Binocrit, 10000 me/ml 1 ml 6 pcs

Erythropoietin is a glycoprotein that stimulates erythropoiesis and activates mitosis and maturation of erythrocytes from erythrocyte progenitor cells. The molecular weight of erythropoietin is about 32000-40000 Da. The protein fraction is about 58% of the molecular weight and includes 165 amino acids. Four hydrocarbon chains are linked to the protein by three N-glycoside bonds and one O-glycoside bond. Epoetin alfa, produced using genetically engineered technology, is a purified glycoprotein; its amino acid and carbohydrate composition is identical to that of human erythropoietin excreted from the urine of anemic patients.

Binocrit has the highest possible degree of purification according to modern technological capabilities. In particular, in quantitative analysis of the active ingredient of Binocrit, even trace amounts of cell lines are not detected.

The biological activity of epoetin alfa was confirmed in the experiment in vivo (researches were carried out on healthy rats and rats with anemia as well as on mice with polycythemia). After epoetin alfa injection, the number of erythrocytes, reticulocytes, hemoglobin concentration and 59Fe absorption rate increase. In in vitro studies, incubation with epoetin alfa revealed increased incorporation of 3H-thymidine in erythroid nucleus-containing cells of the spleen (in mouse spleen cell culture). Studies on human bone marrow cell culture showed that epoetin alfa specifically stimulates erythropoiesis and has no effect on leukopoiesis. Cytotoxic effects of erythropoietin on human bone marrow cells were not detected.

Erythropoietin is a growth factor that mainly stimulates the formation of red blood cells. Receptors for erythropoietin can be present on the surface of various tumor cells.

The administration of epoetin alfa is accompanied by an increase in hemoglobin, hematocrit, serum iron, contributes to improved blood supply to tissues and heart function. The most significant effect of epoetin alfa has been noted in anemia caused by chronic renal insufficiency (CKF) and also developed in patients with a number of malignant tumors and systemic diseases.

Pharmacokinetics

Intravenous administration

T_1/2 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, T_1/2 epoetin alfa is about 6 hours .

Subcutaneous administration

The plasma concentration of epoetin alfa is determined significantly lower by subcutaneous administration than by intravenous administration, the T_max of epoetin alfa in plasma is about 12-18 hours after administration. C_max epoetin alfa when administered subcutaneously is only 1/20th of the concentration when administered intravenously. The drug has no ability to cumulate – the concentration of epoetin alfa in blood plasma 24 hours after the first injection is the same as 24 hours after the last injection. When administered subcutaneously, the T_1/2 of epoetin alfa is difficult to determine; it is about 24 hours. The bioavailability of epoetin alfa when administered subcutaneously is significantly lower than when administered intravenously and is about 20%.

Indications

Anemia

• anemia in adults and children due to chronic renal failure, including.:
• anemia due to chronic renal failure in children and adults on hemodialysis and in adults on peritoneal dialysis;
• Treatment of anemia and reduction of the need for blood transfusions in adults treated with chemotherapeutic agents for solid tumors, malignant lymphoma, or multiple myeloma, and in individuals at high risk of complications from hemotransfusions due to their overall severe condition (due to cardiovascular disease if anemia was also noted before chemotherapy);
• to improve the efficacy of autologous blood transfusion as part of a preoperative blood collection program before surgery in patients with hematocrit levels of 33-39%, to facilitate autologous blood collection and reduce the risks associated with allogeneic hemotransfusions if the expected need for transfused blood exceeds the amount that can be obtained by autologous collection without epoetin alfa. Treatment is indicated in patients with moderately severe 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 anticipated, and for extensive surgical interventions when large volumes of transfused blood may be required (5 or more volumes in men and 4 or more in women);
• for risk reduction during allogeneic blood transfusion in adults without iron deficiency, before elective orthopedic surgery, when there is a high risk of complications during hemotransfusion. Its usage is limited – only in patients with moderate anemia (for example, with hemoglobin concentration of 1013 g/dl) if they are not included into program of autologous blood collection before the surgery with expected blood loss from 900 to 1800 ml;
• anemia in HIV-infected patients treated with zidovudine with endogenous erythropoietin level less than 500 IU/ml.

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Active ingredient

Epoetin alfa

Composition

1 ml of solution for intravenous and subcutaneous administration contains:

the active ingredient:

epoetin alfa 84 µg;

auxiliary substances:

Sodium dihydrophosphate dihydrate,

Sodium hydrophosphate dihydrate,

Sodium chloride,

Glycine,

polysorbate 80,

hydrochloric acid,

sodium hydroxide,

water for injection

How to take, the dosage

Intravenously, subcutaneously.
Treatment with Binocrit should be carried out under supervision of a specialist with appropriate qualification and experience in treatment of patients who are indicated for therapy with drugs – stimulants of erythropoiesis.
Doses
Treatment of symptomatic anemia in adults and children with CPN: Binocrit in patients with CPN is administered intravenously. Due to the fact that clinical manifestations of anemia and residual effects may vary depending on the age, sex and general severity of the disease, individual assessment of each patient is carried out.
The target level of 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.

