Epocrin^® (Solution) Instructions for Use

Marketing Authorization Holder

State Research Institute of Occupational Health FMBA, FSUE (Russia)

Manufactured By

State Research Institute of Occupational Health FMBA, FSUE (Russia)

Packaging and Quality Control Release

State Research Institute of Occupational Health FMBA, FSUE (Russia)

Or

St. Petersburg Research Institute of Vaccines and Sera FMBA, FSUE (Russia)

ATC Code

B03XA01 (Erythropoietin)

Active Substance

Epoetin alfa (Rec.INN registered by WHO)

Dosage Forms

	Epocrin®	Solution for intravenous and subcutaneous administration 1000 IU/1 ml: amp. 10 pcs.
		Solution for intravenous and subcutaneous administration 2000 IU/1 ml: amp. 10 pcs.
		Solution for intravenous and subcutaneous administration 4000 IU/1 ml: amp. 10 pcs.
		Solution for intravenous and subcutaneous administration 10000 IU/1 ml: amp. 10 pcs.

Dosage Form, Packaging, and Composition

Solution for IV and SC administration transparent colorless.

Excipients : albumin, infusion solution 10% in terms of dry albumin – 2.5 mg, sodium citrate pentasesquihydrate – 5.8 mg or sodium citrate dihydrate – 4.776 mg, sodium chloride – 5.84 mg, citric acid monohydrate – 0.057 mg, water for injection – up to 1 ml.

1 ml – ampoules of colorless glass with a capacity of 2 ml (10) – blister strip cassette packs (1) – cardboard packs.

Solution for IV and SC administration transparent colorless.

Excipients : albumin, infusion solution 10% in terms of dry albumin – 2.5 mg, sodium citrate pentasesquihydrate – 5.8 mg or sodium citrate dihydrate – 4.776 mg, sodium chloride – 5.84 mg, citric acid monohydrate – 0.057 mg, water for injection – up to 1 ml.

1 ml – ampoules of colorless glass with a capacity of 2 ml (10) – blister strip cassette packs (1) – cardboard packs.

Solution for IV and SC administration transparent colorless.

Excipients : albumin, infusion solution 10% in terms of dry albumin – 2.5 mg, sodium citrate pentasesquihydrate – 5.8 mg or sodium citrate dihydrate – 4.776 mg, sodium chloride – 5.84 mg, citric acid monohydrate – 0.057 mg, water for injection – up to 1 ml.

1 ml – ampoules of colorless glass with a capacity of 2 ml (10) – blister strip cassette packs (1) – cardboard packs.

Solution for IV and SC administration transparent colorless.

Excipients : albumin, infusion solution 10% in terms of dry albumin – 2.5 mg, sodium citrate pentasesquihydrate – 5.8 mg or sodium citrate dihydrate – 4.776 mg, sodium chloride – 5.84 mg, citric acid monohydrate – 0.057 mg, water for injection – up to 1 ml.

1 ml – ampoules of colorless glass with a capacity of 2 ml (10) – blister strip cassette packs (1) – cardboard packs.

Clinical-Pharmacological Group

Erythropoiesis stimulant

Pharmacotherapeutic Group

Hematopoiesis stimulant

Pharmacological Action

Epoetin alfa is a glycoprotein that specifically stimulates erythropoiesis, activating mitosis and maturation of erythrocytes from erythroid progenitor cells. Recombinant Epoetin alfa is synthesized in mammalian cells into which the gene encoding human erythropoietin has been inserted. In its composition, biological and immunological properties, Epoetin alfa is identical to natural human erythropoietin.

The administration of epoetin alfa leads to an increase in hemoglobin and hematocrit, improved tissue blood supply and heart function. The most pronounced effect of epoetin alfa is observed in anemias caused by chronic renal failure.

In very rare cases, with long-term use of erythropoietin for the treatment of anemic conditions, the formation of neutralizing antibodies to erythropoietin may be observed with or without the development of partial red cell aplasia.

