Jelfa omnadren in conjunction with intravenous heparin in over 40,000 patients with acute myocardial infarction resulted reduce 30-day mortality (6.3%) compared with the use of streptokinase (1.5 million. U. for 60 minutes) together with subcutaneous or intravenous heparin (7.3%). It is shown that after 60 and 90 minutes after thrombolysis in patients treated with jelfa omnadren , was revealed a higher incidence of recanalization patency in the infarct zone than in the case of streptokinase. After 180 minutes after initiation of therapy and later differences in the vascular lumen opening rate was noted.
30 day mortality in patients receiving jelfa omnadren , is reduced compared to patients not receiving the thrombolytic therapy.
When applying jelfa omnadren reduced the release of the enzyme jelfa omnadren alpha-hydroxybutyrate dehydrogenase (HBDH). Patients receiving Actilyse, compared with patients not receiving the thrombolytic therapy, there is significantly less overall deterioration of left ventricular function and less severity of regional mobility disorders left ventricular wall.
In a placebo-controlled study (LATE) showed that the use jelfa omnadren(100 mg in 3 hours) in patients with myocardial infarction (in case of therapy for 6-12 hours after onset of symptoms), resulted in a decrease in mortality within the first 30 days as compared to placebo. The therapeutic effect in patients with clear signs of myocardial infarction can be observed in cases where the treatment is started within 24 hours after onset of symptoms.
Patients with acute massive pulmonary embolism, unstable hemodynamic accompanied applying jelfa omnadren leads to a rapid decrease in thrombus size and reduced pressure in the pulmonary artery, but no death of data.
In two studies conducted in the US (NINDS A / B), which studied the effect of the drug for ischemic stroke (in the first three hours after onset of symptoms), it was found more frequently to achieve a favorable outcome (lack of capacity of patients or the minimum severity of these disorders) on compared with placebo. in the case of initiation of therapy at a later date the effectiveness of the drug is reduced, as shown in 2 European studies and additional research conducted in the United States. The results of the meta-analysis of all patients treated within the first 3 hours after stroke onset, confirmed the positive effect from alteplase.
Despite the increased risk of serious and even fatal intracranial hemorrhage, the probability of a favorable outcome of therapy alteplase compared with placebo increased by 14.9% (95% -doveritelnye intervals: 8.1% and 21.7%). These data do not permit a definitive conclusion concerning treatment effect on mortality. Benefit / risk ratio when used alteplase for 3 hours after stroke onset (given the above warnings) can generally be considered advantageous, although research findings do not allow an unambiguous conclusion regarding treatment effect on mortality.
A meta-analysis of all available clinical data demonstrates that alteplase less effective in patients whose treatment started after 3 chasa (3-6 hours) after the onset of symptoms in comparison to treatment undertaken in the first 3 hours after the development of clinical manifestations, wherein the risk of complications in the first case, higher, leading to unfavorable total benefit / risk ratio.
Due to the relative specificity for fibrin application alteplase 100 mg leads to a moderate reduction of circulating fibrinogen (about 60% after 4 hours), to which 24 hours are generally increased to over 80%.The concentrations of plasminogen and alpha-2-antiplasmin decreased by 4 hours, respectively, 20% and 35% of baseline levels after 24 hours and again increased to more than 80%. A significant and prolonged decrease of the circulating fibrinogen level is only observed in a few patients.
- . Thrombolytic therapy of acute myocardial infarction 90 minutes (accelerated) dose regimen (see “Dosage and Administration”.): For patients in whom treatment can be started within 6 hours after the onset of symptoms; 3-hour dosing regimen (see. “dosage and administration”): for patients in whom treatment can be started between 6 and 12 hours after the onset of symptoms. it is proved that in acute myocardial infarction Actilyse ® reduces mortality in the first 30 days after the onset of infarction.
- Thrombolytic therapy of acute massive pulmonary embolism, accompanied by unstable hemodynamics. This diagnosis should be possible to objectively confirmed, for example, pulmonary angiography, or non-invasive methods, such as imaging light. Clinical studies on mortality and long-term results of treatment of pulmonary embolism was conducted.
- Thrombolytic therapy of acute ischemic stroke. Shows only if started within the first 3 hours of stroke symptoms and if possible intracranial hemorrhage (hemorrhagic stroke) (using appropriate imaging techniques such as computed tomography (CT) of the brain).
