Binocrit

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BINOCHRIT® (BINOCRIT®)

Composition:

Active substance: epoetin alfa;

1 ml of solution contains 16.8 mcg (2000 IU) or 84 mcg (10000 IU) or 336 mcg (40000 IU) of epoetin alfa; 1 mg of epoetin alfa corresponds to 120000 IU;

Excipients: sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid concentrated, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antianaemic preparations. Erythropoietin.

ATC code B03X A01.

Pharmacological properties.

Pharmacodynamics.

Erythropoietin is a glycoprotein that stimulates erythropoiesis and activates mitosis and maturation of erythrocytes from erythroid precursor cells. Receptors for erythropoietin may be present on the surface of various tumor cells. The molecular weight of erythropoietin is approximately 32,000–40,000 daltons. The protein fraction accounts for approximately 58% of the molecular weight and consists of 165 amino acids. Four carbohydrate chains are attached to the protein via three N-glycosidic bonds and one O-glycosidic bond. Epoetin alfa, produced using recombinant DNA technology, is a purified glycoprotein. It is identical to human erythropoietin isolated from urine of anemic patients in terms of amino acid sequence and carbohydrate composition.

Binocrit® has the highest degree of purification achievable by current manufacturing technologies. In particular, quantitative analysis of the active substance in Binocrit® did not detect even trace amounts of host cell lines used in the production process.

The biological activity of epoetin alfa has been confirmed in in vivo experiments (studies were conducted in healthy rats and rats with anemia, as well as in mice with polycythemia). Following administration of epoetin alfa, the number of erythrocytes and reticulocytes, hemoglobin concentration, and the rate of 59Fe uptake increase.

In vitro studies involving incubation with epoetin alfa demonstrated enhanced incorporation of 3H-thymidine into nucleated erythroid cells of the spleen (in mouse spleen cell culture). Studies using human bone marrow cell cultures showed that epoetin alfa specifically stimulates erythropoiesis and does not affect leukopoiesis. No cytotoxic effect of erythropoietin on human bone marrow cells has been observed.

Erythropoietin is a growth factor that primarily stimulates the production of red blood cells. Erythropoietin receptors may be present on the surface of various tumor cells.

Administration of epoetin alfa results in increased hemoglobin, hematocrit, and serum iron levels, and promotes improved tissue perfusion and cardiac function. The most pronounced effect of epoetin alfa is observed in anemias associated with chronic renal failure, as well as in patients with certain malignant neoplasms and systemic diseases.

Treatment of patients with chemotherapy-induced anemia

Overall survival in clinical trials cannot be adequately explained by differences in the incidence of thrombosis and related complications between patients receiving recombinant human erythropoietin and those in the control group.

Meta-analyses consistently indicate a significantly increased relative risk of thromboembolic events in cancer patients receiving recombinant human erythropoietin.

Adult patients with renal insufficiency not yet undergoing dialysis

A randomized, prospective study evaluated 1,432 patients with anemia due to chronic renal insufficiency who were not undergoing dialysis. Patients were assigned to receive epoetin alfa treatment aimed at maintaining hemoglobin levels at either 13.5 g/dL (above the recommended hemoglobin concentration) or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization due to congestive heart failure) occurred in 125 (18%) of 715 patients in the higher hemoglobin group, compared to 97 (14%) of 717 patients in the lower hemoglobin group (hazard ratio [HR] 1.3, 95% CI: 1.0, 1.7, p = 0.03).

Pooled retrospective analyses of clinical trials with erythropoiesis-stimulating agents (ESAs) were conducted in patients with chronic renal failure (undergoing or not undergoing dialysis, with or without diabetes mellitus). A trend toward increased risk of all-cause mortality, cardiovascular complications, and cerebrovascular events was observed with higher cumulative ESA doses, regardless of diabetes status or dialysis. In a prospective, randomized, double-blind, placebo-controlled study involving 375 patients with anemia and various non-myeloid malignant neoplasms receiving non-platinum-based chemotherapy.

Survival and tumor progression were evaluated in five controlled trials involving a total of 2,833 patients, four of which were double-blind, placebo-controlled studies and one was an open-label study. The studies included patients receiving chemotherapy (two studies), or populations not receiving ESAs: patients with anemia due to malignancy not receiving chemotherapy, and patients with head and neck cancer receiving radiotherapy. The target hemoglobin concentration was >13 g/dL (8.1 mmol/L) in two studies and 12–14 g/dL (7.5–8.7 mmol/L) in the other three. In the open-label study, no difference in overall survival was observed between patients treated with recombinant human erythropoietin and those in the control groups. In the four placebo-controlled studies, the hazard ratios for overall survival ranged from 1.25 to 2.47 in favor of the control groups. These studies consistently demonstrated a statistically significant, unexplained excess in mortality among patients with anemia associated with various common malignancies who received recombinant human erythropoietin compared to control groups. The overall survival rate in these studies cannot be satisfactorily explained by differences in thrombosis incidence and related complications between patients receiving recombinant human erythropoietin and those in the control group.

