Epovitan

General characteristics. Structure:

Active ingredient: erythropoetin recombinant person;

1 syringe contains 2000 ME, 4000 ME or 10000 ME erythropoetins of the recombinant person.

excipients: a seralbumin of the person, sodium chloride, dihydrophosphate sodium a dihydrate, phosphate dinatrium dodecahydrate, water for injections.

Pharmacological properties:

Erythropoetin – the glycoprotein consisting of 165 amino acids is formed in kidneys and stimulates division and differentiation of predecessors of an erythroidal sprout in marrow. ЭПОВИТАН® for injections – the drug of erythropoetin of the person made with use of technology of receiving recombinant DNA. Drug is produced by cells of mammals into which the gene of erythropoetin of the person and therefore the sequence of the amino-acid remains at it same, as well as at the emitted natural erythropoetin is entered.

Indications to use:

Treatment of patients with anemia at the chronic renal failure (CRF):
symptomatic anemias;
the anemia demanding transfusions.

The anemia which arose at tumoral processes.

Route of administration and doses:

As well as at use of any other parenteral medicines, drug EPOVITAN before use is checked for lack of visible foreign particles and discoloration of solution.

The initial dose of drug makes 50 ME/kg, 3 times a week in the form of a slow subcutaneous or intravenous injection within 1-2 minutes. Further increase in a dose depends on the response to initial therapy. If necessary it is possible to increase a dose by 25 ME/kg each 4 weeks. If increase in hemoglobin exceeds 20 g/l after purpose of 50 ME/kg, the dose needs to be modified, having cancelled one introduction to week. The purpose of treatment is achievement of level of hemoglobin of 100 g/l (a hematocrit of 30%). At achievement of therapeutic effect, usually appoint a maintenance dose of 25-50 ME/kg 2-3 times a week. Patients who begin therapy at the low level of hemoglobin (60 g/l) need to appoint higher maintenance dose, than that with which treatment began not less than 80 g/l at hemoglobin level. The dose needs to be adjusted depending on age. Anyway, the maximum dose should not exceed 200 МЕ/кг/день, 3 times a week.

Drug EPOVITAN cannot be used in the form of intravenous infusions or in mix with other drugs.

Hypodermic introduction. The maximum volume of hypodermic administration of drug on one site makes 1 ml. In need of use of large volumes hypodermic introduction is carried out in several sites. Subcutaneously the drug should be administered in an extremity or in a front wall of a stomach.

Before therapy or during it it is necessary to determine the level of a reserve of iron and, if necessary to appoint iron preparations. At poisonings with aluminum or infectious diseases the answer can be slowed down. Even if the patient does not demand dialysis, it is necessary to appoint a maintenance dose taking into account weight of an anemic syndrome or age. Report that the hematocrit at the level of 36 – 38% can be supported within   more than 6 months.

Features of use:

Before use it is necessary to check surely the syringe for solution discoloration, for lack of visible foreign particles. It is forbidden to stir up the syringe, - it can lead to a denaturation and loss of activity of a glycoprotein.

Prescription drug EPOVITAN has to be limited by patients with the anemia of a renal origin and anemia which arose owing to tumoral processes.

Patients should appoint drug with care:
with hypertensia (it is known that at use of erythropoetin there is an increase in arterial pressure owing to what there can be hypertensive encephalopathy);
with hypersensitivity to medicines in the anamnesis;
with tendency to an allergy;
with a myocardial infarction, a heart attack of lungs, a brain heart attack, to patients with risk of developing of a thrombembolia (at use of erythropoetin viscosity of blood increases that can induce development of a thromboembolism). As there is a danger of the strengthened coagulation, especially in cases when erythropoetin is appointed at accumulation of autological cells or after operation, it is necessary to provide careful observation of patients;
premature with ventricular or intracerebral bleeding (intracerebral bleedings can amplify under the influence of erythropoetin).

When performing therapy, it is necessary to watch the level of hemoglobin and a hematocrit (approximately  once a week at an early stage of use and 1 every two weeks during a phase of a maintenance therapy) to avoid exceeding of desirable level of a hemogenesis    (≥120 g/l hemoglobin or ≥36% a hematocrit). At signs of exceeding of desirable level of a hemogenesis it is necessary to appoint the corresponding treatment and to cancel drug. Also it is necessary to remember that the hematocrit can increase after drug phase-out therefore the corresponding observation is necessary.

It is necessary to watch a condition of arterial pressure at patients to whom appointed drug, especially, at patients with cardiovascular diseases or risk of developing of a hypertension as during use of drug cases of trombotichesky complications, such as a myocardial infarction, a thromboembolism of a pulmonary artery, disturbance of cerebral circulation and the tranzitorny ischemic attacks were observed. If at the patient sharp increase in a hematocrit is observed (increase by more than 4% during                    the 2 weeks period), it can strengthen hypertensia, at the same time the dose should be modified.

