Epostim (Epoetin beta)

active substance: recombinant human erythropoietin,
auxiliary substances: plasmabumin 20* - 2.50 mg, sodium citrate dihydrate -5.80 mg, sodium chloride - 5.84 mg, citric acid - 0.057 mg, water for injections up to 1 ml.
* human albumin, sodium caprylate, acetyltriptophan.

Farm group: hematopoiesis stimulant.
Pharmacise: Epoetin beta is a glycoprotein that specifically stimulates erythropoiesis, activates mitosis and ripening of red blood cells from the precursor cells of the red blood cell series. Recombinant epoiethin beta is synthesized in mammalian cells, which have a gene encoding human erythropoietin. In terms of composition, biological and immunological properties, epoetine beta is identical to natural human erythropoietin.
The administration of epoetine beta leads to increased hemoglobin and hematocrit, improved blood supply to tissues and heart function. The most pronounced effect of the use of epoietin beta is observed in anemia caused by chronic renal failure. In very rare cases, long-term use of erythropoietin for the therapy of anemic conditions may result in the formation of neutralizing antibodies to erythropoietin with or without the development of partial red cell aplasia.
Pharmacokinetics: When administering epoietin beta in healthy persons and patients with T1/2 uremia - 5-6 hours. When administered epoetine beta, its concentration in the blood increases slowly and reaches a maximum between 12 and 18 hours after administration, T1/2 - 16-24 hours. Bioavailability of epoetin beta when administered - 25-40%.

• Prevention and treatment of anemia in patients with solid tumors resulting from antitumor therapy.
• Anemia in patients with chronic renal failure, including those on hemodialysis.
• Prevention and treatment of anemia in HIV-infected patients caused by zidovudine.
• Prevention and treatment of anemia in patients with myeloma disease, low-malignancy non-Hodzhskin lymphomas, chronic lympholeukemia, in patients with rheumatoid arthritis.
• Treatment and prevention of anemia in premature babies born with a body weight of up to 1.5 kg.
• Preparing patients for surgery with planned large blood loss.

• Hypersensitivity to Epistim or its components,
• partial red cell aplasia after previous therapy with erythropoietin,
• uncontrolled arterial hypertension,
• the impossibility of providing adequate anticoagulant therapy,
• myocardial infarction and acute cerebral circulation disorders within a month after the event,
• unstable angina or increased risk of deep vein thrombosis and thromboembolism as part of a pre-deposit blood collection program before surgery,
• porphyria.

With caution:
In patients with plateletosis, moderate anemia (Hb 100-130 g/l or hematocrit 30-39%, without Fe deficiency), thrombosis (in history), sickle cell anemia, malignant neoplasms, refrastructive anemia, epilepsy and chronic liver failure, as well as patients with a body weight of less than 50 kg (to increase the volume of donor blood for subsequent autotransfusion).

Since there is no sufficient experience in the use of erythropoietin during pregnancy and lactation in humans, epoietin beta should be prescribed only if the expected benefits of its use exceed the possible risk to the fetus and mother.

The cardiovascular system may experience dose-dependent increase in blood pressure, deterioration of blood hypertension (most often in patients with uremia), in some cases hypertension, a sharp increase in blood pressure with symptoms of encephalopathy (headache, confusion) and generalized tonic-clonic seizures. Antihypertensive drugs or reduce the dose of Epostim are prescribed to correct blood pressure.

Patients with uremia may develop hyperkalemia and hyperphosphatemia. A diet is prescribed as treatments.

Plateletosis may be observed on the part of the circulatory authorities, in some cases shunt thrombosis (patients on hemodialysis with a tendency to hypotension or with aneurysm, stenosis, etc.). The use of Epostim can lead to the development of hyperviscosity syndrome (acute encephalopathy, reduced the effectiveness of hemodialysis), increased creatinine and urea levels (an increase in dialysis time is required, dialysis index - KT/Y1,4-1,6).

Skin allergic reactions to the components of the drug are rarely observed: rash, urticaria, itching, anaphylactoid reactions, reactions at the injection site. Local reactions can manifest themselves in the form of hyperemia, burning, weak or moderate soreness at the place of administration (more often occur during subcutaneous administration).

In rare cases, influenza-like syndrome (fever, chills, headaches, weakness, arthralgia, myalgia) may develop mainly at the beginning of treatment. It is very rare for immune reactions (induction of antibody formation with or without partial red cell aplasia), exacerbation of porphyria.

Simultaneous use of cyclosporin may require correction of the latter's dose due to increased erythrocyte binding. Experience in clinical use of Epictim has not yet revealed any facts of its pharmacological incompatibility with other drugs. However, in order to avoid possible incompatibility or decreased activity, Epostim should not be mixed with solutions of other drugs.

