2010/09/17

Actilyse

Composition, structure and packing

Lyophilisates for solution for infusion in the form of white or pale-yellow mass, almost odorless.

1 vial. 1 ml of p-pa alteplase 50 mg 1 mg.

Excipients: L-arginine, phosphoric acid, polysorbate 80.

Solvent: sterile water d / and (50 ml). international nonproprietary name, as recommended by WHO, in Russia decided to write an international name - alteplaza.

Clinico-pharmacological group: thrombolytic - tissue plasminogen activator.

Pharmacological action

Thrombolytic. Recombinant human tissue plasminogen activator, a glycoprotein, directly activates the conversion of plasminogen into plasmin. When i / in the introduction of the drug is relatively inactive in the systemic circulation. Activated after binding to fibrin, inducing the conversion of plasminogen into plasmin, which leads to the dissolution of fibrin clot.

Application Aktilize a dose of 100 mg for 90 min with a / in the introduction of heparin in more than 40 000 patients with acute myocardial infarction led to a decrease in 30-day mortality (6.3%) compared with streptokinase (1.5 million units. In for 60 min) simultaneously with the n / a or / in the introduction of heparin (7.3%).

It is shown that after 60 minutes and 90 minutes of thrombolysis in patients receiving Aktilize, detected a higher incidence of restoring patency of vessels in the infarction area than with streptokinase. After 180 minutes after initiation of therapy and later differences in the frequency of vascular permeability were observed.

In applying Aktilize has decreased 30-day mortality after myocardial infarction compared with patients not receiving thrombolytic therapy.

In applying Aktilize decreases the release of the enzyme α-hydroxybutyrate dehydrogenase (HBDH). In patients treated Aktilize, compared with patients not receiving thrombolytic therapy, there is less significant damage to the overall function of the left ventricle of the heart and lower the severity of impaired regional left ventricular wall motility.

Application Aktilize a dose of 100 mg for 3 h in patients with myocardial infarction (in the case of initiation of therapy within 6-12 hours after onset of symptoms), leading to a reduced 30-day mortality compared with placebo. The therapeutic effect in patients with confirmed myocardial infarction was observed in those cases when the treatment started within 24 h after onset of symptoms.

Patients with acute massive pulmonary embolism accompanied by unstable hemodynamics, the use Aktilize leads to a rapid decrease in the size of thrombus and reduce the pressure in the pulmonary artery, but the mortality data are not available.

In applying the drug in ischemic stroke (the first 3 h after onset of symptoms), it was found more frequently to achieve a favorable result (no violation of the minimum capacity of patients or severity of these disorders) compared with placebo. In the case of initiation of therapy at a later date the effectiveness of the drug decreases. The meta-analysis of all patients who received therapy during the first 3 h after stroke, confirmed the presence of a positive effect alteplazy.

Despite the increased risk of serious and even fatal intracranial hemorrhages likelihood of a favorable outcome of therapy compared with placebo was 14.9% (95% confidence interval: 8.1% and 21.7%). These data do not permit a definite conclusion on the impact of therapy on mortality. The benefit / risk in the case of alteplazy within 3 h after stroke (given the above caveats) could generally be regarded as favorable, although these studies did not allow a clear conclusion on the impact of therapy on mortality. Meta-analysis of all available clinical data shows that alteplaza less effective in patients whose treatment began within 3-6 h after onset of symptoms, compared with therapy to be undertaken in the first 3 h after the development of clinical manifestations. The risk of complications of therapy of stroke in the first case, higher, which leads to an unfavorable ratio of total benefit / risk. Because of the relative specificity with respect to the use of fibrin alteplazy a dose of 100 mg leads to a moderate decrease in the level of circulating fibrinogen (about 60% after 4 h), which by 24 h, typically increases by more than 80%. Concentrations of plasminogen and alpha 2-antiplasmin after 4 h decrease, respectively, to 20% and 35% from baseline, and after 24 h again increased to more than 80%. A significant and prolonged decline in the level of circulating fibrinogen was noted only in a small number of patients.

Pharmacokinetics

Aktilize rapidly excreted from the bloodstream and metabolized mainly in the liver. Plasma clearance of the drug is 550-680 ml / min. T1 / 2 in α-phase of 4-5 min. After 20 minutes in the plasma will be less than 10% of the initial quantity of the drug.

For the remaining quantity of the drug T1 / 2 in β-phase is about 40 minutes.

