EPOBIOCRYNE

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EPOBIOCRIUM (Epobiocrinum)

Composition:

Active substance: Epoetin alfa;

1 ml of solution contains 1000 IU, or 2000 IU, or 4000 IU, or 10,000 IU of recombinant human erythropoietin;

Excipients: human albumin, sodium citrate, sodium chloride, citric acid monohydrate; water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antianaemic medicinal products. Erythropoietin.

ATC code B03XA01.

Pharmacological properties.

Pharmacodynamics.

Recombinant human erythropoietin is biologically and immunologically equivalent to natural human erythropoietin – a glycoprotein hormone that acts as a mitotic stimulator and regulates erythropoiesis, the process of red blood cell formation from hematopoietic stem cell precursors. In healthy individuals, erythropoietin is normally synthesized in the kidneys (90%) and Kupffer cells of the liver (10%). Its production level is determined by blood oxygen saturation. Erythropoietin stimulates proliferation and differentiation of erythroid cells into mature red blood cells. Its action occurs at early stages of erythropoiesis, affecting erythroid burst-forming units (BFU-E) and erythroid colony-forming units (CFU-E), followed by proerythroblasts, erythroblasts, and reticulocytes (the sensitivity of these cells to erythropoietin is proportional to their stage of maturation). Erythropoietin normalizes hemoglobin and hematocrit levels and alleviates symptoms associated with anemia.

The molecular mass of epoetin alfa is approximately 30,600 daltons. The protein component accounts for approximately 60% of the molecular mass and consists of 165 amino acids. Four carbohydrate chains are attached to the protein via three N-glycosidic bonds and one O-glycosidic bond.

Pharmacokinetics.

Intravenous administration. After intravenous administration, the elimination half-life in individuals with normal renal function is approximately 4 hours; in patients with impaired renal function, it is about 5 hours. The elimination half-life in children is approximately 6 hours.

Subcutaneous administration. Plasma concentrations following subcutaneous administration are significantly lower than those after intravenous administration. After subcutaneous injection, drug concentration in blood increases slowly and reaches peak levels 12–18 hours post-administration. The maximum plasma concentration after subcutaneous administration is lower than that after intravenous administration (approximately 1/20 of the intravenous value).

No cumulative effect has been observed; measured serum erythropoietin concentrations remain at similar levels regardless of whether the drug concentration is measured 24 hours after the first injection or 24 hours after the last injection.

There are no data on whether recombinant human erythropoietin can cross the placental barrier or be excreted in breast milk. However, the substance does not cross the blood-brain barrier.

The elimination half-life after subcutaneous administration is approximately 24 hours.

The bioavailability of the drug after subcutaneous administration is significantly lower than after intravenous administration and is approximately 20%.

Clinical characteristics.

Indications.

Treatment of symptomatic anemia associated with chronic renal failure:

• treatment of anemia associated with chronic renal failure in children and adults on hemodialysis and in adult patients on peritoneal dialysis;
• treatment of severe renal anemia accompanied by clinical symptoms in adult patients with renal insufficiency who have not yet undergone hemodialysis.

Treatment of anemia and reduction of the volume of required blood transfusions in adult patients receiving chemotherapy due to non-myeloid tumor, malignant lymphoma, or multiple myeloma, and in whom transfusion risk is increased, as assessed by general patient condition (including cardiovascular status, existing anemia prior to initiation of chemotherapy).

EpoBioKrīn may be used within a pre-deposit program prior to major surgical interventions in patients with moderate manifestations of anemia (hemoglobin level 10–13 g/dL (6.2–8.1 mmol/L), absence of iron deficiency) to facilitate autologous blood donation and reduce the risk associated with the use of allogeneic blood transfusions, when the expected need for transfused blood exceeds the amount that can be obtained by autologous blood collection without the use of epoetin alfa.

EpoBioKrīn is administered to adult patients with mild to moderate anemia (hemoglobin within 10–13 g/dL in the absence of iron deficiency) prior to extensive orthopedic surgeries with an expected moderate degree of blood loss (900–1800 mL of blood) to reduce the need for allogeneic blood transfusions and facilitate recovery of the erythropoiesis system.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Development of pure red cell aplasia as a result of treatment with epoetin alfa (see section "Special warnings and precautions for use").

Uncontrolled hypertension.

Contraindications related to autologous blood donation programs in patients receiving epoetin alfa.

Severe coronary, peripheral arterial, carotid, or cerebrovascular diseases, as well as recent myocardial infarction or stroke in patients undergoing elective orthopedic surgery who have not participated in an autologous blood donation program. Inability to apply adequate antithrombotic prophylaxis in surgical patients.