Pharmacokinetics.

Intravenous administration

The elimination half-life (T1/2) of epoetin alfa after repeated intravenous administration is approximately 4 hours in healthy volunteers and approximately 5 hours in patients with chronic renal failure. In children, the T1/2 of epoetin alfa is approximately 6 hours.

Subcutaneous administration

After subcutaneous administration, plasma concentrations of epoetin alfa are significantly lower than after intravenous administration. The time to reach maximum plasma concentration (Tmax) of epoetin alfa is approximately 12–18 hours after administration. The maximum concentration (Cmax) after subcutaneous administration is only 1/20th of that achieved after intravenous administration.

The drug does not accumulate—plasma concentrations of epoetin alfa 24 hours after the first injection are comparable to those 24 hours after the last injection. The half-life (T1/2) of epoetin alfa after subcutaneous administration is difficult to determine but is approximately 24 hours. The bioavailability of epoetin alfa after subcutaneous administration is significantly lower than after intravenous administration and is approximately 20%.

Safety preclinical data

Long-term carcinogenicity studies have not been conducted. Conflicting reports in the literature based on in vitro analyses of human tumor samples suggest that erythropoietins may act as tumor proliferators. The clinical significance of this hypothesis remains unclear.

Clinical characteristics.

Indications.

• Treatment of symptomatic anemia associated with chronic kidney disease:
  • treatment of anemia related to chronic kidney disease in adults and children on hemodialysis, and in adult patients undergoing peritoneal dialysis;
  • treatment of severe renal anemia associated with clinical symptoms in adult patients with kidney insufficiency who have not yet started hemodialysis.
• Treatment of anemia and reduction of the need for blood transfusions in adult patients receiving chemotherapy due to non-myeloid malignancies, malignant lymphoma, or multiple myeloma, and who are at increased risk of transfusions based on overall clinical condition (cardiovascular status, existing anemia at the start of chemotherapy).
• To increase the amount of autologous blood within a predeposit program prior to major surgical interventions. The use of the drug should be carefully weighed against the risk of thromboembolic complications. Treatment should be applied only to patients with moderate anemia (hemoglobin levels 10–13 g/dL (6.2–8.1 mmol/L), absence of iron deficiency), when collection of autologous blood is impossible or insufficient, or when the expected need for blood transfusion is very high (4 or more units for women and 5 or more for men).
• In adult patients with mild to moderate anemia (hemoglobin levels between 10–13 g/dL or 6.2–8.1 mmol/L, without iron deficiency) prior to major orthopedic surgery with anticipated moderate blood loss (900 to 1800 mL), to reduce the need for allogeneic blood transfusions and to support erythropoiesis recovery.
• Treatment of symptomatic anemia (hemoglobin level ≤ 10 g/dL) in adults with low or intermediate-1 risk myelodysplastic syndrome and low serum erythropoietin levels (< 200 mU/mL).

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Pure red cell aplasia that has developed after treatment with erythropoietin.
• Uncontrolled arterial hypertension.
• All contraindications related to autologous blood donation programs in patients treated with epoetin alfa.
• Epoetin alfa is contraindicated in patients undergoing elective orthopedic surgery who have not participated in an autologous blood donation program, if they have severe coronary, peripheral arterial, carotid, or cerebrovascular disease, or have recently suffered myocardial infarction or stroke.
• Surgical patients in whom adequate antithrombotic prophylaxis cannot be administered for any reason.

Interaction with other medicinal products and other forms of interaction.

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 epoetin alfa. Since cyclosporine binds to red blood cells, a potential drug interaction exists.

When epoetin alfa and cyclosporine are used concomitantly, cyclosporine blood levels should be monitored and the dose adjusted if necessary, due to increasing hematocrit levels.

There are no data on interactions between epoetin alfa and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) regarding hematological differentiation or tumor cell proliferation in in vitro biopsy samples.

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

Special precautions for use.

Traceability

To improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

General

All patients receiving epoetin alfa should be continuously monitored for arterial blood pressure and, if necessary, blood pressure should be controlled. Epoetin alfa should be used with caution in patients with untreated, poorly treated, or difficult-to-control hypertension. During treatment, initiation or intensification of antihypertensive therapy may become necessary. If blood pressure cannot be controlled, epoetin alfa should be discontinued.

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

Epoetin alfa should be used with caution in patients with epilepsy, a history of seizures, or medical conditions associated with a predisposition to seizure activity (e.g., CNS infections or brain metastases).

Epoetin alfa should be used with caution in patients with chronic hepatic insufficiency. The safety of epoetin alfa has not been established in patients with impaired liver function.

