Eprex^® (Solution) Instructions for Use

ATC Code

B03XA01 (Erythropoietin)

Active Substance

Epoetin alfa (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Erythropoiesis stimulant

Pharmacotherapeutic Group

Hematopoiesis stimulant

Pharmacological Action

Erythropoiesis stimulator. It is a purified glycoprotein. It affects the division and differentiation of progenitor cells. Epoetin alfa is produced by mammalian cells with an integrated gene encoding the synthesis of human erythropoietin. In its biological properties, Epoetin alfa does not differ from human erythropoietin.

The protein fraction constitutes about 58% of the molecular mass and consists of 165 amino acids. Four carbohydrate chains are attached to the protein by three N-glycosidic bonds and one O-glycosidic bond. The molecular weight of erythropoietin is approximately 32,000-40,000 Daltons.

After administration of the drug, the number of erythrocytes, reticulocytes, hemoglobin level, and the rate of ⁵⁹Fe uptake increase. In bone marrow cell culture, it has been shown that Epoetin alfa selectively stimulates erythropoiesis without affecting leukopoiesis.

Epoetin alfa has a minimal ability to induce antibody formation.

No carcinogenicity studies have been conducted.

Epoetin alfa does not cause mutations in bacterial genes (Ames test), chromosomal aberrations in mammalian cells, or mutations in the HGPRT locus genes.

One study revealed no difference in the frequency of bone marrow fibrosis in dialysis patients treated with Epoetin alfa for three years and in similar patients not treated with Epoetin alfa.

Pharmacokinetics

Absorption and Distribution

The serum concentration of the drug after s/c administration is significantly lower than after i/v administration. After s/c administration, C_max is reached in 12-18 hours. V_d is approximately equal to the plasma volume. The bioavailability of the drug after s/c administration is about 25%.

Elimination

T_1/2 after i/v administration is 5-6 hours, regardless of the severity of the disease. T_1/2 after s/c administration is approximately 24 hours.

Indications

• Anemia associated with chronic renal failure in adults and children (including patients on hemodialysis or peritoneal dialysis);
• Anemia in cancer patients with non-myeloid tumors (for prevention and treatment);
• Anemia in HIV-infected patients receiving zidovudine therapy, with an endogenous erythropoietin level of less than 500 IU/ml;
• As part of a predeposit program prior to major surgical intervention in patients with a hematocrit level of 33-39% to facilitate the collection of autologous blood and reduce the risk associated with the use of allogeneic hemotransfusions, if the expected need for blood transfusion exceeds the amount that can be obtained by autologous collection without the use of epoetin alfa;
• Prior to major surgery with an expected blood loss of 900-1800 ml (2-4 units) in adult patients without anemia or with mild to moderate anemia (hemoglobin level 100-130 g/l) to reduce the need for allogeneic hemotransfusions and facilitate the recovery of erythropoiesis.

ICD codes

Dosage Regimen

Solution

Before use, the solution should be carefully inspected for visible particles or color change. The drug should not be shaken, as this may lead to denaturation of the glycoprotein and loss of drug activity. Eprex^® does not contain preservatives, so the individual packaging is intended for single use only.

I/V administration

The duration of the injection is at least 1-5 minutes. Slower administration is preferable for patients who experience the development of a flu-like syndrome upon drug administration.

For patients on hemodialysis, the drug injection is performed through the needle into the fistula after the dialysis procedure. To rinse the connecting tubes and ensure satisfactory administration of the drug into the circulation system, 10 ml of isotonic sodium chloride solution is administered after the injection of Eprex^®.

It is forbidden to administer the drug as an i/v infusion or mix it with other medicines.

S/C administration

The maximum volume of a single s/c injection should not exceed 1 ml; if it is necessary to administer larger volumes, several injection sites should be used. The drug is administered under the skin of the shoulder, thigh, or anterior abdominal wall.

When changing the method of administration, the drug is administered at the previous dose, then the dose is adjusted if necessary (to achieve the same therapeutic effect with s/c administration, a dose 20-30% lower than with i/v administration is required).

