Producer: Boehringer Ingelheim Pharma (Beringer Ingelkhaym Pharma) Germany
Code of automatic telephone exchange: B01AD02
Release form: Firm dosage forms. The powder lyophilized for preparation of solution for infusions.
General characteristics. Structure:
Active ingredient: 1 mg of an alteplaza in 1 ml of solution (50 mg of an alteplaza in a bottle of 50 ml).
Excipients: L-arginine, phosphoric acid, polysorbate 80, solvent (water for injections).
Pharmacodynamics. AKTILIZE® active component - an alteplaza, is a recombinant human fabric plasminogen activator, a glycoprotein which directly activates transformation of plasminogen into plasmin. After intravenous administration of an alteplaz remains rather inactive in system of circulation. It is activated, contacting fibrin that causes transformation of plasminogen into plasmin and leads to dissolution of a clot of fibrin.
Use АКТИЛИЗЕ® (100 mg within 90 minutes) together with intravenous administration of heparin more than at 40000 patients with an acute myocardial infarction led (research GUSTO) to decrease in 30-day mortality (6,3%) in comparison with use of Streptokinasa (1,5 million units within 60 minutes) together with hypodermic or intravenous administration of heparin (7,3%). It is shown that in 60 and 90 minutes after a thrombolysis at the patients receiving АКТИЛИЗЕ® higher frequency of recovery of passability of vessels in a heart attack zone, than in case of use of Streptokinasa came to light. In 180 minutes after the beginning of therapy and after distinctions in the frequency of opening of a gleam of vessels it was not noted.
30 day mortality at the patients receiving АКТИЛИЗЕ® decrease in comparison with the patients who are not receiving thrombolytic therapy.
At use АКТИЛИЗЕ® enzyme release alpha hydroxybutyrate dehydrogenase (HBDH) decreases. At the patients receiving AKTILIZE in comparison with the patients who are not receiving thrombolytic therapy less considerable damage of the general function of a left ventricle of heart and smaller expressiveness of regional disturbances of mobility of walls of a left ventricle is noted.
In placebo - a controlled research (LATE) it is shown that use АКТИЛИЗЕ® (100 mg within 3 hours) at patients with a myocardial infarction (in case of the beginning of therapy within 6-12 hours after emergence of symptoms), led to reduction of mortality in the first 30 days in comparison with placebo. The medical effect at patients with accurate symptoms of a myocardial infarction can be noted and when treatment began within 24 hours after emergence of symptoms.
At patients with an acute massive embolism of the pulmonary artery which is followed by an unstable hemodynamics, use АКТИЛИЗЕ® leads to bystry reduction of the sizes of blood clot and pressure decrease in a pulmonary artery, however data on mortality are absent.
In two researches conducted in the USA (NINDS A/B) in which the effect of drug at an ischemic stroke was studied (in the first three hours after the beginning of symptoms) more frequent achievement of favorable result (lack of capacity of patients or the minimum degree of manifestation of these disturbances) in comparison with placebo is established.
In case of the beginning of therapy in later terms efficiency of drug decreases that was shown in 2 European researches and in the additional research conducted in the USA.
Results of meta-analysis of all patients receiving therapy within the first 3 hours after the beginning of a stroke confirmed existence of positive effect at an alteplaza.
Despite the increased risk of serious and even fatal intracraneal hemorrhages, probability of development of a favorable result of therapy alteplazy in comparison with placebo increased by 14,9% (95% - confidence intervals: 8,1% and 21,7%). These data do not allow to draw a certain conclusion concerning influence of therapy on mortality. The ratio advantage/risk in case of use of an alteplaza within 3 hours after the beginning of a stroke (taking into account the stated above cautions) in general can be considered favorable though data of researches do not allow to draw an unambiguous conclusion concerning influence of therapy on mortality.
Meta-analysis of all available clinical data shows that the alteplaza is less effective at patients whose treatment begins 3 hours later (in 3-6 hours) after the beginning of symptoms, in comparison with the therapy undertaken in the first 3 hours after development of clinical manifestations, at the same time risk of complications in the first case higher that the advantage/risk leads to an adverse result of a ratio.
Owing to relative specificity concerning fibrin, use of an alteplaza in a dose of 100 mg leads to moderate reduction of level of the circulating fibrinogen (approximately to 60% in 4 hours) which, as a rule, increases by 24 o'clock more than to 80%. Concentration of plasminogen and alpha 2 - anti-plasmin in 4 hours decrease, respectively, to 20% and 35% of initial levels, and in 24 hours increase more than to 80% again. Considerable and long reduction of level of the circulating fibrinogen is noted only at several patients.
