Hemax

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEMAX (HEMAX)

Composition:

Active substance: erythropoietin (epoetin alfa);

One vial contains erythropoietin (epoetin alfa) 1,000 IU, 2,000 IU, 3,000 IU, 4,000 IU, 10,000 IU, 20,000 IU, or 40,000 IU;

Excipients: mannitol (E 421), sodium chloride, sodium dihydrogen phosphate dihydrate, sodium phosphate dodecahydrate, human albumin.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: white, homogeneous, dense powder.

Pharmacotherapeutic group. Agents affecting the blood and hematopoietic system. Antianemic agents. Other antianemic agents. Erythropoietin.

ATC code B03XA01.

Pharmacological properties.

Pharmacodynamics.

Hemax is a medicinal product whose active pharmaceutical ingredient is epoetin alfa (recombinant human erythropoietin, r-HuEPO). Epoetin is a glycoprotein containing 165 amino acids, produced using recombinant technology. It is produced by genetically modified mammalian cells containing the erythropoietin gene. The product is highly purified and contains an amino acid sequence identical to that of natural human erythropoietin.

Erythropoietin induces erythropoiesis by stimulating the division and differentiation of erythroid precursor cells, resulting in an increased number of red blood cells and hematocrit. Erythropoietin also stimulates the release of reticulocytes from the bone marrow into the bloodstream, where they mature into erythrocytes. Normally, serum erythropoietin concentration ranges from 10 to 30 IU/mL and is regulated by tissue oxygenation levels. When tissue oxygen levels decrease, erythropoietin concentration increases 100–1000-fold. The same phenomenon is observed in anemias.

Pharmacokinetics.

Hemax (active substance – epoetin alfa) is administered parenterally (subcutaneously or intravenously). Reticulocyte count increases within 7–10 days after administration of the drug. Red blood cell count, hematocrit, and hemoglobin levels typically rise within 2–6 weeks after administration of epoetin alfa. The magnitude and speed of response depend on the dose of the drug and the availability of serum iron stores. Maximum plasma concentration is achieved within 15 minutes after a single intravenous dose and within 5–24 hours after a single subcutaneous injection. The peak serum erythropoietin level may persist from 12 to 16 hours after subcutaneous administration, and erythropoietin remains detectable in serum 24 hours after administration.

The elimination half-life of epoetin alfa ranges from 4 to 13 hours following intravenous or subcutaneous administration. The half-life after the first dose is longer than that observed after two or more weeks of treatment initiation. Typically, erythropoietin levels return to baseline within 24 hours. After subcutaneous administration, maximum plasma concentration occurs within 5–24 hours, and subsequent decline in concentration proceeds more slowly.

Studies in healthy adult volunteers have shown that the half-life after intravenous administration is 20% shorter than in patients with renal insufficiency. The half-life of Hemax after subcutaneous administration in healthy adult volunteers is 20.8 ± 6.3 hours. After discontinuation of Hemax therapy, hematocrit begins to decrease within 2 weeks.

Clinical characteristics.

Indications.

• Treatment of symptomatic anemia associated with chronic renal failure:
  • in adults and children on hemodialysis and in adult patients on peritoneal dialysis;
  • in adult patients with renal insufficiency who have not yet undergone hemodialysis, for treatment of severe anemia of renal origin accompanied by clinical symptoms.
• Treatment of anemia and reduction of the need for blood transfusions in adult patients receiving chemotherapy due to solid tumors, malignant lymphoma, or multiple myeloma, and who are at increased risk of transfusion as assessed by overall patient condition (including cardiovascular status, pre-existing anemia prior to initiation of chemotherapy).
• Hemax is indicated within a pre-deposit program to facilitate collection of autologous blood in patients with moderate anemia (hemoglobin level 10–13 g/dL (6.2–8.1 mmol/L), absence of iron deficiency). Treatment should be initiated only when blood-sparing procedures are impossible or insufficient (in cases where major planned surgery is expected to result in significant blood loss – 4 or more units of blood for women and 5 or more units for men).
• Hemax is indicated in adult patients without iron deficiency prior to major planned orthopedic surgery with a high risk of transfusion-related complications, to reduce the use of allogeneic blood transfusions. The use of the drug should be limited to adult patients with moderate anemia (hemoglobin level within 10–13 g/dL) who do not participate in an autologous blood collection program and who have an expected moderate blood loss (900–1800 mL).
• Hemax is indicated for treatment of symptomatic anemia (hemoglobin level ≤ 10 g/dL) in adult patients with low- or intermediate-1-risk primary myelodysplastic syndrome (MDS) and low serum erythropoietin levels (<200 mU/mL).