Patients with chronic renal failure

In patients with chronic renal failure, Eprex^® can be used i/v and s/c. I/V administration of the drug is preferable for patients on hemodialysis. In patients with chronic renal failure not receiving dialysis and in patients on peritoneal dialysis, the drug can be administered s/c.

The optimal hemoglobin level for adult patients is 100-120 g/l, for children — 95-110 g/l.

If patients have concomitant clinically significant coronary artery disease or chronic heart failure, the maintained hemoglobin level should not exceed the upper limit of the optimal value.

The drug dose is 50 IU/kg of body weight. During dose selection, the dose of Eprex^® is increased if the hemoglobin level increases by less than 10 g/l per month.

Adult patients on hemodialysis

In this category of patients, Eprex^® is preferably administered i/v.

Treatment is divided into two phases: the anemia correction phase and the maintenance phase.

Anemia correction phase

Eprex^® is administered at a dose of 50 IU/kg of body weight 3 times a week. If necessary, the dose can be increased (no more than once every 4 weeks) by 25 IU/kg of body weight 3 times a week until the optimal hemoglobin level is reached.

Maintenance therapy

The dose for maintaining the optimal hemoglobin level is 30-100 IU/kg of body weight 3 times a week. Available data suggest that patients with severe anemia (hemoglobin level less than 60 g/l) require a higher maintenance dose.

Adult patients on peritoneal hemodialysis

In this category of patients, the drug can be used i/v and s/c.

Anemia correction phase

The drug is administered at a dose of 50 IU/kg of body weight 2 times a week. If necessary, the dose can be gradually increased by 25 IU/kg of body weight (no more than once every 4 weeks) 2 times a week until the optimal hemoglobin level is reached.

Maintenance therapy

The usual dose for maintaining the optimal hemoglobin level is from 25-50 IU/kg of body weight 2 times a week.

Adult patients with chronic renal failure not receiving dialysis

In this category of patients, the drug can be used i/v and s/c.

Anemia correction phase

Eprex^® is administered at a dose of 50 IU/kg of body weight 3 times a week. If necessary, the dose can be increased (no more than once every 4 weeks) by 25 IU/kg of body weight 3 times a week until the optimal hemoglobin level is reached.

Maintenance therapy

The usual dose for maintaining the optimal hemoglobin level is 17-33 IU/kg of body weight 3 times a week.

Children on hemodialysis, regardless of age

Anemia correction phase

Eprex^® is administered at a dose of 50 IU/kg of body weight 3 times a week i/v. If necessary, the dose can be increased (no more than once every 4 weeks) by 25 IU/kg of body weight 3 times a week until the optimal hemoglobin level is reached.

Maintenance phase

Usually, children weighing less than 30 kg require a higher maintenance dose than adults and children weighing more than 30 kg. In clinical studies, after six months of therapy with Eprex^®, the following maintenance doses of epoetin alfa were established.

Available data suggest that patients with severe anemia (hemoglobin level less than 68 g/l) require a higher maintenance dose than patients with less severe anemia.

Patients suffering from cancer

For the treatment of anemia in cancer patients, Eprex^® is administered s/c.

The optimal hemoglobin level should be 120 g/l in men and women and should not be exceeded. Eprex^® can be prescribed to patients with symptomatic anemia, for the prevention of anemia in patients receiving chemotherapy and having a baseline low hemoglobin level during the first course of chemotherapy (for example, a decrease in hemoglobin level by 10-20 g/l with a baseline hemoglobin level of 110-130 g/l or a decrease of more than 20 g/l with a baseline hemoglobin level above 130 g/l).

