Description
Release form
Solution for intravenous and subcutaneous administration
Packaging
6 syringes 1 ml each.
Pharmacological action of
Erythropoietin is a glycoprotein that stimulates erythropoiesis, activates mitosis and the maturation of red blood cells from erythrocyte progenitor cells. The molecular weight of erythropoietin is about 32000-40000 Yes. The protein fraction is about 58% of the molecular weight and includes 165 amino acids. Four hydrocarbon chains are linked to a protein by three N-glycosidic bonds and one O-glycosidic bond. Epoetin alpha, obtained using genetic engineering technology, is a purified glycoprotein, in amino acid and carbohydrate composition it is identical to human erythropoietin, excreted from the urine of patients with anemia.
Binocrit has the highest possible degree of purification in accordance with modern technological capabilities. In particular, in the quantitative analysis of the active substance of the drug, Binocrit does not even determine the trace amounts of cell lines on which the drug is produced.
The biological activity of epoetin alpha was confirmed in an in vivo experiment (studies were performed in healthy rats and rats with anemia, as well as in mice with polycythemia). After administration of epoetin alpha, the number of red blood cells, reticulocytes, hemoglobin concentration, and 59Fe absorption rate increase. In vitro studies, when incubated with epoetin alpha, an increase in the incorporation of 3H-thymidine in erythroid nucleated spleen cells (in mouse spleen cell culture) was detected. Studies on a culture of human bone marrow cells have shown that epoetin alpha specifically stimulates erythropoiesis and does not affect leukopoiesis. The cytotoxic effect of erythropoietin on human bone marrow cells was not detected.
Erythropoietin is a growth factor that mainly stimulates the formation of red blood cells. Erythropoietin receptors may be present on the surface of various tumor cells.
The administration of epoetin alpha is accompanied by an increase in hemoglobin, hematocrit, serum iron, and improves blood supply to tissues and heart function. The most significant effect of epoetin alfa was noted in anemia caused by chronic renal failure (CRF), as well as in patients with a number of malignant neoplasms and systemic diseases.
Pharmacokinetics
Intravenous administration of
T1 / 2 epoetin alfa after repeated intravenous administration is about 4 hours in healthy volunteers and about 5 hours in patients with chronic renal failure. In children, T1 / 2 of epoetin alpha is about 6 hours.
Subcutaneous administration of
With subcutaneous administration, the concentration of epoetin alpha in the blood plasma is determined to be significantly lower than with intravenous administration, Tmax of epoetin alpha in the blood plasma is about 12-18 hours after administration. Cmax of epoetin alfa for subcutaneous administration is only 1/20 of the concentration for intravenous administration. The drug does not have the ability to cumulate – the concentration of epoetin alpha in the blood plasma 24 hours after the first injection is determined to be the same as 24 hours after the last injection. With subcutaneous administration of T1 / 2 epoetin alpha is difficult to determine, it is about 24 hours. The bioavailability of epoetin alpha with subcutaneous administration is significantly lower than with intravenous administration, and is about 20%.
Indications
anemia in adults and children due to chronic renal failure, including: anemia due to chronic renal failure in children and adults on hemodialysis, as well as adults on peritoneal dialysis
severe renal anemia, accompanied by clinical symptoms in adults with kidney failure who have not had hemodialysis
treatment of anemia and reduction the need for a blood transfusion in adults receiving treatment with chemotherapeutic drugs for solid tumors, malignant lymphoma or multiple myeloma, as well as in individuals with a high risk of hemotransfusion complications due to a general severe condition (due to cardiovascular diseases, if anemia was noted even before chemotherapy was started)
in order to increase the efficiency of autologous blood transfusion as part of a pre-collection program for blood collection before surgery in patients with a hematocrit level of 33 39%, to facilitate the collection of autologous blood and reduce the risk associated with the use of allogeneic blood transfusions, if the expected need for transfused blood exceeds the amount that can be obtained by autologous collection without the use of epoetin alpha. Treatment is indicated for patients with moderate anemia (with a hemoglobin concentration of 10 13 g / dl or 6.2 8.1 mmol / l), without iron deficiency, if significant blood loss is expected, as well as with extensive surgical interventions, when a large volume of transfused blood may be required (5 or more volumes in men and 4 or more in women)
in order to reduce the risk of allogeneic blood transfusion in adults without iron deficiency before elective orthopedic surgery, if there is a high risk of complications during blood transfusions. The use of the drug is limited – only in patients with moderate anemia (for example, with a hemoglobin concentration of 1013 g / dl), if they are not included in the autologous blood collection program before surgery with an expected blood loss of 900 to 1800 ml of
anemia in HIV- infected patients receiving zidovudine therapy with an endogenous erythropoietin level of less than 500 IU / ml.
