Рекормон®

General characteristics. Structure:

Active ingredient: 1000 PIECES, 2000 PIECES, 10 000 PIECES, 20 000 PIECES, 30 000 PIECES of an epoetin beta.

Excipients: urea, sodium chloride, sodium hydrophosphate, sodium dihydrophosphate, Calcii chloridum, polysorbate 20, glycine, a L-leucine, L-izoleytsin, L-threonine, L-glutaminic acid, L-phenylalanine, water for injections.

Recombinant erythropoetin a beta, identical human, the providing effective method of treatment of anemia in combination with a high profile of safety and excellent portability. It is the most tested drug for treatment of renal anemia, at all stages of HBP and in therapy of anemia at oncological patients which experience of use in clinical practice makes more than 15 years. Numerous researches showed that treatment of anemia by Rekormon is highly effective.

Pharmacological properties:

Pharmacodynamics. Epoetin a beta - the glycoprotein consisting of 165 amino acids which, being a mitogenetic factor and hormone of a differentiation, promotes formation of erythrocytes from partially determined erythrogenesis progenitors.

Recombinant эпоэтин a beta, received by method of genetic engineering, on the amino-acid and carbohydrate structure it is identical to erythropoetin of the person.

Epoetin a beta after intravenous and hypodermic administration increases number of erythrocytes, reticulocytes and hemoglobin level, and also iron inclusion speed (59Fe) in cells, specifically stimulates an erythrogenesis, without influencing a leukopoiesis. Cytotoxic action of an epoetin a beta on marrow or on cells of skin of the person is not revealed.

Pharmacokinetics. Absorption. At hypodermic administration of drug by the patient with uraemia long absorption provides the plateau of concentration of drug in serum, time of achievement of the maximum concentration - 12-28 h.

Bioavailability of an epoetin a beta at hypodermic introduction - 23-42% in comparison with intravenous administration.

Distribution. The volume of distribution is equal to the volume of the circulating plasma or exceeds it twice.

Removal. At patients with uraemia and at healthy volunteers the elimination half-life at intravenous administration makes 4-12 h. The elimination half-life of a terminal phase at hypodermic introduction is more, than after intravenous administration, also makes, on average, 13-28 h.

Pharmacokinetics at special groups of patients. The pharmacokinetics of an epoetin a beta at patients with a liver failure was not studied.

Indications to use:

- Symptomatic anemia at a chronic disease of kidneys at the patients who are on dialysis.

- Symptomatic anemia of renal genesis at the patients who are not receiving dialysis yet.

- Treatment of symptomatic anemia at the adult patients with solid and hematologic not myeloid tumors receiving chemotherapy.

- Increase in volume of the donor blood intended for the subsequent autotransfusion. It is necessary to take the registered risk of emergence of the thromboembolic phenomena into account. Use according to this indication is shown only at patients with moderate anemia (Nv of 100-130 g/l (6.21-8.07 mmol/l), without deficit of iron) if it is impossible to receive enough stored blood, and a planned large elective 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 the 34th week of pregnancy.

Route of administration and doses:

Treatment of anemia at patients with a chronic disease of kidneys. Subcutaneously or intravenously (within 2 minutes). The patient who is on a hemodialysis – via the arteriovenous shunt at the end of dialysis session. It is preferable to the patient who is not receiving a hemodialysis to administer the drug subcutaneously, in order to avoid a puncture of peripheral veins.

The treatment purpose – an indicator of hemoglobin (Hb) of 100-120 g/l. Hb should not exceed 120 g/l. At increase in Hb more, than in 4 weeks the dose of drug should be reduced by 20 g/l (1.3 mmol/l). At patients with arterial hypertension, cardiovascular and cerebrovascular diseases week increase Hb and its target indicators should be defined individually, depending on a clinical picture. It is necessary to make careful observation of the patient for the purpose of selection of the minimum dose sufficient for ensuring the maximum effect of drug.

Treatment by the drug Rekormon® is carried out in 2 steps. Correction stage. Subcutaneously - an initial dose - 20 ME/kg 3 times a week. At insufficient increase in Hb (less than 2.5 g/l a week) it is possible to increase a dose each 4 weeks by 20 ME/kg 3 times a week. The total week dose of drug can be divided into daily introductions also.

Intravenously - an initial dose - 40 ME/kg 3 times a week. At insufficient increase in Hb in a month it is possible to increase a dose to 80 ME/kg 3 times a week. If necessary, further it is necessary to increase a dose by 20 ME/kg 3 times a week, with a monthly interval.