Contraindications.

• Uncontrolled arterial hypertension;
• development of pure red cell aplasia (PRCA) following treatment with any erythropoietin (see section "Special precautions");
• hypersensitivity to human albumin;
• hypersensitivity to drugs derived from mammalian cell lines;
• hypersensitivity to the active substance or any of the excipients of the drug;
• severe coronary, peripheral arterial, carotid, or cerebrovascular diseases, as well as recent myocardial infarction or stroke in patients undergoing major planned orthopedic surgery who have not participated in an autologous blood collection program;
• inability to administer adequate antithrombotic prophylaxis in surgical patients;
• contraindications related to autologous blood collection programs in patients receiving epoetin alfa.

Interaction with other medicinal products and other forms of interaction.

No interactions between Hemax and other medicinal products have been observed.

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

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

Since cyclosporine binds to erythrocytes, a potential drug interaction is possible. When Hemax is used concomitantly with cyclosporine, blood levels of cyclosporine should be monitored and the dose adjusted if hematocrit levels increase.

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 in vitro biopsy samples.

In adult women 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 Hemax. The drug should be used with caution in patients with untreated hypertension, inadequately treated hypertension, or poorly controlled hypertension. Treatment with Hemax 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 therapy 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 severe, migraine-like, shooting headache.

Epoetin alfa should be used with caution in patients with epilepsy, history of seizures, or medical conditions that are risk factors for seizure development, such as central nervous system (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, 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 thrombovascular events with thrombotic complications should be carefully weighed against the expected benefits, especially in patients with existing risk factors, including obesity and history of thrombovascular events (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 fatal outcomes when the drug is used at hemoglobin levels above the target range indicated for use.

During treatment, a mild, dose-dependent increase in platelet count within the normal range may occur. This parameter decreases during further treatment. Cases of thrombocytosis have also been reported. Platelet counts should be monitored regularly during the first 8 weeks of treatment.

Serum ferritin levels (or serum iron concentration) should be determined in all patients before and during treatment with Hemax. Iron supplementation should be administered as needed. Lack of clinical response to Hemax treatment requires investigation for potential contributing factors, such as iron, folic acid, or vitamin B12 deficiency, aluminum intoxication, intercurrent infections, inflammatory processes, trauma, hemolysis, or bone marrow fibrosis of any etiology.

All other causes of anemia (iron, folic acid, or vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, hemolysis, or bone marrow fibrosis of any origin) must be identified and treated before initiating epoetin alfa therapy or deciding to increase the dose. In most cases, serum ferritin levels decreased simultaneously with an increase in hematocrit.

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

To ensure optimal response to epoetin alfa treatment, adequate iron supply must be maintained:

• For patients with chronic kidney disease, iron supplementation (200–300 mg/day orally for adults and 100–200 mg/day for children, calculated as elemental iron) is recommended if serum ferritin is below 100 ng/mL;
• For patients with oncological diseases, iron supplementation (200–300 mg/day orally, calculated as elemental iron) is recommended if transferrin saturation is below 20%;
• For patients participating in an autologous blood donation program, iron supplementation (200 mg/day orally, calculated as elemental iron) is recommended several weeks before starting blood collection to achieve sufficient iron stores before therapy initiation and during epoetin alfa treatment;
• For patients scheduled for extensive elective orthopedic surgery, iron supplementation (200 mg/day orally, calculated as elemental iron) is recommended throughout epoetin alfa treatment. Iron supplementation should be initiated before starting epoetin alfa therapy whenever possible to achieve sufficient iron stores.

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

Severe treatment-related skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be life-threatening or fatal, have been reported with epoetin therapy. More severe cases have occurred with prolonged-release epoetins.