Interaction with other medicinal products and other types of interactions.

There are no data indicating that treatment with epoetin alfa affects the metabolism of other medicinal products.

Medicinal products that suppress erythropoiesis may reduce the response to treatment with epoetin alfa.

Since cyclosporine binds to erythrocytes, there is a potential for drug interaction. When EpoBioKrīn and cyclosporine are used concomitantly, cyclosporine blood levels should be monitored and the dose adjusted if necessary.

There is no evidence of interaction between epoetin alfa and G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor) regarding hematological differentiation or tumor cell proliferation in biopsy samples in vitro.

In patients with metastatic breast cancer, subcutaneous administration of epoetin alfa at a dose of 40,000 IU/mL concomitantly with trastuzumab at a dose of 6 mg/kg did not affect the pharmacokinetics of trastuzumab.

Special precautions for use.

Arterial pressure should be continuously monitored in all patients during treatment with EPOBIOCRIN. The medicinal product should be used with caution in patients with untreated hypertension or poorly controlled hypertension. Treatment with EPOBIOCRIN may necessitate initiation or intensification of antihypertensive therapy. If blood pressure cannot be controlled, administration of epoetin alfa should be discontinued.

Cases of hypertensive crisis with encephalopathy and seizures, requiring immediate medical evaluation and intensive treatment, have also been observed in patients with normal or low blood pressure at the beginning of treatment. Particular attention should be paid to the sudden onset of migraine-like shooting headache, which may be a warning sign (see section "Adverse reactions").

Epoetin alfa should be used with caution in patients with epilepsy, history of seizures, or medical conditions that are risk factors for seizures, such as CNS infections or brain metastases.

Epoetin alfa should be used with caution in patients with chronic hepatic insufficiency. The safety of epoetin alfa in this patient population has not been established.

Patients receiving erythropoiesis-stimulating agents are at increased risk of vascular disorders with thrombotic complications (see section "Adverse reactions"), including venous and arterial thrombosis and embolism (including fatal outcomes), such as deep vein thrombosis, pulmonary embolism, retinal vein thrombosis, and myocardial infarction. Cases of stroke (including ischemic stroke, hemorrhagic stroke, and transient ischemic attacks) have also been reported.

Before initiating epoetin alfa therapy, the risks of vascular disorders with thrombotic complications should be carefully weighed, especially in patients with existing risk factors, including obesity and history of vascular disease (e.g., deep vein thrombosis, pulmonary embolism, and stroke).

Hemoglobin levels should be closely monitored in all patients due to the potential increased risk of thromboembolic complications and mortality when the medicinal product is used at hemoglobin levels above the target range indicated for use.

During treatment, a moderate dose-dependent increase in platelet count within normal limits may occur. This parameter decreases during further treatment. Cases of thrombocytosis have also been reported. Regular monitoring of platelet count is recommended during the first 8 weeks of treatment.

All other causes of anemia (iron deficiency, folic acid deficiency, vitamin B12 deficiency, aluminum toxicity, infection or inflammation, blood loss, hemolysis, or bone marrow fibrosis of any origin) must be identified and treated before initiating epoetin alfa therapy and before deciding to increase the dose. In most cases, serum ferritin levels decreased simultaneously with an increase in hematocrit. To ensure optimal response to epoetin alfa therapy, adequate iron supply must be ensured (see section "Dosage and administration"):

• Patients with chronic renal insufficiency are recommended to take iron (200–300 mg/day for adults and 100–200 mg/day for children orally, calculated as elemental iron) if serum ferritin levels are below 100 ng/mL;
• Patients with oncological diseases are recommended to take iron (200–300 mg/day orally, calculated as elemental iron) if transferrin saturation is below 20%;
• Patients participating in autologous blood donation programs are recommended to take iron (200 mg/day orally, calculated as elemental iron) several weeks before the start of autologous blood collection to achieve significant iron stores before the start of therapy and throughout the course of epoetin alfa treatment;
• Patients undergoing major elective orthopedic surgery are recommended to take iron (200 mg/day orally, calculated as elemental iron) throughout the course of epoetan alfa treatment. Iron supplementation should be initiated, if possible, before starting epoetin alfa therapy to achieve significant iron stores.

Very rare cases of development or worsening of existing porphyria have been reported in patients receiving epoetin alfa. Epoetin alfa should be used with caution in patients with porphyria.

With long-term treatment with epoetin alfa, severe skin-related adverse reactions may occur, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be life-threatening or fatal (see section "Adverse reactions").

Patients should be informed about possible skin-related adverse reactions. If signs and symptoms of skin-related adverse reactions occur, epoetin alfa treatment should be immediately discontinued and alternative treatment options considered.