Irrespective of a way of introduction, the maximum dose should not exceed 720 ME/kg a week.

Maintenance therapy. For maintenance of a target indicator of Hb (100-120 g/l) the dose should be reduced twice from previous in the beginning. Afterwards the maintenance dose is selected individually, at an interval of 2 or 4 weeks. At hypodermic introduction the week dose can be entered for 1 reception or to divide into 3 or 7 introductions to week. At stabilization of a state against the background of single introduction to week it is possible to pass to single introduction with a two-week interval, in this case increase in a dose can be necessary.

Treatment by the drug Rekormon® is, as a rule, carried out is long. In need of it it is possible to interrupt at any time. Treatment of symptomatic anemia at the patients with solid and hematologic not myeloid tumors receiving chemotherapy. The drug is administered subcutaneously, in an initial dose 30000 ME in a week (450 ME/kg a week), once or the week dose can be divided into 3 or 7 introductions.

Therapy by the drug Rekormon® is shown at Hb of ≤110 g/l (6.83 mmol/l). The indicator of Hb should not exceed 130 g/l (8.07 mmol/l).

At increase in Hb on 10 g/l (0.62 mmol/l) in 4 weeks - therapy should be continued in the same dose.

At increase in Hb less than on 10 g/l (0.62 mmol/l) in 4 weeks - the dose should be doubled.

In the absence of increase in Hb on 10 g/l (0.62 mmol/l) in 8 weeks - treatment should be interrupted since the response to therapy by the drug Rekormon® is improbable.

Treatment should be continued within 4 weeks after the termination of chemotherapy.

The maximum dose should not exceed 60000 ME in a week. At achievement of a target indicator of Hb for the specific patient the dose of drug should be reduced by 25-50%.

For prevention of increase in Hb more than 130 g/l can be required further reduction of a dose.

At increase of Hb more than on 20 g/l (1.3 mmol/l) a month, it is necessary to lower a drug Rekormon® dose by 25-50%.

Training of patients for capture of donor blood for the subsequent autohemotrasfusion.

Intravenously (within 2 minutes) or subcutaneously, 2 times a week for 4 weeks. When the hematocrit indicator at the patient (≥ 33%) allows to carry out blood sampling, Rekormon® should be entered 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:

1. 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.
2. The blood volume which will be taken from the patient is expressed in units (one unit is equivalent to 180 ml of erythrocytes).
3. The possibility of donorship depends, mainly, on blood volume at this patient and an initial hematocrit. Both indicators define an endogenous erythrocyte reserve which is 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 ³ 45 kg).

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

The maximum dose should not exceed 1600 ME/kg a week at intravenous administration and 1200 ME/kg a week at hypodermic introduction.

Prevention of anemia at premature newborns. Subcutaneously, 250 ME/kg 3 times a week, as soon as possible, are preferable from the 3rd day of life, within 6 weeks.

Dosing at special groups of patients. Children and teenagers. At children and teenagers the dose of drug depends on age: as a rule, than the age is less, especially high doses of the drug Rekormon® are required. But, as the individual answer to drug cannot be predicted, it is reasonable to begin with the standard mode of dosing (see. "Treatment of anemia at patients with a chronic disease of kidneys" and "Prevention of anemia at premature newborns"). 

At treatment of the anemia associated with a chronic disease of kidneys, children should not appoint Rekormon® up to 2 years.

Advanced age. In clinical trials need for change of a dose is not defined.

Route of administration. The unit-dose syringe with the drug Rekormon® is ready to the use. The solution which is contained in it is sterile and does not contain preservatives. It is necessary to apply only the light transparent or slightly opalescent solution which is not containing visible inclusions. If after an injection in the syringe tube there was a drug quantity, its repeated introduction is inadmissible.

Application instruction syringe tube. Before an injection it is necessary to wash up hands.
1. To take out one unit-dose syringe from packaging and to be convinced that solution is transparent, colourless and does not contain visible inclusions. To remove a cap from the syringe.
2. To take out one needle from packaging, to put on it the syringe and to remove a protective cap from a needle.
3. To remove air from the syringe and a needle, holding the syringe vertically, carefully advancing the piston up. To press the piston until in the syringe there is no necessary dose of the drug Rekormon®.
4. To wipe skin in the place of an injection with the cotton wool moistened with alcohol. A big and index finger to take skin pleated. Holding the case of the syringe is closer to a needle, to enter a needle under skin. To enter drug Rekormon® solution. To quickly take out a needle and to press the place of a prick sterile dry cotton wool.

