Erythropoetin

General characteristics. Structure:

Active ingredient: 500 ME or 2000 ME recombinant erythropoetins of the person.

Excipients: albumine solution of 10% (in terms of dry albumine), the buffer isotonic citrate: sodium citrate, sodium chloride, citric acid, water for injections.

Pharmacological properties:

Pharmacodynamics. Epoetin a beta - the glycoprotein which is specifically stimulating an erythrogenesis activates a mitosis and maturing of erythrocytes from progenitors of an erythrocyte row. Recombinant эпоэтин the beta is synthesized in cells of mammals which the gene coding human erythropoetin is built in. On the structure, biological and immunological properties эпоэтин a beta it is identical to natural erythropoetin of the person. The beta leads introduction of an epoetin to increase in hemoglobin and a hematocrit, At use of Erythropoetin for women of reproductive age resuming of periods is possible. The patient should be warned about a possibility of approach of pregnancy and need of use of reliable methods of contraception prior to therapy.

Considering the possible more expressed effect of Erythropoetin, its dose should not exceed a dose of the epoetin a beta used in the previous course of treatment. Within the first two weeks the dose is not changed, estimate a ratio the dose/answer. After that the dose can be reduced or increased according to above to the submitted scheme.

During treatment before establishment of an optimum maintenance dose patients with uraemia should avoid occupations potentially dangerous types of activity, the demanding increased concentration of attention and speed of psychomotor reactions, because of increase in risk of increase in arterial pressure at the beginning of therapy.

The beta leads introduction of an epotin to increase in hemoglobin and a hematocrit, improvement of blood supply of fabrics and cardiac performances. The most expressed effect of use of an epoetin a beta is observed at the anemias caused by a chronic renal failure. Seldom or never, at prolonged use of erythropoetin for therapy of anemic states formation of neutralized antibodies to an epoetin a beta with development of a partial krasnokletochny aplasia or without it can be observed.

Pharmacokinetics. At intravenous administration of Erythropoetin at healthy faces and patients with uraemia the elimination half-life makes 5-6 h. At hypodermic administration of Erythropoetin its concentration in blood increases slowly and reaches a maximum during from 12 to 28 h after introduction, the elimination half-life makes 13-28 h. At intravenous administration the elimination half-life makes 4-12 h. Bioavailability of Erythropoetin at hypodermic introduction makes 25-40%.

Indications to use:

Treatment of anemia of renal genesis at patients with a chronic renal failure, including being on dialysis.

Prevention and treatment of anemia at the adult patients with solid tumors receiving chemotherapy platinum drugs which can cause anemia (карбоплатин 75 mg/sq.m on a cycle, карбоплатин 350 mg/sq.m on a cycle).

Treatment of anemia at the adult patients with a multiple myeloma, nekhodzhkinsky lymphoma of low degree of a zlokachestvennost and a chronic lymphocytic leukosis receiving antineoplastic therapy at relative insufficiency of endogenous erythropoetin (it is defined as concentration of erythropoetin in serum, disproportionately low concerning anemia degree).

Increase in volume of the donor blood intended for the subsequent autotransfusion. At the same time advantages of use of an epoetin a beta need to be correlated to increase in risk of thromboembolisms at its use. The patient with moderate anemia (level of hemoglobin of 100-130 g/l or a hematocrit of 30-39%, without deficit of iron) drug is appointed only if it is not possible to receive enough stored blood, and a planned large operative measure can demand the large volume of blood (> 4 units for women or> 5 units for men).

Prevention of anemia at the premature newborns who were born with the body weight of 750-1500 g to 34 weeks of pregnancy.

Route of administration and doses:

Treatment of anemia at patients with a chronic renal failure.

П / to or in / century. At in introduction solution should be entered within 2 minutes, the patient on a hemodialysis — via the arteriovenous shunt at the end of dialysis session. It is preferable to the patient who is not on a hemodialysis to administer the drug п / to, in order to avoid a puncture of peripheral veins.

The treatment purpose — achievement of level of a hematocrit equal to 30-35%, or elimination of need of hemotransfusion. Weekly increase of a hematocrit should not exceed 0,5%. It is not necessary to exceed its level of 35%. At patients with arterial hypertension, cardiovascular and cerebrovascular diseases weekly increase of a hematocrit and its target indicators should be defined individually, depending on a clinical picture. For some patients the optimum indicator of a hematocrit — is lower than 30%.