Treatment of anemia in patients with chronic renal failure:
Epicism is injected intravenously or subcutaneously. Patients on hemodialysis are administered through an arteriovenous shunt at the end of the dialysis session. When changing the method of administration, the drug is injected at the previous dose, then the dose is corrected if necessary (in the subcutaneous method of administration of Epostim, a dose of 20-30% less is required to achieve the same therapeutic effect than with intravenous administration). Treatment

The epicism includes two stages:
1. Correction stage: At subcutaneous administration of Epostima, the initial single dose is 30 IU/kg 3 times a week. In intravenous administration of Epostima, the initial one-time dose is 50 IU/kg. The correction period lasts until optimal hemoglobin levels are reached (100-120 g/l in adults and 95-110 g/l in children) and hematocrit (30-35%). These indicators need to be monitored weekly. The following situations may occur:
1) Hematocrit increases from 0.5 to 1.0% per week. In this case, the dose is not changed until optimal performance is reached.
2) Hematocrit growth rate is less than 0.5% per week. In this case, it is necessary to increase the single dose by 1.5 times.
3) Growth rate more than 1.0% per week. In this case, it is necessary to reduce the single dose of the drug by 1.5 times.
4) Hematocrit remains low or decreases. It is necessary to analyze the causes of resistance.

The effectiveness of therapy depends on the right individual treatment scheme.

2. Stage of supportive therapy: To maintain hematocrit at 30-35%, the dose of Epostima achieved during the correction stage should be reduced by 1.5 times. Then the supporting dose of Epostim is selected individually taking into account the dynamics of hematocrit and hemoglobin. After stabilization of hemodynamic indicators, it is possible to switch to the administration of Epicism once every 1-2 weeks.

Prevention and treatment of anemia in patients with solid tumors:
Before starting treatment, it is recommended to determine the level of endogenous erythropoietin. At a serum concentration of erythropoietin less than 200 IU/l, the initial dose of Epostim is 150 IU/kg intravenously 3 times a week. In the subcutaneous method of administration, the initial dose of Epostim can be reduced to 100 IU/kg 3 times a week. In the absence of an answer, it is possible to increase the dose to 300 IU/kg 3 times a week. Further dose increases do not seem advisable. It is not recommended to prescribe erythropoietin to patients with endogenous erythropoietin in serum above 200 IU/l.

During Epostim therapy, it is undesirable to increase hemoglobin levels by more than 20 g/l per month or above 140 g/l. If hemoglobin levels increase by more than 20 g/l per month, the dose of Epostim should be reduced by 2 times. If the hemoglobin level exceeds 140 g/l, Epostim is canceled until the hemoglobin level drops ≤120 g/l, after which treatment resumes at a dose of 50% of the dose at which the drug was canceled.

Prevention and treatment of anemia in patients with HIV infection: Intravenous administration of Epostim at a dose of 100-150 IU/kg 3 times a week is effective in HIV-infected patients receiving zidovudine therapy, provided that the endogenous erythropoietin levels in the patient's serum are less than 500 IU/l and the dose of zidovudine is less than 4200 mg per week. Subcutaneous administration can reduce the dose of Epostim by 1.5 times.

Prevention and treatment of anemia in patients with myeloma disease, low-malignancy non-Hodzhskin lymphomas and chronic lympholeukemia: In these patients, the expediency of treatment with epoetine beta is due to inadequate synthesis of endogenous erythropoietin against the background of anemia. At a hemoglobin content below 100 g/l and whey erythropoietin below 100 IU/l, Epostim is injected subcutaneously at the starting dose of 100 IU/kg three times a week. Laboratory control of hemodynamic indicators is carried out weekly. If necessary, the dose of Epostim is adjusted up or downwards every 3-4 weeks. If hemoglobin levels increase by 10 g/l after 4 weeks, treatment continues at the same dose. If hemoglobin increases by less than 10 g/l after 4 weeks, it is possible to increase the dose to 300 IU/kg 3 times a week. If hemoglobin levels have not increased by at least 10 g/l after 8 weeks of Epistom therapy, the effect is unlikely, the drug should be canceled.

If hemoglobin levels increase by more than 20 g/l in 4 weeks of therapy, the dose of Epostim should be reduced by 2 times. If hemoglobin levels exceed 140 g/l, Epistim treatment is suspended until hemoglobin levels decrease to ≤ 130 g/l, after which the therapy continues at a dose equal to 50% of the one at which the therapy was suspended.

In chronic lymphocyte leukemia, Epostim treatment lasts up to 4 weeks after the end of chemotherapy. The maximum dose should not exceed 300 IU/kg 3 times a week.

Treatment should be resumed only if the most likely cause of anemia is the insufficient production of endogenous erythropoietin.