As during use of drug EPOVITAN there can be a hyperpotassemia, it is necessary to modify a diet respectively.

At patients of advanced age it is necessary to consider the high level of complications from cardiovascular and urinary systems. It is necessary to control the arterial pressure, biochemical indicators of blood, to watch neurologic symptoms.

Use in pediatrics was not investigated.

Due to the risk of emergence of occlusion of the shunt and the rest of blood in a container for a hemodialysis, monitoring of haemo kinetic volume in shunts or containers is necessary for a hemodialysis. In such cases it is necessary to apply necessary measures, for example, repeated installation of the shunt or increase in a dose of anticoagulants.

In case of unexpected reduction of effect, it is necessary to look at the patient for the typical reasons of lack of the answer to this drug, such as deficit of iron, folic acid, B12 vitamin, aluminum accumulation, existence of inflammatory or infectious process, bleedings or hemolysis. In case of hypoplastic anemia of an unknown etiology the marrow research is necessary. After establishment of the diagnosis of hypoplastic anemia it is necessary to check existence of antibodies to erythropoetin and to stop administration of drug. As antibodies to erythropoetin render cross activity to other drugs of erythropoetin, they should not be applied. It is necessary to check also other origins of hypoplastic anemia for purpose of the corresponding treatment.

Use during pregnancy or feeding by a breast

It is not necessary to appoint drug to the pregnant women and women planning pregnancy as safety of use of drug EPOVITAN for pregnant women was not studied. It is possible to appoint drug only in cases when the advantage at use for mother exceeds risk for a fruit.

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

It is necessary to use drug at the initial stages of treatment carefully in connection with a possibility of development of pathological hypertensia, up to transition to optimum maintenance doses.

Side effects:

Shock: as in rare cases shock can develop, it is necessary to provide careful observation of the patient. At emergence of disturbances in the state of health, drug it is necessary to cancel and appoint the corresponding treatment.

Cardiovascular system: increase in arterial pressure, fibrinferments of vessels, for example in the site of the lacrimal channels, etc., can sometimes arise tachycardia.

Hypertensive encephalopathy: it is necessary to appoint drug on condition of careful observation of arterial pressure, a hematocrit and other indicators as when developing encephalopathy the headache is observed, disturbance of consciousness, a spasm and other symptoms caused by sharp increase in arterial pressure can also arise intracerebral bleeding.

Encephalopathy: as there is a risk of developing of encephalopathy, it is necessary to provide careful observation of the patient. At emergence of disturbances in the state of health drug it is necessary to cancel and appoint the corresponding treatment.

Skin: there can sometimes be an itch, rash, акнэ.

Liver: the hepatosis which sometimes is followed by increase in levels of nuclear heating plant, ALT, LDG, ShchF, the general bilirubin, etc.

Alimentary system: there can sometimes be nausea, vomiting, appetite loss, diarrhea, an abdominal cavity pain.

Blood: sometimes the quantity of leukocytes and eosinophils increases. At premature children reduction of quantity of granulocytes can be observed. In blood serum the level of potassium, urea, creatinine and uric acid can sometimes increase. Premature children can have a rickets. About cases of hypoplastic anemia among patients with HPN which appointed erythropoetin during the period from several months to several years, it was reported seldom.

Another: there can be hemorrhages in an eyeground, a splenomegaly, nasal bleedings, sometimes a headache, dizziness, fever, slight increase of temperature, feeling of heat, an indisposition, an arthralgia, a mialgiya, bitterness in a mouth, convulsion and the century swelled.

EPOVITAN is usually well transferred. Side effects about which it is reported are a frequent effect of HPN and are not necessarily caused by erythropoetin use.

Patients with a chronic renal failure

Side effects which met at more than 5% of the patients who were taking part in the double blind person, placebo - the controlled research are presented in table 1. In total these researches included over 300 patients with HPN.