Treatment by Erythropoetin is carried out in 2 steps: initial therapy (correction stage). At п / to introduction the initial dose makes 20 ME/kg of body weight 3 times a week. At insufficient increase in a hematocrit (less than 0,5% a week) a dose can be increased monthly by 20 ME/kg of body weight 3 times a week. The total week dose can be divided also into daily introductions in smaller doses or to enter at one time.

At in administration of drug the initial dose makes 40 ME/kg of body weight 3 times a week. At insufficient increase in a hematocrit in a month it is possible to increase a dose to 80 ME/kg 3 times a week. If there is a need for further increase in a dose, it is necessary to increase it by 20 ME/kg 3 times a week with a monthly interval. Irrespective of a way of introduction the highest dose — no more than 720 ME/kg of body weight a week. Maintenance therapy. For maintenance of a hematocrit at the level of 30-35%, at first the dose should be reduced half from a dose in the previous injection. Afterwards the maintenance dose is selected individually, at an interval of 1-2 weeks. At п / to introduction the week dose can be entered once or for 3-7 introductions to week.

At children the dose depends on age (as a rule, than the age of the child, especially high doses of an epoetin a beta to it is less are required). However, as it is not possible to predict the individual answer, it is reasonable to begin with the recommended mode.

Treatment by Erythropoetin is carried out, as a rule, for life. In need of it it is possible to interrupt at any time.

Prevention of anemia at premature newborns. П / to in a dose of 250 ME/kg of body weight 3 times a week. Treatment epoetiny a beta has to begin as soon as possible, it is preferable about 3 days of life and to proceed 6 weeks. Prevention and treatment of anemia at patients with solid tumors.

П / to, dividing a week dose into 3-7 introductions. Treatment with Erythropoetin is shown to the patients with solid tumors receiving chemotherapy platinum drugs at hemoglobin level prior to the beginning of chemotherapy not higher than 130 g/l. An initial dose — 450 ME/kg of body weight a week. If in 4 weeks the level of hemoglobin increases insufficiently, the dose should be doubled. Treatment duration — no more than 3 weeks after the termination of chemotherapy. If during the first cycle of chemotherapy hemoglobin level, despite treatment epoetiny the beta, decreases more than by 10 g/l, further use of drug can be inefficient.

It is necessary to avoid increase in hemoglobin more than on 20 g/l a month or to level over 140 g/l. At hemoglobin increase more than on 20 g/l a month the dose of an epoetin a beta needs to be lowered by 50%. If the level of hemoglobin exceeds 140 g/l, drug is cancelled until it does not decrease to level <120 g/l, and then resume therapy in a dose, half the smaller previous week.

Treatment of anemia at patients with a multiple myeloma, a nekhodzhkinsky lymphoma of low degree of a zlokachestvennost or a chronic lymphocytic leukosis.

At patients with a multiple myeloma, a nekhodzhkinsky lymphoma of low degree of a zlokachestvennost or a chronic lymphocytic leukosis insufficiency of endogenous erythropoetin is usually noted. It is diagnosed on a ratio between degree of anemia and insufficient concentration of erythropoetin in serum.

At the level of hemoglobin, g/l	Concentration of erythropoetin in serum, ME/ml
> 90 <100	≤ 100
> 80 ≤ 90	≤ 180
≤ 80	≤ 300

The above-stated parameters should be determined not earlier than in 7 days after the last hemotransfusion and the last cycle of cytotoxic chemotherapy.

The drug is administered п / to; the week dose can be divided into 3 or 7 introductions. The recommended initial dose — 450 ME/kg of body weight a week. If in 4 weeks the level of hemoglobin increases not less than by 10 g/l, treatment is continued in the same dose. If in 4 weeks hemoglobin increases less than by 10 g/l, it is possible to increase a dose to 900 ME/kg of body weight a week. If in 8 weeks of treatment the level of hemoglobin did not increase at least by 10 g/l, the positive effect is improbable, and drug should be cancelled.

Clinical trials showed that at a chronic lymphocytic leukosis reaction to therapy epoetiny the beta steps on 2 weeks later, than at patients with a multiple myeloma, a nekhodzhkinsky lymphoma and solid tumors. Treatment should be continued to 4 weeks after the termination of chemotherapy.

The highest dose should not exceed 900 ME/kg of body weight a week. If in 4 weeks of treatment the level of hemoglobin increases more than on 20 g/l, the dose of Erythropoetin should be reduced half. If the level of hemoglobin exceeds 140 g/l, treatment by drug needs to be interrupted before decrease it up to the size <130 g/l then therapy is resumed in a dose, half the smaller previous week. Treatment should be resumed only if insufficiency of Erythropoetin is the most probable cause of anemia.