Contraindications The drug Micardis should not be used in cases where there is an increased risk of bleeding:
- significant bleeding currently or within the previous 6 months, haemorrhagic diathesis;
- concomitant use of oral anticoagulants, such as warfarin sodium (an international standardized ratio> 1.3);
- central nervous system diseases in history (including neoplasm, aneurysm surgery on the brain or spinal cord);
- intracranial (including subarachnoid) hemorrhage at present or in history; suspicion of hemorrhagic stroke;
- severe uncontrolled hypertension;
- major surgery or significant trauma within the previous 10 days (including any injury, coupled with the acute myocardial infarction), recent head injury;
- prolonged or traumatic cardiopulmonary resuscitation (> 2 minutes), delivery within 10 days prior; recently produced an incompressible puncture a blood vessel (eg subclavian or jugular vein);
- severe liver disease, including liver failure, cirrhosis, portal hypertension jelfa omnadren (including esophageal varices) and active hepatitis;
- hemorrhagic retinopathy, for example, diabetes (impairment may indicate the presence of hemorrhagic retinopathy); Other hemorrhagic diseases of the eye;
- bacterial endocarditis, pericarditis;
- acute pancreatitis;
- confirmed gastric ulcer or duodenal ulcer in the past three months;
- arterial aneurysm, malformations of the arteries / veins;
- neoplasm with increased bleeding risk;
- Hypersensitivity to the drug
In the case of treatment for acute myocardial infarction and pulmonary embolism, besides the above, there is a contraindication following:
- A history of stroke.
In the case of treatment for acute ischemic stroke, in addition to the above, the following contraindications:
- the beginning of symptoms of ischemic stroke more than 3 hours before the start of the infusion, or the absence of precise information about the time of onset of symptoms;
- rapid improvement in acute ischemic stroke, or mild symptoms at the beginning of the infusion;
- hard flowing stroke, based on clinical data (e.g., if the exponent NIHSS> 25) and / or the results of the respective imaging methods;
- cramps in the beginning of a stroke;
- information about a stroke or serious head injury during the previous 3 months;
- the occurrence of a previous stroke and diabetes mellitus;
- heparin within 48 hours prior to the stroke, if at a given time is increased activated partial thrombin time (APTT);
- the use of antiplatelet agents at the time of infusion and within the first 24 hours after infusion;
- platelet counts less than 100,000 / mm 3 ;
- systolic blood pressure above 185 mm Hg. v., or diastolic blood pressure greater than 110 mm Hg. Art, or the need for intensive care (intravenous drugs) to lower blood pressure to these limits.;
- Blood glucose levels <50 or> 400 mg / dl.
The drug Micardis ® is not indicated for the treatment of acute stroke in children and adolescents under 18 years of age and in adults over 80 years.
Precautions In the following cases, the appointment of Actilyse should carefully assess the extent of the expected benefits and the possible risk of bleeding:
- Recently made an intramuscular injection or small recent interventions such as biopsies, puncture of major vessels, cardiac massage during resuscitation.
- Diseases (not mentioned in the list of contraindications), in which an increased risk of bleeding.
In the treatment of acute myocardial infarction and acute pulmonary embolism should further bear in mind the following special warnings and precautions:
- Systolic blood pressure> 160 mm Hg. Art.
- Older age at which may increase the risk of intracranial hemorrhage. Because elderly patients the likelihood of a positive outcome of the treatment is also increased, requires careful assessment of the benefit-risk.
In the treatment of acute ischemic stroke should further bear in mind the following special warnings and precautions: The use of Actilyse ® in patients with acute ischemic stroke, compared to the use of this drug for other indications, accompanied by a markedly increased risk of intracranial haemorrhage as the bleeding occurs predominantly in necrotic region. This is especially to be taken into account in the following cases:
- all the states listed in the “Contra”, and in general all conditions characterized by a high risk of bleeding;
- the presence of small asymptomatic aneurysms of the cerebral vessels;
- in patients who previously were treated with aspirin or other antiplatelet agents, possible increased risk of intracerebral haemorrhage, particularly if the application of Actilyse ® launched at a later date.Given the increased risk of cerebral hemorrhage applied alteplase dose should not exceed 0.9 mg / kg (maximum dose of 90 mg).
Treatment should not be initiated later than 3 hours after the onset of symptoms due to an unfavorable benefit / risk ratio, which is due to the following factors: the positive effect of the treatment decreases as the late start of therapy; mortality increased primarily in patients previously treated with acetylsalicylic acid; increased risk of bleeding.