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

If a patient develops a severe skin reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis during epoetin treatment, re-administration of this drug is contraindicated.

The trade name of the erythropoiesis-stimulating agent used in treatment should be clearly documented in the patient's medical record. Switching 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 epoetin administration, primarily in patients with chronic kidney disease. Cases of pure red cell aplasia have also been reported in patients with hepatitis C receiving interferon and ribavirin concurrently with erythropoiesis-stimulating agents. Epoetin alfa is not indicated for the treatment of anemia associated with hepatitis C.

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

In case of paradoxical hemoglobin decrease and development of severe anemia associated with low reticulocyte count, Hemax treatment should be immediately discontinued, and testing for anti-erythropoietin antibodies and bone marrow examination should be performed to confirm the diagnosis of pure red cell aplasia (PRCA).

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 kidney disease.

In patients with chronic kidney disease receiving epoetin alfa, hemoglobin levels should be monitored regularly until stable levels are 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 kidney disease, the achieved hemoglobin level should not exceed the upper limit of the desired hemoglobin concentration. Clinical studies have shown an increased risk of mortality and serious cardiovascular adverse events when erythropoiesis-stimulating agents are used to achieve hemoglobin concentrations above 12 g/dL (7.5 mmol/L).

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

The dose of Hemax should be increased cautiously in patients with chronic kidney disease, as high cumulative doses of erythropoietin may be associated with increased risks of mortality and serious cardiovascular and cerebrovascular events. In patients with inadequate response to epoetin therapy, alternative approaches to manage poor response should be considered.

Patients with chronic kidney disease receiving subcutaneous Hemax 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 epoetin alfa dose.

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

Thrombosis of vascular access has been observed in hemodialysis patients, especially in those prone to hypotension or with arteriovenous fistula complications (e.g., stenosis, aneurysms, etc.). Such patients are recommended to undergo vascular access evaluation and thrombosis prophylaxis, for example, with acetylsalicylic acid.

Hyperkalemia has been observed in isolated cases, although a causal relationship has not been established. Serum electrolyte levels should be monitored in patients with chronic kidney disease. In case of increased serum potassium levels, in addition to appropriate hyperkalemia treatment, temporary discontinuation of Hemax should be considered until potassium levels normalize.

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

Based on current information, the use of Hemax for anemia treatment in adult pre-dialysis patients with kidney disease does not accelerate progression of kidney disease.

Treatment of patients with chemotherapy-induced anemia.

In oncology patients receiving epoetin alfa, hemoglobin levels should be monitored regularly until stable levels are 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, epoetins cannot exclude the possibility of stimulating the growth of certain tumor types.

The impact of erythropoiesis-stimulating agents on tumor progression or reduced progression-free survival cannot be excluded. Studies using epoetin alfa and other erythropoiesis-stimulating agents have been 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 mortality when used to increase hemoglobin levels to 12 g/dL (7.5 mmol/L) in patients with active malignancy not receiving chemotherapy or radiotherapy. Erythropoiesis-stimulating agents are contraindicated in this patient group;
• Increased risk of disease progression or death by 9% in the group receiving epoetin alfa and standard treatment, and a 15% increased risk, statistically not negligible, 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).

Given the above, in certain clinical situations, blood transfusion may be preferred for anemia treatment in cancer patients. The decision to use recombinant erythropoietins should be based on a benefit-risk assessment for each 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 typically a 2–3-week delay between erythropoietin administration and the appearance of erythropoietin-induced blood cells. This should be considered when evaluating treatment appropriateness (especially regarding patients with transfusion needs).

Patients undergoing surgery and participating in autologous blood donation programs.

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

Patients undergoing extensive elective orthopedic surgery.

Standard hemotransfusion practices should always be followed in the pre- and postoperative periods. Patients undergoing extensive elective orthopedic surgery should receive appropriate antithrombotic prophylaxis, as thrombotic and vascular complications may occur after surgery, especially in patients with concomitant cardiovascular diseases. Particular caution should be exercised in treating patients predisposed to deep vein thrombosis. Moreover, in patients with an initial hemoglobin level >13 g/dL, the risk 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.

Diet.

As hematocrit increases, patients' appetite typically increases, leading to higher food intake. Measures should be taken to prevent increased potassium intake.