Training of patients for capture of donor blood for the subsequent autohemotrasfusion. In/in or п / to two times a week for 4 weeks. When the hematocrit indicator at the patient (> 33%) allows to carry out blood sampling, эпоэтин a beta enter at the end of the procedure. Throughout all course of treatment the hematocrit should not exceed 48%.

The dose of drug is defined by the doctor-transfuziolog and the surgeon individually, depending on what volume of blood will be taken from the patient and from his erythrocyte reserve. The blood volume which will be taken from the patient depends on estimated blood loss, the available techniques of preservation of blood and the general condition of the patient; it has to be sufficient to avoid hemotransfusion from other donor. The blood volume which will be taken from the patient is expressed in units (one unit is equivalent to 180 ml of erythrocytes).

The possibility of donorship depends, mainly, on blood volume at this patient and an initial hematocrit. Both indicators define an endogenous erythrocyte reserve which can be calculated by the following formula:

endogenous erythrocyte reserve = the volume of blood (ml) x (a hematocrit — 33): 100

women: volume of blood (ml) = 41 (ml/kg) x body weight (kg) + 1200 (ml)

men: the volume of blood (ml) = 44 (ml/kg) x the body weight (kg) + 1600 (ml) (at body weight> 45 kg).

The indication to use of Erythropoetin and its single dose are determined by nomograms, proceeding from the required volume of donor blood and an endogenous erythrocyte reserve.

The highest dose — at in introduction no more than 1600 ME/kg of body weight a week; at п / to introduction — 1200 ME/kg of body weight a week.

Features of use:

As at pregnancy and during breastfeeding the person has no sufficient experience of use of erythropoetin, it is necessary to appoint Erythropoetin only if the expected advantages of its use exceed possible risk for a fruit and mother.

As anaphylactoid reactions were in certain cases noted, the first dose of drug has to be entered under control of the doctor.

Inadequate use of drug by healthy people (for example as dope) can cause the sharp increase in an indicator of a hematocrit which is followed by life-threatening complications from cardiovascular system.

During treatment it is necessary to control weekly arterial pressure and to carry out the general blood test, including definition of a hematocrit, thrombocytes and ferritin. In the first 8 weeks of therapy weekly calculation of uniform elements and especially thrombocytes is necessary. At increase in number of thrombocytes norms or more are higher than on 150 - 109/l from initial size treatment by Erythropoetin should be interrupted.

At the patients with uraemia who are on a hemodialysis it is recommended to control the ABP, including between dialysis sessions. Because of increase in a hematocrit often it is required to increase a heparin dose, besides, timely prevention of thromboses and early audit of the shunt is necessary. In before - and the postoperative period hemoglobin should be controlled more often if its initial level made less than 140 g/l. During treatment by Erythropoetin it is necessary to control periodically the level of potassium and phosphates in blood serum. At emergence of a hyperpotassemia it is necessary to cancel temporarily Erythropoetin before potassium concentration normalization.

In most cases along with increase in a hematocrit ferritin level in serum decreases. Therefore and with serum ferritin level less than 100 mkg/l or transferrin saturation less than 20% are recommended to all patients with anemia of renal genesis oral administration of iron preparations in a dose of 200-300 mg/days. By the patient with oncological and hematologic diseases therapy of iron preparations is carried out by the same principles, at the same time patients with a multiple myeloma, a nekhodzhkinsky lymphoma of low degree of a zlokachestvennost or a chronic lymphocytic leukosis with transferrin saturation less than 25% can enter 100 mg of iron a week in / century.

To premature children peroral therapy by iron preparations in a dose of 2 mg a day has to be appointed as soon as possible (not later than to the 14th day of life). The dose of iron is korrigirut depending on the level of serumal ferritin. If it with firmness remains at the level of lower than 100 mkg/ml or there are other signs of deficit of iron, it is necessary to increase a dose of iron preparations to 5-10 mg/days and to carry out therapy to stopping of signs of insufficiency of iron.

Side effects:

Undesirable reactions are listed according to the following gradation: often (<1%, <10%); infrequently (> 0,1%, <1%); seldom (> 0,01%, <0,1%); very seldom (<0,01%), including separate messages.

From cardiovascular system: at patients with anemia with a chronic renal failure most often — increase in the arterial pressure (AP) or strengthening of already available arterial hypertension, especially in case of bystry increase in a hematocrit. In this case it is recommended to appoint medicamentous anti-hypertensive therapy, in the absence of effect the beta is recommended to interrupt temporarily therapy epoetiny. At certain patients (including with earlier normal or low ABP) — hypertensive crisis with the encephalopathy phenomena (headaches, confusion of consciousness, sensitive and motive disturbances — disturbances of the speech, gait, up to toniko-clonic spasms), the demanding acute medical assistance and an intensive care. Special attention should be paid on suddenly arising migrenepodobny pains.

