Emaveil
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EMAVAIL (EMAVAIL)
Composition:
Active substance: recombinant human erythropoietin;
1 ml of solution contains recombinant human erythropoietin 2000 IU, 3000 IU, 4000 IU, 10000 IU;
Excipients: human serum albumin, sodium chloride, sodium citrate, citric acid monohydrate, water for injections.
Pharmaceutical form. Solution for injection.
Main physicochemical characteristics: clear, colorless liquid.
Pharmacotherapeutic group. Antianaemic agents. Erythropoietin.
ATC code B03XA01.
Pharmacological properties.
Pharmacodynamics.
Erythropoietin is a glycoprotein hormone predominantly produced by the kidneys in response to hypoxia and plays a key role in the production of red blood cells. Erythropoietin is involved in all stages of erythropoiesis, primarily affecting the maturation of erythroid cells into erythrocytes. After binding of erythropoietin to its receptor on the cell surface, signal transduction is activated, preventing apoptosis and stimulating proliferation of erythroid cells. Recombinant human erythropoietin (epoetin alfa), produced by culturing in Chinese hamster ovary cells, consists of a sequence of 165 amino acids identical to human erythropoietin; the functional properties of these epoetins do not differ. The molecular mass of epoetin alfa is
32,000–40,000 daltons.
Erythropoietin is a growth factor that primarily stimulates the production of red blood cells. Erythropoietin-sensitive receptors may be present on the surface of various tumor cells.
Pharmacokinetics.
Absorption
After subcutaneous administration, serum levels of epoetin alfa reach maximum between 12 and 18 hours after injection. There is no accumulation after repeated administration
of 600 IU/kg subcutaneously once weekly.
The absolute bioavailability of the drug following subcutaneous administration is approximately
20% in healthy volunteers.
Distribution
After intravenous administration of 50 and 100 IU/kg doses to healthy volunteers, the mean volume of distribution was 49.3 ml/kg. After intravenous administration of epoetin alfa to patients with chronic renal failure, the volume of distribution ranged from 57–107 ml/kg after a single dose of 12 IU/kg to
42–64 ml/kg after multiple doses of 48–192 IU/kg, respectively. Thus, the volume of distribution is slightly greater than plasma capacity.
Elimination
The elimination half-life after repeated intravenous administration is approximately 4 hours and about 24 hours after subcutaneous administration in healthy volunteers.
Mean values of apparent clearance with administration regimens of 150 IU/kg three times weekly and 40,000 IU once weekly in healthy volunteers were 31.2 and
12.6 ml/hour/kg, respectively. When the same doses were administered to cancer patients with anemia, apparent clearance values were 45.8 and 11.3 ml/hour/kg, respectively. In most cancer patients with anemia receiving cycles of chemotherapy, subcutaneous administration of erythropoietin at doses of 40,000 IU once weekly and
150 IU/kg three times weekly resulted in lower apparent clearance values compared to those in healthy volunteers.
Linearity/Non-linearity
In healthy volunteers receiving epoetin alfa at doses of 150 and 300 IU/kg intravenously three times weekly, dose-proportional increases in serum concentrations of epoetin alfa were observed. Single subcutaneous administration of doses
of 300–2400 IU/kg epoetin alfa demonstrated linear relationships between mean Cmax and dose, and between mean AUC and dose. In healthy volunteers, an inverse relationship between apparent clearance and administered dose was observed.
In studies evaluating extended-interval dosing regimens
(40,000 IU once weekly and 80,000, 100,000, and 120,000 IU once every two weeks), linear but non-proportional relationships between mean Cmax and dose and between mean AUC and dose at steady state were observed.
Pharmacokinetic/Pharmacodynamic relationship
Epoetin alfa demonstrates dose-dependent effects on hematological parameters regardless of the route of administration.
Children
In children with chronic renal failure, after repeated intravenous administration of epoetin alfa doses, the elimination half-life ranged from 6.2 to 8.7 hours. The pharmacokinetic profile of epoetin alfa in children is similar to that in adults.
Pharmacokinetic data in neonates are limited.
Study data on intravenous administration of erythropoietin in 7 preterm neonates with very low birth weight and 10 healthy adult volunteers demonstrated a 1.5- to 2-fold greater volume of distribution in preterm infants compared to healthy volunteers, and clearance values approximately 3 times higher than in healthy volunteers.