Pharmacokinetics

After IV administration of epoetin alfa in healthy individuals and patients with uremia, the T_1/2 is 5-6 hours.

After SC administration of epoetin alfa, its concentration in the blood increases slowly and C_max is reached between 12 and 18 hours after administration, with a T_1/2 of 16-24 hours.

The bioavailability of epoetin alfa after SC administration is 25-40%.

Indications

Anemia associated with chronic renal failure in adults on hemodialysis or peritoneal dialysis, as well as severe anemia of renal origin accompanied by clinical symptoms in adult patients with renal failure not yet on dialysis.

Anemia associated with chronic renal failure in children on hemodialysis or peritoneal dialysis.

Anemia in adult cancer patients with solid (non-myeloid) tumors, malignant lymphoma or multiple myeloma receiving chemotherapy (for the treatment of anemia and reduction of transfusion requirements).

Anemia in adult HIV-infected patients receiving zidovudine therapy, with endogenous erythropoietin concentration less than 500 IU/ml.

As part of a predeposit program prior to major surgery in adult patients with a hematocrit of 33-39%, to facilitate the collection of autologous blood and reduce the risk associated with the use of allogeneic blood transfusions, if the expected need for transfused blood exceeds the amount that can be collected by autologous collection without the use of epoetin alfa.

Prior to major surgery with expected average blood loss (2-4 units or 900-1800 ml) in adult patients with mild or moderate anemia (hemoglobin >10 and ≤13 g/dl) to reduce the need for allogeneic blood transfusions and improve the recovery of erythropoiesis.

ICD codes

Dosage Regimen

Administer subcutaneously or intravenously. Set the dosage regimen individually based on indication, concomitant diseases, therapy regimen, and patient age.

For anemia in chronic renal failure in adult patients on dialysis, initiate with 50-100 IU/kg three times per week intravenously. For adult patients not on dialysis, initiate with 50-100 IU/kg subcutaneously three times per week. Adjust the dose to achieve a target hemoglobin not exceeding 120 g/L. Increase the dose no more than once per month. Reduce the dose if the hemoglobin level approaches 120 g/L or increases by more than 20 g/L in one month. Discontinue if the hemoglobin level exceeds 130 g/L.

For anemia in pediatric chronic renal failure patients on dialysis, initiate with 50 IU/kg three times per week intravenously. Use the same dose adjustment principles as for adults.

For anemia in adult cancer patients receiving chemotherapy, initiate with 450 IU/kg subcutaneously once per week or 150 IU/kg three times per week. Discontinue after 8 weeks if the hemoglobin increase is less than 10 g/L or if transfusions are still required. Withhold the dose if the hemoglobin exceeds 130 g/L and resume at a 25% reduced dose when the hemoglobin falls below 120 g/L.

For anemia in adult HIV-infected patients receiving zidovudine, initiate with 4000 IU subcutaneously three times per week. Adjust the dose based on hemoglobin response. Discontinue if no response occurs after 8 weeks.

For the predeposit autologous blood program in adults, administer 600 IU/kg subcutaneously twice weekly for 3 weeks prior to surgery. Ensure adequate iron supplementation throughout the regimen.

For major elective surgery in anemic adults, administer 300 IU/kg subcutaneously daily for 10 days before surgery, on the day of surgery, and for 4 days after. An alternative regimen is 600 IU/kg subcutaneously once weekly on days -21, -14, -7 and on the day of surgery. Initiate antithrombotic prophylaxis. Do not use in patients with a baseline hemoglobin >130 g/L.

Monitor hemoglobin regularly until stable, then periodically. Monitor iron stores (ferritin, transferrin saturation) before and during therapy. Administer supplemental iron if serum ferritin is below 100 mcg/L or transferrin saturation is below 20%. Monitor blood pressure before and during therapy. Adjust antihypertensive therapy as needed.