Serious skin adverse reactions associated with the use of epoetin alfa, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be life-threatening or fatal, have been reported. Most severe cases occurred with long-acting epoetins.

Before administration, patients should be informed about signs and symptoms of skin reactions and closely monitored. If signs or symptoms suggestive of these reactions occur, epoetin alfa should be immediately discontinued and alternative treatment considered.

If a patient develops a serious skin reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis due to epoetin alfa, treatment with epoetin alfa must not be restarted.

An increased incidence of thrombotic/vascular complications has been observed in patients receiving erythropoiesis-stimulating agents. These include venous and arterial thrombosis, embolism (including fatal outcomes), such as deep vein thrombosis, pulmonary embolism, retinal vein thrombosis, and myocardial infarction. Additionally, stroke (including cerebral infarction, cerebral hemorrhage, and transient ischemic attacks) has been reported.

The reported risk of these thrombotic/vascular complications should be carefully weighed against the benefits of epoetin alfa treatment, especially in patients with existing risk factors for thrombotic/vascular complications, including obesity and a history of thrombotic/vascular 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 events and mortality if treatment is administered at hemoglobin levels exceeding the recommended concentration range for the indication.

During treatment with epoetin alfa, a moderate, dose-dependent increase in platelet count within the normal range may occur. This parameter decreases during continued treatment. In addition, cases of thrombocytosis above normal levels have been reported. Platelet counts should be monitored regularly during the first 8 weeks of treatment.

All other causes of anemia (iron, folic acid, or vitamin B12 deficiency, aluminum toxicity, concomitant infections or inflammatory processes, blood loss, hemolysis, and bone marrow fibrosis of any etiology) must be identified and treated before initiating epoetin alfa therapy and when considering dose escalation. In most cases, serum ferritin levels decrease concurrently with rising hematocrit. To ensure optimal response to epoetin alfa, adequate iron availability must be ensured, and iron supplementation should be administered if necessary:

• for patients with chronic renal insufficiency, iron supplementation (elemental iron 200–300 mg/day orally for adults and 100–200 mg/day orally for children) is recommended if serum ferritin is below 100 ng/mL;
• for oncology patients, iron supplementation (elemental iron – 200–300 mg/day orally) is recommended if transferrin saturation is below 20%;
• for patients participating in an autologous blood collection program, iron supplementation (elemental iron – 200 mg/day orally) should be initiated several weeks before the start of autologous blood collection to achieve high iron stores prior to starting epoetin alfa therapy and continued during treatment;
• for patients undergoing planned major elective orthopedic surgery, iron supplementation (elemental iron – 200 mg/day orally) should be administered during epoetin alfa treatment. If possible, iron supplementation should be initiated before starting epoetin alfa therapy to achieve adequate iron stores.

Very rarely, development or worsening of pre-existing porphyria has been observed in patients treated with epoetin alfa. Epoetin alfa should be used with caution in patients with porphyria.

To improve traceability of erythropoiesis-stimulating agents, the brand name of the administered erythropoiesis-stimulating agent should be clearly documented in the patient's medical record.

Patients should be switched from one erythropoiesis-stimulating agent to another only under physician supervision.

True erythrocytic aplasia

Cases of antibody-mediated pure erythrocytic aplasia have been reported after several months or years of subcutaneous administration of epoetin alfa, primarily in patients with chronic renal insufficiency. Isolated cases of pure erythrocytic aplasia have also been observed in patients with hepatitis C who received interferon and ribavirin concurrently with erythropoiesis-stimulating agents. The use of epoetin alfa is not approved for the treatment of anemia associated with hepatitis C.

Patients who experience a sudden loss of treatment efficacy, manifested by a decrease in hemoglobin levels (1–2 g/dL or 0.62–1.25 mmol/L per month) and increased transfusion requirements, should be referred for reticulocyte count assessment and evaluation of typical causes of reduced clinical response (e.g., iron, folic acid, or vitamin B12 deficiency, aluminum toxicity, concomitant infections or inflammatory processes, blood loss, hemolysis, and bone marrow fibrosis of any etiology).

In cases of paradoxical hemoglobin decline and development of severe anemia associated with low reticulocyte count, treatment with epoetin alfa should be interrupted and anti-erythropoietin antibodies tested. Bone marrow examination should be performed to confirm the diagnosis of pure erythrocytic aplasia.

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

Treatment of symptomatic anemia in adults and children with chronic renal insufficiency

Data on the immunogenicity of subcutaneous epoetin alfa in patients at risk of developing antibody-dependent pure erythrocytic aplasia, such as patients with renal anemia, are insufficient. Therefore, in patients with renal anemia, the medicinal product should be administered intravenously.

In patients with chronic renal insufficiency receiving epoetin alfa, hemoglobin levels should be measured regularly until a stable level is achieved and periodically thereafter.