Renal impairment
In patients with chronic renal failure, the elimination half-life of epoetin alfa after intravenous administration is slightly longer compared to healthy volunteers and is approximately 5 hours.
Clinical characteristics.
Indications.
Treatment of symptomatic anemia associated with chronic kidney disease:
- treatment of anemia associated with chronic kidney disease in children and adults on hemodialysis and adult patients on peritoneal dialysis;
- treatment of severe symptomatic renal anemia in adult patients with renal insufficiency who have not yet undergone hemodialysis.
Treatment of anemia and reduction of the volume of required blood transfusions in adult patients receiving chemotherapy due to non-myeloid 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).
Emaweil may be used within a pre-deposit program prior to major surgical interventions in patients with moderate anemia (hemoglobin levels 10–13 g/dL (6.2–8.1 mmol/L), absence of iron deficiency) to facilitate collection of autologous blood and reduce risks associated with allogeneic blood transfusions, when the expected need for blood transfusion exceeds the amount obtainable by autologous blood collection without using epoetin alfa.
Emaweil is indicated for adult patients with mild to moderate anemia (hemoglobin 10–13 g/dL in the absence of iron deficiency) prior to undergoing extensive orthopedic surgery with anticipated moderate blood loss (900–1800 mL of blood) to reduce the need for allogeneic blood transfusions and to facilitate recovery of the erythropoietic system.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Development of pure red cell aplasia (PRCA) due to treatment with any erythropoietin (see section "Special warnings and precautions for use").
Uncontrolled hypertension.
Contraindications related to autologous blood donation programs in patients treated with epoetin alfa.
Severe coronary, peripheral arterial, carotid, or cerebrovascular diseases, as well as recent myocardial infarction or stroke in patients scheduled for major elective orthopedic surgery who have not participated in an autologous blood donation program.
Inability to administer appropriate antithrombotic prophylaxis in surgical patients.
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 treatment with epoetin alfa.
Since cyclosporine binds to erythrocytes, a potential drug interaction may occur. When epoetin alfa and cyclosporine are used concomitantly, cyclosporine blood levels 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 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 and controlled in all patients during treatment with Emaveil. The drug should be used with caution in patients with untreated hypertension, inadequately treated hypertension, or poorly controlled hypertension. Antihypertensive therapy may need to be initiated or intensified during treatment with Emaveil. If blood pressure cannot be controlled, epoetin alfa should be discontinued.
Cases of hypertensive crisis with encephalopathy and seizures requiring immediate medical attention 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, shooting, migraine-like headache, which may be a warning sign (see section "Side effects").
Epoetin alfa should be used with caution in patients with epilepsy, a history of seizures, or medical conditions associated with a predisposition to seizures, such as CNS infections or brain metastases.
Epoetin alfa should be used with caution in patients with chronic hepatic insufficiency. The safety of epoetin alfa in patients with impaired liver function has not been established.
Patients receiving erythropoiesis-stimulating agents have an increased incidence of thrombovascular events (see section "Side effects"), 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 cerebrovascular events (including ischemic stroke, cerebral hemorrhage, and transient ischemic attacks) have also been reported.
The risk of thrombovascular events versus the expected benefit of treatment should be carefully weighed, especially in patients with existing risk factors, including obesity and a 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.
All other causes of anemia (iron deficiency, folic acid deficiency, vitamin B12 deficiency, aluminum toxicity, infection or inflammation, blood loss, hemolysis, or bone marrow fibrosis of any origin) must be identified and treated before initiating epoetin alfa therapy and before deciding to increase the dose. In most cases, serum ferritin levels decreased simultaneously with an increase in hematocrit. To ensure an optimal response to epoetin alfa treatment, adequate iron supply must be ensured (see section "Dosage and administration"):
- Patients with chronic kidney disease are recommended to take iron (200–300 mg/day for adults and 100–200 mg/day for children orally, calculated as elemental iron) if serum ferritin levels are below 100 ng/mL;
- Patients with oncological diseases are recommended to take iron (200–300 mg/day orally, calculated as elemental iron) if transferrin saturation is less than 20%;
- Patients participating in an autologous blood donation program are recommended to take iron (200 mg/day orally, calculated as elemental iron) several weeks before the start of autologous blood collection to achieve significant iron stores before starting therapy and during the course of epoetin alfa treatment;
- Patients undergoing major elective orthopedic surgery are recommended to take iron (200 mg/day orally, calculated as elemental iron) during the course of epoetan alfa treatment. Iron supplementation should be initiated, if possible, before starting epoetin alfa therapy to achieve significant iron stores.