Adverse Reactions

From the hematopoietic system: very rarely – erythropoietin antibody-mediated partial red cell aplasia, thrombocythemia.

From the immune system infrequently – hypersensitivity reactions; rarely – anaphylactic reactions.

From metabolism infrequently – hyperkalemia; frequency unknown – porphyria.

From the nervous system frequently – headache, seizures; frequency not established – cerebrovascular complications (including stroke, comprising cerebral infarction and intracerebral hemorrhage), transient ischemic attack, hypertensive encephalopathy.

From the organ of vision frequency unknown – retinal vessel thrombosis.

From the cardiovascular system: frequently – arterial hypertension (including hypertensive crisis), arterial and venous (including fatal cases) thromboses and embolisms: deep vein thrombosis, arterial thrombosis (including myocardial infarction), arteriovenous shunt thrombosis of aneurysm, pulmonary embolism.

From the respiratory system frequently – cough; frequency unknown – respiratory congestion.

From the digestive system: very frequently – diarrhea, nausea, vomiting.

From the skin and subcutaneous tissues frequently – skin rash; frequency unknown – urticaria, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the musculoskeletal system frequently – arthralgia, myalgia, bone pain, limb pain.

Other very frequently – increased body temperature; frequently – chills, flu-like syndrome, peripheral edema, local reactions.

Contraindications

Hypersensitivity to epoetin alfa; uncontrolled arterial hypertension; patients with severe pathology of the coronary, carotid, cerebral and peripheral vessels, including those who have recently suffered myocardial infarction or acute cerebrovascular accident (within the predeposit blood collection program prior to major surgery); patients with partial red cell aplasia who have been treated with any erythropoietin; patients who, for any reason, are not receiving adequate prophylactic antithrombotic therapy; pregnancy, breastfeeding period.

With caution

Patients with epilepsy, epileptic syndrome (including in history) or with diseases that can provoke epileptic activity (for example, CNS infections or brain metastases), thrombocythemia, thrombosis (in history), obliterating diseases of peripheral vessels and other vascular complications, gout, with sickle cell anemia, with iron deficiency, vitamin B₁₂ or folic acid deficiency; with coronary artery disease, partial red cell aplasia, malignant neoplasms of the bone marrow, in patients with porphyria.

Use in Pregnancy and Lactation

The use of epoetin alfa is contraindicated during pregnancy and breastfeeding.

In some female patients with chronic renal failure during treatment with epoetin alfa, resumption of menstruation was noted. The possibility of pregnancy and the need for contraceptive measures should be discussed with the patient before starting therapy.

Use in Hepatic Impairment

Epoetin alfa should also 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. Due to reduced metabolism in patients with impaired liver function, the use of epoetin alfa may lead to enhanced erythropoiesis.

Use in Renal Impairment

In patients with chronic renal failure and clinically significant coronary artery disease or congestive heart failure, the maintenance hemoglobin level should not exceed the upper limit of the optimal recommended level (no more than 10-12 g/dl in adults).

Pediatric Use

Can be used in children according to indications, in recommended doses and regimens.

Special Precautions

Blood pressure must be adequately controlled before and after initiation of epoetin alfa therapy. During therapy with epoetin alfa, antihypertensive therapy may need to be prescribed. If blood pressure cannot be reduced with antihypertensive agents, epoetin alfa therapy should be discontinued.

A hypertensive crisis, accompanied by encephalopathy and seizures, requiring immediate medical intervention, can also occur during epoetin alfa therapy in patients who previously had normal or low blood pressure. Particular attention should be paid to a sudden onset of shooting migraine-like headache as a possible signal of an impending crisis.

Antibody-mediated true erythroid aplasia (TEA) has been observed in patients treated with epoetin. Cases of this disease have also been occasionally reported in patients with hepatitis C treated with interferon and ribavirin when treatment with erythropoiesis-stimulating agents was simultaneously administered, therefore they are not approved for the treatment of anemia associated with hepatitis C.