The initial dose, for prevention or treatment of anemia, should be 150 IU/kg of body weight 3 times a week. Alternatively, the initial dose can be 450 IU/kg of body weight once a week s/c. If after 4 weeks of treatment the hemoglobin level has increased by at least 10 g/l or the reticulocyte count has increased by more than 40,000 cells/µl above the baseline level, then the dose of Eprex^® remains the same (150 IU/kg of body weight) or 450 IU/kg of body weight once a week. If after 4 weeks of treatment the increase in hemoglobin level is less than 10 g/l and the increase in reticulocyte count is less than 40,000 cells/µl compared to the baseline level, then over the next 4 weeks the dose is increased to 300 IU/kg of body weight. If after an additional 4 weeks of treatment at a dose of Eprex^® 300 IU/kg the hemoglobin level has increased by at least 10 g/l or the reticulocyte count has increased by more than 40,000 cells/µl, then the existing dose of Eprex^® (300 IU/kg of body weight) is maintained. If after 4 weeks of treatment at a dose of 300 IU/kg of body weight the hemoglobin level increases by less than 10 g/l and the increase in reticulocyte count is less than 40,000 cells/µl compared to the baseline level, treatment should be discontinued. In case of an increase in hemoglobin by more than 20 g/l within a month or achievement of hemoglobin of 120 g/l, the drug dose must be reduced by 25%. If the hemoglobin level exceeds 120 g/l, it is necessary to suspend treatment until the hemoglobin level decreases below 120 g/l and then continue the administration of Eprex^® at a dose 25% lower than the initial dose.

Therapy with Eprex^® should continue for one month after the end of the chemotherapy course.

Serum ferritin level (or serum iron level) must be determined in all patients before starting and during treatment with Eprex^®. If necessary, additional iron intake is prescribed.

HIV-infected patients receiving zidovudine therapy

It is recommended to determine the baseline level of endogenous erythropoietin in the blood serum before starting treatment with Eprex^®. Conducted studies show that at an erythropoietin level of more than 500 IU/ml, the effect of therapy with Eprex^® is unlikely.

Anemia correction phase

The drug is prescribed at a dose of 100 IU/kg of body weight 3 times a week s/c or i/v for 8 weeks. If after 8 weeks of therapy a satisfactory effect has not been achieved (for example, to reduce the need for hemotransfusions or to achieve an increase in hemoglobin level), the dose can be gradually increased (no more than once every 4 weeks) by 50-100 IU/kg of body weight 3 times a week. If a satisfactory effect from therapy with Eprex^® at a dose of 300 IU/kg of body weight 3 times a week has not been achieved, then a response to further therapy at higher doses is unlikely.

Maintenance phase

After achieving a satisfactory effect in the anemia correction phase, the maintenance dose should ensure a hematocrit level within 30-35%, depending on changes in the zidovudine dose, the presence of concomitant infectious or inflammatory diseases. If the hematocrit is more than 40%, the administration of Eprex^® should be discontinued until the hematocrit decreases to 36%. When resuming therapy, the dose of epoetin alfa should be reduced by 25% with subsequent adjustment to maintain the required hematocrit level. The hemoglobin level in HIV-infected patients receiving zidovudine therapy should not exceed 120 g/l.

Serum ferritin level (or serum iron level) must be determined in all patients before starting and during treatment with Eprex^®. If necessary, additional iron intake is prescribed.

Adult patients participating in an autologous blood collection program before surgical interventions

It is recommended to use i/v administration of the drug.

Epoetin alfa should be administered after the blood collection procedure. Before prescribing Eprex^®, all contraindications to autologous blood collection should be taken into account. Before surgery, Eprex^® should be prescribed 2 times a week for 3 weeks. At each doctor’s visit, a portion of blood is taken from the patient (if hematocrit ≥33% and/or hemoglobin level ≥110 g/l) and stored for autologous transfusion. The recommended dose of Eprex^® is 600 IU/kg of body weight 2 times a week.

Serum ferritin level (or serum iron level) must be determined in all patients before starting and during treatment with Eprex^®. If necessary, additional iron intake is prescribed.

If anemia is present, its cause must be established before starting therapy with Eprex^®. Adequate iron intake must be ensured as soon as possible by prescribing an oral iron preparation at a dose of 200 mg/day (based on ferrous iron) and maintaining iron intake at this level throughout the entire course of therapy.