Very rare cases of development or worsening of existing porphyria have been reported in patients receiving epoetin alfa. Epoetin alfa should be used with caution in patients with porphyria.
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 during treatment with long-acting epoetins.
Patients should be informed about signs and symptoms of skin-related adverse reactions, and careful monitoring should be performed. If signs or symptoms suggestive of such reactions occur, Emaveil should be discontinued immediately, and alternative treatments should be considered.
If a patient develops a severe skin reaction, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, while receiving Emaveil, treatment with this drug must not be resumed under any circumstances.
The trade name and batch number of erythropoiesis-stimulating agents used in treatment must be clearly documented in the patient's medical record. Switching a patient from one erythropoiesis-stimulating agent to another is possible only under physician supervision.
True erythrocytic aplasia (PRCA)
Cases of antibody-mediated pure red cell aplasia (PRCA) have been reported after several months or years of subcutaneous administration of epoetin alfa, 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 concomitantly with erythropoiesis-stimulating agents. Epoetin alfa is not indicated 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 of 1–2 g/dL per month) with an increased need for transfusions should be referred for reticulocyte count testing and evaluation for typical causes of reduced clinical response (iron, folic acid, or vitamin B12 deficiency, aluminum toxicity, infection or inflammation, blood loss, hemolysis, or bone marrow fibrosis of any origin).
In the case of paradoxical hemoglobin decrease and development of severe anemia associated with low reticulocyte count, treatment with Emaveil should be discontinued immediately, and testing for anti-erythropoietin antibodies should be performed, along with bone marrow examination 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 patients and children with chronic kidney disease
Patients with chronic kidney disease receiving epoetin alfa should have hemoglobin levels 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 (see section "Dosage and administration"). Clinical trials 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 benefit from using epoetins at hemoglobin concentrations higher than necessary to control anemia symptoms and prevent blood transfusions.
Dose escalation of Emaveil should be performed cautiously in patients with chronic kidney disease, as high cumulative doses of epoetin may be associated with increased risks of mortality, severe cardiovascular, and cerebrovascular events. In cases of inadequate response to epoetin therapy, alternative approaches to managing poor response should be considered (see section "Dosage and administration").
Patients with chronic kidney disease receiving Emaveil subcutaneously should be regularly monitored for loss of treatment efficacy, defined as a decrease or loss of response to epoetin alfa in patients who previously responded to therapy. Loss of efficacy is characterized by a persistent decrease in hemoglobin levels despite increasing doses of epoetin alfa (see section "Side effects").
With extended dosing interval regimens (administration of epoetin alfa less frequently than once weekly), hemoglobin levels may decrease in some patients, who may require dose increases. Hemoglobin levels should be monitored regularly.
Thrombosis of vascular access shunts has been observed in hemodialysis patients, particularly in those prone to hypotension or with complications of arteriovenous fistulas (e.g., stenosis, aneurysms, etc.). Such patients should undergo shunt evaluation and thrombosis prophylaxis, for example, with acetylsalicylic acid.
Hyperkalemia has been observed in isolated cases, although a causal relationship has not been established. Electrolyte levels in serum should be monitored in patients with chronic kidney disease. In case of increased blood potassium levels, in addition to appropriate hyperkalemia treatment, temporary discontinuation of Emaveil should be considered until potassium levels normalize.
Due to increased hematocrit levels, patients on hemodialysis receiving Emaveil often require increased heparin doses during dialysis. Inadequate heparinization may lead to dialysis system occlusion.
According to current information, the use of Emaveil for the treatment of anemia in adult pre-dialysis patients with kidney disease does not accelerate the progression of kidney failure.
Treatment of patients with anemia caused by chemotherapy
In patients with oncological diseases 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 detected on the surface of various tumor cells. As with other growth factors, stimulation of the growth of certain tumor types by epoetins cannot be excluded.
