The main component is recombinant human urokinase (referred to as rhPro-UK) with a molecular weight of 50KDa ± 5KDa. RhPro-UK is obtained by expressing Chinese hamster ovary cells (CHO cells) constructed by genetic engineering methods.
Each contains: Recombinant Human Urokinase 5mg
Human blood albumin 6mg
[Character] White loose body, clear, colorless and transparent liquid after reconstitution.
[Specifications] 5mg (500,000 IU) / piece.
For the treatment of acute ST-segment elevation myocardial infarction, a dose of 50mg. First, 20 mg (4) of recombinant human urokinase for injection was dissolved in 10 ml of normal saline, and then the intravenous bolus was completed within 3 minutes. The remaining 30 mg (6) was dissolved in 90 ml of normal saline, and the intravenous drip was completed within 30 minutes.
Note: After adding normal saline, gently topple over 1-2 times, do not shake it violently, so as to avoid foaming of the recombinant human urokinase solution for injection and reduce the curative effect.
Those who use heparin during treatment should pay attention to the heparin infusion dose and monitor the aPTT value. The aPTT value should be controlled 1.5 to 2.5 times before heparin administration.
The most common adverse reaction with recombinant human urokinase for injection is bleeding. There are two types of thrombolytic-related bleeding reactions:
-Bleeding on the skin surface or bleeding at the puncture site;
-Internal bleeding, usually gastrointestinal, urogenital, retroperitoneal, central nervous system or parenchymal bleeding;
Clinical studies of recombinant human urokinase for injection have shown that only a small number of patients develop ecchymosis, bleeding from the nose and gums, but no special treatment is required. Gastrointestinal, genitourinary, or retroperitoneal bleeding is rare, and intracranial bleeding is rarely reported (<1%).
Thrombolysis should be discontinued if significant visceral hemorrhage occurs, especially cerebral hemorrhage. rhPro-UK is a thrombolytic agent with selective effects on fibrin, so it has a slight effect on the coagulation system, and generally does not require the administration of coagulation factors.
The use of recombinant human urokinase for injection generally does not cause allergic reactions. If an allergic reaction occurs, instillation should be stopped and appropriate treatment given.
Occasional arrhythmias can be treated with standard anti-arrhythmic measures.
-Recombinant human urokinase for injection should not be used in people with a high risk of bleeding, such as:
-Recently (within 30 days) patients with active bleeding (gastrointestinal ulcer, hemoptysis, hemorrhoids, blood in the stool, etc.);
-Surgery or biopsy performed within three months, cardiopulmonary resuscitation (extracorporeal cardiac massage, intracardial injection, tracheal intubation), history of vascular puncture and trauma in the compression site cannot be performed
-Control of unsatisfactory hypertension (blood pressure ≥180 / 110mmHg) or aortic dissection aneurysm cannot be ruled out;
-Persons with a history of hemorrhagic stroke and vascular embolism (including TIA);
-Shock not responding to volume expansion therapy and vasopressors;
-Pregnancy, bacterial endocarditis, mitral valve disease, atrial fibrillation, and high suspicion of thrombosis in the left ventricle;
-Bleeding disorders or bleeding tendencies, severe liver and kidney dysfunction, and progressive disease;
-Diabetic patients with retinopathy;
-Patients with unconsciousness.
As with other thrombolytic drugs, the expected therapeutic effect and the possible risks should be weighed when using the drug. For example, the risk of intracranial hemorrhage increases in elderly patients, and the benefits of treatment in elderly patients increase, so the benefits and disadvantages of treatment should be weighed.
For the bleeding tendency not mentioned in the contraindications, the dosage of recombinant human urokinase for injection should not exceed 50mg, otherwise the risk of intracranial hemorrhage will increase. In addition, experience with repeated medications is limited.
Before using recombinant human urokinase for injection, the following tests are recommended, such as clotting time, prothrombin time, and activated partial thromboplastin time.
[Medication for pregnant and lactating women]
Animal experiments showed that at a dose of 1 mg / kg in mice, no abortion, death, or malformation were observed in female mice, but individual animals still saw mild intrauterine bleeding. Therefore, as with other thrombolytic drugs, pregnant women are contraindicated.
Breastfeeding women have not used the drug for related trials, so please use as prescribed by your doctor.
[Children's medication] No related trials have been done.
[Medication for the elderly] Use with caution in patients older than 75 years of age, see precautions.
[Drug interaction] Recombinant human urokinase for injection cannot be mixed with other drugs, and it can neither be used in the same infusion bottle, nor in the same infusion pipeline (including heparin).