Patients in the pre- and postoperative period, not participating in an autologous blood collection program

It is recommended to use s/c administration of the drug at a dose of 600 IU/kg of body weight per week for 3 weeks preceding the surgery (21st, 14th, and 7th days before the operation), and on the day of the operation. If necessary, when for medical reasons it is necessary to shorten the preoperative period, Eprex^® can be prescribed daily at a dose of 300 IU/kg of body weight for 10 days before the operation, on the day of the operation, and for 4 days after the operation. If the hemoglobin level in the preoperative period reaches 150 g/l and above, the use of epoetin alfa should be discontinued. Before starting therapy with epoetin alfa, it is necessary to ensure that patients do not have iron deficiency.

All patients should receive an adequate amount of iron (orally 200 mg/day based on ferrous iron) throughout the entire course of treatment. If possible, additional oral iron intake should be ensured before starting therapy with Eprex^® to provide adequate iron stores in the patient’s body.

Rules for self-administration of the drug

When administering Eprex^® s/c, the amount of drug administered is usually no more than 1 ml per single injection. Eprex^® is prescribed separately; it is not allowed to mix it with other injection solutions.

Do not shake syringes or vials with Eprex^®. Prolonged vigorous shaking may damage the product. If the product has been shaken vigorously, it should not be used.

The syringes are equipped with a PROTECS^® needle protection device to prevent needle injury after its use (this is also indicated on the cardboard box).

1. Remove the syringe from the refrigerator. The solution must be brought to room temperature (for 15-30 minutes).
2. Check the syringe for correct dosage, expiration date, absence of damage, as well as the clarity of the solution and the absence of its freezing.
3. Choose the injection site. Suitable sites for injection are the upper thigh area and the anterior abdominal wall, except for the periumbilical area. Injection sites should be alternated daily.
4. Wash your hands. Clean the injection site with an antiseptic swab to disinfect it.
5. Remove the packaging from the syringe, holding the syringe body and pulling off the packaging without twisting it. It is forbidden to press the plunger, touch the needle, or shake the syringe.
6. Form a skin fold between the thumb and forefinger. Do not squeeze it.
7. Insert the needle to its full length.
8. Determine the likelihood of puncturing a blood vessel. Gently pull back the plunger. If blood enters the syringe, the needle should be removed and an attempt should be made to perform the injection at another site.
9. Press the plunger all the way down to inject the entire solution. It should be pressed without effort and evenly, continuing to hold the skin fold. The needle protection device is not activated until the full dose is administered.
10. With the plunger pushed as far as possible, remove the needle and release the skin fold.
11. Remove the thumb from the plunger. Allow the needle to move until it is completely covered by the protective cap.
12. Press an antiseptic swab to the injection site for a few seconds after completion.
13. Place the used syringe into a safety container.

Only one dose from each syringe should be used. If solution remains in the syringe after injection, the syringe must still be discarded and not reused.

Predominantly at the beginning of treatment, an influenza-like syndrome may develop: dizziness, drowsiness, fever, headache, joint and muscle pain, weakness.

From the cardiovascular system most frequently – dose-dependent increase in BP, worsening of arterial hypertension (most often in patients with chronic renal failure); rarely – hypertensive crisis (malignant arterial hypertension) with symptoms of encephalopathy (headache, confusion) and generalized tonic-clonic seizures (even in patients with normal BP before treatment with epoetin alfa).

From the blood coagulation system rarely – thrombocytosis, shunt thrombosis (in patients on hemodialysis, especially those prone to arterial hypotension or having complications of the arteriovenous fistula, including stenosis, aneurysm); myocardial ischemia, myocardial infarction, stroke, transient ischemic attack, deep vein thrombosis, arterial thrombosis, pulmonary embolism, arterial aneurysms, retinal vessel thrombosis, and clogging of the artificial kidney system.

In rare cases, patients with chronic renal failure receiving erythropoietin for several months or years may develop partial red cell aplasia (erythroblastopenia).