An impact of erythropoiesis-stimulating agents on tumor progression or reduced progression-free survival cannot be excluded. In controlled clinical trials, the use of Emaveil and other erythropoiesis-stimulating agents was associated with reduced locoregional tumor control or overall survival:
- Reduced locoregional control in patients with progressive head and neck cancer receiving radiotherapy when used to increase hemoglobin levels above 14 g/dL (8.7 mmol/L);
- Reduced overall survival and increased number of deaths due to disease progression within 4 months in patients with metastatic breast cancer receiving chemotherapy when used to increase hemoglobin levels to 12–14 g/dL (7.5–8.7 mmol/L);
- Increased risk of mortality when used to increase hemoglobin levels to 12 g/dL (7.5 mmol/L) in patients with active malignant disease not receiving chemotherapy or radiotherapy. Erythropoiesis-stimulating drugs are contraindicated in this patient group;
- 9% increased risk of disease progression or death in the group receiving epoetin alfa and standard treatment, and a 15% increased risk, statistically not excluded, in patients with metastatic breast cancer receiving chemotherapy when used to increase hemoglobin levels to 10–12 g/dL (6.2–7.5 mmol/L).
In view of the above, in certain clinical situations, blood transfusion may be preferred for the treatment of anemia in cancer patients. The decision to use recombinant erythropoietins should be based on an individual benefit-risk assessment for each patient, considering the specific clinical context. Factors to consider in this assessment should include tumor type and stage; degree of anemia; expected life span; treatment setting; and patient preference.
In cancer patients receiving chemotherapy, there is typically a 2–3 week delay between administration of erythropoietin and the appearance of erythropoietin-induced blood cells. This should be considered when evaluating the appropriateness of therapy (especially in patients requiring transfusions).
Patients undergoing surgery and participating in autologous blood donation programs
All special precautions related to autologous blood donation programs, particularly procedures for restoring circulating blood volume, should be observed.
Patients undergoing major elective orthopedic surgery
Appropriate blood transfusion practices should always be followed in the pre- and postoperative periods.
Patients undergoing major elective orthopedic surgery should receive appropriate antithrombotic prophylaxis, as thrombotic and vascular complications may occur after surgery, especially in patients with concomitant cardiovascular diseases. Particular caution should be exercised in treating patients predisposed to deep vein thrombosis. Additionally, the risk of postoperative thrombotic or vascular complications associated with epoetin alfa therapy is significantly higher in patients with an initial hemoglobin level > 13 g/dL. Therefore, the use of epoetin alfa in patients with an initial hemoglobin level > 13 g/dL is not recommended.
This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.
Use during pregnancy or breastfeeding.
Pregnancy
There are currently no controlled studies on the use of Emaveil in pregnant women. Animal studies have shown reproductive toxicity. Therefore, Emaveil should be used in pregnant women only if the potential benefit outweighs the possible risk to the fetus. The use of epoetin alfa in pregnant women participating in an autologous blood donation program before surgery is not recommended.
Breastfeeding period
It is unknown whether exogenous epoetin alfa is excreted in breast milk. Epoetin alfa should be used with caution in women who are breastfeeding. The decision to continue or discontinue breastfeeding or to continue or discontinue epoetin alfa treatment should be made, taking into account the benefits of breastfeeding for the child and the benefits of epoetin alfa treatment for the woman.
The use of epoetin alfa in patients participating in an autologous blood donation program before surgery during breastfeeding is not recommended.
Fertility
No studies on the effect of epoetin alfa on fertility in men or women have been conducted.
Ability to affect reaction speed when driving or operating machinery.
No studies on the effect on reaction speed when driving or operating machinery have been conducted.
Method of Administration and Dosage
Epoetin alfa can be administered by subcutaneous and intravenous injections.
As with any parenteral medicinal product, the epoetin alfa solution should be inspected visually for particulate matter and discoloration prior to administration.
Intravenous administration
Epoetin alfa is administered by injection over a period of 1 to 5 minutes, depending on the dose. For patients undergoing hemodialysis, the bolus injection can be administered directly during the dialysis procedure via the venous access port in the dialysis line. Alternatively, the drug may be administered at the end of the hemodialysis session through the fistula or catheter, followed by a 10 mL flush with isotonic sodium chloride solution to ensure proper delivery and distribution into the circulation.
Slow intravenous injection is preferred for patients experiencing symptoms resembling flu-like reactions.
Epoetin alfa must not be administered as an intravenous infusion or mixed with other medicinal products.