Pregnancy and lactation Experience with Micardis ® during pregnancy and breastfeeding is very limited. When diseases are directly life-threatening, it is necessary to weigh the relationship between the benefits and potential risks.The question of alteplase penetration into breast milk has not been studied. In this regard, the use of Actilyse ® during pregnancy and lactation is not recommended.
Dosage and administration Actilyse ® should be applied as soon as possible after the onset of symptoms.
- myocardial infarction
- a) A 90-minute (accelerated) mode dosing for patients with myocardial infarction, in which the treatment can be started within 6 hours after symptom onset: 15 mg – intravenous (i / v) bolus, 50 mg – in / in infusion for the first 30 minutes, followed by 35 mg infused over 60 minutes to a maximum dose of -100 mg.In patients weighing less than 65 kg total dose is corrected for body weight: 15 mg – in / bolus, 0.75 mg / kg (max 50 mg) for 30 min intravenous (i / v) dropwise, followed by infusion 0.5 mg / kg (max 35 mg) for 60 minutes.
- b) 3-hour dosing schedule for patients in whom the treatment may be initiated between 6 and 12 hours after the onset of symptoms jelfa omnadren: 10 mg – intravenously, 50 mg – in / infusion during the first hour, followed by I / infusion rate of 10 mg over 30 minutes, to achieve for 3 hours maximum dose of 100 mg. The recommended maximum dose of alteplase in acute myocardial infarction is 100 mg.Patients with body weight below 65 kg the total dose should not exceed 1.5 mg / kg. The recommended maximum dose of alteplase in acute myocardial infarction is 100 mg.
Adjuvant therapy: Aspirin should be administered as soon as possible after the onset of symptoms, the use of this drug was continued during the first months after myocardial infarction. Recommended dosage: 160 – 300 mg per day. It should be started simultaneously heparin a period of 24 hours or more; (in case of accelerated dosing regimen alteplase – at least 48 hours). It is recommended to start with I / bolus of 5000 U / h before the start of thrombolytic therapy. Subsequently, heparin is administered by infusion at a rate of 1000 U / hr. The dose of heparin should be adjusted depending on the results of re-determination of activated partial thrombin time, APTT (values should exceed the initial level of 1.5 – 2.5 times).
- Pulmonary embolism total dose of 100 mg, to be administered within 2 hours. The greatest experience obtained by using the following dosing regimen: 10 mg / bolus over 1-2 minutes, 90 mg / in infusion for 2 hours . In patients weighing less than 65 kg total dose should not exceed 1.5 mg / kg.Adjuvant therapy: After applying Actilyse ® , in the case where the APTT values less than twice the upper limit of normal should be started (or continued) heparin infusion. The dose of heparin should be adjusted depending on the results of re-determination of APTT (values should exceed the initial level of 1.5 – 2.5 times).
- Ischemic stroke: The recommended dose of 0.9 mg / kg (max 90 mg) is administered by infusion for 60 minutes after the initial I / bolus dose, of 10% of the total dose.Therapy should be initiated as soon as possible after the onset of symptoms (preferably within 3 hours).Adjuvant therapy: The safety and efficacy of the above treatment regimen used in combination with heparin and acetylsalicylic acid in the first 24 hours after symptom onset, not well understood. In this regard, in the first 24 hours after start of therapy Actilyse ® use of acetylsalicylic acid or intravenous heparin should be avoided. If the use of heparin jelfa omnadren is required for other indications (e.g., for the prevention of deep vein thrombosis), its dose should not exceed 10 000 IU per day, wherein the drug is administered subcutaneously.
Instructions for use / treatment Dry substance contained in the vial Actilyse ® injection (10, 20, 50 or 100 mg) is dissolved in sterile water for injection such that the final concentration of alteplase was 1 mg / ml (as indicated below the table) .
|Bottle Actilyse ®||10 mg||20 mg||50 mg||100 mg|
|The volume of water for injection was added to the dry matter|
|Final concentration: 1 mg of alteplase / ml||10 ml||20 ml||50 ml||2 x 50 ml|
Thus, to obtain a final concentration of alteplase, component 1 mg / ml in a vial Actilyse ® , containing a dry matter, should be added to the entire volume of the supplied solvent. After dilution the resulting solution is administered intravenously as described above.
The resulting solution can be subsequently diluted with sterile saline (0.9%) to alteplase minimum concentration of 0.2 mg / ml. The resulting solution was initially not be diluted with water for injection or solutions for infusion based on carbohydrates, such as dextrose.