Hemoglobin concentrations above 12 g/dL (7.5 mmol/L) over a prolonged period are not recommended. If the hemoglobin concentration increases more than 2 g/dL (1.25 mmol/L) per month or exceeds 12 g/dL (7.5 mmol/L) for a long time, the dose of Binocrit should be reduced by 25%. If the hemoglobin concentration is more than 13 g/dl (8.1 mmol/l), it is necessary to stop the treatment until hemoglobin decreases to 12 g/dl (7.5 mmol/l) and then resume the therapy with Binocrit, reducing the initial dose by 25%.

Hemoglobin concentrations may be higher or lower than optimal (target) values due to interindividual variability.

The treatment should be prescribed in such a way that the lowest effective dose of Binocrit provides the necessary control of hemoglobin and clinical manifestations of the disease.

Physical iron concentration in plasma should be monitored before and during treatment; if necessary additional iron preparations are prescribed.

Adult patients receiving hemodialysis
Treatment is carried out in two stages.

The correction phase. Binocrit is administered intravenously at a dose of 50 IU/kg 3 times per week. If necessary, the dose is adjusted gradually over a period of 4 weeks.

Increasing or decreasing the dose no more than 25 IU/kg 3 times a week.

The maintenance therapy phase. Dose adjustment in order to maintain the necessary level of hemoglobin 10-12 g/dl (6.2-7.5 mmol/l).

The recommended weekly dose of Binocrit is from 75 to 300 IU/kg, administered intravenously 25-100 IU/kg 3 times a week.
In patients with severe anemia (hemoglobin Application in children receiving hemodialysis
Treatment is carried out in two stages.

The correction stage. Binocrit is administered intravenously at a dose of 50 IU/kg 3 times a week. If necessary, the dose is adjusted gradually over a period of 4 weeks. Increasing or decreasing the dose no more than 25 IU/kg 3 times a week.

The maintenance therapy stage. Dose adjustment in order to maintain the necessary level of hemoglobin 9.5-11 g/dl (5.9-6.8 mmol/l).
In most cases in children with body weight less than 30 kg, higher maintenance doses should be used than in children with higher body weight and adults.

Binocrit is administered subcutaneously.

The recommended dose of Binocrit is 600 IU/kg once a week during the 3 weeks preceding surgery (21, 14, and 7 days before surgery) and on the day of surgery. If the preoperative period is shorter than 3 weeks, Binocrit should be administered daily at a dose of 300 IU/kg for 10 consecutive days, before surgery, on the day of surgery, and for 4 days after surgery. If preoperative Hb concentration is 15 g/dL (9.38 mmol/L) or higher, the drug should be discontinued. It should be ensured that patients have no iron deficiency before starting treatment with Binocrit.

All patients treated with Binocrit should receive adequate divalent iron (200 mg/day orally) during the whole course of therapy.

Interaction

There are no data on interaction of epoetin alfa with other drugs. However, when concomitant use with cyclosporine interaction is possible because the drug binds with red blood cells.

If the treatment by the drug Binocrit is carried out concomitantly with cyclosporine it is necessary to monitor the concentration of cyclosporine according to the degree of hematocrit increase.

There are no data on interactions between epoetin alfa and granulocyte colony stimulating factor (G-CSF) or granulocyte monocyte colony stimulating factor (GM-CSF).

To avoid incompatibility or decreased activity, it is not recommended to mix with solutions and other medications.

Special Instructions

BP should be checked and closely monitored in all patients when Binocrit is prescribed. Caution should be exercised when using epoetin alfa in patients with hypertension if they are not receiving the necessary treatment, the prescribed treatment is inadequate, or the hypertension is poorly controlled. In this case, it may be necessary to initiate or intensify antihypertensive therapy that has already been used. If BP cannot be normalized, treatment with epoetin alfa should be discontinued. Binocrit is used with caution in the presence of epilepsy and chronic hepatic insufficiency.

CPH and cancer patients should have their hemoglobin levels monitored regularly until stable values are achieved and periodically thereafter.

Strict monitoring of hemoglobin levels is mandatory for all patients because of the increased potential risk of thromboembolic complications and the increasing number of fatal cases where patients have been treated at hemoglobin levels greater than the established norm for the indication.