Subcutaneous administration
The maximum volume for subcutaneous injection at a single site is 1 mL. If larger volumes are required, multiple injection sites should be used.
The subcutaneous injection 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 Emawayl subcutaneously, they should be properly instructed on correct dosing and administration techniques.
Treatment of symptomatic anemia in adult and pediatric patients with chronic kidney disease
For patients with chronic kidney disease, intravenous administration is preferred when feasible (e.g., patients on hemodialysis). In cases where intravenous administration is not practical (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.
Emawayl should be used to increase hemoglobin levels to no more than 12 g/dL (7.5 mmol/L). Increases in hemoglobin levels exceeding 2 g/dL (1.25 mmol/L) within a 4-week period should be avoided. If such increases occur, the dose should be reduced as described below.
Due to individual variability, hemoglobin levels may fluctuate above or below the target range in individual patients.
Hemoglobin levels should be monitored and the dose adjusted accordingly to maintain levels between 10 g/dL (6.2 mmol/L) and 12 g/dL (7.5 mmol/L). In pediatric patients, the recommended target hemoglobin range is 9.5–11 g/dL (5.9–6.8 mmol/L).
Sustained hemoglobin levels above 12 g/dL (7.5 mmol/L) should be avoided. If hemoglobin concentration increases by at least 2 g/dL (1.25 mmol/L) per month or sustained levels exceed 12 g/dL (7.5 mmol/L), the epoetin dose should be reduced by 25%. If hemoglobin levels exceed 13 g/dL (8.1 mmol/L), treatment should be discontinued until hemoglobin decreases to 12 g/dL (7.5 mmol/L), after which therapy should be resumed at a dose 25% lower than the previous dose.
Patients should be closely monitored to ensure that the lowest approved erythropoiesis-stimulating agent dose provides adequate control of anemia symptoms.
Serum ferritin (or serum iron concentration) should be measured in all patients before initiating and during treatment with Emawayl. Iron supplementation should be administered as needed. Other types of anemia (e.g., vitamin B12 or folic acid deficiency) must be ruled out prior to initiating Emawayl therapy. Lack of clinical response to Emawayl requires investigation of potential underlying causes, such as iron, folic acid, or vitamin B12 deficiency, aluminum intoxication, intercurrent infections, inflammatory conditions, trauma, hemolysis, or bone marrow fibrosis of any etiology.
Adult patients on hemodialysis
For patients undergoing hemodialysis, the drug is administered intravenously.
Treatment is divided into two phases.
Correction phase
50 IU/kg three times weekly.
If necessary, the dose may be increased stepwise (no more frequently than once every 4 weeks) by 25 IU/kg three times weekly until the optimal hemoglobin concentration (10–12 g/dL, or 6.2–7.5 mmol/L) is achieved.
Maintenance phase
Dose adjustment to maintain the desired hemoglobin level (Hb) between 10 and 12 g/dL (6.2–7.5 mmol/L).
The recommended weekly dose ranges from 75 to 300 IU/kg.
Available data suggest that patients with very low initial hemoglobin levels (< 6 g/dL, or < 3.75 mmol/L) may require higher maintenance doses to achieve the target concentration compared to patients with less severe anemia (hemoglobin > 8 g/dL, or > 5 mmol/L).
Pediatric patients on hemodialysis
Treatment is divided into two phases.
Correction phase
50 IU/kg three times weekly, administered intravenously.
If necessary, dose increases may be made 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 (Hb) between 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 weighing over 30 kg. Clinical studies after 6 months of treatment established the following maintenance doses of epoetin alfa:
| Body weight (kg) |
Dose (IU/kg for 3 weeks) |
|
| 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 the desired concentration compared to patients with less severe anemia (hemoglobin > 6.8 g/dL or > 4.25 mmol/L).
Adult patients with renal insufficiency in the pre-dialysis period
For patients with renal insufficiency in the pre-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 per week.
Dose adjustments may be necessary by increasing the dose by 25 IU/kg three times per week, with intervals between increases of at least 4 weeks, until hemoglobin levels reach 10–12 g/dL (6.2–7.5 mmol/L).