In patients with chronic renal insufficiency, 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 maintenance 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 reactions when erythropoiesis-stimulating agents are used to achieve hemoglobin levels above 12 g/dL (7.5 mmol/L).

Doses of epoetin alfa should be increased cautiously in patients with chronic renal insufficiency, as high cumulative doses of epoetin may be associated with increased risks of mortality and serious cardiovascular and cerebrovascular events. In patients with inadequate response to epoetin therapy at low hemoglobin levels, alternative explanations for poor response should be considered.

Controlled clinical trials have not demonstrated significant benefits from using epoetins to increase hemoglobin concentration above the level required to control anemia symptoms or avoid blood transfusions.

Patients with chronic renal insufficiency receiving Binocrit® subcutaneously should be regularly monitored for loss of efficacy, defined as absent or reduced response to Binocrit® therapy in patients who previously responded to such treatment. This is characterized by a persistent decrease in hemoglobin levels despite increasing doses of epoetin alfa.

In some patients receiving epoetin alfa at extended intervals (less than once weekly), adequate hemoglobin levels may not be maintained. These patients may require dose increases. Hemoglobin levels should be monitored regularly.

In patients on hemodialysis, shunt thrombosis has been observed, particularly in those prone to hypotension or with arteriovenous fistula complications (e.g., stenosis, aneurysms). Shunt monitoring and thrombosis prophylaxis (e.g., with acetylsalicylic acid) are recommended for such patients.

There have been isolated reports of hyperkalemia, although causality has not been established. Electrolyte levels in serum should be monitored in patients with chronic renal insufficiency. If increased serum potassium levels are detected, in addition to appropriate treatment of hyperkalemia, temporary discontinuation of epoetin alfa should be considered until serum potassium levels are fully corrected.

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

Based on current information, correction of anemia with epoetin alfa in adult patients with renal insufficiency not currently on hemodialysis does not accelerate the progression of renal failure.

Treatment of patients with chemotherapy-induced anemia

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

Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be present on the surface of various tumor cells. As with all growth factors, there is a theoretical concern that epoetins may stimulate tumor growth. In several controlled studies, epoetins have not been shown to improve overall survival or reduce the risk of tumor progression in patients with cancer-associated anemia.

Results from controlled clinical trials of epoetin alfa and other erythropoiesis-stimulating agents have shown:

• reduced locoregional control in patients with progressive head and neck cancer receiving radiotherapy when these agents were used to achieve hemoglobin levels above 14 g/dL (8.7 mmol/L),
• reduced overall survival and increased number of disease-related deaths within 4 months in metastatic breast cancer patients receiving chemotherapy when these agents were used to achieve hemoglobin levels between 12 and 14 g/dL (7.5–8.7 mmol/L),
• increased risk of mortality when these agents were used to achieve a hemoglobin level of 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,
• 9% increased risk of disease progression or death in the epoetin alfa group from primary analysis and 15% increased risk in metastatic breast cancer patients receiving chemotherapy when Binocrit® was administered to achieve hemoglobin levels between 10 and 12 g/dL (6.2 to 7.5 mmol/L).

Given 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 an individual benefit-risk assessment involving the patient, taking into account 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 lag between administration of erythropoiesis-stimulating agents and the appearance of erythropoietin-induced red blood cells. This should be considered when evaluating treatment response (especially in patients requiring transfusions).

Surgical patients participating in an autologous blood collection program

All specific warnings and precautions associated with an autologous blood collection program should be considered, particularly regarding planned fluid volume replacement.

Patients undergoing planned major elective orthopedic surgery

Good practice in blood transfusion management should always be followed in the perioperative period.

Patients undergoing planned major elective orthopedic surgery should receive adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially those with concomitant cardiovascular diseases. In addition, particular caution should be exercised in treating patients predisposed to deep vein thrombosis. Moreover, in patients with a stable hemoglobin level >13 g/dL, the possibility that epoetin alfa treatment may be associated with an increased risk of postoperative thrombotic or vascular complications should not be excluded. Therefore, epoetin alfa should not be administered to patients with a stable hemoglobin level >13 g/dL. This medicinal product contains less than 1 mmol/l sodium (23 mg) per dose (sodium-free).

Prior to administration, Binocrit® may be removed from the refrigerator and stored at a temperature not exceeding 25°C for a period not exceeding 3 days. Do not shake!

Use during pregnancy or breastfeeding

Adequate controlled studies of epoetin alfa use in pregnant women have not been conducted. Reproductive toxicity has been observed in animal studies. Therefore:

• Binocrit® may be used in pregnant women with chronic renal insufficiency only if the anticipated benefit to the mother clearly outweighs the potential risk to the fetus.
• Use of epoetin alfa is not recommended during pregnancy or breastfeeding for patients participating in an autologous blood collection program prior to surgery.

