AKTILIZE
Active material: Alteplaza
When ATH: B01AD02
CCF: Trombolitik – Tissue plasminogen activator
ICD-10 codes (testimony): I21, i26, I63
When CSF: 01.12.11.07
Manufacturer: BOEHRINGER INGELHEIM INTERNATIONAL GmbH (Germany)
Pharmaceutical form, composition and packaging
Valium for solution for infusion as a white or pale yellow mass, almost odorless.
| 1 fl. | 1 ml ready-r-ra | |
| alteplaza * | 50 mg | 1 mg |
Excipients: L-arginine, phosphoric acid, polysorbate 80.
Solvent: sterile water d/and (50 ml).
Bottles of colorless glass (1) together with the solvent (fl. 1 PC.) – cardboard boxes.
* international non-proprietary name, recommended by the WHO – al′teplaza.
Pharmacological action
Trombolitik. Recombinant human tissue plasminogen activator, glycoprotein, directly activates transformation plazminoguena in plazmin.
When in/with the introduction of the drug is relatively inactive in the system bloodstream. Activated after fibrin-binding, inducing transformation plazminoguena in plazmin, that leads to the dissolution of fibrin clot.
Use Aktilize® dose 100 mg for 90 mines in conjunction with on/in the introduction of heparin more than 40 000 patients with acute myocardial infarction has resulted in a reduction of 30-day mortality (6.3%) compared to streptokinase (1.5 million. Power. during 60 m) simultaneously with the p/c or/in the introduction of heparin (7.3%). Displaying, that through 60 Mines and 90 Ming trombolizisa in patients, receiving Aktilize®, revealed a higher frequency of reconstruction blood vessel passage in the area of infarction, than when applying the streptokinase. Through 180 minutes after the start of therapy and later differences in the incidence of vascular patency were observed.
When applying Aktilize® declining 30-day mortality after myocardial infarction compared to patients, not receiving trombolitičeskuû therapy.
When applying Aktilize® reduced release of the enzyme α-gidroksibutirat dehydrogenase. Patients, receiving Aktilize®, compared to patients, not receiving trombolitičeskuû therapy, less noted significant damage to the overall function of the left ventricle of the heart and reduced the severity of regional left ventricular wall mobility violations.
Use Aktilize® dose 100 mg for 3 h in patients with myocardial infarction (in the case of therapy for 6-12 h after the onset of symptoms), resulted in a reduction of 30-day mortality compared to placebo. Therapeutic effect in patients with confirmed myocardial infarction observed in those cases, When the treatment was started within 24 h after the onset of symptoms.
In patients with acute massive pulmonary emboli, accompanied by an unstable hemodynamic, use Aktilize® leads to rapid decreases in size blood clot and reduce the pressure in the pulmonary artery, However, there are no data on mortality.
In applying the drug in ischemic stroke (first 3 h after the onset of symptoms), more frequent achieving favourable results (lack of capacity violations patients or minimum extent of these violations) compared to placebo.
In case of later therapy efficacy decreases. Results of a meta-analysis of all patients, receiving treatment during the first 3 h after the onset of stroke, confirmed the presence of a positive effect of alteplazy.
Despite the increased risk of serious and even fatal intracranial hemorrhage the likelihood of a favorable outcome of therapy compared with placebo was 14.9% (95%-confidence intervals: 8.1% and 21.7%). These data do not permit a specific conclusion on the impact of therapy on mortality. Benefit/risk ratio in the case of the application of alteplazy during 3 h after the onset of stroke (taking into account the above caveats) as a whole can be considered favourable, Although research data do not allow a clear conclusion on the impact of therapy on mortality.
A meta-analysis of all available clinical data shows, that alteplaza less effective in patients, treatment that begins in 3-6 h after the onset of symptoms, compared with therapy, undertaken in the first 3 hours after development of clinical manifestations. The risk of complications of therapy of stroke in the first case, a higher, that leads to the adverse outcome of risk/benefit ratio.