Maintenance phase
During the maintenance phase, Emoveyel can be administered three times per week, or, in the case of subcutaneous administration, once per week or once every two weeks. Doses and intervals between administrations should be adjusted to maintain the desired hemoglobin (Hb) level of 10 to 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 per week, 240 IU/kg (maximum up to 20,000 IU) once per week, or 480 IU/kg (maximum up to 40,000 IU) once every two weeks.
Adult patients undergoing peritoneal dialysis
For patients undergoing peritoneal dialysis, if intravenous access is not available, the drug may be administered subcutaneously.
Treatment is divided into two phases.
Correction phase
50 IU/kg twice per week.
Maintenance phase
The usual dose to maintain the desired hemoglobin (Hb) level of 10 to 12 g/dL (6.2–7.5 mmol/L) is 25 to 50 IU/kg twice per week, 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 Emoveyel subcutaneously. Symptoms of anemia and complications may vary depending on the patient's age, sex, and disease-related conditions; therefore, individual clinical assessment by the physician is necessary.
Due to individual variability, periodic hemoglobin levels in each patient may be higher or lower than the desired level. Hemoglobin levels should be monitored and the dose adjusted accordingly, aiming to maintain levels between 10 g/dL (6.2 mmol/L) and 12 g/dL (7.5 mmol/L). Sustained hemoglobin levels above 12 g/dL (7.5 mmol/L) should be avoided. Instructions for dose adjustment when hemoglobin levels exceed 12 g/dL (7.5 mmol/L) are described below.
Epoetin alfa therapy should be continued for one month after discontinuation of chemotherapy.
The initial dose for treating anemia in this patient group is 150 IU/kg three times per week. As an alternative, epoetin alfa may be administered at an initial dose of 450 IU/kg subcutaneously once per week.
If, after 4 weeks of initial dose administration, hemoglobin levels increase 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 per week or 450 IU/kg subcutaneously once per week. If, after 4 weeks of initial dose administration, hemoglobin levels increase 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 per week or 40,000 IU once per week.
If, after 4 weeks of treatment with the increased dose of 300 IU/kg three times per week, hemoglobin levels increase by ≥ 1 g/dL (≥ 0.62 mmol/L) or reticulocyte count increases to ≥ 40,000 cells/mL, the dose should remain unchanged. However, if hemoglobin levels increase by < 1 g/dL (< 0.62 mmol/L) or reticulocyte count increases by < 40,000 cells/mL, the clinical response is considered negative and treatment should be discontinued. Recommended dosing regimen:
Patients should be closely monitored to ensure that the lowest approved dose of erythropoiesis-stimulating agents provides adequate control of anemia symptoms.
Dose adjustment to maintain target hemoglobin level of 10–12 g/dL
If the rate of hemoglobin increase exceeds 2 g/dL (1.25 mmol/L) per month and the total hemoglobin level approaches 12 g/dL (7.5 mmol/L), the dose of Emoveyel should be reduced by 25–50%, depending on the rate of hemoglobin increase. If hemoglobin levels exceed 13 g/dL (8.1 mmol/L), therapy should be temporarily discontinued until levels decrease to 12 g/dL (7.5 mmol/L), after which 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 is recommended. Epoetin alfa should be administered after each blood donation procedure.
Patients with moderate anemia (hematocrit level 33–39%) who require ≥ 4 units of blood should be treated with epoetin alfa at a dose of 600 IU/kg twice per week for 3 weeks prior to surgery. Using this regimen, ≥ 4 units of blood can be collected in 81% of patients treated with epoetin alfa compared to 37% of patients treated with placebo. Epoetin alfa therapy reduces the risk of allogeneic blood transfusion by 50% compared to patients not receiving epoetin alfa.
All patients receiving epoetin alfa require 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.
Adult patients undergoing elective orthopedic surgery
Subcutaneous administration is recommended.
The recommended dosing regimen is 600 IU/kg per week for 3 weeks prior to surgery (on days 21, 14, and 7 before surgery) and on the day of surgery.
If, for medical reasons, the preoperative period needs to be shortened to less than 3 weeks, Emoveyel should be administered daily at a dose of 300 IU/kg for 10 consecutive days before surgery, on the day of surgery, and for 4 days after surgery. If hematological tests during the preoperative period show hemoglobin levels reaching 15 g/dL or higher, epoetin alfa administration must be completely discontinued.
All patients receiving epoetin alfa require 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.
Children.
