Binocrit^® (Solution) Instructions for Use

ATC Code

B03XA01 (Erythropoietin)

Active Substance

Epoetin alfa (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Erythropoiesis stimulant

Pharmacotherapeutic Group

Hematopoiesis stimulant

Pharmacological Action

A glycoprotein that specifically stimulates erythropoiesis, activating the mitosis and maturation of erythrocytes from erythroid progenitor cells. Recombinant Epoetin alfa is synthesized in mammalian cells into which the gene encoding human erythropoietin has been inserted. In its composition, biological and immunological properties, Epoetin alfa is identical to natural human erythropoietin.

The administration of epoetin alfa leads to an increase in hemoglobin and hematocrit, improved tissue blood supply and heart function. The most pronounced effect of epoetin alfa is observed in anemias caused by chronic renal failure.

In very rare cases, with long-term use of erythropoietin for the treatment of anemic conditions, the formation of neutralizing antibodies to erythropoietin may be observed with or without the development of pure red cell aplasia.

Pharmacokinetics

With intravenous administration of epoetin alfa in healthy individuals and patients with uremia, the T_1/2 is 5-6 hours.

With subcutaneous administration of epoetin alfa, its concentration in the blood increases slowly, and C_max is reached between 12 and 18 hours after administration, with a T_1/2 of 16-24 hours.

The bioavailability of epoetin alfa with subcutaneous administration is 25-40%.

Indications

Anemia associated with chronic renal failure in adults on hemodialysis or peritoneal dialysis, as well as severe anemia of renal origin accompanied by clinical symptoms in adult patients with renal failure not yet on dialysis.

Anemia associated with chronic renal failure in children on hemodialysis or peritoneal dialysis.

Anemia in adult cancer patients with solid (non-myeloid) tumors, malignant lymphoma, or multiple myeloma receiving chemotherapy (for the treatment of anemia and reduction of transfusion requirements).

Anemia in adult HIV-infected patients receiving zidovudine therapy, with an endogenous erythropoietin concentration of less than 500 IU/ml.

As part of a predeposit program prior to major surgical intervention in adult patients with a hematocrit of 33-39%, to facilitate the collection of autologous blood and reduce the risk associated with the use of allogeneic hemotransfusions, if the expected need for blood transfusion exceeds the amount that can be obtained by the method of autologous collection without the use of epoetin alfa.

Before major surgery with expected average blood loss (2-4 units or 900-1800 ml) in adult patients with mild or moderate anemia (hemoglobin >10 and ≤13 g/dl) to reduce the need for allogeneic hemotransfusions and improve the recovery of erythropoiesis.

ICD codes

Dosage Regimen

Administer Binocrit subcutaneously or intravenously.

Establish the dosage regimen individually based on indication, clinical condition, and patient age.

For anemia in adult patients with chronic renal failure, initiate treatment at 50 International Units per kilogram of body weight three times per week intravenously for hemodialysis patients or subcutaneously for peritoneal dialysis and pre-dialysis patients.

Adjust the dose to achieve a target hemoglobin not exceeding 12 g/dL.

Increase the dose no more frequently than once every four weeks if the hemoglobin rise is less than 1 g/dL per month.

Reduce the dose by approximately 25% if the hemoglobin approaches 12 g/dL or rises more than 1 g/dL in any two-week period.

For anemia in pediatric patients with chronic renal failure on dialysis, initiate at 50 International Units per kilogram of body weight three times per week intravenously or subcutaneously.

For anemia in adult cancer patients on chemotherapy, initiate at 450 International Units per kilogram of body weight subcutaneously once per week or 150 International Units per kilogram three times per week.

Discontinue therapy after 8 weeks if no response is observed.

For anemia in HIV-infected patients receiving zidovudine, initiate at 100 International Units per kilogram subcutaneously or intravenously three times per week for 8 weeks.

For the predeposit autologous blood program in adults, administer 600 International Units per kilogram subcutaneously twice weekly for 3 weeks prior to surgery.

For reduction of allogeneic blood transfusion in anemic adults prior to major elective non-cardiac, non-vascular surgery, administer 300 International Units per kilogram subcutaneously daily for 10 days before surgery, on the day of surgery, and for 4 days after.

Monitor hemoglobin regularly and adjust dose to avoid excessive rise.