Carcinogenic and mutagenic properties.

The carcinogenic potential of Hemax has not been evaluated. Epoetin does not induce genetic mutations in bacteria or chromosomal aberrations in mammalian cells.

Effect on fertility.

In pregnant rats, a tendency toward a slight increase in embryo mortality was observed after intravenous administration of epoetin at doses of 100–500 IU/kg.

Reduced drug efficacy or lack of response.

If patients receiving epoetin at maintenance doses exhibit reduced response or no response at all, the following causes should be excluded:

• Iron deficiency
• Infection, inflammation, tumors
• Occult blood loss
• Hematological disorders (thalassemia, myelodysplasia, etc.)
• Hemolysis
• Aluminum intoxication
• Vitamin B12 or folic acid deficiency
• Cystic fibrosis
• Pure red cell aplasia.

Sodium chloride.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy.

Sufficient studies on the use of Hemax in pregnant women have not been conducted. Animal studies have shown reproductive toxicity. Therefore, this drug should be prescribed to pregnant women only if the potential benefit justifies the potential risk to the fetus. The use of epoetin alfa in pregnant women participating in autologous blood donation programs is not recommended.

Animal studies in pregnant rats showed a slight increase in embryo mortality, whereas no adverse effects were observed in pregnant rabbits at a dose of 500 IU/kg.

Breastfeeding.

Human erythropoietin is normally present in breast milk, although the role of erythropoietin from breast milk remains unclear. 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 treatment should be made by weighing the benefits of breastfeeding for the child against the benefits of epoetin alfa treatment for the woman.

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

Fertility.

No studies have been conducted on the effect of epoetin alfa on fertility in men or women.

Ability to affect reaction speed when driving or operating machinery.

No specific studies have been conducted on this issue. However, considering that adverse reactions such as headache, fatigue, and others may occur during Hemax administration, patients taking this drug should refrain from driving or operating machinery.

Method of Administration and Dosage

All other causes of anemia (iron deficiency, folic acid deficiency, vitamin B12 deficiency, aluminum poisoning, 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 dosage adjustments should be made if necessary. To achieve an optimal response to epoetin alfa treatment, adequate iron supply should be ensured, and iron supplementation should be administered as needed (see section "Special Warnings and Precautions for Use").

Treatment of symptomatic anemia in adult patients with chronic kidney disease.

Symptoms and complications of anemia may vary depending on age, sex, and concomitant diseases; therefore, individual assessment of the patient's condition and disease course by a physician is required.

The recommended target hemoglobin level is 10 to 12 g/dL (6.2–7.5 mmol/L). Gemax is used to increase hemoglobin levels up to a maximum of 12 g/dL (7.5 mmol/L). Increases in hemoglobin greater than 2 g/dL (1.25 mmol/L) within 4 weeks should be avoided. If such an increase occurs, the dose should be reduced as described below.

Due to individual variability, some patients may have hemoglobin levels higher or lower than the desired target range. Hemoglobin levels should be monitored and doses adjusted accordingly to maintain levels within the recommended range of 10 g/dL (6.2 mmol/L) to 12 g/dL (7.5 mmol/L).

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

Patients should be closely monitored to ensure that the lowest effective dose of Gemax is used to control anemia and its symptoms, maintaining hemoglobin levels no higher than 12 g/dL (7.5 mmol/L).

Doses of erythropoiesis-stimulating agents should be increased cautiously in patients with chronic kidney disease. In patients with poor response to treatment, other potential causes of inadequate response should be considered (see section "Special Warnings and Precautions for Use").

Gemax treatment is divided into two phases: correction phase and maintenance phase.

Adult patients undergoing hemodialysis.

Intravenous administration is preferred for patients undergoing hemodialysis.

Correction phase.

Initial dose: 50 IU/kg three times weekly.

The dose may be increased or decreased by 25 IU/kg (three times weekly) as needed to achieve the desired hemoglobin level of 10–12 g/dL (6.2–7.5 mmol/L). Dose adjustments should be made stepwise, no more frequently than once every 4 weeks.

Maintenance phase.

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

The dose should be adjusted appropriately to maintain the desired hemoglobin level of 10–12 g/dL (6.2–7.5 mmol/L).