At patients with solid tumors, a multiple myeloma, nekhodzhkinsky lymphoma or a chronic lymphocytic leukosis headaches, increase in the ABP which can be stopped by purpose of HP can seldom be noted.

From bodies of a hemopoiesis: patients with a renal failure and anemia can have a dozozavisimy increase in number of thrombocytes (which is not going beyond norm and disappearing at therapy continuation) especially later in/in introductions. Very seldom the thrombocytosis develops. Because of increase in a hematocrit often it is required to increase a heparin dose during a hemodialysis. At an inadequate geparinizition obstruction of dialysis system is possible. Thrombosis of shunts, especially at patients with a tendency to hypotension or with complications of an arteriovenous fistula can develop (for example a stenosis, aneurism, etc.). In similar situations early audit of the shunt and timely prevention of thromboses is recommended (acetylsalicylic acid).

In most cases along with increase in a hematocrit the content of ferritin in serum decreases. In some cases at patients with uraemia — increase in levels of potassium and phosphates in serum.

At some patients with solid tumors, a multiple myeloma, nekhodzhkinsky lymphoma or a chronic lymphocytic leukosis decrease in serumal indicators of exchange of iron is noted. Clinical trials showed that the frequency of thromboembolisms at oncological patients at treatment with Erythropoetin is slightly higher, than for lack of such therapy or when using placebo; however the accurate causal relationship is not established with drug.

At premature newborns decrease in content of ferritin in serum is in most cases noted, small increase in number of thrombocytes, especially for 12-14 day of life can be noted.

At the patients preparing for blood donation for the subsequent autotransfusion and receiving эпоэтин a beta increase in number of thrombocytes, as a rule, not going beyond norm, and higher frequency of tromboembolic episodes is noted though their causal relationship using drug is not established.

Others: seldom — skin allergic reactions in the form of rash, an itch, a small tortoiseshell or reaction in the place of an injection. Separate cases of anaphylactoid reactions are described. However in controlled clinical trials the frequency of hypersensitivity reactions did not increase.

In some cases, especially at the beginning of therapy, grippopodobny symptoms, such as fever, a fever, a headache, extremity and bones pains, an indisposition were noted. These reactions were expressed poorly or moderately and disappeared within several hours or days.

Interaction with other medicines:

At simultaneous use of Erythropoetin and cyclosporine there can be a need of dose adjustment of the last because of increase in its binding by erythrocytes.

Experience of a clinical use of Erythropoetin did not elicit the facts of its pharmacological incompatibility with other medicines so far.

Nevertheless, in order to avoid possible incompatibility or decrease of the activity, Erythropoetin cannot be mixed with solutions of other medicines.

Contraindications:

Hypersensitivity to drug or its components, a partial krasnokletochny aplasia after earlier carried out therapy by any epoetin a beta, uncontrollable arterial hypertension, impossibility of performing adequate anticoagulating therapy, a myocardial infarction within a month after the event, unstable stenocardia or the increased risk of a deep vein thrombosis and thromboembolisms within the predeposit program of collecting blood before surgeries, a porphyria.

With care. Patients with thrombosis (in the anamnesis), with malignant new growths, with drepanocytic anemia, with moderate anemia without deficit of iron, with a thrombocytosis, with refractory anemia, epilepsy, a chronic liver failure, a nephrosclerosis, at patients with body weight have less than 50 kg for increase in volume of donor blood for the subsequent autotransfusion.

Overdose:

Symptoms: hypertensia, hyperglobulia, hypergemoglobinemia, sharp increase in size of a hematocrit.

Treatment: symptomatic. In case of hypertensia it is necessary to exclude excess hydration. In the presence of a hyperglobulia and an overhydratation actions for removal of excess of liquid are necessary.

At the high level of hemoglobin and a hematocrit the phlebotomy is shown.

Storage conditions:

In the dry, protected from light place at a temperature from 2 to 8 °C. To store in the place, unavailable to children! A period of validity - 2 years. Not to use after expiry date of the validity.

Issue conditions:

According to the recipe

Packaging:

Solution for intravenous and hypodermic administration of 500 ME/ml or 2000 ME/ml, in ampoules on 1 ml. On 5 ampoules in a blister strip packaging, on 1 or 2 blister strip packagings and the application instruction in a pack from a cardboard.