Information on the trade name of erythropoiesis-stimulating agents used in treatment must be clearly documented in the patient's medical record. Switching a patient from one erythropoiesis-stimulating agent to another is possible only under physician supervision.

Pure red cell aplasia (PRCA).

Cases of antibody-mediated pure red cell aplasia (PRCA) have been reported after several months or years of subcutaneous administration of epoetin, primarily in patients with chronic renal insufficiency. Cases of pure red cell aplasia have also been reported in patients with hepatitis C receiving interferon and ribavirin concomitantly with erythropoiesis-stimulating agents. Epoetin alfa is not indicated for the treatment of anemia associated with hepatitis C.

Patients experiencing sudden loss of therapeutic efficacy (manifested by a decrease in hemoglobin level of 1–2 g/dL per month) with increased need for transfusions should be referred for reticulocyte count testing and evaluation of typical causes of reduced clinical response (iron, folic acid, or vitamin B12 deficiency, aluminum toxicity, infection or inflammation, blood loss, hemolysis, or bone marrow fibrosis of any origin).

In case of paradoxical decrease in hemoglobin and development of severe anemia associated with low reticulocyte count, treatment with EPOBIOCRIN should be interrupted, testing for anti-erythropoietin antibodies should be performed, and bone marrow examination should be conducted to confirm the diagnosis of pure red cell aplasia.

Patients should not be treated with other erythropoiesis-stimulating agents due to the possibility of cross-reactivity.

Treatment of symptomatic anemia in adult and pediatric patients with chronic renal insufficiency.

In patients with chronic renal insufficiency receiving epoetin alfa, hemoglobin levels should be regularly monitored until a stable level is achieved, then periodically. The rate of hemoglobin increase 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 to minimize the risk of arterial hypertension.

In patients with chronic renal insufficiency, the achieved hemoglobin level should not exceed the upper limit of the desired hemoglobin concentration (see section "Dosage and administration"). In clinical studies, an increased risk of mortality and serious cardiovascular adverse reactions was observed when erythropoiesis-stimulating agents were used to achieve hemoglobin concentrations above 12 g/dL (7.5 mmol/L).

Controlled clinical trials did not demonstrate significant benefits of using epoetins at hemoglobin concentrations above the level required to control anemia symptoms and prevent blood transfusions.

Dose escalation of EPOBIOCRIN should be done cautiously in patients with chronic renal insufficiency, as high cumulative doses of erythropoietin may be associated with increased risk of mortality, serious cardiovascular, and cerebrovascular events. In patients with inadequate response to epoetin therapy, alternative approaches to manage inadequate response should be considered (see section "Dosage and administration").

Patients with chronic renal insufficiency receiving EPOBIOCRIN subcutaneously should be regularly monitored for loss of treatment efficacy, defined as a decrease or loss of response to epoetin alfa in patients who previously responded to therapy. Loss of efficacy is characterized by a persistent decrease in hemoglobin level despite increasing doses of epoetin alfa (see section "Adverse reactions").

With extended dosing interval regimens (administration of epoetin alfa less frequently than once weekly), hemoglobin levels may decrease in some patients, who may require dose increases. Hemoglobin levels should be monitored regularly.

In hemodialysis patients, shunt thrombosis has been observed, particularly in those prone to hypotension or with complications of arteriovenous fistulas (e.g., stenosis, aneurysms, etc.). These patients are recommended to undergo shunt evaluation and thrombosis prophylaxis, for example, with acetylsalicylic acid.

Hyperkalemia has been observed in isolated cases, although a causal relationship has not been established. In patients with chronic renal insufficiency, serum electrolyte levels should be monitored. In case of increased blood potassium levels, in addition to appropriate hyperkalemia treatment, temporary discontinuation of EPOBIOCRIN should be considered until hyperkalemia is fully corrected.

Due to increased hematocrit, patients on hemodialysis receiving EPOBIOCRIN often require increased heparin doses during dialysis. Inadequate heparinization may lead to dialysis system occlusion.

According to current information, the use of EPOBIOCRIN in pre-dialysis patients does not accelerate progression of renal insufficiency.

Treatment of patients with chemotherapy-induced anemia.

In oncology patients receiving epoetin alfa, hemoglobin levels should be regularly monitored until a stable level is achieved, then periodically.

Epoetins are growth factors that primarily stimulate erythrocyte production. Erythropoietin receptors have also been identified on the surface of various tumor cells. As with other growth factors, stimulation of certain tumor types by epoetins cannot be excluded.