When the dose was 85 mg / person in healthy subjects, no serious adverse reactions were seen. Clinical studies have shown that when patients with acute myocardial infarction use recombinant human urokinase for injection 50mg / person and 60mg / person, the safety and opening rate are good, there is no statistical difference between the two groups. The recommended dosage is 50 mg / person / time, and the larger dose should not exceed 60 mg / person / time.
This product has completed Phase I, Phase II and Phase III clinical trials in 18 general hospitals from 2001 to June 2005.
The main research object of the trial was patients with acute ST-segment elevation myocardial infarction within 6 hours of onset.
The administration method is divided into two steps. First, 10 ml of normal saline is used to dissolve 20 mg of recombinant human urokinase for injection by intravenous injection within 3 minutes, and then the remaining dose is dissolved by 90 ml of physiological saline within 30 minutes of intravenous drip.
MAIN OUTCOME MEASURES: Coronary angiography showed infarct-related arterial opening; ECG changes; detection of coagulation system indicators; liver and kidney function and other safety indicators.
1) Drug effectiveness results
A total of 222 trials were conducted in the phase II clinical trial, of which 155 were recombinant human urokinase for injection and 67 in the control urokinase (UK) group. Different doses and modes of administration were explored, including statistical models such as random dose control and positive drug control at different stages. The clinically effective dose of recombinant human urokinase for injection in patients with acute ST-elevation myocardial infarction And security exploratory research. The research results show that the thrombolytic effect of recombinant human urokinase for injection increases with the increase of the total dose of the drug, and has a certain compliance relationship with the total dose. There is also a certain correlation. Phase II trials have shown that the thrombolytic drug has good safety and effectiveness. Among them, the 50% group (20mg + 30mg; 30 minutes instillation) TIMI-2 + 3 grade opening rate reached 78.26%, TIMI-3 grade 60.8%, In the 60mg group (20mg + 40mg; 30 minutes instillation), the activation rate of TIMI-2 + 3 grade reached 64.71%, and TIMI-3 grade reached 64.71%. Provides a more accurate experimental dosing regimen for phase III clinical trials.
The phase III clinical trial was a randomized, single-blind, multi-center, parallel controlled trial of positive drugs. It was divided into three groups: 50 mg of recombinant human urokinase for injection, 60 mg of recombinant human urokinase for injection, and 1.5 million UK units. A total of 328 trials were conducted. Among them, 110 cases of recombinant human urokinase for injection; 110 cases; 115 cases of recombinant human urokinase for injection; 103 cases of 1.5 million units in the UK.
The results of the phase Ⅲ clinical trial study showed that the use of recombinant human urokinase for injection 50mg and 60mg for acute ST-segment elevation myocardial infarction within 6 hours of onset of intravenous thrombolysis, the infarct-related artery has a higher opening rate: Coronary angiography opening rate of recombinant human urokinase for injection 50mg group reached 78.5% of TIMI-2 + 3 grade, of which TIMI-3 opening rate reached 59.1%, which was significantly higher than that of control group UK 1.5 million unit infarct coronary angiography opening rate ( TIMI-2 + 3 is 51.6% and TIMI-3 is 36.8%);
2) Drug safety results:
The results of Phase I clinical tolerance test of recombinant human urokinase for injection showed that the healthy subjects were well tolerated at the doses of 5mg, 20mg, 35mg, 50mg, 65mg, 75mg, and 85mg. Obvious toxic side effects were observed. Recombinant human urokinase for injection has no significant effect on blood biochemical parameters, liver and kidney function, and fibrinolytic system in normal human body, and has a certain prolonged effect on the activated partial thromboplastin time.
