Epodarba^® (Solution) Instructions for Use

Marketing Authorization Holder

Pharmapark, LLC (Russia)

Manufactured By

Pharmstandard-UfaVITA OJSC (Russia)

ATC Code

B03XA02 (Darbepoetin alfa)

Active Substance

Darbepoetin alfa (Rec.INN registered by WHO)

Dosage Form

Epodarba®

Solution for injection 30 mcg

Dosage Form, Packaging, and Composition

Solution for injection

0.3 ml – syringes – carton packs – By prescription

Clinical-Pharmacological Group

Erythropoiesis stimulant

Pharmacotherapeutic Group

Antianemic drugs; other antianemic drugs

Pharmacological Action

Hemopoiesis stimulator, antianemic drug. Darbepoetin alfa is produced using gene technology in Chinese hamster ovary (CHO-K1) cells. It stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Darbepoetin alfa contains five N-linked carbohydrate chains, while the endogenous hormone and recombinant human erythropoietins (rHuEPO) have only three chains. The additional sugar residues, from a molecular point of view, do not differ from those present in the endogenous hormone. Due to the increased carbohydrate content, Darbepoetin alfa has a longer T_1/2 compared to rHuEPO, and consequently, greater in vivo activity. Despite these changes in molecular structure, Darbepoetin alfa retains very narrow specificity for the erythropoietin receptor.

Erythropoietin is a growth factor that primarily stimulates the formation of red blood cells. Erythropoietin receptors can be expressed on the surface of various tumor cells.

Pharmacokinetics

The pharmacokinetics of darbepoetin alfa were studied in patients with chronic renal failure after intravenous and subcutaneous administration. The T_1/2 was 21 h (standard deviation /SD/ 7.5) after intravenous administration. The clearance of darbepoetin alfa was 1.9 ml/h/kg (SD 0.56), and the V_d was approximately equivalent to the plasma volume (50 ml/kg). After subcutaneous administration, the bioavailability was 37%. After monthly subcutaneous administration of darbepoetin alfa at doses from 0.6 to 2.1 mcg/kg, the T_1/2 was 73 h (SD 24). The longer T_1/2 of darbepoetin alfa after subcutaneous administration, compared to intravenous, is due to absorption kinetics. In clinical studies, minimal drug accumulation was observed with any route of administration. Preclinical studies have demonstrated that the renal clearance of darbepoetin is minimal (up to 2% of total clearance) and does not affect the serum T_1/2 of the drug.

The pharmacokinetics of darbepoetin alfa were studied in children (3-16 years) with chronic renal failure, on or not on dialysis, with sampling from the time of a single subcutaneous or intravenous administration up to one week (168 h) after administration. The sampling periods were of the same duration as in adults with chronic renal failure, and comparison showed that the pharmacokinetics of darbepoetin alfa in adults and children with chronic renal failure are similar. After intravenous administration, there was an approximately 25% difference between adults and children regarding AUC_0-∞; however, this difference for children was less than the two-fold range of AUC_0-∞. After subcutaneous administration, the AUC_0-∞ value in adults and children was similar. Both after intravenous and subcutaneous administration, the T_1/2 of the drug in children and adults with chronic renal failure was similar.

After subcutaneous administration of the drug at a dose of 2.25 mcg/kg to adult cancer patients, the mean C_max of darbepoetin alfa, amounting to 10.6 ng/ml (SD 5.9), was established on average within 91 h (SD 19.7). These parameters corresponded to linear dose pharmacokinetics over a wide range (from 0.5 to 8 mcg/kg with weekly administration and from 3 to 9 mcg/kg with administration every two weeks). Pharmacokinetic parameters did not change with multiple dosing over 12 weeks (weekly or every two weeks administration). An expected moderate increase (less than 2-fold) in serum drug concentration was noted at steady state, but no signs of accumulation were detected upon repeated administration. Pharmacokinetic studies were performed involving patients with chemotherapy-induced anemia who, in combination with chemotherapy, received subcutaneous injections of darbepoetin alfa at a dose of 6.75 mcg/kg every three weeks. In this study, the mean T_1/2 was 74 (SD 27) h.

Indications

Treatment of symptomatic anemia in adults and children with chronic renal failure.

Treatment of symptomatic anemia in adult patients with non-myeloid malignancies receiving chemotherapy.

ICD codes

Dosage Regimen

Depending on the indications, age, and patient’s condition, the initial dose for subcutaneous or intravenous administration is 0.45 mcg/kg, or for subcutaneous administration 0.75 mcg/kg, 2.25-6.75 mcg/kg. The maintenance dose, frequency of administration, and duration of treatment depend on the effectiveness and clinical situation. Treatment is carried out under the control of hemoglobin levels.

Adverse Reactions

Allergic reactions: anaphylactic reactions, angioedema, allergic bronchospasm, rash and urticaria.

From the cardiovascular system very common – increased blood pressure.

Dermatological reactions common – rash, erythema.

From the hematopoietic system thromboembolism.

Local reactions pain at the injection site.

Other pure red cell aplasia (mainly in patients with chronic renal failure who received the drug subcutaneously).