Moderate dose-dependent increases in platelet counts within the normal range may be observed during treatment with Binocrit. This amount decreases again with continuation of therapy. During the first 8 weeks after the start of therapy, it is recommended to monitor platelet count regularly.

All of these additional anemia factors should also be considered when increasing the dose of Binocrit in patients with neoplasms.

In the perioperative period, all blood values should be monitored closely.

PKKA
After several months or years of treatment with subcutaneous erythropoietin injections, cases of antibody-mediated PKKA have been very rarely observed. If patients have a significant decrease in the efficacy of therapy due to a decrease in hemoglobin concentration (1-2 g/dL per month) with an increased need for hemotransfusions, the reticulocyte count should be checked and the typical causes of non-response to the drug (e.g., iron, folic acid or vitamin B12 deficiency, aluminum intoxication, infection or inflammation, hemorrhage or hemolysis) investigated.

If anemia-mediated reticulocyte counts (e.g., reticulocytic index) are low (If PKKA mediated through erythropoietin antibodies is suspected, therapy with Binocrit should be stopped immediately. Any other erythropoietin therapy should not be prescribed because of the risk of cross-reactivity. If indicated, patients may be given necessary therapy, such as hemotransfusions.

In the event of a paradoxical decrease in hemoglobin concentration and development of severe anemia due to low reticulocyte counts, treatment with epoetin should be stopped immediately and an erythropoietin antibody test performed. There is evidence of such manifestations in patients with hepatitis C treated with interferon and ribavirin simultaneously with epoetin. Epoetin is not indicated for treatment of hepatitis C-induced anemia.

Patients with CKD
There are limited data on immunogenicity with subcutaneous administration of Binocrit in patients at risk for antibody-mediated PKKA, such as those with renal anemia. As a consequence, patients with renal anemia should be given the drug intravenously.

In order to minimize the risks of increased hypertension for patients with CKD, 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 CKD, hemoglobin concentrations during maintenance treatment should not exceed the HGH recommended in the Administration and Dose section. The results of clinical studies have shown an increased risk of fatal outcomes and severe cardiovascular events when administering erythropoiesis-stimulating agents to increase hemoglobin concentration above 12 g/dL (7.5 mmol/L).

In clinical studies in controlled settings, no significant benefit has been found associated with the use of epoetins against the background of increasing hemoglobin concentration above the level necessary to control the symptoms of anemia and prevent hemotransfusions. Cases of shunt thrombosis have been reported in patients on hemodialysis, particularly when prone to hypotension or due to the formation of arteriovenous fistulas (e.g. stenosis, aneurysm, etc.). Early shunt correction and thrombosis prophylaxis, e.g. with acetylsalicylic acid, is recommended in these patients.

In isolated cases, hyperkalemia has been observed. Treatment of anemia may result in increased appetite and increased need for potassium and protein. The dialysis regimen should be periodically adjusted to maintain adequate urea, creatinine, and potassium levels. Serum electrolytes should be checked in patients with CKD. If elevated (or increasing) serum potassium levels are detected, the feasibility of withdrawing epoetin alfa treatment until potassium levels normalize should be evaluated.

At the time of treatment with epoetin alfa, an increase in heparin dose is often required during hemodialysis due to an increase in hematocrit number. If heparinization cannot be maximally effective, the dialysis regimen may need to be discontinued.
Treatment of anemia with epoetin alfa in adult patients with renal failure who are not yet on dialysis has not been reported to cause progression of renal failure.

Adult cancer patients with symptomatic anemia undergoing chemotherapy
In some clinical situations, blood transfusions should be used to treat anemia in patients with cancer. The decision to administer recombinant erythropoietins should be made taking into account the balance of benefits and possible risks for each patient individually and the specific clinical situation. Factors to consider are: type and stage of disease; degree of anemia; life expectancy; setting in which the patient will be treated; and wishes of the patient.

When evaluating the appropriateness of epoetin alfa therapy (risk of transfusion for the patient) in cancer patients receiving chemotherapy, a delay of 2-3 weeks after epoetin alfa administration before erythropoietin stimulation should be considered.

In order to minimize the risk of thrombotic events, it is necessary to ensure that hemoglobin levels and the rate of increase are not exceeded.

Because of the increasing incidence of venous thrombotic complications in cancer patients treated with erythropoietin-stimulating drugs, this risk and benefit of epoetin alfa treatment should be carefully evaluated, especially in cancer patients who are at increased risk of venous thrombotic complications, such as those with a history of obesity or a family history of venous thrombotic events (including deep venous thrombosis).

Adult patients participating in an autologous blood collection program prior to surgical procedures
All specific precautions related to autologous blood collection programs must be observed, especially for regular blood transfusions.