Contraindications
hypersensitivity to the active substance and excipients that make up the
partial red cell aplasia (PKCA), uncontrolled arterial hypertension arisen after treatment with
erythropoietin
patients who for some reason cannot receive effective treatment for the prevention of
thrombosis myocardial infarction or stroke, occurred within 1 month before the planned treatment, unstable angina pectoris with high risk of thrombosis and thrombosis history of disease (in the framework of increasing the efficiency of autologous blood transfusion)
severe damage to the coronary, peripheral arteries, carotid arteries, and also cerebral vessels, including in patients who have recently suffered a myocardial infarction or stroke (as part of the pre-deposit program for collecting blood before an extensive surgical operation and not participating in the autologous blood transfusion program).
Caution: malignant neoplasms, epileptic syndrome (including history), chronic renal and hepatic insufficiency, thrombocytosis, thrombosis (history), acute blood loss, sickle-cell anemia, hemolytic anemia, iron, B12, or folic acid deficiency.
Pregnancy and lactation
Appropriate controlled trials of the use of epoetin alfa in women during pregnancy have not been conducted. Based on animal studies, reproductive toxicity has been identified. As a result, patients with chronic renal failure should use Binocrit during pregnancy only if the expected benefit to the mother significantly exceeds the risk to the fetus.
The use of epoetin alfa is not recommended during pregnancy or lactation in patients participating in the autologous blood collection program before surgery.
Special instructions
When prescribing Binocrit in all patients, blood pressure should be checked and strictly controlled. Caution is advised to use epoetin alfa in patients with hypertension if they do not receive the necessary treatment, the prescribed treatment is inadequate, or hypertension is poorly controlled. In this case, it may be necessary to start or strengthen the antihypertensive therapy that has already been used. If blood pressure cannot be normalized, treatment with epoetin alfa should be discontinued. Binocrit is used with caution in the presence of epilepsy and chronic liver failure.
Patients with chronic renal failure and cancer patients should regularly monitor hemoglobin levels until stable values ² ¹ ² ¹are achieved and periodically thereafter.
Careful monitoring of hemoglobin levels is mandatory for all patients due to the increased potential risk of thromboembolic complications and an increase in the number of fatal cases when patients received treatment at a hemoglobin level exceeding the established norm for the use of the drug as indicated.
During treatment with Binocrit ®, a moderate dose-dependent increase in platelet count within normal limits may be observed. With the continuation of the course of therapy, this indicator decreases again. During the first 8 weeks after starting therapy, it is recommended to regularly monitor the platelet count.
Before starting therapy, all other causes of anemia (iron deficiency, hemolysis, blood loss, vitamin B12 or folic acid deficiency) must be ruled out. In most cases, the serum ferritin level decreases with a simultaneous increase in hematocrit.
All of the listed additional factors of anemia should also be considered when increasing the dose of Binocrit in patients with neoplasms.
During the perioperative period, it is necessary to carefully monitor all blood counts.
PKCA
After months or years of treatment with erythropoietin using subcutaneous injections, cases of developing PKCA mediated through antibodies have been very rare. If the effectiveness of therapy sharply decreases in patients due to a decrease in hemoglobin concentration (1-2 g / dl per month) due to an increased need for blood transfusions, it is necessary to check the number of reticulocytes and study the typical reasons for the lack of response to the drug (for example, iron, folic acid or vitamin B12 deficiency aluminum intoxication, infection or inflammation, bleeding or hemolysis).