In patients with chronic renal failure who experience a sudden loss of efficacy, determined by a decrease in hemoglobin (10-20 g/L per month) with an increased need for transfusions, a reticulocyte count should be performed and an examination for typical causes of lack of response (e.g., iron, folic acid or vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, hemolysis and bone marrow fibrosis of any origin) should be conducted.

If the anemia-corrected reticulocyte count (i.e., reticulocyte “index”) is low (< 20000/µl or < 0.5%), and the platelet and leukocyte counts are normal, and if other causes for the loss of effect are not identified, the concentration of antibodies to erythropoietin should be determined, and the possibility of a bone marrow examination to diagnose TEA should be considered.

If antibody-mediated anti-erythropoietin TEA is suspected, therapy with epoetin alfa should be discontinued immediately. Treatment with any other erythropoiesis-stimulating agents should not be initiated, as there is a risk of cross-reaction. If indicated, patients may receive appropriate therapy, such as blood transfusion.

Epoetin alfa must be used with caution in patients with epilepsy, a history of epileptic seizures and diseases associated with epileptic seizures (e.g., CNS infections and brain metastases).

Epoetin alfa should also 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. Due to reduced metabolism in patients with impaired liver function, the use of epoetin alfa may lead to enhanced erythropoiesis.

The risk of thrombotic vascular complications and the benefit of treatment with epoetin alfa should be carefully weighed, especially in patients with risk factors.

All patients should be carefully monitored for hemoglobin levels due to the potentially increased risk of thromboembolic events and fatal outcomes observed in patients with elevated hemoglobin levels during therapy with epoetin alfa.

The safety and efficacy of epoetin alfa therapy in patients with underlying hematological diseases, such as hemolytic anemia, sickle cell anemia, thalassemia, have not been studied.

During treatment with epoetin alfa, 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.

Before starting therapy with epoetin alfa, as well as when deciding to increase its dose, other causes of anemia should be assessed and treated (iron, folic acid or vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, hemolysis and bone marrow fibrosis of any origin). In most cases, serum ferritin concentrations decrease simultaneously with the increase in hematocrit. To achieve an optimal response to Epoetin alfa, adequate iron stores should be ensured with the introduction, if necessary, of additional iron supplements, depending on the indications.

Erythropoiesis-stimulating agents are not necessarily equivalent. Therefore, it must be clarified that patients should be switched from one erythropoiesis-stimulating agent to another only with the approval of the attending physician.

Epoetin alfa has a minimal ability to induce antibody formation. Carcinogenicity studies have not been conducted.

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

Patients with chronic renal failure during treatment with epoetin alfa need to have their hemoglobin level measured regularly until it reaches stable values, with periodic monitoring thereafter.

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. The dose should be reduced if the hemoglobin level reaches 120 g/L.

In patients with chronic renal failure, the maintained hemoglobin level should not exceed the upper limit. A hemoglobin level of 130 g/L and above may lead to an increased risk of cardiovascular complications, including death.

Patients with chronic renal failure and an insufficient hemoglobin response to therapy with erythropoiesis-stimulating agents may be at an even greater risk of cardiovascular complications and mortality than other patients.

Shunt thromboses have occurred in patients on hemodialysis, especially in patients with a tendency to hypotension or with complications of arteriovenous fistulas (e.g., stenoses, aneurysms, etc.). In these patients, early shunt check and thrombosis prevention by administration of, for example, acetylsalicylic acid are recommended.

In isolated cases, hyperkalemia has been observed, although its causal relationship with the use of the drug has not been established. Serum electrolytes should be monitored in patients with chronic renal failure. If the serum potassium level is elevated or increasing, then, in addition to appropriate treatment of hyperkalemia, the possibility of discontinuing epoetin alfa administration until the serum potassium level is corrected should be considered.