Ensure adequate iron stores before and during treatment; administer iron supplementation if necessary.

Do not shake the solution; inspect visually for particulate matter and discoloration before administration.

Discard any unused portion of the solution; do not pool or mix with other drugs.

Adverse Reactions

From the hematopoietic system: very rarely – erythropoietin antibody-mediated pure red cell aplasia, thrombocythemia.

From the immune system: uncommon – hypersensitivity reactions; rarely – anaphylactic reactions.

From metabolism: uncommon – hyperkalemia; frequency unknown – porphyria.

From the nervous system: common – headache, seizures; frequency not established – cerebrovascular complications (including stroke, comprising cerebral infarction and intracerebral hemorrhage), transient ischemic attack, hypertensive encephalopathy.

From the organ of vision: frequency unknown – retinal vessel thrombosis.

From the cardiovascular system: common – arterial hypertension (including hypertensive crisis), arterial and venous (including fatal cases) thromboses and embolisms: deep vein thrombosis, arterial thrombosis (including myocardial infarction), arteriovenous shunt thrombosis, aneurysm, pulmonary embolism.

From the respiratory system: common – cough; frequency unknown – respiratory congestion.

From the digestive system: very common – diarrhea, nausea, vomiting.

From the skin and subcutaneous tissues: common – skin rash; frequency unknown – urticaria, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the musculoskeletal system: common – arthralgia, myalgia, bone pain, limb pain.

Other: very common – increased body temperature; common – chills, flu-like syndrome, peripheral edema, local reactions.

Contraindications

Hypersensitivity to epoetin alfa; uncontrolled arterial hypertension; patients with severe pathology of the coronary, carotid, cerebral, and peripheral vessels, including those who have recently suffered a myocardial infarction or acute cerebrovascular accident (within the predeposit blood collection program before major surgery); patients with pure red cell aplasia who have received therapy with any erythropoietin; patients who, for any reason, are not receiving adequate prophylactic antithrombotic therapy; pregnancy, breastfeeding period.

With caution

Patients with epilepsy, epileptic syndrome (including in the anamnesis) or with diseases that can provoke epileptic activity (for example, CNS infections or brain metastases), thrombocytosis, thrombosis (in the anamnesis), obliterating diseases of peripheral vessels and other vascular complications, gout, with sickle cell anemia, with deficiency of iron, vitamin B₁₂ or folic acid; with coronary artery disease, pure red cell aplasia, malignant neoplasms of the bone marrow, in patients with porphyria.

Use in Pregnancy and Lactation

The use of epoetin alfa is contraindicated during pregnancy and breastfeeding.

In some female patients with chronic renal failure, menstruation resumed during treatment with epoetin alfa. The possibility of pregnancy and the need for contraceptive measures should be discussed with the patient before starting therapy.

Use in Hepatic Impairment

Epoetin alfa should also be used with caution in patients with chronic hepatic insufficiency. The safety of epoetin alfa in patients with impaired liver function has not been established. Due to reduced metabolism in patients with impaired liver function, enhanced erythropoiesis may occur when using epoetin alfa.

Use in Renal Impairment

In patients with chronic renal failure and clinically significant coronary artery disease or congestive heart failure, the maintenance hemoglobin level should not exceed the upper limit of the optimal recommended level (no more than 10-12 g/dl in adults).

Pediatric Use

It is possible to use in children according to indications, in recommended doses and regimens.

Special Precautions

Blood pressure must be adequately controlled before and after starting therapy with epoetin alfa. During therapy with epoetin alfa, the appointment of antihypertensive therapy may be necessary. If it is impossible to reduce blood pressure with antihypertensive agents, therapy with epoetin alfa must be discontinued.

A hypertensive crisis, accompanied by encephalopathy and seizures, requiring immediate medical intervention, can also occur during therapy with epoetin alfa in patients who previously had normal or low blood pressure. Particular attention should be paid to a suddenly occurring shooting migraine-like headache as a possible signal of an impending crisis.

Antibody-mediated true erythroid aplasia (TEA) has been observed in patients treated with epoetin. Cases of this disease have also been occasionally reported in patients with hepatitis C treated with interferon and ribavirin when treatment with erythropoiesis-stimulating agents was simultaneously administered, therefore they are not approved for the treatment of anemia associated with hepatitis C.