Pharmacokinetics. АКТИЛИЗЕ® it is quickly brought out of a blood-groove and metabolized mainly in a liver (the plasma clearance makes 550-680 ml/min.). Significant plasma elimination half-life (T1/2α) makes 4-5 minutes. It means that in 20 minutes in plasma there are less than 10% of initial amount of drug. It is shown what for the remained amount of the drug T1/2β makes about 40 minutes.
Indications to use:
1. Thrombolytic therapy of an acute myocardial infarction.
- the 90-minute (accelerated) dosing mode (see. "Route of administration and doses"): for patients at whom treatment can be begun within 6 hours after development of symptoms;
- the 3-hour mode of dosing (see. "Route of administration and doses"): for patients at whom treatment can be begun in an interval between 6 and 12 hours after development of symptoms.
It is proved what at acute myocardial infarction АКТИЛИЗЕ® reduces mortality in the first 30 days after the beginning of a heart attack.
2. Thrombolytic therapy of an acute massive embolism of the pulmonary artery which is followed by an unstable hemodynamics. This diagnosis has to be, whenever possible, confirmed objectively, for example, with an angiography of a pulmonary artery, or noninvasive methods, for example, a tomography of lungs. Clinical trials concerning mortality and the long-term results of treatment of a pulmonary embolism it was not carried out.
3. Thrombolytic therapy of an acute ischemic stroke. It is shown only if begins within the first 3 hours after development of symptoms of a stroke and if intracraneal hemorrhage (a hemorrhagic stroke) is excluded (by means of the corresponding methods of visualization, for example, to the computer tomography (CT) of a brain).
Route of administration and doses:
АКТИЛИЗЕ® it is necessary to apply as soon as possible after the beginning of symptoms.
1. Myocardial infarction
◦а) the 90-minute (accelerated) dosing mode for patients with a myocardial infarction at whom treatment can be begun within 6 hours after the beginning of symptoms:
15 mg - intravenously (in/in) struyno,
50 mg - in/in infusion within the first 30 minutes, with the subsequent infusion of 35 mg within 60 minutes before achievement of the maximum dose of-100 mg.
At patients with body weight less than 65 kg adjust a total dose taking into account body weight:
15 mg - in/in struyno,
0,75 mg/kg (at most 50 mg) within 30 minutes intravenously (in/in) kapelno, with the subsequent infusion of 0,5 mg/kg (at most 35 mg) within 60 minutes.
◦б) the 3-hour mode of dosing for patients at whom treatment can be begun in an interval between 6 and 12 hours after development of symptoms:
10 mg - intravenously struyno,
50 mg - in/in infusion within the first hour, with the subsequent in/in infusion with a speed of 10 mg within 30 minutes, before achievement within 3 hours of the maximum dose of 100 mg.
The recommended maximum dose of an alteplaza at an acute myocardial infarction makes 100 mg.
At patients with body weight less than 65 kg the total dose should not exceed 1,5 mg/kg.
The recommended maximum dose of an alteplaza at an acute myocardial infarction makes 100 mg.
Auxiliary therapy. Acetylsalicylic acid has to be appointed as soon as possible after the beginning of symptoms, use of this drug is continued within the first months after a myocardial infarction. The recommended dose: 160 - 300 mg a day. Use of heparin for 24 h or more has to be at the same time begun; (in case of the accelerated mode of dosing of an alteplaza - on at least 48 h). It is recommended to begin with in/in jet introductions of 5000 Pieces/h prior to thrombolytic therapy. In the subsequent heparin is entered infusionally with a speed of 1000 Pieces/h. The dose of heparin should be adjusted depending on results of repeated definition of the activated partial thrombin time of AChTV (values have to exceed initial level by 1,5 - 2,5 times).
2. Embolism of a pulmonary artery
The total dose making 100 mg has to be entered during 2 h.
The greatest experience is got when using the following mode of dosing:
10 mg in/in struyno within 1-2 minutes,
90 mg in/in kapelno during 2 h.
At patients with body weight less than 65 kg the total dose should not exceed 1,5 mg/kg.
Auxiliary therapy. After use АКТИЛИЗЕ®, in that case when AChTV values less than exceed the upper bound of norm twice, infusional use of heparin has to be begun (or it is continued). The dose of heparin has to be to be adjusted depending on results of repeated definition of AChTV (values have to exceed initial level by 1,5 - 2,5 times).