The drug Micardis ® can not be mixed with other drugs (even with heparin) or in a vial for infusion, either in the total system for intravenous administration.
Side effects The most frequent adverse reactions associated with the use of Actilyse ® , is a bleeding, which leads to a decrease in hematocrit and / or hemoglobin. Bleeding associated with thrombolytic therapy can be divided into two main categories:
- external bleeding (usually from places of punctures or damaged blood vessels);
- internal bleeding from the gastrointestinal, urinary tract, bleeding in the retroperitoneal space, bleeding in the brain or bleeding from parenchymal organs.
The following figures are based on the results of clinical trials of Actilyse ® in 8299 patients with acute myocardial infarction. Embolization case of cholesterol crystals were not observed in a population of patients who participated in clinical studies, based on a single report.
In comparison to studies of myocardial infarction, the number of patients with pulmonary embolism and stroke, which are involved in clinical trials (within 0-3 hours after onset of symptoms of the disease), was very small. Therefore, small numerical jelfa omnadren differences noted when comparing with the data obtained in myocardial infarction were most likely a consequence of the small sample size. In addition to intracranial hemorrhage (as a side effect of stroke) and reperfusion arrhythmias (as a side effect in myocardial infarction), there is no clinical evidence to suggest qualitative and quantitative differences in the spectrum of side effects Micardis drug ® in the case of its use omnadren in pulmonary embolism and acute ischemic stroke, or myocardial infarction.
Application of myocardial infarction:
Violations of the heart:
|Often:||reperfusion arrhythmias, which can be life-threatening and require the use of conventional antiarrhythmic therapy|
Application of myocardial infarction and pulmonary embolism:
Disorders of the nervous system:
The use in acute ischemic stroke:
Disorders of the nervous system:
|Often:||intracranial hemorrhage. The main adverse events were symptomatic intracranial hemorrhage (their rate reached 10%). However, the increase was not established morbidity or total mortality.|
Application of myocardial infarction, pulmonary embolism and acute ischemic stroke:
Disorders of the gastrointestinal tract:
|Often:||gastrointestinal bleeding, nausea, vomiting. Nausea and vomiting may also be symptoms of a myocardial infarction.|
|Infrequently:||bleeding in the retroperitoneal space, bleeding from the gums.|
Violations of a general nature and reactions at the site of injection:
|Often:||external bleeding, normally from punctures or places of damaged blood vessels.|
Damage toxic effects and complications of the procedures associated with the use of the drug:
|Infrequently:||anaphylactoid reaction. They usually are mild, but in some cases may be life-threatening. Possible rash, urticaria, bronchospasm, angioedema, hypotension, shock or any other allergic reactions. In the case of these reactions, a common anti-allergic therapy jelfa omnadren should be used. It was found that a relatively large proportion of patients with similar reactions simultaneously used ACE inhibitors. Anaphylactic reactions (in the strict sense of the term, that is due to IgE) on Micardis ® is not known. In rare cases, there was a transient antibody formation to Actilyse ® (in low titers), but the clinical significance of this phenomenon has not been established.|
|Rarely:||Crystals cholesterol embolization, which can lead to side effects relevant affected viscera.|
The reactions identified in special studies:
|Often:||decreased blood pressure|
|Often:||increased body temperature.|
Reproductive system and breast:
|Often:||bleeding from the urinary tract.|
From the side of respiratory organs, organs of the chest cavity and mediastinum:
The need for surgical and therapeutic procedures:
|Often:||need for blood transfusion.|
On the part of the vessels:
|Infrequently:||thromboembolism, which may be accompanied by the appropriate consequences from the affected organs.|
|Rarely:||bleeding from parenchymal organs.|
Overdose Despite the relative specificity of drug effects on fibrin, an overdose may result in a clinically significant reduction in the level of fibrinogen and other clotting factors.
In most cases it is enough to stop the introduction of Actilyse ® and wait for the physiological recovery of these factors. However, if you develop severe bleeding, recommended infusion of fresh frozen plasma or fresh blood; if necessary, you can assign a synthetic antifibrinolytic agent.
Interactions with other medications No specific studies interaction jelfa omnadren of Actilyse ® with other drugs commonly used in acute myocardial infarction, have been conducted.
The use of drugs that affect blood clotting or altering platelet function prior to, during or after the initiation of therapy Micardis ® may increase the risk of bleeding.
Concomitant use of ACE inhibitors may increase the risk of anaphylactoid reactions. These reactions are observed in a relatively large proportion of patients treated with ACE inhibitors.