It is unknown whether exogenous epoetin alfa passes into 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 benefit of breastfeeding to the child and the benefit of epoetin alfa treatment to the woman.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect on the ability to drive or operate machinery have not been conducted.

Method of Administration and Dosage

Treatment with Binokrit® should be conducted under the supervision of physicians experienced in managing patients with the aforementioned indications.

Binokrit® may be administered via subcutaneous and intravenous injections. As with any parenteral medicinal product, Binokrit® should be inspected visually for particulate matter and discoloration prior to administration.

Intravenous administration.

Binokrit® should be administered by injection over a period of 1 to 5 minutes, depending on the dose. For patients undergoing hemodialysis, the bolus injection may be administered directly during the procedure via an appropriate venous port in the dialysis line. Alternatively, the drug may be administered after completion of hemodialysis through the fistula or catheter, followed by administration of 10 mL of isotonic sodium chloride solution to flush the system and ensure proper distribution of the drug into the circulation. Slow administration is preferred for patients exhibiting symptoms of cold-like illness. Binokrit® 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 administered at multiple sites. The subcutaneous route should be administered in the extremities or the anterior abdominal wall. If, in the physician’s opinion, the patient or caregiver is capable of safely and effectively self-administering Binokrit® subcutaneously, they should be properly instructed in correct dosing and administration techniques.

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

In patients with chronic kidney disease, the intravenous route is preferred whenever feasible (e.g., patients on hemodialysis). In cases where intravenous administration is not feasible (e.g., patients not yet on hemodialysis or those on peritoneal dialysis), epoetin alfa may be administered subcutaneously.

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

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

Due to individual variability, hemoglobin levels may transiently exceed or fall below the target range in individual patients.

Hemoglobin levels should be monitored and the dose adjusted accordingly to maintain levels within the range of 10 g/dL (6.2 mmol/L) to 12 g/dL (7.5 mmol/L). In pediatric patients, the recommended optimal hemoglobin range is 9.5 to 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 levels exceed 12 g/dL (7.5 mmol/L), the epoetin dose may be reduced by 25%. If hemoglobin exceeds 13 g/dL (8.1 mmol/L), treatment should be discontinued until hemoglobin decreases to 12 g/dL (7.5 mmol/L), after which epoetin alfa therapy 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 initiation and throughout treatment with Binokrit®. Iron supplementation should be administered as needed. Other types of anemia (e.g., vitamin B12 or folate deficiency) must be ruled out prior to initiating Binokrit® therapy. Lack of clinical response to Binokrit® treatment requires investigation for contributing factors such as iron, folate, 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, intravenous administration is preferred whenever vascular access is available.

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 target hemoglobin concentration of 10–12 g/dL (6.2–7.5 mmol/L) is achieved.

Maintenance phase.

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

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

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

Children on hemodialysis.

For pediatric patients on hemodialysis, intravenous administration is preferred whenever vascular access is available.

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 target 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 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. The following maintenance doses of epoetin alfa have been established:

Body weight (kg)	Dose (IU/kg 3 times per week)
	Mean dose	Usual maintenance dose
< 10	100	75-150
10-30	75	60-150
> 30	33	30-100

Available data indicate that patients with very low initial hemoglobin levels (< 6.8 g/dL, or < 4.25 mmol/L) may require higher doses to maintain concentrations compared to patients with less severe anemia (Hb > 6.8 g/dL or > 4.25 mmol/L).

Anemia in patients with chronic kidney disease prior to initiation of dialysis or on peritoneal dialysis

The safety and efficacy of Binokrit® in patients with chronic kidney disease and anemia prior to initiation of dialysis or on peritoneal dialysis have not been established.

Adult patients with kidney disease in the post-dialysis period.

For patients with kidney disease in the post-dialysis period, if intravenous access is not available, the drug may be administered subcutaneously.

Treatment is divided into two phases.

Correction phase.

50 IU/kg three times weekly.

Dose adjustments, if necessary, may be made by increasing the dose in increments of 25 IU/kg three times weekly, with intervals between dose escalations of at least 4 weeks, until the hemoglobin level reaches the target range of 10–12 g/dL (6.2–7.5 mmol/L).

Maintenance phase.

During the maintenance phase, Binokrit® 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). Extending 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 on peritoneal dialysis.

For patients on peritoneal dialysis without access to intravenous administration, the drug may be administered subcutaneously.

Treatment is divided into two phases.

Correction phase.

50 IU/kg twice weekly.

Maintenance phase.

The usual maintenance dose to achieve the desired hemoglobin level of 10 to 12 g/dL (6.2–7.5 mmol/L) is 25 to 50 IU/kg twice weekly, administered as two equal injections.

Treatment of patients with anemia caused by chemotherapy.

Patients with anemia (e.g., hemoglobin concentration ≤ 10 g/dL (6.2 mmol/L)) should receive Binokrit® subcutaneously. Symptoms of anemia and complications may vary depending on age, sex, and disease-related conditions; therefore, individual clinical assessment by the physician is necessary.