Instructions for destruction of unused drug or expired. Eagles and the syringe tubes are intended only for disposable. The used needles and the syringe tubes should be placed in the container (capacity) protected from punctures. This container (capacity) should be stored in the places unavailable to children. The filled container should be utilized according to recommendations of the medical specialist.

Hit of medicines to the environment has to be minimized. It is not necessary to utilize drug by means of sewage or together with household waste. It is whenever possible necessary to use special systems for utilization of medicines.

Features of use:

Pregnancy and period of feeding by a breast. Epoetin a beta has no teratogenic effect on animals. Information on safety of use of the drug Rekormon® during pregnancy, during childbirth and the feeding period is received by a breast at post-registration use of drug. At pregnancy or in the period of the sorts Rekormon® it is necessary to appoint with care as there is no sufficient experience of use at pregnancy and during childbirth. Endogenous erythropoetin cosecretes in breast milk and is completely soaked up in digestive tract of the newborn. The choice between feeding continuation by a breast or continuation of therapy by the drug Rekormon® is done taking into account advantage of therapy for mother and advantage of breastfeeding for the child. 

It is necessary to specify the trade name of drug in medical documentation of the patient. Drug Rekormon® replacement with any biological medicine demands approval of the attending physician.

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

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

It is regularly necessary to control indicators of thrombocytes, a hematocrit and Hb against the background of therapy by the drug Rekormon®.

It is necessary to use with care the drug Rekormon® at refractory anemia in the presence of blasttransformirovanny cells, epilepsy, a thrombocytosis and a chronic liver failure. Prior to treatment by the drug Rekormon® it is necessary to exclude deficit of B12 vitamin and folic acid since they reduce efficiency of therapy.

It is necessary to exclude deficit of iron prior to treatment by the drug Rekormon®, and also during the entire period of therapy. If necessary additional therapy iron preparations according to clinical recommendations can be appointed.

At treatment of patients with severe forms of a fenilketonuriya it is necessary to take into account availability of phenylalanine as excipient: in everyone the syringe tube – to 0.3 mg (in dosages 1000 ME, 2000 ME) or to 0.6 mg (10000 ME, 20000 ME, 30000 ME).

Lack of effect: the most frequent reasons of the incomplete response to treatment by the means stimulating an erythrogenesis are deficit of iron and an inflammation (as result of uraemia or the progressing metastatic cancer). The following states reduce efficiency of treatment by the means stimulating an erythrogenesis: chronic blood loss, marrow fibrosis, the sharp increase in concentration of aluminum caused by a hemodialysis, deficit of folic acid or B12 vitamin, hemolysis. If all listed states are excluded and at the patient sudden decrease in Hb, a reticulocytopenia is observed and antibodies to erythropoetin are found, it is necessary to conduct a marrow research for an exception of a partial krasnokletochny aplasia (PKKA). At development of PKKA therapy by the drug Rekormon® needs to be stopped and patients should not be transferred to therapy by other stimulators of an erythrogenesis.

PKKA caused by the antibodies neutralizing anti-erythropoetin can be associated with therapy by erythrogenesis stimulators including with therapy by the drug Rekormon® (0.107 cases for 10000 patsiyento-years when using the drug Rekormon® for treatment of anemia of renal genesis intravenously and subcutaneously; 0.158 cases for 10000 patsiyento-years at hypodermic administration of the drug Rekormon® for treatment of anemia of renal genesis). It is not recommended to transfer patients to therapy by the drug Rekormon® at suspicion on existence or at the confirmed existence of the antibodies neutralizing erythropoetin.

Effect on tumoral growth: epoetina are growth factors which generally stimulate formation of erythrocytes. Eritropoetinovy receptors can be present at a surface of various tumor cells. It is impossible to exclude that the means stimulating an erythrogenesis can stimulate growth of a malignancy of any type.

In clinical trials at treatment of anemia at oncological patients epoetiny a beta of statistically reliable deterioration in an indicator of survival and progressing of a tumor it is not registered.

