Epirubitsin

General characteristics. Structure:

Active ingredient: epirubicin hydrochloride;

1 ml of solution of a soderzhitepirubitsin of a hydrochloride, in terms of 100% substance, 2,0 mg;

auxiliary a veshchestva:natriya chloride, Acidum hydrochloricum diluted water for injections.

Pharmacological properties:

Pharmacodynamics. Epirubitsin is an antineoplastic antibiotic of group of anthracyclines. Action of an epirubitsin is explained by linkng with DNA. Epirubitsin quickly gets into cells, is localized in kernels and inhibits synthesis of nucleic acids and a mitosis. Epirubitsin is active rather wide range of experimental tumors, in particular leukoses of L1210 and P388, SA180 sarcomas (solid and astsitny forms), a melanoma of B16, a carcinoma of a mammary gland, a carcinoma of lungs Lewis and carcinomas of a large intestine 38. Activity of an epirubitsin concerning tumors of the person, transplantirovanny is proved to beztimusny naked mice (melanomas, carcinomas of a mammary gland, lungs, a prostate gland and an ovary).

Pharmacokinetics. After intravenous administration of drug in doses of 60-150 mg/sq.m of a body surface process of decrease in concentration of an epirubitsin in plasma a shelter of patients with normal function of a liver and kidneys has three-phase exponential character. The first phase very short, and an elimination half-life in a terminal phase makes about 40 hours. The specified doses are in the range of pharmacokinetic linearity as in respect of indicators of plasma clearance, and metabolism (the upper bound of the line section – a dose of 150 mg/sq.m of a body surface). The main identified metabolites of an epirubitsin is эпирубицинол (13-OH эпирубицин) and glucuronides of an epirubitsin and an epirubitsinol.

After intravesical introduction at patients with a bladder in situ carcinoma the level of an epirubitsin in a blood plasma usually low (<10 ng/ml), that is the considerable system resorption does not occur. At patients with injuries of a mucous membrane of a bladder (for example, owing to development of tumors, cystitis or surgical intervention) degree of a resorption of an epirubitsin is higher.

4-O - glyukuronization distinguishes эпирубицин from doxorubicine and explains its more bystry removal and smaller toxicity. Concentration of the main metabolite (epirubitsinol) in a blood plasma is lower, than the epirubitsina, and decreases approximately in proportion to concentration of initial connection.

Epirubitsin is brought preferential by a liver. High rates of plasma clearance (0,9 l/min) demonstrate that slow removal of drug is explained by wide distribution in fabrics. With bile in 72 hours about 40% of a dose are excreted, it is the main way of removal. With urine in 48 hours about 9-10% of a dose are excreted.

Epirubitsin does not get through a blood-brain barrier.

Pharmaceutical characteristics.

The main physical and chemical svoystva:prozrachny solution of red color.

Incompatibility. Any alkaline solution at long contact causes hydrolysis of an epirubitsin. Epirubitsin is forbidden to mix with heparin because of chemical incompatibility owing to which at a certain ratio of drugs in solution the deposit can be formed. Epirubitsin and solution for infusions it is not necessary to mix with other medicines in one syringe or an infusional bottle.

Indications to use:

Breast cancer; widespread ovarian cancer; carcinoma of the stomach, liver cancer, pancreatic cancer, rectum cancer; lung cancer; sarcomas of soft tissues; cancer of the head and neck; malignant lymphoma; leukoses. At intravesical use: papillary transitional cell cancer of a bladder; in situ carcinoma; prevention of a recurrence of superficial cancer of bladder after a transurethral resection.

Route of administration and doses:

Only intravenous and intravesical administration of drug is allowed.

It is necessary to take all measures for prevention of paravenous administration of drug. In case of an ekstravazation it is necessary to stop introduction immediately.

Solutions for infusions prepare by cultivation of an epirubitsin 0,9% by solution of sodium of chloride or 5% glucose solution. Solutions for infusions prepare ex tempore and use right after preparation.

Usual doses for adults.

At monotherapy эпирубицин it is recommended to enter intravenously in a dose 60-90 mg/sq.m of a body surface. Courses of therapy are repeated bucketed in 21 days depending on hematologic indicators and function of marrow of the patient.

At development of toxic effects, in particular a heavy neutropenia / нейтропенической fever and thrombocytopenia (which can not pass to 21go day), administration of drug is deferred or reduce further doses.