If the content of reticulocytes, taking into account anemia (for example, the reticulocyte index) is low (If you suspect the appearance of PACA mediated through antibodies to erythropoietin, you should immediately stop therapy with Binocrit. It is forbidden to prescribe any other therapy with erythropoietin because of the risk of a cross-reaction. If indicated, patients may be prescribed the necessary therapy, such as blood transfusion.
In the case of a paradoxical decrease in hemoglobin concentration and the development of severe anemia due to the low content of reticulocytes, it is necessary to immediately stop treatment with epoetin and test for the presence of antibodies to erythropoietin. There is evidence of such manifestations in patients with hepatitis C treated with interferon and ribavirin simultaneously with epoetin. Epoetin is not intended for the treatment of hepatitis C anemia.
Patients with chronic renal failure
Immunogenicity with subcutaneous administration of the drug Binocrit in patients at risk of developing PKKA mediated through antibodies, such as with renal anemia, is limited. As a result, in patients with renal anemia, the drug should be administered intravenously.
In order to minimize the risks of increased hypertension for patients with chronic renal failure, the rate of increase in hemoglobin should be approximately 1 g / dl (0.62 mmol / l) per month and should not exceed 2 g / dl (1.25 mmol / l) per month.
In patients with chronic renal failure, the hemoglobin concentration at the supportive stage of treatment should not exceed VGN recommended in the section ² ÑDosage and Administration ² Ñ. The results of clinical studies showed an increased risk of fatal outcomes and severe cardiovascular disorders with the introduction of erythropoiesis-stimulating drugs in order to increase the hemoglobin concentration of more than 12 g / dl (7.5 mmol / l).
When conducting clinical trials under controlled conditions, there were no significant benefits, associated with the use of epoetins against the background of an increase in hemoglobin concentration above the level necessary to control the symptoms of anemia and prevent blood transfusions. In patients with hemodialysis, there have been cases of shunt thrombosis, in particular with a tendency to hypotension or due to the formation of arteriovenous fistulas (e.g. stenosis, aneurysm, etc.). Such patients are recommended early correction of the shunt and the prevention of thrombosis, for example with acetylsalicylic acid.
In some cases, hyperkalemia was observed. Treating anemia can lead to increased appetite and increased need for potassium and protein. Periodically, the dialysis regimen should be adjusted in order to maintain the necessary indicators of urea, creatinine and potassium. In patients with chronic renal failure, it is necessary to check the content of electrolytes in the blood serum. If an elevated (or increasing) level of serum potassium is detected, the appropriateness of canceling treatment with epoetin alpha should be assessed until the potassium level is normalized.
During treatment with epoetin alfa, an increase in the dose of heparin during hemodialysis is often required due to an increase in the hematocrit. If heparinization cannot be as effective as possible, dialysis procedures may need to be canceled.
According to available data, treatment of anemia with epoetin alfa in adult patients with renal failure who are not yet dialyzed does not cause progression of renal failure.
Adult cancer patients with symptomatic anemia, undergoing
chemotherapy In some clinical situations, a blood transfusion should be used to treat anemia in cancer patients. The decision on the appointment of recombinant erythropoietins must be taken, taking into account the ratio of benefits and possible risks for each patient individually and the characteristics of the clinical situation. The following factors should be taken into account: type and stage of neoplasm development, degree of anemia, life expectancy, environment in which the patient will undergo treatment, the patient ² ¢s wishes.
When evaluating the appropriateness of epoetin alfa therapy (risk of blood transfusion for a patient) in cancer patients receiving chemotherapy, it is necessary to take into account a delay of 2-3 weeks after administration of epoetin alfa until the formation of red blood cells against the background of erythropoietin stimulation.
In order to minimize the risk of thrombotic events, it is necessary to ensure that the level of hemoglobin and its rate of increase do not exceed acceptable values.
Due to the increase in the number of cases of venous thrombotic complications in cancer patients receiving erythropoietic stimulating drugs, the risk and benefit of treatment with epoetin alfa should be carefully evaluated, especially in cancer patients with an increased risk of developing venous thrombotic complications, for example, against the background of obesity or the presence of venous thrombotic diseases in family history (including deep venous thrombosis or pulmonary thromboembolism).
Adult patients participating in an autologous blood collection program before
surgery All special precautions must be observed, related to autologous blood collection programs, especially with regular blood transfusions.