3. Ischemic stroke:
The recommended dose of 0,9 mg/kg (at most 90 mg) is entered infusionally within 60 minutes after initial in/in jet introductions of the dose of drug making 10% of the size of a total dose. Therapy has to be begun as soon as possible after the beginning of symptoms (it is desirable within 3 hours).
Auxiliary therapy. Safety and efficiency of the mode of therapy stated above applied in combination with heparin and acetylsalicylic acid in the first 24 hours after the beginning of symptoms, are studied insufficiently. In this regard in the first 24 hours after the beginning of therapy АКТИЛИЗЕ® of use of acetylsalicylic acid or intravenous administration of heparin it is necessary to avoid. If use of heparin is required according to other indications (for example, for prevention of a deep vein thrombosis), its dose should not exceed 10 000 ME a day, at the same time the drug is administered subcutaneously.
Instructions on the use/address. The dry matter which is contained in bottle АКТИЛИЗЕ® for injections (10, 20, 50 or 100 mg) is dissolved in sterile conditions by water for injections so that final concentration of an alteplaza made 1 mg/ml (according to the table provided below).
|Bottle АКТИЛИЗЕ®||10 mg||20 mg||50 mg||100 mg|
|The water volume for injections added to dry matter|
|Final concentration: 1 mg á½ÔÑ»½áºÙ/ml||10 ml||20 ml||50 ml||2 x 50 ml|
Thus, for obtaining final concentration of the alteplaza making 1 mg/ml all volume of the enclosed solvent has to be added to bottle АКТИЛИЗЕ® containing dry matter.
After cultivation the received solution is entered intravenously as it is described above.
The received solution in the subsequent can be dissolved with sterile normal saline solution (0,9%) to the minimum concentration of an alteplaza of 0,2 mg/ml.
The solution received originally cannot be dissolved with water for injections or solutions for infusions on the basis of carbohydrates, for example, of a dextrose.
The drug AKTILIZE® cannot be mixed with other medicines (even with heparin), neither in a bottle for infusion, nor in the general system for intravenous administration.
Features of use:
The doctor having experience of performing thrombolytic therapy and a possibility of control of its efficiency has to carry out treatment АКТИЛИЗЕ®. When using АКТИЛИЗЕ®, also as well as other thrombolytic drugs, it is recommended to have on hand the standard resuscitation equipment and the corresponding medicines.
General measures of precaution. Bleeding. The most frequent complication of therapy АКТИЛИЗЕ® is bleeding. Simultaneous use of heparin can promote developing of bleeding. As АКТИЛИЗЕ® dissolves fibrin, there can be bleeding from places of recent punctures. Therefore thrombolytic therapy demands careful observation of zones of possible bleeding (including injection sites of a catheter, arterial and venous punctures, cuts and injections. It is necessary to avoid use of rigid catheters, intramuscular injections and unreasonable manipulations during treatment of AKTILIZE.
In case of developing of heavy bleeding, in particular cerebral, fibrinolitic therapy, and also use of heparin have to be immediately stopped. If within 4 hours prior to the beginning of bleeding heparin was applied, it is necessary to consider a question of expediency of use of protamin. In rare instances when the conservative measures stated above are inefficient, bleeding proceeds, use of blood preparations can be shown. Tranfuzionny administration of cryoprecipitate, freshly frozen plasma and thrombocytes can be appointed according to the clinical and laboratory indicators defined repeatedly after each introduction. Infusion of cryoprecipitate it is desirable to carry out 1 g/l to achievement of concentration of fibrinogen. It is possible to consider the possibility of use of anti-fibrinolitic means (for example, traniksaminovy acid), however special researches were not conducted.
At an acute myocardial infarction and an embolism of a pulmonary artery it is not necessary to apply АКТИЛИЗЕ® in the dose exceeding 100 mg, and at an acute ischemic stroke - in a dose more than 90 mg since the risk of intracraneal hemorrhage increases.
Experience of use АКТИЛИЗЕ® for children is still limited.
After the end of treatment of steady antibody formation to the recombinant human activator of fabric plasminogen it was not observed. The systematized experience of repeated use АКТИЛИЗЕ® is not available. In case of development of anaphylactoid reaction, infusion it is necessary to stop and appoint the corresponding treatment. Regular control of portability of treatment, especially at the patients who are at the same time receiving APF inhibitors is recommended (see. Side effects).