 Patients with a chronic disease of kidneys or with malignant tumors, receiving chemotherapy, can have episodes of increase in the ABP and deterioration in a course of already available arterial hypertension, especially at sharp increase in Hb. Increase in the ABP can be eliminated medicamentally, in the absence of effect the temporary break in treatment by the drug Rekormon® is necessary. It is regularly recommended to control arterial pressure (especially at the beginning of therapy), including between dialysis sessions at patients with anemia of renal genesis. Certain patients with a chronic disease of kidneys can have a hypertensive crisis with the encephalopathy phenomena even at the normal or low ABP. Immediate consultation of the therapist is necessary and especially when developing sudden acute migrenepodobny headaches.

During treatment the drug Rekormon® recommends to control periodically potassium level in blood serum. At emergence of a hyperpotassemia it is necessary to cancel temporarily Rekormon® before potassium concentration normalization.

To patients with a chronic disease of kidneys trenutsya increase in a dose of heparin during the hemodialysis session owing to increase in Hb. Occlusion of dialysis system at an inadequate geparinization is possible. Early audit of the shunt and timely prevention of thromboses is recommended (for example, reception of acetylsalicylic acid).

Perhaps moderate dozozavisimy increase in quantity of thrombocytes within norm, especially later in/in purposes of the drug Rekormon®, with the subsequent independent return to normal values at therapy continuation. In the first 8 weeks of therapy weekly calculation of uniform elements and, especially, thrombocytes is necessary.

If Rekormon® appoint before an intake of autologous donor blood, it is necessary to adhere to recommendations about the procedure of donorship:
- blood can be taken only from patients with the size of a hematocrit of ³33% (or hemoglobin not less than 110 g/l (6.83 mmol/l));
- extra care should be observed at patients with body weight less than 50 kg;
- the blood volume which is taken away in one step should not exceed 12% of the settlement volume of blood of the patient.

Increase in quantity of thrombocytes within norm at the patients receiving Rekormon® before an intake of autologous donor blood therefore it is necessary to control number of thrombocytes weekly is possible. Treatment with the drug Rekormon® is interrupted at increase in thrombocytes more than on 150Õ109/l or at a thrombocytosis.

Treatment by the drug Rekormon® is shown only to those patients, it is the most important to them to avoid a homologous hemotransfusion, in view of a ratio risk advantage at a homologous transfusion.

Perhaps slight increase of number of thrombocytes at prevention of anemia at premature newborns (up to 12-14 in the afternoon) therefore regular control of thrombocytes is recommended.

The decision on use of the drug Rekormon® for the patients with a nephrosclerosis who are not receiving dialysis needs to be accepted individually as it is impossible to exclude completely a possibility of more bystry deterioration in function of kidneys.

In most cases along with increase in hemoglobin concentration of ferritin in serum decreases. Therefore and with concentration of ferritin of serum 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 (Fe2+) 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, nekhodzhkinsky lymphoma or a chronic lymphocytic leukosis with transferrin saturation less than 25% can enter 100 mg of Fe3 + in a week intravenously. To premature children peroral therapy by iron preparations in a dose of 2 mg of Fe2 + in days has to be appointed as soon as possible (the latest - 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.

The patient with moderate anemia before a planned large operative measure drug is appointed taking into account advantage of use of an epoetin a beta and increase in risk of tromboembolic episodes.

At the patients preparing for blood donation for the subsequent autotransfusion as they have instructions on temporary deficit of iron, peroral therapy by iron preparations (Fe2+) in a dose of 300 mg a day it is necessary to begin along with therapy by the drug Rekormon® and to continue before normalization of indicators of ferritin. If despite peroral replacement therapy by iron, signs of insufficiency of iron develop (level of ferritin of £20 mkg/l or saturation of transferrin less than 20%), it is necessary to consider a question of additional intravenous administration of iron preparations.

Influence on ability to drive the car and work with mechanisms. Researches on studying of influence of drug on ability to drive the car and work with mechanisms were not conducted. Proceeding from the mechanism of action and a profile of safety, Rekormon® does not possess such action.

Side effects:

Cardiovascular system. Frequent: emergence or strengthening of already available arterial hypertension (> 1%, <10%), especially in case of bystry increase in a hematocrit; hypertensive crisis with the encephalopathy phenomena (headaches and confusion of consciousness, sensitive and motive disturbances - disturbances of the speech, gait, up to toniko-clonic spasms), tromboembolic episodes at oncological patients (> 0.1%, <1%) and at the patients preparing for autotransfusion (the accurate causal relationship is not established with drug).

Nervous system. Headaches (> 1%, <10%), including suddenly arising migrenepodobny headaches.