Allergic reactions most frequently – skin rash, eczema, urticaria, pruritus; in some cases – anaphylactoid reactions, angioedema.

Local reactions hyperemia, burning, mild or moderate pain at the injection site may occur (more common with SC administration).

Other rarely – potentially serious complications associated with respiratory distress or decreased BP; immune reactions to drug administration.

Contraindications

• Patients with partial red cell aplasia who have received therapy with any erythropoietin;
• Uncontrolled arterial hypertension;
• Severe pathology of coronary, carotid, cerebral, and peripheral vessels, including recently experienced myocardial infarction or acute cerebrovascular accident (within the framework of a predeposit blood collection program before major surgery);
• Patients who, for any reason, are unable to receive adequate prophylactic antithrombotic therapy;
• Pregnancy;
• Period of lactation (breastfeeding);
• Hypersensitivity to the components of the drug.

Eprex^® should be used with caution in patients with epileptic syndrome (including history), epilepsy, thrombocytosis, thrombosis (in history), obliterating peripheral vascular diseases and other vascular complications, gout, sickle cell anemia, in iron deficiency, B₁₂-deficiency or folate deficiency states, coronary artery disease.

In patients with diagnosed porphyria, the drug should be used with great caution, as in rare cases, patients with hepatic insufficiency may experience exacerbation of porphyria when using Eprex^®.

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

Use in Pregnancy and Lactation

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

The use of Eprex^® during pregnancy and lactation is contraindicated.

The teratogenicity of the drug in humans has not been studied.

It is not known whether the drug is excreted in breast milk, therefore, when treating with Eprex^®, breastfeeding must be discontinued.

In experimental studies in rats and rabbits, no teratogenic effect of epoetin alfa was found.

Use in Renal Impairment

In patients with chronic renal failure on hemodialysis, or without hemodialysis, in children on hemodialysis, regardless of age, Eprex^® must be administered IV. SC administration is not permitted.

Pediatric Use

Use is possible according to the dosing regimen.

Geriatric Use

Use is possible according to the dosing regimen.

Special Precautions

If a patient with chronic renal failure experiences a sharp decrease in the effectiveness of erythropoietin therapy (defined as a decrease in hemoglobin content by 10-20 g/L over one month with an increased need for transfusions), it is necessary to determine the reticulocyte count and conduct an examination to identify one of the typical causes of resistance (iron deficiency, folic acid, or vitamin B₁₂ deficiency, severe aluminum intoxication, concomitant infectious or inflammatory processes, bleeding, hemolysis). If the reticulocyte count is less than 20,000/µL (or less than 0.5%), the platelet and leukocyte counts are normal and if there are no other causes of loss of effectiveness, it is necessary to test for the presence of antibodies to erythropoietin and examine the bone marrow to diagnose partial red cell aplasia.

If partial red cell aplasia is suspected, treatment with epoetin alfa should be stopped immediately. Similar drugs should not be prescribed due to the possibility of cross-reactivity of antibodies to erythropoietin with other erythropoietins. If indicated, appropriate therapy (hemotransfusions) may be performed.

In patients with chronic renal failure receiving Eprex^® as SC injections, it is necessary to regularly monitor the effectiveness of therapy, defined as the absence or decrease in response to erythropoietin administration in patients who were previously susceptible to this therapy.

To reduce the risk of arterial hypertension, the rate of increase in hemoglobin level should be approximately 10 g/L (maximum 20 g/L) per month.

For all patients receiving epoetin alfa, regular monitoring of hemoglobin level once a week until a stable level is reached and periodic monitoring thereafter is necessary. With an initial hemoglobin level of 140 g/L in the pre- and postoperative period, hemoglobin level monitoring is performed more frequently.

Before and after starting therapy with Eprex^®, BP must be adequately controlled. If it is impossible to reduce blood pressure with antihypertensive agents, therapy with Eprex^® must be discontinued.