High doses for adults.

Epirubitsin in high doses apply to monotherapy of the first line of patients:

-   small-celled lung cancer: in a dose of 120 mg/sq.m of a body surface each 3 weeks;

-   not small-celled lung cancer (planocellular, macrocellular cancer, adenocarcinoma): in a dose of 135 mg/sq.m of a body surface in the 1st day of a course or 45 mg/sq.m in the 1st, 2nd and 3rd days of a course, with repetition of courses each 3 weeks.

The drug is administered by intravenous bolyusny injections lasting 3-5 min. or by vnutrenny infusions lasting up to 30 minutes.

Cancer therapy of a mammary gland.

At adjuvant chemotherapy of a breast cancer of early stages with damage of regional lymph nodes эпирубицин it is recommended to enter intravenously in doses from 100 mg/sq.m of a body surface (once in the 1st day of a course) to 120 mg/sq.m of a body surface (in the divided doses in the 1st and 8th days of a course) into combinations with cyclophosphamide and                  5-ftoruratsily intravenously, and also Tamoxifenum orally. Courses are repeated with frequency in 3-4 weeks.

Patients with dysfunction of marrow owing to the previous himio-or radiation therapy, advanced age or neoplastic infiltration of marrow are recommended to appoint lower doses – 60-75 mg/sq.m of a body surface at traditional therapy and 105-120 mg/sq.m – at high-dose therapy. The general course dose can be divided and entered within 2-3 days in a row.

At the combined chemotherapy epirubitsiny and other cytotoxic drugs of a dose it is recommended to reduce.

In the table the general recommendations concerning doses at monotherapy and the combined chemotherapy of various tumors are included below.

Oncological disease                  Dose of an epirubitsin

                                   Monotherapy           Combination therapy

Widespread cancer of an ovary       of 60-90                mg/sq.m 50-100 mg/sq.m
 
Carcinoma of the stomach                        of 60-90                 mg/sq.m 50 mg/sq.m
 
Small-celled lung cancer            of 120                 mg/sq.m 120 mg/sq.m

                Doses usually enter in the 1st day of a course or in the 1st, 2nd and 3rd days of a course.

                       Courses are repeated bucketed in 3 weeks.
Treatment of patients with abnormal liver functions.

As эпирубицин it is removed by preferential gepatobiliarny system, doses for patients with abnormal liver functions need to be reduced depending on bilirubin level in blood serum.

Bilirubin level          Dose decline
 
24-51 µmol/l                 for 50%
 
> 51 µmol/l                  for 75%
 
Treatment of patients with renal failures.

As renal excretion of an epirubitsin is insignificant, decrease in doses for patients with moderate renal failures is not required. However correction of doses can be necessary for patients with creatinine level in blood serum over 5 mg/dl.

Intravesical use

Epirubitsin it is possible to apply vnutripuzyrno to treatment of superficial cancer of bladder and a carcinoma of in situ.

Epirubitsin it is not necessary to apply vnutripuzyrno to treatment of the invasive tumors which got through a bladder wall. In such cases of more effective the system chemotherapy or surgical intervention is.

Epirubitsin is also successfully applied to intravesical prevention of a recurrence after a transurethral resection of superficial tumors of a bladder.

The following schemes of intravesical therapy epirubitsiny are recommended:

·        Superficial cancer uric puzyrya:8 instillations on 50 mg / 50 ml weekly (drug 0,9% part with solution of sodium of chloride or the sterile distilled water). At emergence of local toxic dosage effects reduce to 30 mg / 50 ml.

·        A carcinoma of in situ:do of 80 mg / 50 ml (depending on individual portability).

·        Profilaktika:po of 50 mg / 50 ml weekly for 4 weeks, then monthly for 11 months.

                   Preparation of solutions for intravesical instillations
Dose          Volume       of the drug Solvent Volume             Total amount of solution
epirubitsina   (эпирубицин 2 mg/ml) (sterile distilled    instillations
                                      water or 0,9% solution
                                         chloride sodium)

30                                                           mg 15 ml 35 ml 50 ml
 
50                                                           mg 25 ml 25 ml 50 ml
 
80                                                            mg 40 ml 10 ml 50 ml

Solution has to be in a bladder for 1-2 hours. For prevention of dilution of solution urine the patient has to abstain from reception of any liquid for 12 hours before instillation. During the procedure the patient needs to turn periodically on sides, and at the end to empty a bladder.