Cautions Actilyse treatment ® should hold a doctor who has experience of thrombolytic therapy and the possibility of monitoring its effectiveness. When using Actilyse ® , as well as other thrombolytic agents, it is recommended to have at the disposal of the standard resuscitation equipment and related drugs.
General Precautions Bleeding The most common complication of therapy Actilyse ® is bleeding. The simultaneous use of heparin may contribute to bleeding. Since Actilyse ® dissolves the fibrin may occur bleeding from recent puncture sites. Therefore, thrombolytic therapy requires careful monitoring of possible areas of bleeding (including catheter site, arterial and venous punctures, cuts and injections. Avoid using rigid catheters, intramuscular injections and groundless manipulation during treatment with Actilyse.
In case of heavy bleeding, in particular cerebral, fibrinolytic therapy and heparin should be discontinued immediately. In the event that within 4 hours prior to the start of bleeding, heparin was used, it should consider the appropriateness of the use of protamine. In rare cases, when the above conservative measures are ineffective, the bleeding continues, it can be shown the use of blood products. Tranfuzionnoe introduction of cryoprecipitate, fresh frozen plasma and platelets may be appointed in accordance with clinical and laboratory parameters pamidronic acid to be determined again jelfa omnadren after each administration. Infusion is preferably carried out cryoprecipitate fibrinogen to achieve a concentration of 1 g / l. You can consider using antifibrinolytic agents (eg, traniksaminovoy acid), but special studies have not been conducted.
In acute myocardial infarction and pulmonary embolism should not be used Actilyse ® in a dose exceeding 100 mg, and in acute ischemic stroke – in a dose of 90 mg, as increased risk of intracranial hemorrhage.
Experience in the use of Actilyse in children is limited.
After treatment sustained production of antibodies against recombinant human tissue plasminogen activator were not observed. Systematize the experience re-use Actilyse ® is not available. In the case of anaphylactoid reaction, the infusion should be discontinued and appropriate treatment. Recommended regular monitoring of the tolerability of treatment, especially in patients concomitantly receiving ACE inhibitors (see. The side effects).
In the treatment of acute myocardial infarction should further bear in mind the following special warnings and precautions:
Arrhythmias Coronary thrombolysis may cause arrhythmias associated with reperfusion.
Antagonists of glycoprotein IIb / IIIa. Experience with glycoprotein PLPa antagonists within the first 24 hours after the start of treatment available.
Thromboembolism use of thrombolytic agents may increase the risk of venous thromboembolism in patients with thrombosis of the left heart, such as mitral stenosis or atrial fibrillation.
In the treatment of acute stroke should further bear in mind the following special warnings and precautions: Treatment should be carried out exclusively by an experienced doctor who have skills and experience in providing intensive neurological care in a specialized department, having the opportunity to spend the whole complex imaging studies.
It is necessary to monitor blood pressure (BP) during treatment and for 24 hours thereafter. An increase in systolic blood pressure> 180 mm Hg. Art. or diastolic blood pressure> 105 mm Hg. Art. It recommended intravenous antihypertensive drugs.
The therapeutic effect is reduced in patients who have had previous stroke, or if you have uncontrolled diabetes. In these patients, the ratio of benefit-risk is considered less favorable, but still remained positive. Patients with very little risk of stroke is greater than the potential benefits, so the use of Actilyse ® is not recommended. Patients with very severe jelfa omnadren stroke are at increased risk of intracranial hemorrhage and death in these cases, Micardis ® should not be used.
In patients with large infarcts of the brain there is an increased risk of adverse outcomes, including express intracerebral hemorrhage and death. In such cases, you should carefully weigh the risks and benefits of therapy.
At the stroke probability of a favorable outcome of treatment decreases with increasing age and with increasing stroke severity and increased levels of blood glucose. At the same time, the probability of a serious breach of legal capacity, and death or severe intracranial hemorrhage is increased regardless of treatment. Actilyse ® should not be used in patients older than 80 years in the case of severe stroke (clinical data and / or data imaging studies) and in those cases where the initial values of blood glucose of <50 mg / dL or> 400 mg / dl.
Reperfusion of ischemic area may lead to cerebral edema in the infarcted zone. Due to the increased risk of hemorrhage use of platelet aggregation inhibitors should not be initiated within the first 24 hours following thrombolysis with alteplase help. Running low dose t3 clen cycle trying to lose bodyfat isn’t a real hot idea imo. balkan pharmaceuticals