System of a hemopoiesis. The Dozozavisimy increase in number of thrombocytes (which is not going beyond norm and disappearing at therapy continuation), especially after intravenous administration of drug. Rare: thrombocytosis (<0.01%). Thrombosis of shunts (> 0.01%, <0.1%) (it is possible at an inadequate geparinization), especially at patients with a tendency to a lowering of arterial pressure is (ABP) or with complications of an arteriovenous fistula (for example, a stenosis, aneurism, etc.).

Laboratory indicators. Decrease in concentration of ferritin in serum along with increase in Hb, decrease in serumal indicators of exchange of iron. Patients with uraemia have a passing hyperpotassemia (the accurate causal relationship is not established with administration of drug), a hyperphosphatemia.

At premature newborns. Decrease in concentration of ferritin in serum (> 10%), small increase in number of thrombocytes, especially up to the 12-14th day of life.

Others. Rare (from ≥1/10000 to ≤1/1000) - skin allergic reactions: rash, itch, urticaria; reactions in the place of an injection. Very rare (≤1/10000) - anaphylactoid reactions; grippopodobny symptoms (especially at the beginning of therapy) are usually expressed poorly or moderately and disappear in several hours or several days: fever, fever, headaches, extremity or bones pains, indisposition.

Post-marketing observation: against the background of therapy the drug Rekormon® registered separate cases (0.107 cases for 10000 patsiyento-years when using the drug Rekormon® for treatment of anemia of renal genesis intravenously and subcutaneously and 0.158 cases for 10000 patsiyento-years at hypodermic administration of the drug Rekormon® for treatment of anemia of renal genesis) the partial krasnokletochny aplasia caused by formation of the antibodies neutralizing anti-erythropoetin (see. "Special instructions").

Interaction with other medicines:

The data obtained so far did not reveal any interactions of the drug Rekormon® with other drugs. In order to avoid incompatibility or decrease of the activity of drug it is impossible to use other solvent and to mix drug with other medicines or injection solutions.

Contraindications:

Hypersensitivity to an epoetin a beta or to any of drug components in the anamnesis; uncontrollable arterial hypertension.

Myocardial infarction or stroke within the previous month, unstable stenocardia or the increased risk of a deep vein thrombosis (at a venous thromboembolism in the anamnesis) – at appointment for increase in volume of donor blood for autohemotrasfusion.

With care. Refractory anemia in the presence of blasttransformirovanny cells, a thrombocytosis, epilepsy and a chronic liver failure.

Body weight is less than 50 kg for increase in volume of donor blood for the subsequent autotransfusion.

Overdose:

Therapeutic index of the drug Rekormon® very wide, however, it is necessary to take into account the individual response to therapy in an initiation of treatment. The excessive pharmakodinamichesky answer, i.e. an excessive erythrogenesis with zhizneugrozhayushchy cardiovascular complications is possible. At a high rate of Hb it is necessary to interrupt therapy with the drug Rekormon® temporarily (see. "Route of administration and doses"). If necessary the phlebotomy can be carried out.

Storage conditions:

Period of validity 2 years. Not to use after the period of validity specified on packaging.

At a temperature of 2-8 °C in the place protected from light. Not to freeze. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Syringe tubes 1000 ME/0.3 of ml, 2000 ME/0.3 ml, 10000 ME/0.6 ml, 20000 ME/0.6 ml, 30000 ME/0.6 ml.

On 1000 ME/0.3 ml, 2000 ME/0.3 ml, 10000 ME/0.6 ml, 20000 ME/0.6 ml, 30000 ME/0.6 ml in the syringe tubes which case is manufactured of colourless glass of a hydrolytic class 1 (EF), closed on the one hand the piston manufactured of plastic on which end there is a disk from the brombutilovy rubber laminated by fluoroelastomer; on the other hand – a cap of gray color from brombutilovy rubber. The injection cannula is placed in the plastic container which is hermetically corked by PVH/PE/A1 triplex.

3 syringe tube on 1000 ME/0.3 ml, 2000 ME/0.3 ml, 10000 ME/0.6 ml, 20000 ME/0.6 ml together with 3 injection cannulas is packed separately (1 unit-dose syringe and 1 needle) into a blister strip packaging from a film polyvinyl chloride also by papers with the laminated covering. 2 blister strip packagings together with the application instruction place in a cardboard pack.

1 unit-dose syringe on 30000 ME/0.6 ml together with 1 injection cannula is packed (1 unit-dose syringe and 1 injection cannula) into a blister strip packaging. 1 or 4 blister strip packagings together with the application instruction place in a cardboard pack.