Features of use:

Only the prepared personnel have to work with drug.

It is necessary to prepare solutions for infusions in aseptic conditions in the specially allotted room.

It is necessary to use protective clothes (one-time gloves, masks, points, dressing gowns and hats or overalls).

It is necessary to undertake all measures for prevention of hit of solutions of an epirubitsin in eyes. If all this happened, eyes should be washed out immediately a large amount of water and/or 0,9% solution of sodium of chloride and to address the ophthalmologist.

At hit of solutions of an epirubitsin on skin the affected area is washed out water or solution of sodium of bicarbonate with soap. However it is not necessary to rub skin a brush not to damage it. After removal of gloves it is always necessary to wash hands.

When spraying or pouring solution of an epirubitsin the contaminated place needs to be processed (to fill in) with divorced solution of sodium of hypochloride (with concentration of active chlorine of 1%), it is desirable for a long time (for the night), and then to wash out water.

Pregnant medical employees cannot work with drug.

Epirubitsin does not contain preservatives therefore unused drug needs to be utilized immediately.

The unused remains of drug, and also all tools and materials contacting with epirubitsiny at preparation and administration of solutions for infusions and cleaning need to be destroyed according to the approved procedure of recycling of cytotoxic substances.

Treatment epirubitsiny has to be carried out under control of the qualified oncologist. There has to be available a diagnostic equipment and conditions for treatment of possible complications owing to a miyelosupresiya, especially at high-dose therapy.

As эпирубицин can have genotoksichesky effect, men are not recommended to conceive children in the course of treatment and for 6 months after the end of therapy epirubitsiny.

Considering a possibility of development of irreversible infertility owing to treatment epirubitsiny, the male patients wishing to become fathers in the future are recommended to resort to a sperm cryopreservation prior to therapy. Women cannot become pregnant during treatment epirubitsiny. Patients (both women, and men) of reproductive age need to use effective contraceptive remedies throughout treatment by drug and for 6 months after the end of therapy epirubitsiny.

Ekstravazation of drug can cause heavy damage of fabrics and a necrosis. Administration of drug in veins of the small size or repeated introduction to the same vein can cause a vein sclerosis.

Before an initiation of treatment epirubitsiny it is necessary to conduct careful examination of the patient with definition of the main hematologic indicators and functions of heart.

Before the beginning and during each course of therapy it is necessary to define quantity of erythrocytes, leukocytes, neutrophils and thrombocytes. The leukopenia and a neutropenia at treatment epirubitsiny usually tranzitorny are also more expressed at treatment by high doses. The minimum quantity of leukocytes and neutrophils is observed in 10-14 days after administration of drug. Indicators are usually normalized up to 21st day. Thrombocytopenia (<100000/mm3) is noted at a small amount of patients, even at high-dose therapy.

Heavy stomatitis or inflammation of mucous membranes have to be treated prior to therapy epirubitsiny.

When determining the most admissible cumulative dose of an epirubitsin it is necessary to take into account the accompanying therapy by other potentially cardiotoxic drugs. It is necessary to appoint a cumulative dose over 900-1000 mg/sq.m of a body surface carefully (at treatment both usual, and high doses) as at exceeding of this level the risk of development of irreversible congestive heart failure sharply increases.

Before the beginning and after the termination of each course of therapy the ECG is recommended to conduct a research. Such changes of an ECG as flattening or inversion of a tooth T, a depression of a segment of ST or arrhythmia (usually tranzitorny and reversible), are not the basis for the therapy termination by drug. At cumulative doses <900 mg/sq.m of a body surface cardiotoxic effects are noted seldom. However in the course of treatment epirubitsiny it is necessary to control carefully function of heart to minimize risk of development of heart failure of that type which is noted at treatment by other anthracyclines. In case of development of heart failure эпирубицин it is necessary to cancel.