Epoetin alfa is indicated for the treatment of anemia caused by chronic renal insufficiency in children aged 1 to 18 years who are on dialysis.
Overdose.
Epoetin alfa has a wide therapeutic window. Overdose effects reflect the maximum expression of the hormone's pharmacological activity. In cases of excessively high hemoglobin levels, phlebotomy may be performed. Symptomatic therapy may be applied if necessary.
Adverse Reactions
The most common adverse reaction during treatment with epoetin alfa in oncology patients and patients with chronic renal failure is dose-dependent increase in arterial blood pressure or worsening of pre-existing hypertension. Blood pressure should be monitored carefully, especially at the beginning of treatment (see section "Special Warnings and Precautions for Use").
The most frequently observed adverse reactions during clinical trials with epoetin alfa were diarrhea, nausea, vomiting, fever, headache, deep vein thrombosis, pulmonary embolism, convulsions, pyrexia, and rash. Influenza-like symptoms may occur, particularly at the beginning of treatment, including headache, joint and muscle pain, and chills.
During studies evaluating extended dosing intervals of the drug in adult patients with renal insufficiency during the pre-dialysis period, deterioration of airway patency was observed, including upper airway obstruction, nasal congestion, and nasopharyngitis.
In patients receiving treatment with erythropoiesis-stimulating agents, an increased incidence of thrombovascular complications has been observed (see section "Special Warnings and Precautions for Use").
Serious 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 dialysis system occlusion). Cerebrovascular complications (including stroke and cerebral hemorrhage) and transient ischemic attacks, as well as aneurysms and hypersensitivity reactions including rash, urticaria, anaphylactic reactions, and angioneurotic edema, were observed during clinical trials with epoetin alfa.
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 warning sign.
Very rarely (< 1/10,000 patients per year), antibody-mediated pure red cell aplasia has been observed after several months or years of treatment with Eprex.
The overall safety profile of epoetin alfa was evaluated based on data from 2094 patients with anemia out of 3417 patients enrolled in 25 clinical trials. The analysis included data from 228 patients who received epoetin alfa in 4 studies on chronic renal failure [2 studies in pre-dialysis patients (n = 131) and 2 studies in dialysis patients (n = 97)]; 1404 oncology patients who received epoetin alfa in 16 studies on chemotherapy-induced anemia; 147 patients who received epoetin alfa in 2 autologous blood donation studies; 213 patients who received epoetin alfa in 1 study on perioperative use of epoetin alfa; and 102 patients who received epoetin alfa in 2 studies on MDS (myelodysplastic syndrome). The adverse reactions observed with a frequency ≥ 1% in patients receiving epoetin alfa during clinical trials are listed in the table below.
Frequency is defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); unknown (cannot be estimated from available data).
| System organ |
Adverse reaction |
Frequency |
| Blood and lymphatic system disorders |
pure red cell aplasia3, thrombocythemia |
uncommon |
| Metabolism and nutrition disorders |
hyperkalaemia1 |
uncommon |
| Immune system disorders |
hypersensitivity3 |
uncommon |
| anaphylactic reactions3 |
rare |
|
| Nervous system disorders |
headache, stroke |
common |
| seizures, cerebral haemorrhage |
uncommon |
|
| cerebrovascular accident, hypertensive encephalopathy, transient ischaemic attack |
unknown |
|
| Eye disorders |
retinal thrombosis |
unknown |
| Vascular disorders |
arterial hypertension, venous and arterial thrombosis2 |
common |
| hypertensive crisis3 |
unknown |
|
| Respiratory, thoracic and mediastinal disorders |
cough, pulmonary embolism |
common |
| worsening of airway patency |
uncommon |
|
| Gastrointestinal disorders |
diarrhoea, nausea, vomiting |
very common |
| Skin and subcutaneous tissue disorders |
rash |
common |
| urticaria3 |
uncommon |
|
| angioneurotic oedema3 |
unknown |
|
| Musculoskeletal and connective tissue disorders |
arthralgia, bone pain, myalgia, limb pain |
common |
| Congenital, hereditary/genetic disorders |
acute porphyria3 |
rare |
| General disorders and administration site reactions |
fever |
very common |
| chills, influenza-like condition, injection site reactions, peripheral oedema |
common |
|
| lack of response to treatment3 |
unknown |
|
| Investigations |
presence of anti-erythropoietin antibodies |
rare |
| Injury, poisoning and procedural complications |
shunt thrombosis, including dialysis equipment |
common |
1 Frequent in patients undergoing haemodialysis.
2 Including arterial and venous events, with and without fatal outcome, such as deep vein thrombosis, pulmonary embolism, retinal thrombosis, arterial thrombosis (including myocardial infarction), cerebrovascular events (including ischaemic stroke, cerebral haemorrhage), transient ischaemic attacks, shunt thrombosis (including dialysis equipment) and thrombosis at the site of arteriovenous anastomosis.