Due to individual variability, periodic hemoglobin values in each patient may be higher or lower than the target level. Hemoglobin levels should be monitored and dose adjustments made accordingly, aiming to maintain levels between 10 g/dL (6.2 mmol/L) and 12 g/dL (7.5 mmol/L). Hemoglobin levels persistently above 12 g/dL (7.5 mmol/L) should be avoided. Dose adjustment recommendations for hemoglobin levels exceeding 12 g/dL (7.5 mmol/L) are described below.

Epoetin alfa therapy should be continued for 1 month after discontinuation of chemotherapy. The initial dose for treatment of anemia 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, hemoglobin 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, hemoglobin 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. If, after 4 weeks of treatment with the increased dose of 300 IU/kg three times weekly, hemoglobin increases by ≥ 1 g/dL (≥ 0.62 mmol/L) or reticulocyte count increases to ≥ 40,000 cells/mL, the dose should not be further changed.

However, if hemoglobin 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:

150 IU/kg three times weekly

or 450 IU/kg subcutaneously once weekly

Reticulocyte count increased ≥ 40000 cells/mL or hemoglobin level increased by ≥ 1 g/dL

Target hemoglobin level ≤ 12 g/dL

Reticulocyte count increased ≥ 40000 cells/mL or hemoglobin level increased ≥1 g/dL

4 weeks

Discontinuation of treatment

150 IU/kg 3 times a week or 450 IU/kg once a week

Reticulocyte count increased < 40000 cells/mL or hemoglobin level increased < 1 g/dL

300 IU/kg 3 times a week

Reticulocyte count increased < 40000 cells/mL or hemoglobin level increased <1 g/dL

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

Dose selection for maintenance of the target hemoglobin level of 10–12 g/dL.

If the rate of hemoglobin increase exceeds 2 g/dL (1.25 mmol/L) within 1 month and the total hemoglobin level approaches 12 g/dL (7.5 mmol/L), the dose of Binokrit® should be reduced by 25–50%, depending on the rate of hemoglobin rise. If hemoglobin exceeds 13 g/dL (8.1 mmol/L), therapy should be temporarily discontinued until hemoglobin decreases to 12 g/dL (7.5 mmol/L), after which treatment 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 should be used. Epoetin alfa should be administered after each blood donation procedure.

For patients with moderate anemia (hematocrit level 33–39%) who require ≥ 4 units of blood, treatment with epoetin alfa at a dose of 600 IU/kg twice weekly for 3 weeks prior to surgery is recommended. With this regimen, ≥ 4 units of blood can be collected from 81% of patients treated with epoetin alfa, compared to 37% of placebo-treated patients. Epoetin alfa therapy reduces the risk of receiving allogeneic blood transfusion by 50% compared to patients not receiving epoetin alfa.

All patients receiving epoetin alfa must 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 collection program, to ensure sufficient iron stores.

Adult patients undergoing elective orthopedic 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, Binokrit® should be administered daily at a dose of 300 IU/kg for 10 consecutive days prior to surgery, on the day of surgery, and for 4 days postoperatively. If hemoglobin levels reach 15 g/dL or higher during preoperative hematological testing, epoetin alfa administration must be completely discontinued.

All patients receiving epoetin alfa must 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 collection program.

Treatment of symptomatic anemia (hemoglobin level ≤ 10 g/dL) in adults with low or intermediate-1 risk primary myelodysplastic syndrome and low serum erythropoietin levels (< 200 mU/mL).

The drug should be administered subcutaneously.

Epoetin alfa should be prescribed to patients with symptomatic anemia (e.g., hemoglobin level ≤ 10 g/dL (6.2 mmol/L)). The recommended initial dose of epoetin alfa is 450 IU/kg (maximum total dose 40,000 IU), administered subcutaneously once weekly with an interval of at least 5 days.

To maintain hemoglobin levels within the target range of 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L), dose adjustments should be made. An assessment of the initial erythroid response should be performed 8–12 weeks after initiation of therapy. Dose increases or decreases should be made by one dose level at a time (see table below). Hemoglobin concentrations above 12 g/dL (7.5 mmol/L) should be avoided.

Increasing the dose

The maximum weekly dose—1050 IU/kg (total dose 80,000 IU)—should not be exceeded. If a patient loses response to treatment or hemoglobin decreases by ≥1 g/dL during dose reduction, the dose should be increased by one dose level. At least 4 weeks should elapse between dose increases.

Holding and reducing the dose

Epoetin alfa should be withheld when hemoglobin exceeds 12 g/dL (7.5 mmol/L). If hemoglobin falls below 11 g/dL, the same dose or a dose reduced by one level may be reinitiated, depending on the physician’s judgment. Dose reduction by one level should be considered if hemoglobin rises rapidly (>2 g/dL within 4 weeks).