Due to the relative specificity with respect to the use of fibrin alteplazy dose 100 mg leads to a moderate reduction of circulating Fibrinogen level (about 60% through 4 no), which to 24 no, usually, increased by more than 80%. Concentration plazminoguena and alpha 2-antiplazmina via 4 h reduced, respectively, to 20% and 35% from baseline, and by 24 h again increased more than 80%. A significant and prolonged decrease in circulating Fibrinogen level pointed out only a small number of patients.
Pharmacokinetics
Aktilize® quickly from the blood stream and metabolized, mainly, liver. Plasma clearance of the drug is 550-680 ml / min.
T1/2 in the α-phase is 4-5 m. Through 20 mines in the plasma will be less 10% from the initial quantity of the drug. For the remaining quantities of the drug T1/2 in β-phase is about 40 m.
Testimony
is thrombolytic therapy of acute myocardial infarction in the first 6 hours after developing symptoms (90-minute/crash/dosage);
is thrombolytic therapy of acute myocardial infarction between 6 to 12 hours after developing symptoms (3-time dosing regimen);
is thrombolytic therapy of acute massive pulmonary thromboembolism, with hemodynamic instability. Diagnosis should be, possibly, confirmed objectively (eg, angiography of pulmonary artery or non-invasive methods, eg, CT of the lung). Clinical studies regarding mortality and distant results of treatment for pulmonary embolism have been conducted;
is thrombolytic therapy of acute ischemic stroke (shows only, If you designate within 3 hours after developing symptoms of stroke, and if intracranial hemorrhage excluded/hemorrhagic stroke/using the appropriate visualization methods, eg, CT of the brain).
Dosage regimen
Aktilize® You should apply as early as possible from the moment of occurrence of symptoms.
At myocardial infarction with 90-minute (accelerated) mode dosing for patients, which treatment may be commenced within 6 hours after developing symptoms, the drug is prescribed in a dose 15 mg in/in struino, then – 50 mg in/in infusion during the first 30 m, with the subsequent infusion 35 mg for 60 minutes to achieve maximum dose 100 mg.
In Patients weighing less than 65 kg dose should be calculated depending on the body weight. First drug appointed dose of 15 mg in/in struino, then – 750 ug / kg body weight (maximally 50 mg) during 30 min/drip, with the subsequent infusion 500 mg / kg (maximally 35 mg) during 60 m.
At myocardial infarction in 3-hour mode dosing for patients, which treatment may be started between 6 and h 12 hours after developing symptoms, the drug is prescribed in a dose 10 mg in/in struino, then – 50 mg in/in infusion during the first hour, followed in/in infuziei 10 mg for 30 minutes before reaching for 3 h maximum dose 100 mg.
In Patients weighing less than 65 kg the total dose should not exceed 1.5 mg / kg.
The recommended maximum dose of Aktilize® in acute myocardial infarct is 100 mg.
Auxiliary protivosvertyvaûŝaâ therapy shown in patients with myocardial infarction with ST segment according to current international recommendations.
At pulmonary artery thromboembolism Aktilize® give the total dose 100 mg for 2 no. Most experience obtained by using the following dosage: first drug appointed dose of 10 mg in/in struino within 1-2 m, then – 90 mg in/in drip for 2 no.
In Patients weighing less than 65 kg the total dose should not exceed 1.5 mg / kg body weight.
Adjuvant therapy: After applying Aktilize®, If APTT exceeds VGN less than 2 times, You should assign (or continue) heparin infusion. Dose heparin should be adjusted to maintain the ACTV between 50-70 sec (values must exceed the initial level in 1.5-2.5 times).
At ischemic stroke The recommended dose is 0.9 mg / kg (maximally 90 mg), as in/in infusion during 60 minutes after the initial/in a Jet dosage, component 10% the size of the total dose. Therapy should be initiated as soon as possible after the onset of symptoms (preferably within 3 no).