Statement
thrombolytic therapy of acute myocardial infarction in the first 6 h after the development of symptoms (90-minute / rapid / dosing regimen);
thrombolytic therapy of acute myocardial infarction in the period from 6 to 12 h after the development of symptoms (3-hour dosing regimen);
thrombolytic therapy of acute massive pulmonary thromboembolism accompanied by unstable hemodynamics.

The diagnosis should be, if possible, confirmed objectively (eg, pulmonary angiography or non-invasive methods, such as tomography of the lungs).

Clinical studies on mortality and late results of treatment of pulmonary embolism were not carried out;
thrombolytic therapy of acute ischemic stroke (shown only in the case shall be appointed within 3 hours after developing symptoms of a stroke, and if possible intracranial haemorrhage / haemorrhagic stroke / by appropriate imaging techniques, such as computer tomography of the brain).

Dosage regimen

Aktilize should apply as early as possible from the moment of occurrence of symptoms. Myocardial infarction during a 90-minute (accelerated) dosing regimens for patients whose treatment may be commenced within 6 h after the development of symptoms, a drug administered in a dose of 15 mg / per jet, and then - in the form of 50 mg / v infusion during the first 30 minutes, followed by infusion of 35 mg over 60 minutes, until the maximum dose of 100 mg. Patients weighing less than 65 kg dose should be calculated according to body mass. Initially, the drug is prescribed in a dose of 15 mg / per jet, and then - 750 mg / kg body weight (maximum 50 mg) for 30 minutes in / drip, followed by infusion of 500 mg / kg (maximum 35 mg) for 60 min . Myocardial infarction during 3-hour dosing regimens for patients whose treatment can be initiated between 6 h and 12 h after the development of symptoms, the drug is prescribed in doses of 10 mg / per jet, and then - in the form of 50 mg / v infusion during the first hour, followed by a / v infusion of 10 mg for 30 minutes before reaching for 3 h maximum dose of 100 mg. Patients weighing less than 65 kg total dose should not exceed 1.5 mg / kg. The recommended maximum dose Aktilize in acute myocardial infarction is 100 mg.

Auxiliary anticoagulant therapy is indicated in patients with myocardial infarction with ST-segment elevation in accordance with current international recommendations. Pulmonary thromboembolism Aktilize injected a total dose of 100 mg for 2 h. The most experience obtained by using the following dosage regimen: first drug administered in a dose of 10 mg / per jet for 1-2 minutes, then - 90 mg / in infusion over 2 hours in patients weighing less than 65 kg total dose should not exceed 1.5 mg / kg body weight. Auxiliary treatment: after the application Aktilize if APTT exceeds FHG less than 2 times, to assign (or continue) heparin infusion.

The dose of heparin should be adjusted to maintain APTT between 50-70 sec (the value should exceed the initial level of 1.5-2.5 times). In ischemic stroke the recommended dose is 0.9 mg / kg (maximum 90 mg), as in / infusion within 60 minutes after the initial in / jet dose of the drug that makes 10% of the total dose.

Therapy should be initiated as soon as possible after the onset of symptoms (preferably within 3 h). Auxiliary therapy: safety and efficacy of the above modes of therapy used in combination with heparin and acetylsalicylic acid in the first 24 h after onset of symptoms, not well understood. In this regard, in the first 24 h after initiation of therapy Aktilize of acetylsalicylic acid, or in / to the introduction of heparin should be avoided. If heparin is required for other indications (eg, for the prevention of deep vein thrombosis), the dose should not exceed 10 000 ME per day, while the drug is introduced n / k.

Terms of solution for infusion to obtain a final concentration alteplazy, was 1 mg / ml vial Aktilize containing lyophilisates (50 mg) should be added to the entire volume of the supplied solvent (50 ml). After dilution the resulting solution is introduced into / in.

We do not recommend further dilution of the solution obtained with sterile saline (0.9%) below the minimum concentration alteplazy 0.2 mg / ml, possibly because turbidity of the solution. These are the initial solution can not be further diluted with water for injection or infusion solutions on the basis of carbohydrates, such as dextrose.

Aktilize drug should not be confused with other drugs (even with heparin), or in the vial for infusion, nor in the general system for to / in the introduction.

Side effect

The most common adverse event associated with the use Aktilize is bleeding (> 1 / 100, ≤ 1 / 10: massive bleeding,> 1 / 10: any haemorrhages), which leads to a decrease in hematocrit and / or hemoglobin. Perhaps the development of bleeding in any part or the body cavity, which can lead to life-threatening situations, temporary disability or death.