Prevention and treatment of anemia in patients with rheumatoid arthritis: Patients with rheumatoid arthritis have suppression of endogenous erythropoietin synthesis under the influence of increased concentrations of proinflammatory cytokines. Treatment of anemia in these patients is carried out with Epicism when subcutaneous administration at a dose of 50-75 IU/kg 3 times a week. If the hemoglobin content increases by less than 10 g/l after 4 weeks of treatment, the dose of Epostim is increased to 150-200 IU/kg 3 times a week. Further dose increases do not seem appropriate.

Treatment and prevention of anemia in premature babies born with low body weight: To prevent and treat anemia in premature newborns, the administration of Epostima should begin as early as possible, preferably from the 3rd day of life at a dose of 200 IU/kg intravenously or subcutaneously 3 times a week and last no more than 6 weeks. The effect of the drug in premature newborns who have already undergone hemotransfusions is slightly less than in those who have not undergone hemotransfusions.

Preparing patients for surgery with planned large blood loss: The recommended dose of Epostima is 450-600 IU/kg once a week subcutaneously for the 3 weeks of previous surgery (21, 14 and 7 days before surgery) and on the day of surgery. If it is necessary to reduce the time of preoperative preparation, it is possible to use Epostim at a dose of 300 IU/kg subcutaneously daily 10 days before surgery, on the day of surgery and 4 days after surgery.

If hemoglobin levels in the preoperative period are ≥150 g/l, the use of Epostim should be stopped.

All patients should receive oral iron preparations at a dose of 200 mg/day throughout the course of treatment. If possible, additional oral use of iron preparations should be provided before Epistom therapy to create an iron depot in the patient's body.

An overdose of Epicostima may show increased side effects. Treatment is symptomatic, bloodletting is indicated at high levels of hemoglobin and hematocrit.

During treatment, blood pressure should be monitored weekly and general blood tests, including the determination of hematocrit, platelets and ferritin. In patients with uremia who are on hemodialysis due to increased hematocrit, it is often necessary to increase the dose of heparin, in addition, timely thrombosis prevention and early revision of shunt are necessary. In the pre- and postoperative period, hemoglobin should be controlled more often if its initial level was less than 140 g/l. It should be remembered that epoetin beta does not replace hemotransfusion, but reduces the volume and frequency of its use. In patients with controlled arterial hypertension or thrombotic complications, an increase in the dose of hypotensive and/or anticoagulant drugs may be required. In the event of a hypertensive crisis, urgent measures are carried out to provide medical care to the patient, and treatment with epoetine beta should be interrupted.

When epoietin beta is prescribed to patients with liver failure, it may slow down its metabolism and have a pronounced increase in erythropoiesis. The safety of epoetine beta use in this group of patients has not been established. The possibility of the effect of epoetine beta on the growth of some types of tumors, including bone marrow tumors, should also be excluded. It should be taken into account that preoperative increases in hemoglobin levels may serve as a predisposing factor in the development of thrombotic complications. Before starting treatment, possible causes of inadequate response to the drug (iron deficiency, folic acid, cyanocbalomin, severe A13⁺ poisoning, co-morbidities, inflammatory processes and injuries, hidden blood loss, hemolysis, bone marrow fibrosis of various etiologies) should be excluded and, if necessary, correct the treatment. In most patients with uremia, cancer and HIV-infected patients, the level of ferritin in plasma decreases simultaneously with an increase in hematocrit.

Ferritin levels should be determined throughout the course of treatment. If it is less than 100 ng/ml, iron substitution therapy is recommended for oral administration at the rate of 200-300 mg/day (for children 100-200 mg/day). Early childhood oral therapy with iron at a dose of 2 mg/day should be prescribed as soon as possible. Patients who donate autologous blood and are in the pre- or postoperative period should also receive adequate iron therapy at a dose of up to 200 mg/day. In patients with uremia, the correction of anemia with epicethin beta can cause improved appetite and increased absorption of potassium and proteins. In this regard, periodic correction of hemodialysis parameters may be required to maintain urea, creatinine and K⁺ levels within the norm. In these patients, it is also necessary to control the level of electrolytes in the blood serum.

When using epoetine beta in women of reproductive age, menstruation may resume. The patient should be warned about the possibility of pregnancy and the need for reliable contraception methods before starting therapy. During treatment, patients with uremia should avoid potentially dangerous activities requiring increased concentration and rapid psychomotor reactions due to increased risk of increased blood pressure at the beginning of therapy until the optimal support dose is established. Given the possible more pronounced effect of Epostim, its dose should not exceed the dose of recombinant erythropoietin used in the previous course of treatment. During the first two weeks, the dose is not changed, the dose/response ratio is assessed. After that, the dose can be reduced or increased according to the above scheme.

Solution for intravenous and subcutaneous administration