3 See section "Description of selected adverse reactions" below and section "Special warnings and precautions for use".
Description of selected adverse reactions
Hypersensitivity reactions have been reported, including cases of rash (e.g. urticaria), anaphylactic reactions and angioneurotic oedema (see section "Special warnings and precautions for use").
Cases of hypertensive crisis with encephalopathy and seizures requiring immediate medical attention 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 a shooting, migraine-like headache, which may be a warning sign (see section "Special warnings and precautions for use").
Treatment-related severe skin reactions, including Stevens−Johnson syndrome and toxic epidermal necrolysis, which may be life-threatening or fatal, have been reported in patients treated with erythropoietin-stimulating agents (see section "Special warnings and precautions for use").
Very rare cases (< 10,000 cases per patient-year) of antibody-mediated pure red cell aplasia (PRCA) have been reported in patients treated with Emovey for months or years (see section "Special warnings and precautions for use").
Adult patients with low or intermediate-1 risk MDS
In a randomized, double-blind, placebo-controlled study, 4 (4.7 %) patients experienced thrombovascular events (sudden death, ischaemic stroke, embolism and phlebitis). All thrombovascular events occurred in the epoetin alfa treatment group within the first 24 weeks of treatment. Three cases of thrombovascular events were confirmed; the fourth case (sudden death) was not confirmed. Two patients had significant risk factors (atrial fibrillation, heart failure and thrombophlebitis).
Children with chronic kidney disease on haemodialysis
Experience with the use of Emovey in children with chronic kidney disease on haemodialysis during clinical studies and in the post-marketing period is limited. No adverse reactions specific to paediatric patients not listed in the table have been identified; nor have any adverse reactions been identified that do not correspond to the underlying disease.
Patients with kidney disease
In patients with chronic kidney disease, haemoglobin levels above 12 g/dl may be associated with an increased risk of cardiovascular complications, including fatal outcomes.
Cases of shunt thrombosis have been described in some patients on haemodialysis, particularly in patients with a tendency to hypotension or in the presence of complications related to arteriovenous fistula (stenoses, aneurysms, etc.).
Patients with oncological diseases
Thrombotic complications have been observed in patients receiving therapy with erythropoiesis-stimulating agents, including epoetin alfa (see section "Special warnings and precautions for use").
Adult surgical patients
In patients with stable haemoglobin levels between 10 and 13 g/dl undergoing elective orthopaedic surgery, the frequency of thrombotic/vascular complications (most of which were deep vein thrombosis) was similar across different epoetin alfa dose groups and placebo groups, despite limited clinical experience.
Furthermore, in patients with stable haemoglobin levels > 13 g/dl, the possibility that treatment with epoetin alfa may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are required to report any suspected adverse reactions via the national pharmacovigilance system.
Shelf life. 2 years.
Storage conditions.
Store at 2 °C to 8 °C in the original packaging. The cold chain must be maintained during use of the medicinal product. Do not shake or freeze. Keep out of reach of children.
Syringes intended for use or that may be used should be stored at room temperature (not above 25 °C) for a maximum single period of 7 days.
Incompatibilities.
As compatibility studies have not been conducted, the medicinal product must not be mixed with other medicinal products.
Packaging.
1 ml in pre-filled syringes. 1 syringe in a blister pack. 1 blister pack in a carton.
Prescription status. Prescription only.
Manufacturer.
Shenyang Sunshine Pharmaceutical Co., Ltd.
Manufacturer's address.
No.3 A 1, Road 10, Economy and Technology Development Zone, Shenyang, People’s Republic of China.
Marketing Authorization Holder.
Yuria-Pharm LLC.
Marketing Authorization Holder's address.
10 M. Amosova St., Kyiv, 03680, Ukraine.