Dose escalation and de-escalation levels

Increasing the dose

337.5 IU/kg

450 IU/kg

787.5 IU/kg

1050 IU/kg

Dosage reduction

Symptoms and consequences of anaemia may vary depending on age, sex and concomitant diseases; therefore, a physician must assess the clinical course and individual patient's condition.

Instructions for self-administration of injectable preparations (for adult patients with symptomatic anaemia due to renal insufficiency, adult patients receiving chemotherapy or scheduled for orthopaedic surgery, and adult patients with myelodysplastic syndromes only).

This section provides information on how to self-administer Binocrit injections. Do not attempt to self-inject unless you have been properly trained by your doctor or nurse. Binocrit in a pre-filled syringe may be supplied with or without a needle protective cap. Your doctor or nurse will show you how to use it. If you have any doubts about administering the injection or any other questions, seek help from your doctor or nurse.

1. Wash your hands.
2. Remove one syringe from the packaging and take off the protective cap from the injection needle. The syringes are equipped with a scale marked with ring graduations, which allows partial administration of the medication if needed. Each graduation mark corresponds to a volume of 0.1 ml. If administering a partial dose, remove the excess medication from the syringe before injection.
3. Clean the injection site with alcohol.
4. Pinch the skin between your thumb and index finger to form a skin fold.
5. Insert the needle into the skin fold with a quick, confident motion. Inject Binocrit solution according to your doctor's instructions. If you are unsure about the correct dose, consult your doctor or pharmacist for assistance.

Pre-filled syringe without needle protective cap Slowly and evenly press the plunger without releasing the skin fold with your fingers. After administering the medication, remove the needle and release the skin fold. Press the injection site with a dry sterile cotton swab. Dispose of any unused medication and waste. Each syringe is intended for a single injection only.

Pre-filled syringe with needle shield During injection, always hold the skin fold with your fingers, slowly and firmly press the plunger until the medicine is completely administered, i.e. until the plunger stops completely. Do not stop pressing the plunger! After administering the medicine, remove the needle without stopping to press the plunger, and release the skin fold. Press the injection site with a dry sterile cotton swab. Release the plunger. The needle shield will activate immediately and cover the needle. Dispose of any unused medicine and waste. Each syringe is intended for a single injection only.

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. Safety and efficacy of the drug in children under 1 year of age have not been established.

Overdose.

The drug has a wide therapeutic range. Overdose of epoetin alfa results in effects reflecting the maximum expression of the hormone's pharmacological action. In case of exceptionally high hemoglobin levels, phlebotomy may be performed. If necessary, symptomatic therapy should be administered.

Adverse Reactions

The most common adverse reaction during treatment with epoetin alfa was dose-dependent increase in blood pressure or worsening of pre-existing arterial hypertension. Blood pressure monitoring should begin almost immediately with the initiation of therapy. Other commonly observed adverse reactions in clinical studies included deep vein thrombosis, pulmonary embolism, seizures, diarrhea, nausea, headache, flu-like symptoms, pyrexia, rash, and vomiting.

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

In studies with extended dosing intervals in adult patients with renal insufficiency not yet on hemodialysis, worsening of airway patency was observed, including nasal congestion and nasopharyngitis.

An increased frequency of thrombotic/vascular complications was observed in patients receiving erythropoiesis-stimulating agents. Serious frequently observed adverse reactions included venous and arterial thrombosis, embolism (including fatal cases), such as deep vein thrombosis, pulmonary embolism, arterial thrombosis (including myocardial infarction and myocardial ischemia), retinal thrombosis, and shunt thrombosis (including occlusion of the dialysis system). Cerebrovascular complications (including stroke and cerebral hemorrhage) and transient ischemic attacks were also observed during clinical trials with epoetin alfa.

Aneurysms and hypersensitivity reactions have been reported, including rash, urticaria, anaphylactic reactions, and angioedema.

In patients treated with epoetin alfa who had previously normal or low blood pressure, hypertensive crisis with encephalopathy and seizures has been observed, requiring immediate medical attention and intensive care. Particular attention should be paid to sudden, acute migraine-like headache as a possible warning sign.

Very rarely, less than 1 in 10,000 cases per year, antibody-mediated pure red cell aplasia was observed after several months or years of treatment with epoetin alfa (identified during the post-marketing period; frequency based on spontaneous reporting estimates).

Blood and lymphatic system disorders

Thrombocytosis (in patients with malignancies), antibody-mediated pure red cell aplasia, thrombocytosis (in patients with CKD).

Immune system disorders

Anaphylactic reaction, hypersensitivity.

Nervous system disorders

Headache (in patients with malignancies and CKD), seizures (in patients with CKD), hemorrhagic stroke¹, seizures (in patients with malignancies), cerebrovascular stroke¹, hypertensive encephalopathy, transient ischemic attacks.