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

Anemia in adult cancer patients with solid (non-myeloid) tumors, malignant lymphoma or multiple myeloma receiving chemotherapy (for the treatment of anemia and reduction of transfusion requirements)

Erythropoiesis-stimulating agents are growth factors that primarily stimulate the formation of red blood cells. Erythropoietin receptors may be expressed on the surface of many tumor cells. As with other growth factors, there are concerns that erythropoiesis-stimulating agents may stimulate tumor growth. Thus, the decision to administer recombinant erythropoietin should be made based on an assessment of the risk-benefit ratio with the participation of the specific patient and should take into account the specific clinical situation. Factors to be considered in such an assessment include: type and stage of the tumor; severity of anemia; expected life expectancy; conditions under which the patient is receiving treatment; patient preferences.

In clinical studies with recombinant erythropoietin drugs used in combination with other erythropoiesis-stimulating agents, the following was noted:

• Worsening of locoregional control in patients with advanced malignant neoplasms of the head and neck receiving radiation therapy, when these drugs were used to achieve a hemoglobin concentration greater than 140 g/L;
• Decrease in overall survival and increase in mortality associated with disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy, when these drugs were used to achieve a hemoglobin concentration between 120 and 140 g/L;
• Increase in mortality with the use of another erythropoiesis-stimulating agent (darbepoetin alfa) to achieve a hemoglobin concentration of 120 g/L in patients with active malignant neoplasms not receiving chemotherapy or radiation therapy. Erythropoiesis-stimulating agents are not indicated for use in this group of patients.

In patients with cancer receiving chemotherapy, when assessing the suitability of epoetin alfa therapy (especially in patients at risk of transfusion), a delay of 2-3 weeks between the administration of erythropoiesis-stimulating agents and the appearance of erythropoietin-stimulated red blood cells should be taken into account.

If an HIV-infected patient does not respond or the response to epoetin alfa therapy is insufficient, other possible causes of anemia, including iron deficiency, should be considered.

In patients enrolled in an autologous blood collection program and receiving additional treatment with epoetin alfa, all special warnings and special precautions should be taken into account, especially mandatory volume replacement.

Before performing extensive surgery with expected blood loss in the pre- and postoperative period, proper standards for monitoring blood parameters should always be observed.

Patients scheduled for major elective orthopedic surgery should receive antithrombotic prophylaxis, as surgical patients may experience thrombotic and vascular complications, especially patients with underlying cardiovascular disease. In addition, special precautions should be observed in patients predisposed to developing thrombotic complications. Furthermore, in patients with a baseline hemoglobin level > 130 g/L, the possibility cannot be excluded that treatment with epoetin alfa may be associated with an increased risk of postoperative thrombotic vascular complications. Consequently, the use of epoetin alfa is not recommended in patients with a baseline hemoglobin level >130 g/L.

Effect on the Ability to Drive and Operate Machinery

During treatment until the optimal maintenance dose is established, patients with uremia should avoid engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions due to the increased risk of elevated blood pressure at the start of therapy.

Drug Interactions

The effect of epoetin alfa may be enhanced with the simultaneous administration of blood products.

Concomitant use of drugs that suppress erythropoiesis may lead to a decrease in the effectiveness of epoetin alfa.

Epoetin alfa may influence the concentration of cyclosporine when used concomitantly; therefore, additional monitoring of serum cyclosporine levels with subsequent dose adjustment is required.

The stimulatory effect of epoetin alfa on erythropoiesis may be enhanced with the simultaneous intake of iron preparations in case of iron deficiency.

When used concomitantly with anticonvulsant therapy, the tendency to seizures may increase.

When used concomitantly with antihypertensive drugs, their effect may be weakened. There is data on the effect of ACE inhibitors on the action of epoetin alfa drugs when used together.

Epoetin alfa should not be mixed with solutions of other medicinal products.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.