An impact of erythropoiesis-stimulating agents on tumor progression or progression-free survival cannot be excluded. In controlled clinical trials, the use of EPOBIOCRIN and other erythropoiesis-stimulating agents was associated with reduced locoregional tumor control or overall survival:

• Reduced locoregional control in patients with progressive head and neck cancer receiving radiotherapy when used to increase hemoglobin levels above 14 g/dL (8.7 mmol/L);
• Reduced overall survival and increased number of deaths due to disease progression within 4 months in patients with metastatic breast cancer receiving chemotherapy when used to increase hemoglobin levels to 12–14 g/dL (7.5–8.7 mmol/L);
• Increased risk of death when used to increase hemoglobin levels to 12 g/dL (7.5 mmol/L) in patients with active malignant disease not receiving chemotherapy or radiotherapy. Erythropoiesis-stimulating agents are contraindicated in this patient group;
• 9% increased risk of disease progression or death in the group of patients receiving epoetin alfa and standard treatment, and a 15% increased risk, statistically not excluded, in patients with metastatic breast cancer receiving chemotherapy when used to increase hemoglobin levels to 10–12 g/dL (6.2–7.5 mmol/L).

In view of the above, in certain clinical situations, blood transfusion may be preferred for the treatment of anemia in cancer patients. The decision to use recombinant erythropoietins should be based on a benefit-risk assessment for the individual patient, considering the specific clinical context. Factors to consider in this assessment should include tumor type and stage, degree of anemia, expected life expectancy, treatment setting, and patient preference.

In oncology patients receiving chemotherapy, there is generally a 2–3 week delay in response (from initiation of erythropoietin to appearance of erythropoietin-induced blood cells). This should be taken into account when evaluating treatment efficacy (especially in patients requiring transfusions).

Patients undergoing surgery and participating in autologous blood donation programs.

All special precautions related to autologous blood donation programs, especially procedures for restoring circulating blood volume, should be followed.

Patients undergoing major elective orthopedic surgery.

Appropriate hemotransfusion practices should always be followed in the pre- and postoperative periods.

Patients undergoing major elective orthopedic surgery should receive appropriate antithrombotic prophylaxis, as thrombotic and vascular complications may occur after surgery in these patients, especially in the presence of concomitant cardiovascular diseases. Particular caution should be exercised in treating patients prone to deep vein thrombosis. Moreover, in patients with an initial hemoglobin level > 13 g/dL, the likelihood of postoperative thrombotic or vascular complications associated with epoetin alfa therapy is significantly higher. Therefore, the use of epoetin alfa in patients with an initial hemoglobin level > 13 g/dL is not recommended.

Elderly patients

The safety of epoetin alfa in this patient population has not been established.

Use during pregnancy or breastfeeding.

Pregnancy.

There are currently no results from controlled studies on the use of EPOBIOCRIN in pregnant women. Animal studies have shown reproductive toxicity. Therefore, EPOBIOCRIN should be used in pregnant women only if the potential benefit outweighs the possible risk to the fetus. The use of epoetin alfa in pregnant women participating in autologous blood donation programs is not recommended.

Breastfeeding.

It is unknown whether exogenous epoetin alfa is excreted in breast milk. Epoetin alfa should be used with caution in breastfeeding women. The decision to continue or discontinue breastfeeding or to continue or discontinue epoetin alfa therapy should be made considering the benefits of breastfeeding for the child and the benefits of epoetin alfa therapy for the woman.

The use of epoetin alfa in patients participating in autologous blood donation programs during breastfeeding is not recommended.

Fertility.

Studies on the effect of epoetin alfa on fertility in men or women have not been conducted.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect on reaction speed when driving or operating machinery have not been conducted.

Administration and Dosage

Epoetin alfa can be administered by subcutaneous and intravenous injection.

As with any parenteral medicinal product, Eprex should be inspected visually for particulate matter and discoloration before administration.

All other causes of anemia (iron deficiency, folic acid deficiency, vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, hemolysis, or bone marrow fibrosis of any etiology) must be identified and treated prior to initiating therapy with epoetin alfa and before deciding to increase the dosage. To achieve an optimal response to treatment with epoetin alfa, adequate iron supply should be ensured, and iron supplementation should be administered if necessary (see section "Special precautions for use").

Intravenous administration

Epoetin alfa is administered by injection over a period of 1 to 5 minutes, depending on the dose. For patients undergoing hemodialysis, the bolus injection may be given directly during the procedure via the venous port of the dialysis line. Alternatively, the medicinal product may be administered after completion of hemodialysis through the fistula catheter, followed by administration of 10 mL of isotonic sodium chloride solution to flush the system and ensure proper distribution of the medicinal product into the circulation.