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 at the start of treatment (hemoglobin > 8 g/dL or > 5 mmol/L).

Adult patients with pre-dialysis kidney disease.

For pre-dialysis patients with kidney disease who do not have an established intravenous catheter, subcutaneous administration of the drug is permitted.

Correction phase.

Initial dose: 50 IU/kg three times weekly, with subsequent increases as needed by 25 IU/kg (three times weekly), with intervals between dose increases of at least 4 weeks, until hemoglobin levels reach the target range of 10–12 g/dL (6.2–7.5 mmol/L).

Maintenance phase.

During the maintenance phase, Gemax may 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 hemoglobin level of 10–12 g/dL (6.2–7.5 mmol/L). Prolonging the intervals between doses 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.

In the absence of an established intravenous catheter, Gemax may be administered subcutaneously.

Correction phase.

Initial dose: 50 IU/kg twice weekly.

Maintenance phase.

The recommended maintenance dose is 25 to 50 IU/kg twice weekly, administered as two equal injections.

The dose should be appropriately adjusted to maintain the desired hemoglobin level of 10–12 g/dL (6.2–7.5 mmol/L).

Treatment of adult patients with anemia caused by chemotherapy.

Symptoms and complications of anemia may vary depending on age, sex, and concomitant diseases; therefore, individual assessment of the patient's condition and disease course by a physician is required.

Gemax should be administered to patients with anemia (hemoglobin level ≤ 10 g/dL (6.2 mmol/L)). Initial dose: 150 IU/kg subcutaneously three times weekly.

Alternatively, Gemax may be administered at a dose of 450 IU/kg subcutaneously once weekly.

The dose should be appropriately adjusted to maintain the desired hemoglobin level of 10–12 g/dL (6.2–7.5 mmol/L). Due to individual variability, some patients may have hemoglobin levels higher or lower than the desired target. Hemoglobin levels should be monitored and doses adjusted accordingly to maintain levels within the recommended range of 10 g/dL (6.2 mmol/L) to 12 g/dL (7.5 mmol/L). Sustained hemoglobin levels above 12 g/dL (7.5 mmol/L) should be avoided.

If hemoglobin increases by at least 1 g/dL (0.6 mmol/L) or reticulocyte count increases by ≥ 40,000 cells/µL after 4 weeks of treatment, continue Gemax at a dose of 150 IU/kg three times weekly or 450 IU/kg once weekly.

If after 4 weeks of initial dosing, hemoglobin increases by less than 1 g/dL (0.62 mmol/L) or reticulocyte count increases by less than 40,000 cells/µL, the dose should be increased to 300 IU/kg three times weekly.

If after an additional 4 weeks of treatment at 300 IU/kg three times weekly, hemoglobin increases by 1 g/dL (0.62 mmol/L) or more, or reticulocyte count increases by 40,000 cells/µL or more, continue Gemax at 300 IU/kg three times weekly.

However, if hemoglobin increases by less than 1 g/dL (less than 0.62 mmol/L) or reticulocyte count increases by less than 40,000 cells/µL from baseline, the clinical response is considered questionable, and treatment should be discontinued.

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

If hemoglobin increases by more than 2 g/dL (1.25 mmol/L) within one month or exceeds 12 g/dL (7.5 mmol/L), the Gemax dose should be reduced by 25–50%. If hemoglobin exceeds 13 g/dL (8.1 mmol/L), therapy should be temporarily discontinued until levels fall below 12 g/dL (7.5 mmol/L), then resumed at a dose 25% lower than the previous dose.

Recommended dosing regimen:

Patients should be closely monitored to ensure that the lowest approved dose of Gemax is used to control anemia symptoms.

Gemax administration should continue for one month after completion of chemotherapy.

Adult patients participating in autologous blood donation programs prior to surgery.

Patients with moderate anemia (hematocrit 33–39%) who are expected to require ≥ 4 units of blood should receive Gemax at a dose of 600 IU/kg intravenously twice weekly for 3 weeks prior to surgery. Gemax should be administered after each blood donation procedure.

Adult patients prior to major elective orthopedic surgery.