The cardiomyopathy caused by anthracyclines is associated with permanent decrease in amplitude of the QRS complex, lengthening (with an exit for limits of norm) a systolic interval and decrease in FVLZh. It is very important to control regularly (it is desirable by noninvasive methods) function of heart of patients who receive эпирубицин. Changes of an ECG can be indicative in case of the cardiomyopathy caused by anthracyclines, however ECGs of a research are not rather sensitive and specific to tracking of the cardiotoxic damages caused by anthracyclines. For decrease in risk of development of serious cardiological violations in the course of treatment it is regularly recommended to control FVLZh and to cancel immediately эпирубицин at emergence of the first signs of dysfunction of heart. An optimum way of control of function of heart are consecutive measurements of FVLZh by means of a multichannel radionuclide angiography or an ekhokardigrafiya. The first examination is conducted prior to therapy epirubitsiny, then regularly further, in particular at approach to a boundary cumulative dose of anthracyclines. It is extremely important to control carefully function of heart at patients with risk factors of development of cardiotoxicity (in particular at those which received anthracyclines or antratsendiona earlier). It is necessary to apply the same method of definition of FVLZh during the entire period of observations.

Anthracyclines, in particular эпирубицин, it is possible to appoint in a combination with other cardiotoxic drugs only on condition of carrying out frequent control of function of heart. The risk of development of cardiotoxicity is higher at patients who receive anthracyclines after treatment suspension by other cardiotoxic drugs, especially with a long elimination half-life (in particular, trastuzumaby). The elimination half-life of a trastuzumab makes about 28,5 days, and it can circulate in blood up to 24 weeks. Therefore, whenever possible, it is necessary to avoid purpose of anthracyclines for 24 weeks after treatment suspension trastuzumaby. If anthracyclines are appointed before this term, it is necessary to control function of heart very attentively.

Heart failure can develop both in the course of treatment epirubitsiny, and in several weeks after the end of therapy. Heart failure can be resistant to treatment. The risk of development of cardiotoxic defeats is higher at patients who received radiation therapy on the site of a mediastinum or pericardium, and also were treated by other potentially cardiotoxic drugs.

Prior to the beginning of and in the course of therapy epirubitsiny it is recommended to carry out functional hepatic tests (to determine the ALT, nuclear Heating Plant levels, an alkaline phosphatase and bilirubin).

At treatment by cytotoxic drugs, in particular epirubitsiny, the hyperuricemia owing to bystry killing of a tumor can develop. Therefore it is regularly necessary to control the level of uric acid in blood serum for early detection and treatment of this phenomenon. For prevention of development of a hyperuricemia and minimization of possible complications of a syndrome of a lysis of a tumor carrying out hydration, alkalization of urine and preventive use of Allopyrinolum is recommended.

Cases of development of a secondary leukosis (with a preleukemic phase or without it) the unekotory patients receiving anthracyclines, in particular эпирубицин are described. The secondary leukosis develops at use of these drugs in combinations more often with other antineoplastic means which cause DNA damage, in the patients who were earlier receiving intensive cytotoxic care or anthracyclines in high doses. Stage of latency in such cases short (1-3 years).

Introduction of live or live attenuirovanny vaccines to patients with reduced immunity owing to chemotherapy, in particular epirubitsiny, can cause development of heavy or lethal infections. It is necessary to avoid vaccination of the patients receiving эпирубицин, live vaccines. The inactivated vaccines can be appointed, but the response to such vaccination can be weak.

Intravesical introduction of an epirubitsin can cause emergence of symptoms of chemical cystitis (also as a dysuria, a polyuria, a nokturiya, the complicated urination, a hamaturia, discomfort in a bladder, a bladder wall necrosis), and also a bladder spasm. Special attention should be paid on catheterization problems (for example, in case of obstruction of an urethra at massive intravezikalny tumors).

Epirubitsin can paint urine in red color for 1-2 days after introduction.

Ability to influence speed of response at control of motor transport or work with other mechanisms.

At treatment epirubitsiny the specific side effects influencing speed of response at control of motor transport or work with other mechanisms were not noted.

Epirubitsin can make sick and vomiting owing to what ability to manage motor transport and other mechanisms can temporarily be broken.

Side effects:

At treatment epirubitsiny the most serious are side effects from system of blood and digestive tract.

On frequency side reactions are distributed on such categories: very widespread (≥ 1/10), extended (≥ 1/100, <1/10), not widespread (≥ 1/1000, <1/100), seldom widespread (≥ 1/10000, <1/1000), single (<1/10000).

Laboratory indicators: seldom widespread: increase in levels of hepatic transaminases, asymptomatic reduction of the fraction of emission of a left ventricle (FELV).