Slow intravenous injection is primarily recommended for patients experiencing symptoms of flu-like illness.

Epoetin alfa must not be administered as intravenous infusions or mixed with other medicinal products.

Subcutaneous administration

The maximum volume for subcutaneous administration at a single site is 1 mL. If larger volumes are required, subcutaneous injections should be given at multiple sites.

The medicinal product should be administered subcutaneously in the extremities or the anterior abdominal wall.

If, in the physician’s judgment, the patient or caregiver can safely and effectively self-administer Eprex subcutaneously, they should be properly instructed in dosage and administration.

Treatment of symptomatic anemia in adult and pediatric patients with chronic renal failure

In patients with chronic renal failure, intravenous administration is preferred when feasible (e.g., patients on hemodialysis). In cases where intravenous administration is problematic (e.g., patients not yet on hemodialysis or those on peritoneal dialysis), epoetin alfa may be administered subcutaneously.

Symptoms of anemia and complications may vary depending on age, sex, and disease-related conditions; therefore, individual clinical assessment by the physician is essential.

Eprex should be used to increase hemoglobin levels to no more than 12 g/dL (7.5 mmol/L). Increases in hemoglobin levels exceeding 2 g/dL (1.25 mmol/L) within a 4-week period should be avoided. If this occurs, the dose should be reduced as described below.

Due to individual variability, periodic hemoglobin levels in individual patients may be higher or lower than the desired target.

Hemoglobin levels should be controlled by dose adjustment, aiming to maintain levels between 10 g/dL (6.2 mmol/L) and 12 g/dL (7.5 mmol/L). In pediatric patients, the recommended optimal hemoglobin level is 9.5–11 g/dL (5.9–6.8 mmol/L).

Sustained hemoglobin levels above 12 g/dL (7.5 mmol/L) should be avoided. If hemoglobin concentration increases by at least 2 g/dL (1.25 mmol/L) per month or sustained hemoglobin levels exceed 12 g/dL (7.5 mmol/L), the epoetin dose should be reduced by 25%. If hemoglobin levels exceed 13 g/dL (8.1 mmol/L), treatment should be discontinued until hemoglobin decreases to 12 g/dL (7.5 mmol/L), after which therapy with epoetin alfa should be resumed at a dose 25% lower than the previous dose.

Patients should be closely monitored to ensure that the lowest approved dose of erythropoiesis-stimulating agents provides adequate control of anemia symptoms.

Serum ferritin (or serum iron concentration) should be measured in all patients before initiating and during treatment with Eprex. Iron supplementation should be administered if necessary. Other types of anemia (such as vitamin B12 or folic acid deficiency) must be excluded before starting Eprex therapy. Lack of clinical response to Eprex treatment requires investigation for contributing factors such as iron, folic acid, or vitamin B12 deficiency, aluminum intoxication, intercurrent infections, inflammatory conditions, trauma, hemolysis, or bone marrow fibrosis of any etiology.

Adult patients on hemodialysis

For patients on hemodialysis, the medicinal product is administered intravenously.

Treatment is divided into two phases.

Correction phase

50 IU/kg three times weekly.

If necessary, the dose may be increased stepwise (no more frequently than once every 4 weeks) by 25 IU/kg three times weekly until the optimal hemoglobin concentration (10–12 g/dL, or 6.2–7.5 mmol/L) is achieved.

Maintenance phase

Dose adjustment to maintain the desired hemoglobin level (Hb) of 10–12 g/dL (6.2–7.5 mmol/L).

The recommended weekly dose ranges from 75 to 300 IU/kg.

Patients with very low initial hemoglobin levels (<6 g/dL, or <3.75 mmol/L) may require higher maintenance doses than patients with less severe anemia (hemoglobin >8 g/dL, or >5 mmol/L).

Pediatric patients on hemodialysis

For pediatric patients on hemodialysis, the medicinal product is administered intravenously.

Treatment is divided into two phases.

Correction phase

50 IU/kg three times weekly.

If necessary, the dose may be increased stepwise (no more frequently than once every 4 weeks) by 25 IU/kg three times weekly until the optimal hemoglobin concentration of 9.5–11 g/dL (5.9–6.8 mmol/L) is achieved.

Maintenance phase

Dose adjustment to maintain the desired hemoglobin level (Hb) of 9.5–11 g/dL (5.9–6.8 mmol/L).

Children with body weight below 30 kg require higher maintenance doses than adults and children with body weight above 30 kg.