At treatment of an acute myocardial infarction it must be kept in mind in addition the following special cautions and precautionary measures:
Arrhythmias. The coronary thrombolysis can lead to the arrhythmia connected with reperfusion.
Antagonists of a glycoprotein of IIb/IIIa. Experience of use of antagonists of glycoprotein ПЬЛПа within the first 24 hours after an initiation of treatment is absent.
Thromboembolisms. Use of thrombolytic means can increase risk of thromboembolisms at patients with thrombosis of the left departments of heart, for example, at a mitral stenosis or at fibrillation of auricles.
At treatment of an acute stroke it must be kept in mind in addition the following special cautions and precautionary measures. Treatment has to be carried out by exclusively experienced doctor having skills and experience of rendering the intensive neurologic help in the conditions of the specialized department having an opportunity to conduct all complex of neurovisualization researches.
It is necessary to monitorirovat the arterial pressure (AP) during treatment and within 24 hours after its termination. At increase in the systolic ABP> 180 mm of mercury. or diastolic ABP> 105 mm of mercury. intravenous use of anti-hypertensive drugs is recommended.
The medical effect decreases at the patients who had earlier a stroke or in the presence of an uncontrollable diabetes mellitus. At such patients a ratio the advantage risk is considered less favorable though nevertheless remains positive. At patients with very small stroke the risk exceeds the expected advantage therefore use АКТИЛИЗЕ® is not recommended. At patients with very heavy stroke the risk of intracranial bleeding and death is increased, in these cases АКТИЛИЗЕ® it is not necessary to apply.
At patients with extensive heart attacks of a brain the increased risk of a failure, including the expressed intracerebral bleeding and death is noted. In such cases it is necessary to weigh carefully risk and advantage of performing therapy.
At a stroke the probability of favorable result of treatment decreases with increase in age, and also in process of increase in severity of a stroke and at the increased glucose levels in blood. At the same time, the probability of serious violation of capacity and death or serious intracraneal hemorrhage increases regardless of treatment. АКТИЛИЗЕ® it is not necessary to apply at patients 80 years, in case of a heavy stroke (according to clinical data and/or according to the visualizing researches) are more senior and when reference values of glucose of blood make <50 mg/dl or> 400 mg/dl.
Reperfusion of ischemic area can lead to wet brain in a heart attack zone. Because of the increased risk of hemorrhages use of inhibitors of aggregation of thrombocytes should not be begun within the first 24 hours after carrying out a thrombolysis by means of an alteplaza.
Pregnancy and lactation. Experience of use АКТИЛИЗЕ® during the periods of pregnancy and feeding is very limited to a breast. At diseases, directly life-threatening, it is necessary to weigh a ratio between advantage and potential risk. The question of penetration of an alteplaza into breast milk is not studied. In this regard use АКТИЛИЗЕ® during pregnancy and feeding by a breast is not recommended.
The most frequent undesirable reaction connected using АКТИЛИЗЕ® is the bleeding leading to decrease in a hematocrit and/or hemoglobin. The bleedings connected with thrombolytic therapy can be divided into two main categories:
• outside bleeding (as a rule, from places of punctures or damages of blood vessels);
• internal bleedings from a gastrointestinal, urinogenital path, bleeding in retroperitoneal space, hemorrhages in a brain or bleedings from parenchymatous bodies.
The digital data given below are based on results of clinical trials АКТИЛИЗЕ® at 8 299 patients with an acute myocardial infarction. The embolization case crystals of cholesterol which was not observed in population of the patients participating in clinical trials is based on the separate message. In comparison with researches at a myocardial infarction, the number of patients with an embolism of a pulmonary artery and a stroke who participated in clinical trials (within 0-3 hours from the moment of emergence of symptoms of these diseases) was very small. Therefore, the small numerical distinctions noted when comparing with the data obtained at a myocardial infarction were, most likely, a consequence of small volume of selection. In addition to intracraneal hemorrhage (as side effect at a stroke) and reperfusion arrhythmias (as side effect at a myocardial infarction), there are no clinical bases to assume qualitative and quantitative distinctions in a range of side effects of the drug AKTILIZE® in case of its use at an embolism of a pulmonary artery and an acute ischemic stroke, or at a myocardial infarction.
Use at a myocardial infarction. Disturbances from heart. Very often: reperfusion arrhythmias which can threaten life and demand use of the standard antiarrhytmic therapy.