In patients with chronic renal failure who experience a sudden loss of efficacy, determined by a decrease in hemoglobin (10-20 g/l per month) with an increased need for transfusions, it is necessary to perform a reticulocyte count and examination for the presence of typical causes of lack of response (for example, iron, folic acid or vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, hemolysis and bone marrow fibrosis of any genesis). If the anemia-corrected reticulocyte count (i.e., reticulocyte “index”) is low (< 20000/µl or < 0.5%), and the platelet and leukocyte counts are normal, and if other causes of decreased effect are not identified, the concentration of antibodies to erythropoietin should be determined, and the possibility of a bone marrow examination to diagnose TEA should be considered.

If anti-erythropoietin antibody-mediated TEA is suspected, therapy with epoetin alfa should be discontinued immediately. Treatment with any other erythropoiesis-stimulating agents should not be initiated, as there is a risk of cross-reaction. If indicated, patients may receive appropriate therapy, such as blood transfusion.

Epoetin alfa must be used with caution in patients with epilepsy, a history of epileptic seizures, and diseases associated with epileptic seizures (for example, CNS infections and brain metastases).

Epoetin alfa should also be used with caution in patients with chronic hepatic insufficiency. The safety of epoetin alfa in patients with impaired liver function has not been established. Due to reduced metabolism in patients with impaired liver function, enhanced erythropoiesis may occur when using epoetin alfa.

The risk of thrombotic vascular complications and the benefit of treatment with epoetin alfa should be carefully weighed, especially in patients with risk factors.

All patients should be carefully monitored for hemoglobin levels due to the potentially increased risk of thromboembolic events and fatal outcomes observed in patients with elevated hemoglobin levels during therapy with epoetin alfa.

The safety and efficacy of therapy with epoetin alfa in patients with underlying hematological diseases, such as hemolytic anemia, sickle cell anemia, thalassemia, have not been studied.

During treatment with epoetin alfa, regular monitoring of platelet levels is required, especially during the first 8 weeks, as a dose-dependent relative increase in platelet count may develop, which normalizes subsequently without discontinuation of therapy; in rare cases, an absolute increase in platelet count is noted.

Before starting therapy with epoetin alfa, as well as when deciding to increase its dose, other causes of anemia should be assessed and treated (iron, folic acid or vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, hemolysis and bone marrow fibrosis of any genesis). In most cases, serum ferritin concentrations decrease simultaneously with the increase in hematocrit. To achieve an optimal response to Epoetin alfa, adequate iron stores should be ensured with the introduction, if necessary, of additional iron supplements, depending on the indications.

Erythropoiesis-stimulating agents are not necessarily equivalent. Therefore, it must be clarified that patients should be switched from one erythropoiesis-stimulating agent to another only with the approval of the attending physician.

Epoetin alfa has a minimal ability to induce antibody formation. Carcinogenicity studies have not been conducted.

Epoetin alfa, being a growth factor, may have a stimulating effect on some types of tumors, especially on malignant neoplasms of the bone marrow.

Patients with chronic renal failure on therapy with epoetin alfa should have their hemoglobin levels measured regularly until they reach stable values, with periodic monitoring thereafter.

To reduce the risk of arterial hypertension, the rate of increase in hemoglobin level should be approximately 10 g/l (maximum 20 g/l) per month. The dose should be reduced if the hemoglobin level reaches 120 g/l.

In patients with chronic renal failure, the maintained hemoglobin level should not exceed the upper limit. A hemoglobin level of 130 g/l and above may lead to an increased risk of cardiovascular complications, including death.

Patients with chronic renal failure and an insufficient hemoglobin response to therapy with erythropoiesis-stimulating agents may be at an even greater risk of cardiovascular complications and mortality than other patients.

Shunt thromboses have occurred in patients on hemodialysis, especially in patients with a tendency to hypotension or with complications of arteriovenous fistulas (for example, stenoses, aneurysms, etc.). In these patients, early shunt checking and thrombosis prevention by administration of, for example, acetylsalicylic acid are recommended.