Bleeding associated with thrombolytic therapy can be divided into two main categories: - external bleeding (usually from puncture or damage the blood vessels) - Internal bleeding in any part or body cavity. With intracranial hemorrhage may be related to the following neurological symptoms: drowsiness, aphasia, hemiparesis, convulsions.

The case of embolization of cholesterol crystals are not observed in the population of patients who participated in clinical trials, based on a separate communication. In comparison with studies of myocardial infarction the number of patients with pulmonary embolism and stroke, had participated in clinical trials (within 0-3 hours from the time of symptoms of these diseases), it was very small. Therefore, small numerical differences were marked when compared with data obtained during myocardial infarction, were likely a consequence of small sample size.

In addition to intracranial hemorrhage (as a side effect of stroke) and reperfusion arrhythmias (as a side effect of myocardial infarction), there is no clinical evidence to suggest qualitative and quantitative differences in the spectrum of adverse effects of the drug Aktilize if applied with pulmonary embolism and acute ischemic stroke, or myocardial infarction.

Application of myocardial infarction

Since the cardiovascular system: (≥ 1 / 10) - reperfusion arrhythmias (including ventricular fibrillation, extrasystoles, atrial fibrillation, AV-block from the I degree to a full blockade, bradycardia, ventricular fibrillation, ventricular tachycardia), which can be life-threatening and require the use of conventional antiarrhythmic therapy.

Application of myocardial infarction and pulmonary embolism

Since the cardiovascular system: (> 1 / 1000, ≤ 1 / 100) - intracranial hemorrhage (including intracranial hemorrhage, hemorrhagic stroke, haemorrhagic transformation stroke, intracranial hematoma, intracranial hemorrhage).

Use in acute ischemic stroke

From the side of the central nervous system: (> 1 / 100, ≤ 1 / 10) - intracranial hemorrhage (including cerebral hemorrhage, cerebral hematoma, hemorrhagic stroke, haemorrhagic transformation stroke, intracranial hematoma, subarachnoid hemorrhage). The main adverse events were symptomatic intracranial hemorrhage (their frequency was 10%). However, increasing the frequency of complications or overall mortality has not been established.

Application of myocardial infarction, pulmonary embolism and acute ischemic stroke
Since the cardiovascular system: (> 1 / 10000, ≤ 1 / 1000) - bleeding from parenchymatous organs (including intrahepatic bleeding, pulmonary bleeding), bleeding in the eye (≤ 1 / 10000), (> 1 / 1000, ≤ 1 / 100) - pericardial bleeding, thromboembolism, which may be accompanied by corresponding effects on the affected internal organs; (> 1 / 10) - bleeding (eg, hematoma).
On the part of the digestive system: (> 1 / 1000, ≤ 1 / 100) - hemorrhage in the retroperitoneal space (including retroperitoneal hematoma), bleeding from the gums; (> 1 / 100, ≤ 1 / 10) - Gastrointestinal bleeding (including stomach bleeding, bleeding from stomach ulcers, bleeding from the rectum, hematemesis, melena, bleeding from the mouth), nausea and vomiting (may be symptoms of myocardial infarction).
On the part of the respiratory system: (> 1 / 100, ≤ 1 / 10) - bleeding from the respiratory tract (including pharyngeal bleeding, hemoptysis, epistaxis).
From the urinary system: (> 1 / 100, ≤ 1 / 10) - urogenital bleeding (including hematuria, bleeding from the urinary tract).

Allergic reactions: (> 1 / 1000, ≤ 1 / 100) - anaphylactoid reaction (usually mild, but in some cases can be life-threatening) may be rash, urticaria, bronchospasm, angioedema, hypotension, shock, or any other allergic reactions. In the case of these reactions should be applied conventional anti-allergic therapy. Found that a relatively large part of patients with similar reactions simultaneously used ACE inhibitors.

Anaphylactic reactions (ie, due to IgE) for Aktilize unknown.

In rare cases, observed transient formation of antibodies to Aktilize (in low liters), but the clinical significance of this phenomenon is not installed. Local reactions: (> 1 / 100) - external bleeding from the puncture site (bleeding at the injection site) or from damaged blood vessels (including hematoma at the site of setting a catheter, bleeding at the site of setting a catheter, bleeding at the site of puncture). Other: embolization of cholesterol crystals, which can lead to appropriate consequences from the affected internal organs (> 1 / 10000, ≤ 1 / 1000), increased body temperature, ecchymosis, the need for transfusion of whole blood (> 1 / 100, ≤ 1 / 10 ) decrease in blood pressure (> 1 / 10).