Use at a myocardial infarction and an embolism of a pulmonary artery. Disturbances from a nervous system. Seldom: intracraneal hemorrhage.
Use at an acute ischemic stroke. Disturbances from a nervous system. Often: intracraneal hemorrhage. Clinically expressed intracraneal hemorrhages were the main undesirable phenomenon (their frequency reached 10%). However increases in frequency of complications or the general mortality it was not established.
Use at a myocardial infarction, an embolism of a pulmonary artery and an acute ischemic stroke. Disturbances from digestive tract. Often: gastrointestinal bleedings, nausea, vomiting. Nausea and vomiting can be also myocardial infarction symptoms. Infrequently: hemorrhages in retroperitoneal space, an odontorrhagia.
Disturbances of the general character and reaction in a drug injection site. Very often: outside bleedings, usually from places of punctures or from the damaged blood vessels.
Damages, the toxic phenomena and complications owing to the procedures connected using drug. Infrequently: anaphylactoid reactions. They are usually expressed poorly, but in some cases can be life-threatening. Rash, urticaria, a bronchospasm, a Quincke's disease, hypotension, shock or any other allergic reactions are possible. In case of development of these reactions the standard antiallergic therapy has to be applied. It is established that at rather most part of patients with similar reactions inhibitors of an angiotensin-converting enzyme were at the same time applied. Anaphylactic reactions (in strict sense of this concept, that is the caused IgE) on АКТИЛИЗЕ® are not known. Tranzitorny antibody formation to АКТИЛИЗЕ® was in rare instances observed (in low credits), but the clinical importance of this phenomenon is not established. Seldom: embolization by cholesterol crystals that can lead to the corresponding effects from the affected internals.
The reactions revealed at special researches. Very often: lowering of arterial pressure
From reproductive system and chest glands. Often: bleedings from an urinogenital path.
From a respiratory organs, bodies of a chest cavity and mediastinum. Often: nasal bleeding.
Need for holding surgical and therapeutic procedures. Often: need for hemotransfusion.
Interaction with other medicines:
Special researches of interaction of AKTILIZE with other medicines which are usually applied at an acute myocardial infarction were not conducted.
Use of the medicines influencing a blood coagulation or changing function of thrombocytes to, in time or after the beginning of therapy of AKTILIZE can increase risk of bleeding.
Simultaneous use of APF inhibitors can increase risk of anaphylactoid reactions. These reactions were observed at rather most part of the patients receiving APF inhibitors.
Aktiliza should not use drug when there is an increased risk of development of bleedings:
• considerable bleeding now or within the last 6 months, hemorrhagic diathesis;
• a concomitant use of peroral anticoagulants, for example, warfarin (the international standardized relation> 1,3);
• diseases of the central nervous system in the anamnesis (including, new growths, aneurism, surgical intervention on a head or spinal cord);
• intracranial (including subarachnoidal) hemorrhage now or in the anamnesis; suspicion on existence of a hemorrhagic stroke;
• heavy uncontrollable arterial hypertension;
• extensive surgical intervention or a considerable injury during the previous 10 days (including any injury in combination with this acute myocardial infarction), a recent craniocereberal injury;
• long or traumatic cardiopulmonary resuscitation (> 2 min.), childbirth within 10 previous days; recently made puncture of not compressed blood vessel (for example, a subclavial or jugular vein);
• serious illness of a liver, including liver failure, cirrhosis, portal hypertensia (including gullet varicosity) and active hepatitis;
• bacterial endocarditis, pericardis;
• acute pancreatitis;
• the confirmed peptic ulcer of a stomach or duodenum within the last three months;
• arterial aneurisms, defects of development of arteries/veins;
• a new growth with the increased risk of development of bleeding;
• hypersensitivity to drug components
In case of use of drug for treatment of an acute myocardial infarction and an embolism of a pulmonary artery, in addition to above-mentioned, there is the following contraindication:
- The Gemmorragichesky stroke or a stroke of an unknown etiology in the anamnesis
- An ischemic stroke or the tranzitorny ischemic attacks within the last 6 months except for the current acute ischemic stroke within 3 hours.