Adjuvant therapy: the safety and efficacy of the above modes of therapy, used in combination with heparin and acetylsalicylic acid in the first 24 h after the onset of symptoms, studied is not enough. In this regard, in the first 24 h after the start of therapy Aktilize® use of acetylsalicylic acid or in/with the introduction of heparin should be avoided. If heparin is required for other indications (eg, for the prophylaxis of deep vein thrombosis), its dose should not exceed 10 000 ME a day, When this product introduces p/.
Rules for solution for the infusions
To obtain a final concentration of alteplazy, component 1 mg / ml, in a bottle Aktilize®, containing liofilizat (50 mg), You should add the entire volume of the supplied diluent (50 ml). After breeding the resulting solution introducing/in.
It is not recommended to further breeding of the resulting solution sterile saline solution (0.9%) below the minimum concentration of alteplazy 0.2 mg / ml, Since the may sample solution.
Do not initially received further breeding water for injection or infusion solutions based on carbohydrates, eg, dextrose.
Product Aktilize® do not mix with other drugs (even with heparin), Neither vial for infusion, neither in the common system for on/in the introduction.
Side effect
The most common unwanted reaction, related Aktilize®, is bleeding (>1/100, ≤ 1/10: massive bleeding; >1/10: any bleeding), leading to reduced hematocrit and/or hemoglobin.
May develop bleeding in any part or body cavities, that can lead to žizneugrožaûŝej of the situation, temporary incapacity or death.
Bleeding, associated with thrombolytic therapy, can be divided into two main categories:
— External bleeding (usually, from places of punctures or damage blood vessels);
-internal bleeding in any part or body cavities.
With vnutričerepnymi bleeding can be associated following neurological symptoms: drowsiness, afazija, gemiparez, convulsions. A case of cholesterol Crystal embolization, not observed in a population of patients, participating in clinical trials, based on a separate communication.
In comparison with studies of myocardial infarction patients with pulmonary embolism pulmonary artery and stroke, who participated in clinical trials (within 0-3 h from onset of symptoms of these diseases), It was a very small. Therefore, a small numeric differences, marked when compared with the data, from myocardial infarction, We were, probably, the consequence of a small sample size. In addition to intracranial hemorrhage (as a side-effect in stroke) and reperfusion arrhythmias (as a side-effect of myocardial infarct), There is no clinical reason to suppose the qualitative and quantitative differences in the spectrum of side effects of the drug Aktilize® If used with pulmonary embolism and acute ischemic stroke, or myocardial infarct.
Application of myocardial infarct
Cardio-vascular system: (>1/10) – reperfusion arrhythmias (incl. ventricular arrhythmia, arrythmia, Atrial fibrillation, AV-blokada I extent until complete closure, bradycardia, ventricular fibrillation, ventricular tachycardia), that can be life-threatening and require the application of generally accepted scale therapy.
Application of myocardial infarction and pulmonary embolism
CNS: (>1/1000, ≤1/100) – intracranial hemorrhage (incl. cerebral hemorrhage, hemorrhagic stroke, haemorrhagic stroke transformation, intracranial hematoma, intracranial hemorrhage).
Use in acute ischemic stroke
CNS: (>1/100, ≤1/10) – intracranial hemorrhage (incl. cerebral hemorrhage, brain hematoma, hemorrhagic stroke, haemorrhagic stroke transformation, intracranial hematoma, subarachnoid hemorrhage).
The main undesirable were clinically expressed intracranial hemorrhage (their frequency has reached 10%). However, the increase in morbidity or mortality has not been.
Application of myocardial infarct, pulmonary embolism and acute ischemic stroke
On the part of the immune system: (>1/1000, ≤1/100) – anaphylactoid reactions (usually expressed weakly, but in some cases can be life-threatening); possible eruption, hives, bronchospasm, angioedema, hypotension, shock or any other allergic reaction.
In the case of these reactions should apply common anti-allergic therapy. Established, that a relatively large part of patients with similar reactions simultaneously applied ACE inhibitors.
Anaphylactic reactions (ie. arising from IgE) for Aktilize® unknown. In rare cases, there has been a transitory antibodies to Aktilize® (low credits), but the clinical significance of this phenomenon is not installed.