Maintenance doses of epoetin alfa:

Patients with a very low initial haemoglobin level (< 6.8 g/dL, or < 4.25 mmol/L) may require higher doses to maintain concentration compared to patients with less severe anaemia (haemoglobin > 6.8 g/dL, or > 4.25 mmol/L).

Adult patients with renal insufficiency in the pre-dialysis period.

For patients with renal insufficiency who are in the pre-dialysis period and without access to intravenous administration, the medicinal product may be administered subcutaneously.

Treatment is divided into two phases.

Correction phase.

50 IU/kg three times weekly.

If necessary, dose adjustment can be performed by increasing by 25 IU/kg three times weekly, with intervals between increments of at least 4 weeks until haemoglobin levels reach the target range of 10–12 g/dL (6.2–7.5 mmol/L).

Maintenance phase.

During the maintenance phase, Epobiochrin can be administered either three times weekly or, in the case of subcutaneous administration, once weekly or once every two weeks. Doses and intervals between administrations should be adjusted to maintain the desired haemoglobin level (Hb) of 10–12 g/dL (6.2–7.5 mmol/L). Prolonging the intervals between administrations may require dose increases. The maximum dose should not exceed 150 IU/kg three times weekly, 240 IU/kg (maximum up to 20,000 IU) once weekly, or 480 IU/kg (maximum up to 40,000 IU) once every two weeks.

Adult patients undergoing peritoneal dialysis.

For patients undergoing peritoneal dialysis, in the absence of access to intravenous administration, the medicinal product may be administered subcutaneously.

Treatment is divided into two phases.

Correction phase.

50 IU/kg twice weekly.

Maintenance phase.

Typically, the dose required to maintain the desired haemoglobin level (Hb) of 10–12 g/dL (6.2–7.5 mmol/L) ranges from 25 to 50 IU/kg twice weekly, administered as two equal injections.

Treatment of patients with anaemia caused by chemotherapy.

Patients with anaemia (e.g., haemoglobin concentration ≤ 10 g/dL (6.2 mmol/L)) should receive Epobiochrin subcutaneously. Symptoms and complications of anaemia depend on the patient's age, sex, and disease-related conditions; therefore, individual clinical assessment by a physician is necessary.

Due to individual variability, periodic haemoglobin levels in each patient may be higher or lower than the desired level. Haemoglobin levels should be monitored and dosage adjusted accordingly, aiming to maintain levels between 10 g/dL (6.2 mmol/L) and 12 g/dL (7.5 mmol/L). Sustained haemoglobin levels above 12 g/dL (7.5 mmol/L) should be avoided. Dose adjustment recommendations for haemoglobin levels exceeding 12 g/dL (7.5 mmol/L) are described below.

Epoetin alfa therapy should be continued for one month after discontinuation of chemotherapy.

The initial dose for treating anaemia in this patient group is 150 IU/kg three times weekly. As an alternative, epoetin alfa may be administered at an initial dose of 450 IU/kg subcutaneously once weekly.

If after 4 weeks of initial dose therapy haemoglobin increases by at least 1 g/dL (0.6 mmol/L) (or reticulocyte count increases to ≥ 40,000 cells/mL), the dose should remain at 150 IU/kg three times weekly or 450 IU/kg subcutaneously once weekly. If after 4 weeks of initial dose therapy haemoglobin increases by less than 1 g/dL (0.62 mmol/L) or reticulocyte count increases to < 40,000 cells/mL, the dose should be increased to 300 IU/kg three times weekly or 40,000 IU once weekly.

If after 4 weeks of treatment with the increased dose of 300 IU/kg three times weekly, haemoglobin increases by ≥ 1 g/dL (≥ 0.62 mmol/L) or reticulocyte count increases to ≥ 40,000 cells/mL, the dose should remain unchanged. However, if haemoglobin increases by < 1 g/dL (< 0.62 mmol/L) or reticulocyte count increases by < 40,000 cells/mL, the clinical response is considered negative and treatment should be discontinued.

Recommended dosing regimen:

Patients should be closely monitored to ensure that the lowest approved dose of erythropoiesis-stimulating agents provides adequate control of anaemia symptoms.

Dose adjustment to maintain target haemoglobin level of 10–12 g/dL.

If the rate of haemoglobin increase exceeds 2 g/dL (1.25 mmol/L) per month and the total haemoglobin level approaches 12 g/dL (7.5 mmol/L), the dose of Epobiochrin should be reduced by 25–50%, depending on the rate of haemoglobin rise. If haemoglobin exceeds 13 g/dL (8.1 mmol/L), therapy should be temporarily discontinued until levels decrease to 12 g/dL (7.5 mmol/L), after which therapy should be resumed at a dose 25% lower than the previous dose.