Patients undergoing elective orthopedic surgery
For patients undergoing elective orthopedic surgery, it is necessary to establish the cause of the anemia and, if possible, treat the anemia before starting treatment with epoetin alfa. Such patients may have a risk of thrombotic events, which must be carefully evaluated when prescribing treatment for patients in this group.
Patients undergoing elective orthopedic surgery should receive adequate antithrombotic prophylaxis due to the risk of developing venous thrombotic complications in surgical patients, especially those suffering from cardiovascular diseases. Moreover, special precautions must be observed in patients with a predisposition to the development of deep vein thrombosis of the extremities. Patients with an initial hemoglobin level> 13 g / dl (> 8.1 mmol / L) have an increased risk of postoperative thrombotic / venous complications. As a result, the drug should not be prescribed to patients with an initial hemoglobin level> 13 g / dl (> 8.1 mmol / l).
Excipients
This drug contains less than 1 mmol of sodium (23 mg) in one pre-filled syringe, i.e. actually contains no sodium.
Composition of
1 ml of solution for intravenous and subcutaneous administration contains:
Active ingredient: epoetin alpha
Excipients: sodium dihydrogen phosphate dihydrate, sodium hydrogen phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid.
Dosage and Administration
Intravenously, subcutaneously.
Treatment with Binocrit should be carried out under the supervision of a specialist who has the appropriate qualifications and experience in treating patients who are shown to be treated with drugs that stimulate erythropoiesis.
Doses
Treatment of symptomatic anemia in adults and children with chronic renal failure: Binocrit in patients with chronic renal failure is administered iv. Due to the fact that the clinical manifestations of anemia and residual effects may vary depending on the age, gender and general severity of the disease, an individual assessment of the condition of each patient is carried out.
The target hemoglobin concentration is 10 12 g / dl (6.2 7.5 mmol / l) in adults and 9.5 11 g / dl (5.9 6.8 mmol / l) in children.
A prolonged increase in hemoglobin concentration of more than 12 g / dl (7.5 mmol / l) is not recommended. If the hemoglobin concentration rises by more than 2 g / dl (1.25 mmol / l) per month or for a long time exceeds 12 g / dl (7.5 mmol / l), it is necessary to reduce the dose of Binokrit by 25%. If the hemoglobin concentration exceeds 13 g / dl (8.1 mmol / l), it is necessary to stop treatment until hemoglobin is reduced to 12 g / dl (7.5 mmol / l) and then resume therapy with Binocrit, reducing the initial dose by 25%.
Due to interindividual variability, the hemoglobin concentration may be higher or lower than the optimal (target) value.
Treatment should be prescribed so that the minimum effective dose of Binocrit provides the necessary control of hemoglobin and the clinical manifestations of the disease.
Before treatment and during treatment, the concentration of iron in the blood plasma should be monitored, if necessary, additional iron preparations are prescribed.
Adult patients receiving hemodialysis
Treatment is carried out in two stages.
Stage of correction. Binocrit is administered intravenously at a dose of 50 IU / kg 3 times a week. If necessary, adjust the dose gradually, over 4 weeks.
Increase or decrease in dose – not more than 25 IU / kg 3 times a week.
Supportive care phase. Dose adjustment in order to maintain the necessary hemoglobin level of 10-12 g / dl (6.2-7.5 mmol / l).
The recommended total weekly dose of Binocrit is from 75 to 300 IU / kg, administered intravenously at 25-100 IU / kg 3 times a week.
In patients with severe anemia (hemoglobin Use in children receiving hemodialysis
The treatment is carried out in two stages.
Correction step. Binocrit is administered intravenously at a dose of 50 IU / kg 3 times a week. If necessary, the dose is adjusted gradually, over 4 weeks. Increase or decrease in dose – not more than 25 IU / kg 3 times a week.
Stage of maintenance therapy. Dose adjustment in order to maintain the required hemoglobin level of 9.5 11 g / dl (5.9 6.8 mmol / l).
In most cases, children with a body weight of less than 30 kg need to use higher maintenance doses than children with a higher body weight and adults.
Binocrit is administered subcutaneously.