Patients undergoing elective orthopedic surgery

For patients undergoing elective orthopedic surgery, the cause of the anemia must be established and the anemia treated if possible before starting therapy with epoetin alfa. These patients may be at risk for thrombotic events, which must be carefully evaluated when prescribing treatment for this group of patients.

Patients undergoing elective orthopedic surgery should receive adequate antithrombotic prophylaxis due to the risk of venous thrombotic complications in surgical patients, particularly those with cardiovascular disease. In addition, special precautions should be taken in patients with a predisposition to develop deep vein thrombosis of the extremities. Patients with an initial hemoglobin level of >13 g/dL (>8.1 mmol/L) have an increased risk of postoperative thrombotic/venous complications. As a consequence, the drug should not be administered to patients with an initial hemoglobin level of >13 g/dl (>8.1 mmol/l).

Excipients

This medication contains less than 1 mmol of sodium (23 mg) in one pre-filled syringe, which means it actually contains no sodium.

Contraindications

• high sensitivity to the active ingredient and excipients in the drug;
• partial red cell aplasia (PKKA) following erythropoietin treatment;
• uncontrolled arterial hypertension;
• patients who, for whatever reason, cannot receive effective treatment to prevent thrombosis;
• myocardial infarction or stroke that occurred within 1 month prior to planned treatment; unstable angina pectoris;
• Patients at high risk of deep vein thrombosis and history of thromboembolic disease (for increasing the efficacy of autologous blood transfusions);
• Severe lesions of coronary, peripheral arteries, carotid arteries, and cerebral vessels, includingPatients with recent myocardial infarction or stroke (as part of the pre-prescription blood collection program prior to major surgery and not participating in the autologous blood transfusion program).

  With caution: malignant tumors, epilepsy syndrome (including history), chronic renal and hepatic insufficiency, thrombocytosis, thrombosis (history), acute blood loss, sickle cell anemia, hemolytic anemia, iron-, B₁₂– or folate-deficient states.

Side effects

The following side effects are categorized according to organ and system classification and frequency of occurrence: very common (≥1/10); common (≥1/100-

Blood and lymphatic system disorders: infrequent – thrombocythemia (in patients with malignancies); frequency unknown – antibody-mediated PKKA¹, thrombocythemia (in patients with CPN).

Immune system disorders: frequency unknown – anaphylactic reaction, hypersensitivity.

Nervous system disorders: very common – headache (in patients with malignancies); common – seizures (in patients with CKD), headache (in patients with CKD); infrequent – hemorrhagic stroke², seizures (in patients with malignancies); frequency unknown – stroke², hypertensive encephalopathy, transient ischemic attacks.

An organ of vision: frequency unknown – retinal thrombosis.

Particular system disorders: common – lower extremity deep vein thrombosis (in patients with malignant tumors); increased BP; common unknown – lower extremity deep vein thrombosis (in patients with CKD), arterial thrombosis, hypertensive crisis.

Respiratory system disorders: frequent – pulmonary embolism² (in patients with malignancies); frequency unknown – pulmonary embolism² (in patients with CKD).

Gastrointestinal disorders: very common – nausea; common – diarrhea (in patients with cancer), vomiting; infrequent – diarrhea (in patients with CKD).

Skin and its appendages: often – skin rash; frequency unknown – angioedema, urticaria.

Muscular system: very common – arthralgia (in CPN); common – arthralgia (in patients with malignancies); infrequent – myalgia (in patients with malignancies); common unknown – myalgia (in CPN).

Congenital, familial/genetic disorders: frequency unknown – porphyria.

Body in general: very common – hyperthermia (in patients with malignancies); flu-like condition (in COPD); common – flu-like condition (in patients with malignancies); frequency unknown – drug inefficacy, peripheral edema, hyperthermia (in COPD), injection site reactions.

Laboratory findings: frequency unknown – antibodies to erythropoietin¹.

Others: common – dialysis equipment shunt thrombosis (in patients with CKD).

¹ Frequency of manifestations cannot be estimated from clinical studies.
² Including fatal cases.

Overdose

The therapeutic range of the drug is wide.

In case of overdose, symptoms may occur that reflect the extreme pharmacological action of the hormone (increased hemoglobin or hematocrit concentration).

In extremely high hemoglobin or hematocrit levels, phlebotomy may be used.

Symptomatic therapy is indicated if necessary.

Pregnancy use

No properly controlled studies have been conducted on the use of epoetin alfa in women during pregnancy. Animal studies have shown reproductive toxicity.

As a consequence, patients with CKD 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 an autologous blood collection program prior to surgery.

Similarities

Eralfon syringes