Adult patients participating in an autologous blood donation program prior to surgery.

Intravenous administration is recommended.

Epoetin alfa should be administered after each blood donation procedure.

For patients with moderate anaemia (haematocrit level 33–39%) who require ≥ 4 units of blood, treatment with epoetin alfa at a dose of 600 IU/kg twice weekly should be initiated for 3 weeks prior to surgery.

All patients receiving epoetin alfa should receive adequate iron supplementation (200 mg daily orally) throughout the entire treatment course. Iron supplementation should be initiated as early as possible, even several weeks before starting the autologous blood donation program.

Adult patients undergoing elective orthopaedic surgery.

Subcutaneous administration is recommended.

The recommended dosing regimen is 600 IU/kg weekly for 3 weeks prior to surgery (on days 21, 14, and 7 before surgery), and on the day of surgery.

If medical necessity requires shortening the preoperative period to less than 3 weeks, Epobiochrin should be administered daily at 300 IU/kg for 10 consecutive days before surgery, on the day of surgery, and for 4 days after surgery. If preoperative haematological testing shows haemoglobin levels reaching 15 g/dL or higher, epoetin alfa administration must be completely discontinued.

All patients receiving epoetin alfa should receive adequate iron supplementation (200 mg daily orally) throughout the entire treatment course. Iron supplementation should be initiated as early as possible, even several weeks before starting the autologous blood donation program.

Children.

Epoetin alfa is indicated for the treatment of anaemia associated with chronic renal insufficiency in children aged 1 month to 18 years who are on dialysis. The safety and efficacy of the medicinal product in children under 1 month of age have not been established.

Overdose.

The medicinal product has a wide therapeutic window. Overdose of epoetin alfa results in effects reflecting the maximum expression of the hormone's pharmacological action. In cases of excessively high haemoglobin levels, phlebotomy may be performed. Symptomatic treatment should be applied if necessary.

Adverse Reactions

The most common adverse reaction during treatment with epoetin alfa in oncology patients and patients with chronic renal failure is dose-dependent elevation of arterial blood pressure or worsening of pre-existing hypertension. Blood pressure should be monitored from the start of therapy. Other common adverse reactions include deep vein thrombosis, pulmonary embolism, seizures, diarrhea, nausea, headache, flu-like symptoms, pyrexia, rash, and vomiting.

At the beginning of treatment, cold-like symptoms such as headache, muscle and joint pain, and chills may occur. The frequency may vary depending on the indication.

Impaired airway patency may also occur, including nasal congestion and nasopharyngitis.

Serious adverse reactions include venous and arterial thrombosis, embolism (including fatal cases), deep vein thrombosis, pulmonary embolism, arterial thrombosis (including myocardial infarction and myocardial ischemia), retinal thrombosis, and shunt thrombosis (including dialysis system occlusion). Cerebrovascular complications (including stroke and cerebral hemorrhage), transient ischemic attacks, aneurysms, and hypersensitivity reactions, including rash, urticaria, anaphylactic reactions, and angioneurotic edema, may also occur.

Additionally, during treatment with epoetin alfa, hypertensive crisis with encephalopathy and seizures may occur in patients with previously normal or low blood pressure, requiring immediate medical attention and intensive treatment. Particular attention should be paid to sudden, acute migraine-like headache as a possible warning sign.

Very rarely, antibody-mediated pure red cell aplasia may occur after several months or years of treatment.

Frequency of adverse reactions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); frequency not known.

Blood and lymphatic system disorders

Uncommon – thrombocytosis (in cancer patients).

Frequency not known – thrombocytosis (in patients with chronic renal failure).

Very rare – antibody-dependent pure red cell aplasia.

Immune system disorders

Frequency not known – anaphylactic reactions, hypersensitivity reactions.

Anaphylactic reactions occur rarely: potentially serious complications associated with respiratory distress or hypotension; immune reactions (minimal ability to induce antibody formation).

Nervous system disorders

Very common – headache (in cancer patients).

Common – seizures (in patients with chronic renal failure), headache (in patients with chronic renal failure), stroke.

Uncommon – intracranial hemorrhage, seizures (in cancer patients).

Frequency not known – cerebrovascular stroke, hypertensive encephalopathy, transient ischemic attack, dizziness, somnolence.

Eye disorders

Frequency not known – retinal thrombosis.

Cardiac disorders

Frequency not known – myocardial infarction.

Vascular disorders

Common – deep vein thrombosis (in cancer patients), arterial hypertension.

Frequency not known – deep vein thrombosis (in patients with chronic renal failure), arterial thrombosis, hypertensive crisis.