The recommended dose of Binocrit is 600 IU / kg once a week for 3 weeks prior to surgery (21, 14 and 7 days before surgery), as well as on the day of surgery. If the preoperative period is shorter than 3 weeks, Binocrit should be prescribed daily at a dose of 300 IU / kg for 10 consecutive days, before surgery, on the day of surgery and within 4 days after it. If in the preoperative period the concentration of Hb is 15 g / dl (9.38 mmol / L) or higher, the use of the drug must be discontinued. Should make sure that before starting treatment with Binocrit, patients do not have iron deficiency.
All patients receiving Binocrit therapy should receive the necessary amount of ferrous iron (by mouth 200 mg / day) throughout the course of therapy.
Side effects of
From the blood and lymphatic system: infrequently – thrombocythemia (in patients with malignant neoplasms) the frequency is unknown – PKKA mediated through antibodies1, thrombocythemia (in patients with chronic renal failure).
On the part of the immune system: frequency unknown – anaphylactic reaction, hypersensitivity.
From the nervous system: very often – headache (in patients with malignant neoplasms) often – convulsions (in patients with chronic renal failure), headache (in patients with chronic renal failure), hemorrhagic stroke2, convulsions (in patients with malignant neoplasms) frequency unknown – stroke2, hypertensive encephalopathy, transient ischemic attacks.
From the side of the organ of vision: frequency unknown – retinal thrombosis.
From the CCC side: often – deep vein thrombosis of the lower extremities (in patients with malignant neoplasms) increased blood pressure frequency is unknown – deep vein thrombosis of the lower extremities (in patients with chronic renal failure), arterial thrombosis, hypertensive crisis.
On the part of the respiratory system: often – pulmonary thromboembolism2 (in patients with malignant neoplasms) the frequency is unknown – pulmonary thromboembolism2 (in patients with chronic renal failure).
From the gastrointestinal tract: very often – nausea often – diarrhea (in patients with neoplasms), vomiting infrequently – diarrhea (in patients with chronic renal failure).
On the part of the skin and its appendages: often – skin rash, frequency is unknown – angioedema, urticaria.
From the musculoskeletal system: very often – arthralgia (with chronic renal failure) often – arthralgia (in patients with malignant neoplasms) infrequently – myalgia (in patients with malignant neoplasms) the frequency is unknown – myalgia (with chronic renal failure).
Congenital, familial / genetic disorders: frequency unknown – porphyria.
On the part of the body as a whole: very often – hyperthermia (in patients with malignant neoplasms) flu-like state (with chronic renal failure) often – flu-like condition (in patients with malignant neoplasm) the frequency is unknown – drug inefficiency, peripheral edema, hyperthermia (with chronic renal failure), reactions at the injection site.
Laboratory parameters: frequency unknown – antibodies to erythropoietin1.
Others: often – thrombosis of dialysis equipment shunt (in patients with chronic renal failure).
1 Frequency of manifestations cannot be estimated based on clinical studies.
2 Includes fatalities.
Drug interaction
There is no data on the interaction of epoetin alfa with other drugs. However, with simultaneous use with cyclosporine, interaction is possible, since the drug binds to red blood cells. If treatment with Binocrit is carried out simultaneously with cyclosporine, it is necessary to control the concentration of cyclosporine depending on the degree of increase in hematocrit.
There is no data on the interaction between epoetin alpha and granulocyte colony stimulating factor (G-CSF) or granulocyte-monocyte colony stimulating factor (GM-CSF).
In order to avoid incompatibility or decrease in activity, it is not recommended to mix with solutions and other medicines.
Overdose
The therapeutic range of the drug is wide. With overdose, symptoms may occur that reflect the extreme degree of manifestation of the pharmacological action of the hormone (increased concentration of hemoglobin or hematocrit). At extremely high levels of hemoglobin or hematocrit, phlebotomy may be used. If necessary, symptomatic therapy is prescribed.
Storage conditions
At 2-8 ° C (do not freeze).
Expiration date awst
2 years
Deystvuyushtee substance
poÑtin alyfa
Terms and conditions
prescription
Formulation
injection and infusion
Possible product names
binocular syringe 5000 UNITS, 0.5 ml, 6 pcs.