From cordial system: widespread: cardiotoxic effects (changes an ECG, tachycardia, arrhythmia, a cardiomyopathy), congestive heart failure (with such manifestations as the complicated breath, short wind, hypostases, increase in a liver, ascites, a fluid lungs, a pleural exudate, a cantering rhythm), ventricular tachycardia, bradycardia, an atrioventricular block, blockade of a leg of a ventriculonector.

From system of blood and lymphatic system: very widespread: miyelosupresiya (leukopenia, granulocytopenia, neutropenia, febrile neutropenia); widespread: anemia, thrombocytopenia, bleedings.

At patients with various solid tumors at therapy epirubitsiny in high doses the same side effects are noted, as at therapy by usual doses of drug, and, besides, at most of patients the reversible heavy neutropenia develops (<500 neutrophils/mm3 on an extent <7 days). However only a small amount of patients demanded hospitalization and the supporting treatment owing to heavy infectious complications.

From digestive tract: very widespread: the inflammation of mucous membranes (which is usually developing in 5-10 days after an initiation of treatment and shown in the form of stomatitis with painful erosion, ulcers and bleedings, mostly from the parties of language and under language), gastrointestinal bleeding; widespread: nausea, vomiting, diarrhea (which can cause dehydration), anorexia, pain in a stomach, an esophagitis, a hyperpegmentation of a mucous membrane of an oral cavity.

From skin and hypodermic fabrics: very widespread: an allopecia, usually reversible (at 60-90% of patients), the termination of growth of a beard at men; widespread: rushes of blood to the person; not widespread: hypersensitivity of skin to light, changes of a xanthopathy and nails; seldom widespread: small tortoiseshell, erythema, local toxic effects.

From kidneys and urinary system: very widespread: coloring of urine in red color on protyazhenii1-2 days after introduction.

From metabolism: seldom widespread: a hyperuricemia (owing to bystry killing of a tumor), dehydration.

Infections and invasions: seldom widespread: the complications connected with oppression of function of marrow – fever, infections, pneumonia, sepsis, septic shock, bleedings, a hypoxia of fabrics, in isolated cases with a lethal outcome.

Injuries, poisonings and complications of procedures: widespread: chemical cystitis, sometimes hemorrhagic, burning sensation, a pollakiuria (after intravesical use).

High-quality and malignant new growths (including cysts and polyps): seldom widespread: acute lymphoid leukosis, acute myeloid leukosis.

From an organ of sight: not widespread: conjunctivitis, keratitis.

From vascular system: not widespread: thrombophlebitis.

During treatment epirubitsiny at some patients the thromboembolic phenomena, in particular an embolism of a pulmonary artery were noted (in isolated cases – with a lethal outcome).

Effects of the general character and local reactions: widespread: reddening along a vein to which infusion was carried out; local phlebitis, phlebosclerosis; local pain and a necrosis of fabrics (at an ekstravazation); not widespread: headache; seldom widespread: fever, fever, dizziness, indisposition, weakness, adynamy.

From immune system: widespread: allergic reactions (after intravesical use); not widespread: hypersensitivity to light and radiation therapy (resuming of symptoms of radiation defeat); seldom widespread: an anaphylaxis (anaphylactic/anaphylactoid reactions with shock or without it, rashes, an itch, fever, a fever).

From reproductive system and mammary glands: seldom widespread: amenorrhea, azoospermism.

Interaction with other medicines:

Epirubitsin it is possible to apply in a combination with other antineoplastic means.

Interaction of an epirubitsin with Cimetidinum, deksverapamily, deksrazoksany, dotsetaksely, интерфероном-α2b, paklitaksely and quinine was revealed.

Deksverapamil can change pharmacokinetics of an epirubitsin, and, perhaps, to strengthen oppression of function of marrow.

At infusion of an epirubitsin after introduction of a deksrazoksan in high doses (900 mg/sq.m and 1200 mg/sq.m of a body surface) increase in system clearance of an epirubitsin and decrease in the area under pharmacokinetic curve (PFK) is noted.

Increase in concentration of metabolites of an epirubitsin in a blood plasma at introduction of a dotsetaksel is observed at once after an epirubitsin.

At the combined use with интерфероном-α2b the elimination half-life in a terminal phase and the general clearance of an epirubitsin can decrease.

Paklitaksel can change pharmacokinetics of an epirubitsin and his metabolite of an epirubitsinol. At introduction of a paklitaksel before epirubitsiny hematologic toxicity is more expressed, than at introduction of a paklitaksel after an epirubitsin. Epirubitsin can reduce clearance of a paklitaksel.