Respiratory system disorders

Common – pulmonary embolism (in cancer patients), cough.

Uncommon – impaired airway patency.

Frequency not known – pulmonary embolism (in patients with chronic renal failure).

Gastrointestinal disorders

Very common – nausea.

Common – diarrhea (in cancer patients), vomiting.

Uncommon – diarrhea (in patients with chronic renal failure).

Skin and subcutaneous tissue disorders

Common – rash, eczema.

Frequency not known – angioneurotic edema, urticaria, pruritus, Quincke's edema, Stevens-Johnson syndrome, toxic epidermal necrolysis (which may be life-threatening or fatal).

Musculoskeletal, connective tissue and bone disorders

Very common – arthralgia (in patients with chronic renal failure), bone pain, limb pain.

Common – arthralgia (in cancer patients).

Uncommon – myalgia (in cancer patients).

Frequency not known – myalgia (in patients with chronic renal failure).

Congenital, familial and genetic disorders

Frequency not known – porphyria.

General disorders and administration site conditions

Very common – pyrexia (in cancer patients), flu-like symptoms (in patients with chronic renal failure), injection site reactions, peripheral edema.

Common – flu-like symptoms (in cancer patients).

Frequency not known – chills, lack of response to treatment.

Investigations

Frequency not known – presence of antibodies to erythropoietin, hyperkalemia, hyperphosphatemia, increased plasma concentrations of urea, creatinine, and uric acid (in patients with chronic renal failure).

Injury, poisoning and procedural complications

Common – shunt thrombosis, including dialysis equipment (in patients with chronic renal failure).

Patients with chronic renal failure

Hemoglobin levels above 12 g/dL in patients with chronic renal failure may be associated with an increased risk of cardiovascular complications, including fatal outcomes.

In patients undergoing hemodialysis, particularly those with a tendency toward hypotension or complications related to arteriovenous fistula (stenosis, aneurysms, etc.), cases of shunt thrombosis have been reported.

Patients with oncological diseases

Thrombotic complications may occur in patients receiving erythropoiesis-stimulating agents, including epoetin alfa (see section "Special Instructions").

Adult surgical patients

It cannot be excluded that treatment with epoetin alfa in patients with stable hemoglobin levels >13 g/dL may be associated with an increased risk of postoperative thrombotic/vascular complications.

Description of selected adverse reactions

Hypersensitivity reactions have been reported, including cases of rash (including urticaria), anaphylactic reactions, and angioneurotic edema (see section "Special Instructions").

Cases of hypertensive crisis with encephalopathy and seizures requiring immediate medical evaluation and intensive therapy have been observed in patients with normal or low blood pressure at the start of treatment. Particular attention should be paid to the sudden onset of severe, shooting, migraine-like headache, which may be a warning sign (see section "Special Instructions").

Very rarely (<1/10,000 patient-years), cases of antibody-mediated pure red cell aplasia (PRCA) have been reported in patients receiving erythropoietin therapy for several months or years (see section "Special Instructions").

Children with chronic renal failure on hemodialysis

Clinical trial and post-marketing experience with erythropoietin use in children with chronic renal failure on hemodialysis is limited. No adverse reactions specific to pediatric patients not listed in the table have been identified; no adverse reactions inconsistent with the underlying disease have been reported.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals and patients or their legal representatives may report all suspected adverse reactions or lack of efficacy of medicinal products manufactured by LLC "FC "Biopharma" in any convenient way (by mail, email, or phone), in paper or electronic form. Reports of adverse reactions or lack of efficacy of medicinal products manufactured by LLC "FC "Biopharma" should be sent to the Pharmacovigilance Department at the following address: 12 Mykola Amosov Street, Kyiv, 03680, Tel. +38 044 459 4600, email: [email protected]. In case of adverse effects or safety concerns regarding the use of medicinal products manufactured by LLC "FC "Biopharma", please contact the Pharmacovigilance Department.

Additionally, reports of adverse reactions can be submitted via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store in the original packaging protected from light at a temperature of 2 to 8 °C. Do not freeze. Do not shake.

Keep out of reach of children.

Incompatibilities. Due to lack of compatibility studies, EpoBiocrin must not be mixed with other medicinal products.

Packaging. 1000 IU, 2000 IU, 4000 IU, 10,000 IU in pre-filled syringes or vials. Packs of 5 pre-filled syringes or 5 vials in a blister. One blister pack per carton.

Prescription status. Prescription only.

Manufacturer.

LLC "FC "STADA", Ukraine.

Manufacturer's address and location of business operations.

37 Kyivska Street, Bila Tserkva, Kyiv Oblast, 09100, Ukraine.