Recommended dose: 600 IU/kg subcutaneously once 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, Gemax should be administered daily at 300 IU/kg subcutaneously for 10 consecutive days before surgery, on the day of surgery, and for 4 days postoperatively. If hemoglobin reaches 15 g/dL or higher during the preoperative period, Gemax administration must be completely discontinued and subsequent doses withheld.

Adult patients with low- or intermediate-1 risk MDS

Gemax should be administered to patients with symptomatic anemia (hemoglobin ≤ 10 g/dL (6.2 mmol/L)).

Recommended initial dose of Gemax: 450 IU/kg (maximum total dose 40,000 IU) subcutaneously once weekly, with at least 5 days between doses.

The dose should be appropriately adjusted to maintain the desired hemoglobin level of 10–12 g/dL (6.2–7.5 mmol/L). Response to Gemax treatment should be evaluated between 8 and 12 weeks after initiation. Dose increases and decreases should be performed stepwise (see diagram below). Hemoglobin levels above 12 g/dL (7.5 mmol/L) should be avoided.

Dose escalation. The weekly dose should not be increased by more than 10,500 IU/kg (total dose 80,000 IU). If response to treatment is lost or hemoglobin concentration decreases by ≥ 1 g/dL after dose reduction, the dose should be increased by one step. At least 4 weeks should elapse between dose escalations.

Dose maintenance and reduction. Gemax treatment should be temporarily suspended if hemoglobin concentration exceeds 12 g/dL (7.5 mmol/L). Once hemoglobin falls below 11 g/dL, treatment should be resumed at the same dose or one step lower, at the physician’s discretion. Dose reduction should be considered if a rapid increase in hemoglobin (> 2 g/dL within 4 weeks) is observed.

Symptoms and complications of anemia may vary depending on age, sex, and concomitant diseases; therefore, an individual assessment of the patient's disease course and condition is required.

Children.

Treatment of symptomatic anemia in children with chronic renal failure who are on hemodialysis.

Symptoms and complications of anemia may vary depending on age, sex, and concomitant diseases; therefore, an individual assessment of the patient's disease course and condition is required.

In children, the recommended hemoglobin level is from 9.5 g/dL to 11 g/dL (5.9–6.8 mmol/L). Hemax should be used to increase hemoglobin levels up to a maximum of 11 g/dL (6.8 mmol/L). Increases in hemoglobin levels exceeding 2 g/dL (1.25 mmol/L) within 4 weeks should be avoided.

In such cases, the dose should be adjusted appropriately.

Patients should be closely monitored to ensure that the lowest approved dose of Hemax is used to control anemia symptoms.

Treatment consists of two phases: correction phase and maintenance phase.

When an established intravenous catheter is present, the intravenous route of administration is preferred.

Correction phase.

Initial dose: 50 IU/kg intravenously three times weekly.

If necessary, the dose may be increased or decreased by 25 IU/kg (three times weekly) to achieve the desired hemoglobin level of 9.5 g/dL to 11 g/dL (5.9–6.8 mmol/L). Dose adjustments should be made stepwise and no more frequently than once every 4 weeks.

Maintenance phase.

The dose should be adjusted appropriately to maintain the optimal hemoglobin level of 9.5 g/dL to 11 g/dL (5.9–6.8 mmol/L).

In general, children weighing less than 30 kg require higher maintenance doses than adults and children weighing over 30 kg. Pediatric patients with very low initial hemoglobin levels (< 6.8 g/dL, or < 4.25 mmol/L) may require higher maintenance doses compared to patients with higher initial hemoglobin levels (> 6.8 g/dL, or > 4.25 mmol/L).

Treatment of anemia in children with chronic renal failure during the pre-dialysis period or on peritoneal dialysis.

The safety and efficacy of Hemax in children with chronic renal failure and anemia who are not yet on dialysis or are on peritoneal dialysis have not been established. Currently, no dosage recommendations can be made for this patient group.

Treatment of children with anemia caused by chemotherapy.

The safety and efficacy of Hemax in children with anemia caused by chemotherapy have not been established.

Treatment of children participating in autologous blood donation programs prior to surgical procedures.

The safety and efficacy of Hemax in children participating in autologous blood donation programs prior to major surgical procedures have not been established.