On the part of the organ of vision: (≤1/10 000) – bleeding in the eye.
Cardio-vascular system: (>1/10) – bleeding (eg, hematoma), decrease in blood pressure; (>1/1000, ≤1/100) – thromboembolism, that may be affected by the consequences of internal organs, perikardial′noe bleeding; (>1/10 000, ≤1/1000) – bleeding from parenchymatous organs (vnutripečenočnye bleeding, pulmonary hemorrhage).
The respiratory system: (>1/100, ≤1/10) – bleeding from the respiratory tract (glotočnoe bleeding, hemoptysis, nose bleed).
From the digestive system: (>1/100, ≤1/10) – gastrointestinal bleeding (gastrorrhagia, bleeding from stomach ulcers, bleeding from rectum, hematemesis, ground, bleeding from the mouth), nausea and vomiting (may be symptoms of myocardial infarction); (>1/1000, ≤1/100) – bleeding in the retroperitoneal space (retroperitoneal hematoma), Bleeding from the gums.
From the urinary system: (>1/100, ≤1/10) – reproductive tract bleeding (hematuria, bleeding from the urinary tract).
Local reactions: (>1/100) – External bleeding from the puncture sites (bleeding at the injection site) or from damaged blood vessels (incl. hematoma at the site of catheter, bleeding at the site of catheter, bleeding at the site of puncture).
Other: (>1/10 000, ≤1/1000) – cholesterol Crystal embolization, that can lead to the effects of the affected internal organs; (>1/100, ≤1/10) – fever, ecchymosis, the need for whole blood transfusion
Contraindications
- Gyemorragichyeskii diatyez;
— significant bleeding now or in the past 6 Months;
-admission oral anticoagulants, eg, varfarina (INR >1.3);
-central nervous system diseases in history (incl. neoplasms, aneurysm);
is surgery on the brain or spinal cord;
is intracranial (incl. subarachnoid) bleeding now or in history;
— suspicion of hemorrhagic stroke;
— severe uncontrolled hypertension;
-extensive surgery or severe injury during the previous 10 days (including any injury in combination with data from acute myocardial infarction);
— recently transferred craniocerebral injury;
-prolonged or traumatic cardiopulmonary resuscitation (more 2 m);
— birth within the previous 10 days;
— recently produced non-shrinkable puncture of blood vessels (eg, subclavian or jugular vein);
- Severe liver disease, including hepatic failure, cirrhosis of the liver, Portal hypertension (with esophageal varices), active hepatitis;
- Bacterial endocarditis, perikardit;
- Acute pancreatitis;
-confirmed disease hospital of stomach and duodenal ulcers in the past 3 Months;
-aneurysms artery, congenital malformations of the arteries and veins;
— neoplasms with increased risk of bleeding;
- Hypersensitivity to the drug.
In the case of use of the drug for the treatment of acute myocardial infarction and pulmonary embolism, In addition to the above listed contraindications, There are the following contraindications:
-haemorrhagic stroke or stroke of unknown etiology in history;
-ischemic stroke or transient ischemic attack during the last 6 Months (except the current acute ischemic stroke within 3 no).
In the case of use of the drug for the treatment of acute ischemic stroke, In addition to the above listed contraindications, There are the following contraindications:
-early symptoms of ischemic stroke for more than 3 hours before the start of infusions, or the lack of accurate information about the time of onset of the disease;
— rapid improvement in acute ischemic stroke or mild severity of symptoms at the beginning of infusion;
seriously leaky stroke, based on clinical data (eg, If the NIHSS>25) and/or on the results of relevant visualization techniques (computed tomography or magnetic resonance imaging);
is cramping in early stroke;
— information about the migrated stroke or serious injury to the head during 3 previous months;
— the emergence of the previous stroke on a background of diabetes;
-heparin during 48 hours before the start of the stroke, If at this point in time promoted ACTV;
— use of antiplatelet agents at the time of infusion and during 24 hours after infusion;
is the number of platelets <100 000/l;
-sistolicescoe ad above 185 mm Hg. Article. or diastolic HELL above 110 mm Hg. Article. or the necessity of applying intensive care (in/in the introduction of drugs) to reduce HELL to those boundaries;
is the level of glucose in the blood <50 mg / dL or >400 mg / dL.