Table 1

Side reaction             Patients who were treated recombinant     Group of placebo
                                         erythropoetin of the person (N = 200)                     (N = 135)

Hypertensia                                             of 24,0%                                             of 18,5%
 
Headache                                          of 16,0%                                              of 11,9%
 
Arthralgia                                                 of 11,0%                                              of 5,9%
 
Nausea                                                    of 10,5%                                              of 8,9%
 
Hypostasis                                                          of 9,0%                                               of 10,4%
 
Fatigue                                              of 9,0%                                              of 14,1%
 
Diarrhea                                                        of 8,5%                                                of 5,9%
 
Vomiting                                                         of 8,0%                                                of 5,2%
 
Pain in a thorax                                of 7,0%                                                of 8,8%
 
Skin reactions
(in an injection site)                                      7,0%                                                 of 11,9%
 
Adynamy                                                      of 7,0%                                                of 11,9%
 
Dizziness                                          of 7,0%                                                of 12,6%
 
Formation of blood clots                                  of 6,8%                                                   of 2,3%

The expressed side effects at patients with HPN in double blind researches
 
Spasms                                                     of 1,1%                                                of 1,1%
 
CAL/TLA                                                        of 0,4%                                                of 0,6%
 
Myocardial infarction                                          of 0,4%                                               of 1,1%
 
Death                                                           of 0%                                                   of 1,7%

At conduct of clinical trial with involvement of 567 patients on dialysis the most frequent side effects were: hypertensia (0,75%), headache (0,40%), tachycardia (0,31%), nausea and vomiting (0,26%), thrombosis of vessels (0,25%), asthma (0,14%), hyperpotassemia (0,11%) and diarrhea. Other side effects met the frequency of less than 0,1% for the patient in a year. Seldom side effects which arose in several hours after administration of recombinant erythropoetin of the person met, they were easy and temporary; namely grippopodobny symptoms, such as arthralgia and mialgiya. In the analysis of all researches for this time, it is possible to draw a conclusion that recombinant erythropoetin of the person is transferred by patients preferential well, irrespective of a way of introduction.

Patients with tumoral diseases

Side effects which met at more than 10% of the patients with tumoral diseases who were taking part in double blind placebo - the controlled research, lasting up to 3 months, (only 131 patients) are presented in table 2.

Though some statistically reliable differences between the patients accepting recombinant erythropoetin of the person and placebo were noted, the general level of side effects can be explained with tumoral process. Even in clinical trial in which patients (N = 72) were treated during the period up to 32 weeks and the dose made 927 ME/kg, side effects corresponded to a progression of tumoral process. Based on comparison of data of survival and on the patients given about percent to whom stopped treatment by recombinant erythropoetin of the person or placebo for a cause of death, a progression of a disease or side effects (22% and 13% respectively), one may say, that clinical results in two groups similar. Available data on studying of tumors on animal models and definition of proliferation of cells of bioptat of solid tumors at use of recombinant erythropoetin of the person give the grounds to consider that it does not strengthen tumoral growth. It is impossible to exclude probabilities of strengthening of growth of some tumors (for example, myeloid) under the influence of recombinant erythropoetin of the person. The average quantity of leukocytes after therapy by recombinant erythropoetin of the person in comparison with group of placebo did not change.

Table 2.

Side effect             Patients, treated recombinant     Group of placebo (N = 68)
                                        erythropoetin of the person   (N = 63)

Fever                                          of 29%                                              of 19%
 
Diarrhea                                                 of 21%                                               of 7%
 
Nausea                                               of 17%                                             of 32%
 
Vomiting                                                   of 17%                                             of 15%
 
Hypostasis                                                    of 17%                                               of 1%
 
Adynamy                                               of 13%                                              of 16%
 
Fatigue                                       of 13%                                              of 15%
 
Asthma                                                of 13%                                                 of 9%
 
Paresthesias                                           of 11%                                                 of 6%
 
Infections of upper
respiratory tracts                               of 11%                                                of 4%
 
Dizziness                                      of 5%                                               of 12%
 
Pain in a body                                              of 3%                                              of 16%

Interaction with other medicines:

It is forbidden to mix in one syringe with other drugs! Cultivation and administration of drug EPOVITAN after transfusion from original capacity in other ware is inadmissible.

Contraindications:

Hypersensitivity to any of components of drug or to other drugs which receive from cells of mammals or to human albumine; the hypoplastic anemia which arose owing to treatment by erythropoetin drugs; anemia after blood loss; pancytopenia; not controlled hypertensia; aluminum accumulation.

Overdose:

The response to treatment by drug is strictly individual and depends on a dose. At overdose there can be hypertensia symptoms. If the level of hemoglobin increases very quickly, bloodletting can be shown.

Storage conditions:

To store in the place protected from light at a temperature from 2 to 8 ºС. Not to freeze. Periods of storage 2 years.

Issue conditions:

According to the recipe

Packaging:

On 0,5 ml (2000 ME) or on 0,4 ml (4000 ME), or on 1 ml (10 000 ME) in previously filled syringe. On one previously filled syringe put in the blister. On 6 previously filled syringes (on 2000 ME or 4000 ME), on 5 or 6 previously filled syringes (on 10000 ME) in blisters together with the instruction about use put in a cardboard pack.