In case of use of drug for treatment of an acute ischemic stroke, in addition to above-mentioned, there are following contraindications:
- the beginning of symptoms of an ischemic stroke more than in 3 hours prior to infusion, or lack of exact data on time of the beginning of symptoms;
- bystry improvement of a state at acute ischemic a stroke, or weak expressiveness of symptoms by the time of the beginning of infusion;
- hard proceeding stroke, on the basis of clinical data (for example, if NIHSS indicator> 25 (National Institutes of Health Stroke Scale)) and/or by results of the corresponding methods of visualization (a computer tomography or nuclear magnetic resonance);
- spasms at the beginning of a stroke;
- data on the had stroke or a serious injury of the head within 3 last months;
- developing of the previous stroke against the background of a diabetes mellitus;
- use of heparin within 48 hours prior to the beginning of a stroke if at present time the activated partial thrombin time is raised
- use of antiagregant at the time of infusion and within the first 24 hours after infusion;
- number of thrombocytes less than 100 000/mm3;
- systolic arterial pressure is higher than 185 mm of mercury., or diastolic arterial pressure is higher than 110 mm of mercury., or need of use of an intensive care (intravenous administration of drugs) for a lowering of arterial pressure to these borders;
- glucose level in blood <50 or> 400 mg/dl.
Drug AKTILIZE is not shown for therapy of an acute stroke at children and teenagers up to 18 years, and at adults 80 years are more senior.
With care. In the following cases at purpose of AKTILIZE it is necessary to estimate carefully degree of estimated advantage and possible risk of bleeding:
• Recently executed intramuscular injection or small recent interventions, such as a biopsy (needle), a puncture (needle) of large vessels, a cardiac massage at resuscitation.
• The diseases (which are not mentioned in the list of contraindications) at which the risk of bleeding is increased.
At treatment of an acute myocardial infarction and acute embolism of a pulmonary artery it must be kept in mind in addition the following special cautions and precautionary measures:
• Systolic arterial pressure> 160 mm of mercury.
• Advanced age (> 75 years) at which the risk of intracraneal hemorrhage can increase. As at patients of advanced age the probability of a positive take of this treatment also increases, careful assessment of a ratio advantage risk is necessary.
At treatment of an acute ischemic stroke it must be kept in mind in addition the following special cautions and precautionary measures. Use of AKTILIZE for patients with an acute ischemic stroke, in comparison with use of this drug according to other indications, is followed much by the increased risk of intracraneal hemorrhage as bleeding occurs preferential to the necrotic area. It especially should be taken into account in the following cases:
• all states which are characterized by high risk of bleeding;
• existence of small asymptomatic aneurisms of cerebral vessels;
• at patients to whom treatment by acetylsalicylic acid or other antiagregantny means was carried out earlier the increased risk of intracerebral bleeding, especially is possible if use АКТИЛИЗЕ® is begun in later terms. Considering the increased risk of brain hemorrhage, the applied dose of an alteplaza should not exceed 0,9 mg/kg (the maximum dose makes 90 mg).
Treatment should not be begun later, than in 3 hours after the beginning of symptoms, owing to an adverse ratio advantage/risk that it is caused by the following circumstances:
- the positive effect of treatment decreases at the late beginning of therapy;
- mortality increases preferential at the patients who were earlier receiving acetylsalicylic acid;
- the risk of bleeding increases.
Despite relative specificity of impact of drug on fibrin, the overdose can lead to clinically significant decrease in level of fibrinogen and other blood-coagulation factors.
In most cases it is enough to stop introduction АКТИЛИЗЕ® and to expect physiological recovery of these factors. However if serious bleeding develops, infusions of freshly frozen plasma or fresh blood are recommended; if necessary it is possible to appoint synthetic anti-fibrinolitic means.
To store in the place protected from light, at a temperature not above 25 °C. The prepared solution can be stored in the refrigerator 24 hours, and at a temperature not above 25 °C - till 8 o'clock (on a cardboard box and on the label of a bottle with lyophilisate). At a temperature not above 25 °C (on the label of a bottle with solvent). Period of validity 3 years. Not to use drug after expiry date.
According to the recipe
Lyophilisate for preparation of solution for infusions complete with solvent. 1 bottle from colourless glass of type 1 containing 50 mg of lyophilisate for preparation of solution for infusions, corked by the hlorbutilovovy stopper which is rolled up by an aluminum cap and a protective plastic cover of "Flip off" of green color and 1 bottle with solvent of 50 ml from colourless glass of type 1 corked by the hlorbutilovovy stopper which is rolled up by an aluminum cap and a protective plastic cover of "Flip off" of blue color together with the application instruction are enclosed in a cardboard box