Quinine can accelerate initial distribution of an epirubitsin from blood in fabric, and also influence distribution of an epirubitsin in erythrocytes.

At introduction of an epirubitsin in a dose of 100 mg/sq.m of a body surface after therapy by Cimetidinum in a dose of 400 mg 2 times a day were noted by 50% increase in PFK for an epirubitsin and 41% increase in PFK for an epirubitsinol. As changes of PFK for 7dezoksidoksorubitsinola an aglikona and decrease in a hepatic blood-groove were not revealed, the specified phenomenon is not explained by decrease of the activity of enzymes of system of P450 cytochrome.

At the combined use of an epirubitsin and other cytotoxic drugs oppression of function of marrow can amplify.

At purpose of an epirubitsin it is necessary to consider a possibility of the expressed disturbance of a hemopoiesis after preliminary therapy by the drugs oppressing function of marrow (cytostatics, sulfonamide, chloramphenicol, diphenylhydantoin, pyramidon derivatives, anti-retrovirus means, etc.).

The potential risk of development of cardiotoxic defeats is higher at the patients receiving the accompanying therapy by cardiotoxic drugs (for example,             5-ftoruratsit, cyclophosphamide, Cisplatinum, taxons) or the radiation therapy (accompanying or in the anamnesis) on area of a mediastinum.

At the combined use of an epirubitsin and other drugs which can cause heart failure (for example, blockers of calcium channels) it is necessary to control function of heart regularly.

Epirubitsin is metabolized preferential in a liver therefore the accompanying therapy by the drugs influencing function of a liver can change metabolism or pharmacokinetics of an epirubitsin, that is, to influence its efficiency and toxicity.

Contraindications:

Hypersensitivity to an epirubitsin, other anthracyclines and antratsendiona or to drug excipients. A persistent miyelosupresiya owing to the previous himio-or radiation therapy. Receiving earlier maximum cumulative dose of other anthracyclines (for example, doxorubicine or daunorubitsin). The cardiological diseases which are available or in the anamnesis (in particular heart failure of the IV degree, the acute myocardial infarction or a myocardial infarction in the anamnesis which caused heart failure of III or IV degrees, acute inflammatory heart diseases, arrhythmias with serious hemodynamic violations). Acute system (generalized) infections. Heavy abnormal liver functions. Pregnancy. Feeding period breast. Additional contraindications for intravesical use: infections of an uric path; the invasive tumors which got through a bladder wall; problems with catheterization; bladder inflammation; hamaturia; large residual volume of urine; the wrinkled bladder.

Use during pregnancy or feeding by a breast.

It is precisely unknown whether can эпирубицин have teratogenic effect and it is adverse to influence fertility of the person. However perhaps negative impact on a fruit. As well as the majority of other antineoplastic drugs, эпирубицин is mutagen and cancerogenic. Patients (both women, and men) should be warned about possible risk of negative action of an epirubitsin on reproductive function. Patients of reproductive age need to be informed in details about potential harm for a fruit, and also about expediency of carrying out genetic consultation in case of pregnancy throughout treatment epirubitsiny.

Epirubitsin it is not necessary to appoint pregnant. Patients of reproductive age need to use effective contraceptive remedies throughout treatment by drug and for 6 months after the end of therapy epirubitsiny.

Feeding by a breast needs to be stopped prior to therapy epirubitsiny.

Children.

Safety and efficiency of purpose of an epirubitsin are not established to children.

Overdose:

Very high single dose of an epirubitsin can cause an acute degeneration of a myocardium for 24 hours and heavy oppression of function of marrow for 10-14 days. The purpose of therapy of this state is the maintenance therapy of the patient and use of such means as hemotransfusion and creation of sterile conditions at care of the patient. Noted also development delayed (to 6 months after overdose of anthracyclines) heart failure. It is necessary to watch carefully the patient and in case of development of objective symptoms of heart failure to appoint a symptomatic treatment. Epirubitsin is not brought at a hemodialysis.

Storage conditions:

Term godnosti.2 years from datyizgotovleniyain bulk. To store in original packaging, in the refrigerator, at a temperature from 2 °C up to 8 to the °sena to freeze. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

5 ml (10 mg) ili25 ml (50 mg) to the voflakena, 1 bottle in a pack.