In isolated cases, hyperkalemia has been observed, although its causal relationship with the use of the drug has not been established. In patients with chronic renal failure, serum electrolytes should be monitored. If the serum potassium level is elevated or increasing, then, in addition to appropriate treatment of hyperkalemia, the possibility of discontinuing the administration of epoetin alfa until the serum potassium level is corrected should be considered.

Due to the increase in hematocrit during therapy with epoetin alfa, patients on hemodialysis may require an increase in the heparin dose, otherwise occlusion of the dialysis system is possible.

Anemia in adult cancer patients with solid (non-myeloid) tumors, malignant lymphoma, or multiple myeloma receiving chemotherapy (for the treatment of anemia and reduction of transfusion requirements)

Erythropoiesis-stimulating agents are growth factors that primarily stimulate the formation of erythrocytes. Erythropoietin receptors may be expressed on the surface of many tumor cells. As with other growth factors, there are concerns that erythropoiesis-stimulating agents may stimulate tumor growth. Thus, the decision to administer recombinant erythropoietin should be made based on a risk-benefit assessment involving the specific patient and should take into account the specific clinical situation. Factors to consider in such an assessment include: type and stage of the tumor; severity of anemia; expected lifespan; conditions under which the patient is receiving treatment; patient preferences.

In clinical studies with the use of recombinant erythropoietin preparations in combination with other erythropoiesis-stimulating agents, the following was noted:

• Worsening of locoregional control in patients with advanced malignant neoplasms of the head and neck receiving radiation therapy, when these drugs were used to achieve a hemoglobin concentration of more than 140 g/l;
• Reduction in overall survival and increased mortality associated with disease progression at 4 months of use in patients with metastatic breast cancer receiving chemotherapy, when these drugs were used to achieve a hemoglobin concentration of 120 to 140 g/l;
• Increased mortality when using other erythropoiesis-stimulating agents (darbepoetin alfa) to achieve a hemoglobin concentration of 120 g/l in patients with active malignant neoplasms not receiving chemotherapy or radiation therapy. Erythropoiesis-stimulating agents are not indicated for use in this group of patients.

In cancer patients receiving chemotherapy, when assessing the suitability of therapy with epoetin alfa (especially in patients at risk of transfusion), a delay of 2-3 weeks between the administration of erythropoiesis-stimulating agents and the appearance of erythropoietin-stimulated erythrocytes should be taken into account.

If an HIV-infected patient does not respond or the response to therapy with epoetin alfa is insufficient, other possible causes of anemia, including iron deficiency, should be considered.

In patients associated with an autologous blood collection program and receiving additional treatment with epoetin alfa, all special warnings and special precautions should be taken into account, especially – mandatory volume replacement.

Before major surgery with expected blood loss, proper standards for monitoring blood parameters should always be observed in the pre- and postoperative period.

Patients scheduled for major elective orthopedic surgery should receive antithrombotic prophylaxis, as thrombotic and vascular complications can occur in surgical patients, especially in patients with underlying cardiovascular disease. In addition, special precautions should be observed in patients predisposed to the development of thrombotic complications. Moreover, in patients with a baseline hemoglobin level > 130 g/l, the possibility cannot be excluded that treatment with epoetin alfa may be associated with an increased risk of postoperative thrombotic vascular complications. Therefore, the use of epoetin alfa is not recommended in patients with a baseline hemoglobin level >130 g/l.

Effect on ability to drive vehicles and mechanisms

During the treatment period until the optimal maintenance dose is established, patients with uremia should avoid engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions due to the increased risk of increased blood pressure at the beginning of therapy.

Drug Interactions

The effect of epoetin alfa may be enhanced with the simultaneous administration of blood products.

Concomitant use of drugs that suppress erythropoiesis may lead to a decrease in the efficacy of epoetin alfa.

Epoetin alfa may influence the concentration of cyclosporine when used concomitantly; therefore, additional monitoring of the cyclosporine serum level is required with subsequent dose adjustment.

The stimulatory effect of epoetin alfa on erythropoiesis may be enhanced with the simultaneous intake of iron preparations in case of iron deficiency.

When used concomitantly with anticonvulsant therapy, the susceptibility to seizures may increase.

When used concomitantly with antihypertensive drugs, their effect may be weakened. There are data on the influence of ACE inhibitors on the effect of epoetin alfa preparations when used concomitantly.

Epoetin alfa must not be mixed with solutions of other medicinal products.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.