Contraindications
bleeding diathesis;
significant bleeding at the present time or within the previous 6 months;
simultaneous reception of oral anticoagulants such as warfarin (INR> 1.3);
central nervous system disease in history (including tumors, aneurysms);
surgery on the brain or spinal cord;
intracranial (including subarachnoid) hemorrhage at present or in history;
suspected hemorrhagic stroke;
severe uncontrolled arterial hypertension;
extensive surgery or major trauma within the previous 10 days (including any injury combined with the acute myocardial infarction);
recently transferred traumatic brain injury;
prolonged or traumatic cardiopulmonary resuscitation (more than 2 min);
childbirth within the previous 10 days;
recently produced by puncture of incompressible blood vessels (eg, subclavian or jugular Vienna);
severe liver disease, including liver failure, liver cirrhosis, portal hypertension (with varicose veins of the esophagus), active hepatitis;
bacterial endocarditis, pericarditis;
acute pancreatitis;
confirmed gastric and duodenal ulcer in the past 3 months;
aneurysm of the arteries, congenital malformations of the arteries and veins;
neoplasm with increased bleeding risk;
Hypersensitivity to the drug's components.

In the case of the drug for the treatment of acute myocardial infarction and pulmonary embolism, other than the above contraindications, there is a contraindication of the following:
hemorrhagic stroke or stroke of unknown cause in history;
ischemic stroke or transient ischemic attack within the last 6 months (with the exception of the current acute ischemic stroke within 3 h).

In the case of the drug for the treatment of acute ischemic stroke, except the above contraindications, there are the following contraindications:
onset of symptoms of ischemic stroke more than 3 hours before infusion, or the lack of accurate information about the time of onset of illness;
rapid improvement in acute ischemic stroke or mild symptoms at the beginning of infusion;
heavily flowing stroke, based on clinical data (eg, if the exponent NIHSS> 25) and / or the results of the imaging techniques (computed tomography or nuclear magnetic resonance);
cramps in the beginning of a stroke;
information about stroke or serious head injury during the 3 previous months;
occurrence of previous stroke with diabetes mellitus;
heparin within 48 hours prior to stroke, if given time elevated APTT;
the use of antiplatelet agents at the time of infusion and within 24 h after infusion;
platelet count <100 000/mkl;
systolic blood pressure above 185 mm Hg. Art. or diastolic BP above 110 mm Hg. Art. or the need for intensive therapy (IV administration of drugs) to reduce BP to these limits;
blood glucose level <50> 400 mg / dl.

The drug Aktilize not indicated for treatment of acute stroke in children and adolescents under the age of 18 years and adults over the age of 80 years. With care, pre-estimating the degree of anticipated benefits and possible risks of bleeding, use in patients with recently performed a / m injection or biopsy (needle), puncture (needle) of large vessels, cardiac massage in resuscitation, as well as in diseases (not mentioned in the list contraindications) under which the increased risk of bleeding.

Pregnancy and lactation

Clinical experience with Aktilize during pregnancy and lactation is limited. The question of allocating alteplazy with breast milk has not been studied.

If necessary, use of the drug (in diseases that directly threaten life) during pregnancy and lactation should assess the potential benefits of therapy for the mother and the potential risk to the fetus or infant. In connection with this application Aktilize during pregnancy and breastfeeding is not recommended.

Application for violations of liver function

The drug is contraindicated in severe liver disease, including liver failure, liver cirrhosis, portal hypertension (with varicose veins of the esophagus), active hepatitis. Cautions Treatment Aktilize should be a doctor who has experience of thrombolytic therapy and the ability to monitor its effectiveness.

Using Aktilize recommended to have at the disposal of the standard resuscitation equipment and appropriate drugs. The most frequent complication of therapy Aktilize is bleeding. The simultaneous use of heparin may contribute to bleeding. Since Aktilize dissolves fibrin, bleeding can occur from recent puncture sites. Therefore, thrombolytic therapy requires careful monitoring of possible areas of bleeding (including places of a catheter, arterial and venous punctures, cuts and injections).