Treatment of children prior to elective orthopedic surgery.

The safety and efficacy of Hemax in children undergoing elective orthopedic surgery have not been established.

Administration method

Epoetin alfa can be administered via subcutaneous or intravenous injection.

Method of preparing the injection solution: Add the volume of water for injection specified in the table below to each vial containing the lyophilisate.

Active ingredient	1000 IU	2000 IU	3000 IU	4000 IU	10 000 IU	20 000 IU	40 000 IU
Water for injections	1 ml	2 ml	2 ml	2 ml	1 ml	1 ml	1 ml

As with any parenteral medicinal product, epoetin alfa solution should be inspected for the presence of visible particulate matter and discoloration prior to administration.

Intravenous administration.

Hemax is administered intravenously to adult patients participating in an autologous blood donation program prior to surgical procedures. For the treatment of symptomatic anemia in adults and children with chronic renal failure who have intravenous access (hemodialysis patients), intravenous administration is preferred.

Hemax is administered by intravenous injection over 1 to 5 minutes, depending on the dose. In patients undergoing hemodialysis, the bolus injection may be given directly during the procedure via the appropriate venous port in the dialysis line. Alternatively, the drug may be administered after completion of hemodialysis through the catheter fistula, followed by administration of 10 mL of isotonic sodium chloride solution to flush the system and ensure proper distribution of the drug in the circulation.

Slow administration is recommended for patients who experience influenza-like symptoms during treatment (see section "Side Effects").

Hemax must not be administered by intravenous infusion or mixed with other medicinal products.

Subcutaneous administration.

Hemax is administered subcutaneously to adult patients with anemia due to chemotherapy, to patients prior to planned major orthopedic surgery, and to adult patients with low- or intermediate-1-risk MDS.

Subcutaneous administration of Hemax may also be used in the treatment of symptomatic anemia in adult patients with chronic renal failure during the pre-dialysis period or on peritoneal dialysis, in the absence of an established intravenous catheter.

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

The subcutaneous injection should be given in the extremities or in the abdominal wall.

If, in the physician’s opinion, the patient or caregiver is able to safely and effectively self-administer Hemax subcutaneously, they should be properly instructed in the correct dosage and administration technique.

Children.

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

Overdose.

The drug has a wide therapeutic window. Overdose of epoetin alfa results in effects reflecting the maximal pharmacological action of the hormone, i.e., polycythemia and associated symptoms such as headache, dizziness, somnolence, etc. In cases of excessively high hemoglobin levels, phlebotomy may be performed. Symptomatic treatment should be applied if necessary.

In case of overdose, medical attention should be sought immediately at the nearest medical facility or a toxicology center.

Adverse Reactions.

The most common adverse reaction during treatment with epoetin alfa is dose-dependent increase in arterial blood pressure or worsening of pre-existing hypertension. Blood pressure monitoring should be initiated from the beginning of treatment. Other frequently observed adverse reactions in clinical trials with epoetin alfa include deep vein thrombosis, pulmonary embolism, seizures, diarrhea, nausea, headache, flu-like symptoms, pyrexia, rash, and vomiting.

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

During studies evaluating extended dosing intervals of the drug in adult patients with chronic kidney disease during the pre-dialysis period, worsening of airway patency, including upper airways, nasal congestion, and nasopharyngitis were observed.

Among patients receiving erythropoiesis-stimulating agents, an increased incidence of thrombovascular complications has been observed (see section "Special Instructions").

Albumin (human)

Hemax contains albumin derived from human blood. The risk of transmission of viral infections is extremely low considering the manufacturing process of this component. Similarly, the theoretical risk of transmission of the agent causing Creutzfeldt-Jakob disease is also extremely low. There have been no reported cases of transmission of viral agents associated with albumin.

Frequency of adverse reactions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders.

Rare – thrombocytosis, pure red cell aplasia.

Immune system disorders.

Uncommon – hypersensitivity reactions.

Rare – anaphylactic reactions: potentially serious complications associated with respiratory distress or hypotension; immune responses (has minimal potential to induce antibody formation).

Nervous system disorders.

Common – headache.

Uncommon – seizures, stroke, cerebral hemorrhage.

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

Eye disorders.