Product Aktilize® not shown for the treatment of acute stroke in children and adolescents under the age of 18 years of age and adults over the age of 80 years.
FROM caution, previously assessing the degree of perceived usefulness and possible risk of bleeding, the preparation should be applied to the recently completed in/m injection or biopsy (needle), puncture (needle) large vessels, heart massage during resuscitation, as well as diseases (not mentioned in the list of contraindications), where the increased risk of bleeding.
At treatment of acute myocardial infarction and acute pulmonary embolism should further bear in mind the following special warnings and precautions:
-sistolicescoe ad > 160 mm Hg. Art.;
- Old age (>75 years), which may increase the risk of intracranial hemorrhage. Since elderly patients the chance of a positive outcome of this treatment also improves, a thorough evaluation of the ratio of benefit-risk.
At treatment of acute ischemic stroke should further bear in mind the following special warnings and precautions:
Use Aktilize® in patients with acute ischemic stroke, compared to using this drug for other indications, accompanied by markedly increased risk of intracranial hemorrhage, because bleeding occurs mostly in the necrotic area. This is particularly to be taken into account in the following cases:
-all States, characterized by a high risk of bleeding;
— the presence of small asymptomatic aneurysms of the cerebral vessels;
-in patients, previously lincocin acetylsalicylic acid or other antiagregantnymi means, possible increased risk of brain hemorrhage, especially if the use of Aktilize® launched at a later date. Given the increased risk of cerebral hemorrhage, applied dose should not exceed alteplazy 900 mg / kg (The maximum dose is 90 mg).
Treatment should start no later than, than 3 h after the onset of symptoms, due to the unfavourable risk/benefit ratio, because of the following circumstances:
-a positive treatment effect decreases at later beginning therapy;
-mortality increases primarily in patients, previously treated with acetylsalicylic acid;
-increased risk of bleeding.
Pregnancy and lactation
Clinical experience of applying Aktilize® in pregnancy and lactation is limited. The question of the allocation of alteplazy in breast milk is not examined.
If necessary, use of drugs (for diseases, immediately life-threatening) when pregnancy and lactation should assess the expected benefit of the therapy to the mother and the potential risk to the fetus or baby. In connection with this application Aktilize® during pregnancy and breastfeeding is not recommended.
Cautions
Treatment Aktilize® should be a doctor, having the experience of thrombolytic therapy and control its efficiency. When using Aktilize® It is recommended that you have a standard resuscitation equipment and related medicines.
The most frequent complication of therapy Aktilize® is bleeding.
The simultaneous use of heparin can lead to bleeding. Since Aktilize® dissolves fibrin, bleeding can occur from places recent punctures. Therefore, thrombolytic therapy requires careful monitoring of areas of possible bleeding (including the introduction of catheter, arterial and venous puncture, cuts and injections). Avoid using hard catheters, in/m injection and unreasonable manipulation during treatment Aktilize®.
In case of severe bleeding (in particular, cerebral), fibrinolytic therapy, as well as heparin should cease immediately. If during the 4 hours before the start of bleeding used heparin, You should consider the appropriateness of the use of protamine sulfate.
In rare cases,, When the above conservative measures are ineffective, bleeding continues, demonstrates the use of blood products. Tranfuzionnoe introduction of Cryoprecipitate, fresh frozen plasma and platelets should be appointed in accordance with the clinical and laboratory indicators, re-determined after each administration. Infusions of Cryoprecipitate is desirable to achieve the concentration of Fibrinogen 1 g / l. You might want to consider applying antifibrinolitičeskih remedies (eg, tranexamic acid), However, specific studies have been conducted on this aspect.