Avoid the use of rigid catheters, in / m injections and unnecessary manipulation during treatment Aktilize. In case of severe bleeding (especially cerebral), fibrinolysis, and heparin should be stopped immediately. If within 4 h before the onset of bleeding was used heparin, should consider the appropriateness of the use of protamine sulfate. In rare cases, when the above conservative measures are ineffective, the bleeding continues, shows the use of blood products. Tranfuzionnoe introduction of cryoprecipitate, fresh frozen plasma and platelets should be administered in accordance with clinical and laboratory parameters to be determined again after each injection.

Infusion of cryoprecipitate desirable to achieve the concentration of fibrinogen of 1 g / liter. You can consider applying antifibrinoliticheskih means (eg, tranexamic acid), but special studies on this aspect is not carried out. After the end of treatment sustained the formation of antibodies to recombinant human tissue plasminogen activator was not observed. Systematic experience reuse Aktilize not available. In the case of anaphylactoid reaction, infusion should be discontinued and treatment accordingly. It is recommended that regular monitoring of the tolerability of treatment, especially in patients receiving both ACE inhibitors. In acute myocardial infarction and pulmonary embolism should not be used Aktilize a dose exceeding 100 mg.

In acute myocardial infarction reduces mortality Aktilize in the first 30 days after the start of a heart attack. Coronary thrombolysis may result in arrhythmias associated with reperfusion. Concomitant use of antagonists of glycoprotein IIb / IIIa increases the risk of bleeding. The use of thrombolytic agents may increase the risk of thromboembolism in patients with thrombosis of the left heart, such as mitral stenosis or atrial fibrillation.

In acute ischemic stroke should not be used Aktilize in a dose of 90 mg, as an increased risk of intracranial hemorrhage.

Treatment should be an experienced doctor who has the skills and experience in providing intensive neurological care in a specialized department, the capacity to undertake the full range of neuroimaging studies. BP should be monitored during treatment and within 24 hours after its completion.

When the systolic BP> 180 mm Hg. Art. or diastolic BP> 105 mm Hg. Art. recommended in / use of antihypertensive drugs.

Therapeutic effect of decreases in patients who had undergone previous stroke, or if there is uncontrolled diabetes mellitus.

In these patients, the ratio of benefit-risk is considered less favorable, though still remains positive.

In patients with mild stroke (patients with preserved activities of daily living, NIHSS <6) risks outweigh the potential benefits, so the application Aktilize not recommended.

In patients with very severe stroke, increased risk of intracranial hemorrhage and death in these cases Aktilize should not apply.

Patients with extensive brain infarction observed an increased risk of adverse outcomes, including express intracerebral hemorrhage and death. In such cases, should carefully weigh the risks and benefits of therapy.

Stroke probability of a favorable outcome of treatment decreases with increasing age, as well as increasing the severity of stroke and at high levels of glucose in the blood. At the same time, the probability of a serious breach of viability and death or severe intracranial hemorrhage is increased regardless of treatment. Aktilize should not be used in patients older than 80 years, in the case of severe stroke (by clinical data and / or visualizing the data of studies) and in those cases where the initial values of blood glucose of <50> 400 mg / dl. Reperfusion of ischemic may lead to cerebral edema in infarction zone. Because of the increased risk of hemorrhage of inhibitors of platelet aggregation should not begin during the first 24 hours after thrombolysis with alteplazy.

Use in Pediatrics

Experience with Aktilize children is limited.

Overdose

Symptoms: despite the relative specificity to fibrin, an overdose may be a clinically significant reduction in the level of fibrinogen and clotting factors.

Treatment: In most cases, expectant management with the expectation of the physiological regeneration of these factors after the administration Aktilize.

In the event of severe bleeding is recommended transfusion of fresh frozen plasma or fresh whole blood, if necessary, you can assign a synthetic antifibrinolitiki. Drug Interactions: Specific interaction studies Aktilize with other drugs commonly used in acute myocardial infarction, was conducted.

The use of drugs affecting blood clotting or alter the function of platelets before, 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 anaphylactoid reactions. These reactions were observed in relatively greater part of the patients treated with ACE inhibitors.

Pharmaceutical interactions

Aktilize drug should not be confused with other drugs (even with heparin), or in the vial for infusion, nor in the general system for to / in the introduction.

Terms and Conditions of storage

The drug should be stored in a dark place at temperatures not above 25 ° C. Shelf life - 3 years. The mixed solution may be stored in refrigerator 24 hours, at a temperature not exceeding 25 ° C - up to 8 hours