Frequency not known – retinal vein thrombosis.

Cardiac disorders.

Frequency not known – myocardial infarction.

Vascular disorders.

Common – venous and arterial thrombosis, arterial hypertension.

Frequency not known – deep vein thrombosis (in patients with chronic kidney disease), hypertensive crisis.

Respiratory, thoracic and mediastinal disorders.

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

Uncommon – worsening of airway patency.

Frequency not known – pulmonary embolism (in patients with chronic kidney disease).

Gastrointestinal disorders.

Very common – nausea, diarrhea, vomiting.

Skin and subcutaneous tissue disorders.

Common – rash, eczema.

Uncommon – urticaria.

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

Musculoskeletal, connective tissue and bone disorders.

Common – arthralgia, bone pain, limb pain, myalgia.

Congenital, familial and genetic disorders.

Rare – acute porphyria.

General disorders and administration site conditions.

Very common – fever, pyrexia (in cancer patients).

Common – flu-like symptoms, chills, injection site reactions, peripheral edema.

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

Investigations.

Rare – presence of antibodies to erythropoietin.

Frequency not known – hyperphosphatemia, increased plasma concentrations of urea, creatinine, and uric acid (in patients with chronic kidney disease).

Metabolism and nutrition disorders.

Uncommon – hyperkalemia (common among patients undergoing hemodialysis).

Injury, poisoning and procedural complications.

Common – shunt thrombosis, including dialysis equipment (in patients with chronic kidney disease).

Patients with chronic kidney disease.

In patients with chronic kidney disease, hemoglobin levels above 12 g/dL 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 (e.g., stenosis, aneurysms), cases of shunt thrombosis have been reported.

Oncology patients.

Thrombotic complications may occur in patients receiving erythropoiesis-stimulating agents, including epoetin alfa.

Surgical adult patients.

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

Description of selected adverse reactions

Venous and arterial thromboses, with or without fatal outcome, such as deep vein thrombosis, pulmonary embolism, retinal thrombosis, arterial thrombosis (including myocardial infarction and myocardial ischemia), retinal and shunt thrombosis (including occlusion of dialysis systems), thromboses at the site of arteriovenous anastomosis. Cerebrovascular complications (including ischemic stroke, cerebral hemorrhage) and transient ischemic attacks, aneurysms may also occur.

Hypersensitivity reactions have been reported, including rash (e.g., urticaria), anaphylactic reactions, and angioneurotic edema.

Severe skin-related adverse reactions associated with epoetin treatment have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be life-threatening or fatal (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.

Pure red cell aplasia

Since epoetin alfa is a protein-based drug, antibody formation may occur in some patients. Rare cases of pure red cell aplasia have been reported in patients with kidney failure receiving subcutaneous administration of the drug, associated with the presence of neutralizing antibodies to epoetin alfa. In such cases, the use of any erythropoietin-containing product is contraindicated.

Very rare (<10,000 cases per patient-year) cases of antibody-mediated pure red cell aplasia (PRCA) have been reported in patients treated with erythropoietin products for months or years.

Low or intermediate-1 risk MDS adult patients

In a clinical trial, thrombovascular events (sudden death, ischemic stroke, embolism, phlebitis) occurred in 4 (4.7%) patients. All thrombovascular events occurred in the epoetin alfa group and within the first 24 weeks of treatment. Three events were confirmed; the fourth case (sudden death) was unconfirmed. Two patients had significant risk factors (atrial fibrillation, heart failure, and thrombophlebitis).

Children with chronic kidney disease on hemodialysis.

Experience with the use of erythropoietin in children with chronic kidney disease on hemodialysis during clinical trials and in the post-marketing period is limited. No adverse reactions specific to pediatric patients have been identified, nor any adverse reactions not consistent with the underlying disease.

Reporting of adverse reactions after drug registration is important. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store out of reach of children, at temperatures not exceeding 25 °C.

Packaging.

1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. Biosidus S.A. /
Biosidus S.A.

Manufacturer's address and place of business.
Constitucion 4234 (zip code C1254ABX), City of Buenos Aires, Argentine Republic /
Constitucion 4234 (zip code C1254ABX), of the City of Buenos Aires, Argentine Republic.