharing urokinase with drugs affecting platelet function (e.g., acetylsalicylic acid, dipyridamole, indomethacin, phenylbutazone, sulfinpyrazone).
X-ray contrast agents
May impede fibrinolysis. Action urokinase reduced by using epsilon-amino caproic acid, tranexamic acid.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
Store in the dark and away from children at a temperature not higher than 25 В° C.
Shelf life - 3 years.
Do not use after the expiration date printed on the package.