Eye disorders

Retinal vein thrombosis.

Cardiovascular disorders

Deep vein thrombosis of the lower extremities¹ (in patients with malignancies and CKD), increased arterial blood pressure, arterial thrombosis, hypertensive crisis, myocardial infarction.

Respiratory, thoracic and mediastinal disorders

Pulmonary artery thromboembolism¹ (in patients with malignancies and CKD), cough, worsening of airway patency.

Gastrointestinal disorders

Nausea, vomiting, diarrhea (in patients with malignancies and CKD).

Skin and subcutaneous tissue disorders

Rash, angioedema, urticaria.

Musculoskeletal and connective tissue disorders

Arthralgia (in patients with malignancies and CKD), myalgia (in patients with malignancies and CKD), bone and limb pain.

Congenital, familial and genetic disorders

Porphyria.

General disorders and administration site conditions

Flu-like symptoms (in patients with malignancies and CKD), pyrexia (in patients with malignancies and CKD), peripheral edema, injection site reactions, lack of response to treatment.

Investigations

Antibodies to erythropoietin, hyperkalemia.

Other

Shunt thrombosis, including dialysis equipment (in patients with CKD).

¹ Including cases with fatal outcome.

Patients with renal insufficiency

In patients with chronic kidney disease (CKD), hemoglobin levels above 12 g/dL may be associated with an increased risk of cardiovascular complications, including fatal outcomes. In some hemodialysis patients, particularly those with predisposition to arterial hypotension or complications related to arteriovenous fistula (stenosis, aneurysms, etc.), cases of shunt thrombosis have been reported.

Patients with oncological diseases

Thrombotic complications have been observed in patients receiving erythropoiesis-stimulating agents, including epoetin alfa.

Adult surgical patients

In patients undergoing elective orthopedic surgery with stable hemoglobin levels between 10 and 13 g/dL, the frequency of thrombotic/vascular complications (mostly deep vein thrombosis) was similar in the overall group of patients receiving epoetin alfa at various doses and in placebo groups, although clinical experience is limited. Furthermore, in patients with stable hemoglobin levels >13 g/dL, the possibility that epoetin alfa treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded.

Children with chronic kidney disease on hemodialysis

The experience in children with chronic kidney disease on hemodialysis from clinical trials and post-marketing data is limited. In this patient group, no adverse reactions not listed in the table above or inconsistent with the underlying disease have been reported.

Serious skin adverse reactions associated with epoetin alfa use have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be life-threatening or fatal.

Adult patients with low or intermediate risk of myelodysplastic syndrome

In a randomized, double-blind, placebo-controlled multicenter study, thrombotic/vascular complications (sudden death, ischemic stroke, embolism, and phlebitis) occurred in 4 (4.7%) patients. All thrombotic/vascular complications occurred in the epoetin alfa group within the first 24 weeks of the study. Three cases were confirmed as thrombotic/vascular complications, while in the remaining cases (sudden death), thromboembolic complications were not confirmed. Two patients had significant risk factors (atrial fibrillation, heart failure, and thrombophlebitis).

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at 2–8 °C. Do not freeze. Keep out of reach of children.

Packaging.

Dose 16.8 mcg/mL: 0.5 mL (1000 IU) or 1 mL (2000 IU) solution for injection in pre-filled, graduated syringes made of colorless glass, equipped with a plunger with gray rubber stopper, injection needle, gray rubber cap, outer polypropylene cap, and a needlestick injury protection device, or without it.

Carton box containing 2 blister packs with 3 syringes each.

Dose 84 mcg/mL: 0.4 mL (4000 IU), 0.6 mL (6000 IU), 0.8 mL (8000 IU), or 1 mL (10000 IU) solution for injection in pre-filled, graduated syringes made of colorless glass, equipped with a plunger with gray rubber stopper, injection needle, gray rubber cap, outer polypropylene cap, and a needlestick injury protection device, or without it.

Carton box containing 1 blister pack with 1 syringe (0.8 mL or 1 mL), or 2 blister packs with 3 syringes each (0.4 mL, 0.6 mL, 0.8 mL, or 1 mL).

Dose 336 mcg/mL: 0.5 mL (20000 IU), 0.75 mL (30000 IU), or 1 mL (40000 IU) solution for injection in pre-filled, graduated syringes made of colorless glass, equipped with a plunger with gray rubber stopper, injection needle, gray rubber cap, outer polypropylene cap, and a needlestick injury protection device, or without it.

Carton box containing 1 blister pack with 1 syringe, or 2 blister packs with 3 syringes each.

Prescription status. Prescription only.

Manufacturer.

Batch release

Sandoz GmbH – BP Schaftlach.

Manufacturer's location and address of business operations.

Biochemiestrasse 10, 6336 Langkampfen, Austria.