Special attention should be paid to the occurrence of unusual headaches or intensification of headaches.

The safety of Eprex^® in patients with impaired liver function has not been established. In this category of patients, due to slowed metabolism, a more pronounced enhancement of erythropoiesis may be noted.

During treatment with Eprex^®, regular monitoring of platelet levels is required, especially during the first 8 weeks, as a dose-dependent relative increase in platelet count may develop, which normalizes subsequently without discontinuing therapy; in rare cases, an absolute increase in platelet count is noted. Erythropoiesis-stimulating agents are not necessarily equivalent to each other. Patients can be switched from one erythropoiesis-stimulating agent (for example, from Eprex^®) to another only with the permission of the attending physician.

An inadequate response to therapy with Eprex^® is observed with iron deficiency, folic acid deficiency, vitamin B₁₂ deficiency, severe aluminum intoxication, concomitant infectious and inflammatory processes, trauma, occult bleeding, hemolysis, bone marrow fibrosis of various etiologies. Therefore, before starting therapy with Eprex^®, it is necessary to assess the body’s iron stores. Serum ferritin levels must be regularly determined throughout the course of treatment. All patients with a serum ferritin level of less than 100 ng/mL are recommended to be prescribed oral iron preparations at a dose of 200-300 mg/day (children – 100-200 mg/day). Patients with chronic renal failure (with a serum ferritin level of less than 300 ng/mL) are recommended to be prescribed oral iron preparations at a dose of 200-300 mg/day.

In patients with chronic renal failure, correction of anemia may cause improved appetite and increased absorption of potassium and proteins, which may require adjustment of dialysis parameters to maintain urea, creatinine, and potassium levels within normal limits.

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

Regardless of treatment with Eprex^®, in surgical patients with concomitant cardiovascular diseases, thrombotic and vascular lesions may occur as a result of repeated phlebotomies. Therefore, in such patients, usual blood volume replacement should be carried out according to an autologous blood collection program. It should be taken into account that preoperative increase in hemoglobin level in orthopedic patients, regardless of therapy with epoetin alfa, may be a predisposing factor for the development of thrombotic complications requiring appropriate treatment. All patients scheduled for surgery should receive adequate prophylactic antithrombotic therapy.

The use of epoetin alfa in the pre- and postoperative period is not recommended for patients with a hemoglobin level of more than 150 g/L.

In patients with chronic renal failure and clinically significant coronary artery disease or chronic heart failure, the upper limit of hemoglobin level should not exceed 100-120 g/L for adults and 95-110 g/L for children.

Before starting and during treatment with Eprex^®, it is necessary to determine the serum iron level and serum ferritin level in all patients; if necessary, additional prescription of iron preparations is required.

Other possible causes of anemia must be excluded before starting treatment with Eprex^®.

Effect on ability to drive vehicles and machinery

Due to the high risk of developing arterial hypertension at the beginning of therapy, patients with chronic renal failure should avoid potentially hazardous activities, such as driving a car and working with machinery, until the optimal maintenance dose of the drug is established.

Overdose

Overdose of epoetin alfa causes effects reflecting the extreme degree of severity of its pharmacological action. With very high hemoglobin levels, phlebotomy may be used.

Drug Interactions

Data on the interaction of Eprex^® with other drugs are absent.

With simultaneous use of Eprex^® with cyclosporine, an effect on the concentration of the latter in plasma is possible (when using this combination, it is necessary to monitor the concentration of cyclosporine in plasma and, if necessary, adjust its dose).

Pharmaceutical interactions

The drug must not be diluted and transferred from the original packaging into any other container; Eprex^® must not be administered in mixtures with other drugs.

Storage Conditions

The drug should be stored in a place protected from light, out of the reach of children, at a temperature from 2°C (35.6°F) to 8°C (46.4°F), do not shake, do not freeze.

Shelf Life

Shelf life – 1.5 years. Do not use after the expiration date.

Packaging intended for use can be stored at room temperature (not higher than 25°C (77°F)) for no more than 7 days in a row.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

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