The results of phase Ⅱ and Ⅲ trials show that the use of recombinant human urokinase for intravenous thrombolytic therapy in patients with acute myocardial infarction during hospitalization and subsequent follow-up observations showed that the original recombinant human urokinase for injection was good. Security. Thrombolytic therapy has not shown any adverse effects on the patient's blood system, liver and kidney functions, and other important organ functions; occasional severe bleeding (such as cerebral hemorrhage), death, and other serious complications and general complications after thrombolytic therapy Occurs rarely. The relative bleeding rate and mortality in the control UK group were higher than those in the two groups of recombinant human urokinase group for injection;
3) Adverse Drug Reactions:
This product is a plasminogen activator class thrombolytic drug. The most common comorbidity that may occur during use is bleeding. The coagulation index should be closely monitored before and after using this drug. During the test, the types of bleeding that have occurred in this product can be divided into: (1) internal bleeding: involving intracranial, gastrointestinal, urogenital or respiratory tract (2) superficial or superficial bleeding: mainly in venipuncture and blood collection sites, arterial puncture Or recent surgical intervention. Most bleeding response researchers judge that it is not related to thrombolytic drugs. At the same time, researchers have found that heparin may increase the bleeding risk of recombinant human urokinase for injection. It is recommended that any bleeding should be discontinued immediately if a bleeding reaction occurs during use. Used drugs such as heparin or antiplatelets. Try to avoid intramuscular injection and non-critical treatment of patients within the first few hours after treatment. It is found that the incidence of subcutaneous hematoma at the venipuncture point after thrombolysis is high in the test. It is recommended that when the venipuncture is performed within a few hours after treatment, it is best to use manual compression of the blood vessel and pressurize the bandage to stop bleeding for at least 30 min. No bleeding. Patients with more hematuria in the trial may be related to the use of urinary catheterization after bedridden.
In addition, it was found that coronary thrombolysis may be accompanied by reperfusion arrhythmias, such as sinus bradycardia, accelerated ventricular self-rhythm, early ventricular depolarization, and ventricular tachycardia, which are indistinguishable from the common arrhythmias of acute myocardial infarction, and Can be treated with standard anti-arrhythmic measures.
[Pharmacology and Toxicology]
Recombinant human urokinase for injection is a plasminogen activator, which can directly activate plasminogen on the surface of the thrombus to transform into plasmin. Intravenous administration of the drug, rhPro-UK shows a relatively inactive state in the circulatory system, and has little effect on plasma endogenous plasminogen. It is only activated by kininase or plasmin on the surface of the thrombus, and partially becomes double Strand UK, the latter activates plasminogen that has been altered in the configuration of the thrombus surface to become plasmin, which partially dissolves the thrombin fibrin. When E-fragment is exposed to thrombin fibrin, rhPro-UK can directly activate plasminogen bound to two lysine residues at the C-terminus of the fragment, its activity is increased by 500 times, and a large amount of plasmin is generated to cause thrombosis. Fibrin is rapidly degraded and the thrombus dissolves. rhPro-UK is a specific plasminogen activator that specifically dissolves blood clots in the body. The results of pharmacodynamic tests showed that rhPro-UK had a significant thrombolytic effect on coronary and pulmonary thrombosis in experimental animals, but had no significant effect on the fibrinolytic system in vivo.
Safety Toxicology: Pharmacological studies have shown that rhPro-UK has no significant effect on the general behavior and state of animals, and on the central nervous system, cardiovascular system, respiratory system and digestive system.
Long-term toxicity test: Two-stage Wistar rats were injected intravenously with 3mg / kg, 10mg / kg, and 30mg / kg of this product daily (30 times the human dose), and physiological saline was used as a control group. Continue to observe the plan for 3 weeks, and carry out long-term toxicity test of this product. The results showed that (1) no toxicity symptoms occurred in the three groups of dose groups, and the food intake and weight gain were normal. (2) Histopathological examination and determination of organ coefficients did not find any toxicologically significant changes related to this product. (3) Hematological indicators were tested, and no drug-related changes were seen. Blood biochemical indicators showed that the total cholesterol (Tchol), total protein (TP), and albumin (Alb) contents increased, and returned to normal levels during the recovery period. The prothrombin time (PT), prothrombin time (TT) and activated partial prothrombin time (APTT) were significantly prolonged, and all returned to normal after 24 hours.
Recombinant human urokinase for injection is mainly cleared in the human body and excreted from the urine. Phase I clinical trials showed that after receiving 20mg, 35mg, 50mg, 65mg, 75mg, and 85mg recombinant human urokinase for injection, healthy volunteers had systemic clearance rates of 92 ± 25.0 L / h, 61 ± 19.0 L / h, 46 ± 5.0L / h, 57.4 ± 14.5 L / h, 57.8 ± 13.0 L / h, and 55.7 ± 10.0 L / h, which gradually slowed down as the dose increased, and their half lives were 2.6 hours, 2.4 hours, 1.9 hours, 0.67 hours, 0.66 hours, 0.59 hours. The half-life decreases with increasing dose, indicating that rhPro-UK has a non-linear kinetic process in vivo.
[Storage] Store and transport at 2 ～ 8 ° C, protected from light.
[Packaging] Bottles of medium borosilicate glass controlled injections, 10 per box.
[Validity] 30 months [Executive standard] YBS00422011
[Approval number] National Medicine Standard S20110003