After treatment of sustainable education antibodies to human tissue plasminogen activator recombinase is not observed. Systematic experience reuse Aktilize® not available.
In the case of anafilaktoidnoj reaction, infuziu should be discontinued and appropriate treatment. It is recommended that regular monitoring of tolerance of treatment, especially in patients, at the same time receiving ACE inhibitors.
In acute myocardial infarct and pulmonary embolism should not apply Aktilize® dose, exceeding 100 mg, tk. increased risk of intracranial krovloizliâniâ.
In acute myocardial infarct Aktilize® reduces mortality in the first 30 days after infarction.
Coronary Thrombolysis can lead to arrhythmia, associated with reperfusion.
Concomitant use of glycoprotein IIb/Iiia antagonist increases risk of bleeding.
The use of thrombolytic agents may increase the risk of thromboembolism in patients with thrombosis of left heart, eg, When mitralnom stenoze or with atrial fibrillation.
In acute ischemic stroke should not apply Aktilize® in a dose of 90 mg, because of the increased risk of intracranial hemorrhage.
Treatment should be carried out by an experienced doctor, has the skills and experience providing intensive neurological care, in a specialized branch, having the opportunity to spend an entire complex of neuroimaging research.
It is necessary to monitor AD during treatment, and within 24 hours after the end of the. When you raise systolic HELL>180 mm Hg. Article. or diastolic HELL>105 mm Hg. Article. recommended/use of antihypertensive drugs.
The therapeutic effect is reduced in patients, previously patients stroke, or if you have uncontrolled diabetes. In these patients the benefit-risk ratio is considered to be less favourable, though still remains positive.
In patients with a slight stroke (patients with preserved everyday activity, NIHSS<6) the risk is greater than the expected benefit, Therefore, the use of Aktilize® not recommended.
Patients with very severe stroke increased risk of intracranial hemorrhage and death, in these cases Aktilize® should not be used.
In patients with extensive infarctions of the brain indicated an increased risk of adverse outcome, in t. no. pronounced brain hemorrhages and death. In such cases, you should carefully weigh the risks and benefits of the therapy.
The probability of a favorable outcome in stroke treatment decreases with increasing age, as well as increasing the severity of the stroke and at elevated levels of glucose in the blood. In the same time, the probability of a serious breach of legal capacity and fatal or serious intracranial hemorrhage is increased, regardless of treatment.
Aktilize® It should not be used in patients over 80 years, in case of severe stroke (clinical data and/or according to visualize research) and in those cases, When original values blood glucose make up <50 mg / dL or >400 mg / dL.
The ischemic reperfusion could lead to swelling of the brain in the area of infarction. Due to an increased risk of hemorrhage the use of platelet aggregation inhibitors should not begin within the first 24 hours after the holding of Thrombolysis using alteplazy.
Use in Pediatrics
Experience of applying Aktilize® children have limited.
Overdose
Symptoms: Despite the relative specificity to solubility coefficient, in overdose can occur clinically significant reduction in level of Fibrinogen and coagulation factors.
Treatment: in most cases expectant management with physiological regeneration of these factors after cessation of Aktilize®. If you experience heavy bleeding, transfusion of fresh frozen plasma or whole blood, You can optionally assign a synthetic antifibrinolitiki.
Drug Interactions
Special studies of the interaction of Aktilize® with other drugs, usually used in acute myocardial infarction, not performed.
The use of medicines, affect blood clotting or modify platelet function, to, during or after the start of therapy Aktilize® may increase the risk of bleeding.
The simultaneous use of ACE inhibitors may increase the risk of anaphylactoidnykh reactions. These reactions were observed in relatively more patients, ACE inhibitor.
Pharmaceutical interaction
Product Aktilize® do not mix with other drugs (even with heparin), Neither vial for infusion, neither in the common system for on/in the introduction.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored in a dark place at a temperature of no higher than 25° c. Shelf life – 3 year.
Cooked solution can be stored in the refrigerator 24 no; at a temperature, does not exceed 25° c – to 8 no.