Contraindications

Poorly controlled arterial hypertension; hypersensitivity to darbepoetin alfa, recombinant human erythropoietin.

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies on the safety of use during pregnancy have not been conducted. With caution and after a thorough assessment of the expected benefit of therapy for the mother and the potential risk to the fetus, the use of darbepoetin alfa in pregnant women is possible.

If it is necessary to use darbepoetin alfa during lactation, breastfeeding should be discontinued.

Special Precautions

Use with caution in patients with liver diseases, sickle cell anemia.

Monitoring of blood pressure is necessary in all patients, especially at the beginning of therapy with darbepoetin alfa.

To confirm the effectiveness of erythropoiesis, all patients should have their iron levels determined before and during treatment in order to prescribe, if necessary, additional therapy with iron preparations.

If there is no response to the use of darbepoetin alfa, the cause should be identified. The effectiveness of erythropoiesis-stimulating agents is reduced in case of deficiency of iron, folic acid or vitamin B₁₂ in the body, therefore their levels must be corrected. The erythropoietic response may also be weakened in the presence of concomitant infectious diseases, symptoms of inflammation or trauma, occult blood loss, hemolysis, severe aluminum intoxication, concomitant hematological diseases or bone marrow fibrosis. Reticulocyte count should be considered as one of the evaluation parameters. If typical causes of lack of response are excluded and the patient has reticulocytopenia, a bone marrow examination should be performed. If the bone marrow picture corresponds to that of pure red cell aplasia (PRCA), it is recommended to test for the presence of antibodies to erythropoietin.

PRCA caused by the neutralizing effect of anti-erythropoietin antibodies has been described in connection with the use of recombinant erythropoietins, including Darbepoetin alfa. Most often, such reports concerned patients with chronic renal failure who received the drug subcutaneously. It has been shown that these antibodies cross-react with all erythropoietins. If PRCA is diagnosed, treatment with darbepoetin should be discontinued without subsequent transfer of the patient to a therapeutic regimen including another recombinant erythropoietin.

There are no data on use in patients with impaired liver function. Since the liver is considered the main route of elimination of darbepoetin alfa and rHuEPO, use in patients with liver pathology should be carried out with caution.

When maintaining hemoglobin levels in patients with chronic renal failure, its concentration should not exceed the specified upper limit. In clinical studies, when the target hemoglobin level exceeded 120 g/l while using erythropoiesis-stimulating drugs, patients had an increased risk of mortality and the development of serious cardiovascular complications. In controlled clinical studies, it was not possible to identify significant benefits from the use of epoetins if the hemoglobin concentration exceeds the level necessary to control the symptoms of anemia and eliminate the need for blood transfusions.

Caution is necessary when using darbepoetin alfa in patients with epilepsy. There are reports of seizures occurring during therapy with darbepoetin alfa.

The use of additional therapy with iron preparations is recommended for all patients whose serum ferritin concentration does not exceed 100 mcg/l or whose transferrin saturation level is below 20%.

In patients with chronic renal failure and clinical symptoms of coronary artery disease or congestive heart failure, target hemoglobin levels should be determined individually. In such patients, the maximum hemoglobin content should not exceed 120 g/l, except in cases where the severity of symptoms (for example, angina) requires a different solution.

During the use of darbepoetin alfa, serum potassium levels should be regularly monitored. If an elevated or increasing potassium concentration is detected, the administration of darbepoetin alfa should be discontinued until it normalizes.

Effect on tumor growth

Erythropoietins are growth factors that primarily stimulate the production of red blood cells. Erythropoietin receptors can be expressed on the surface of various tumor cells. As with any growth factors, there is an assumption that erythropoietins can stimulate tumor growth.

In a number of controlled clinical studies in cancer patients receiving chemotherapy, the use of epoetins did not increase overall survival or reduce the risk of tumor progression in patients with cancer-associated anemia.

Controlled clinical studies of darbepoetin alfa and other erythropoiesis-stimulating drugs have shown

• Reduction in time to progression in patients with advanced head and neck cancer receiving radiation therapy, with corrective administration of epoetin to achieve a target hemoglobin level of more than 140 g/l. The use of erythropoiesis-stimulating drugs in such patients is not indicated;
• Reduction in overall survival and increased mortality associated with disease progression over 4 months in patients with metastatic breast cancer receiving chemotherapy, with corrective administration of epoetin to achieve a target hemoglobin value of 120 -140 g/l;
• Increased risk of death with corrective administration of epoetin to achieve a target hemoglobin value of 120 g/l in patients with active malignant tumor who were not receiving either chemotherapy or radiation therapy. The use of erythropoiesis-stimulating drugs in such patients is not indicated.

In accordance with the above, in some clinical situations, blood transfusion should be used to treat anemia in patients with cancer. The decision to prescribe recombinant erythropoietins should be made based on an assessment of the benefit/risk ratio for each individual patient, taking into account the characteristics of the clinical situation. The following factors must be taken into account: type and stage of the tumor process; degree of anemia; life expectancy; the setting in which the patient will be treated; and the patient’s own wishes.

In patients with solid tumors or lymphoproliferative malignancies, if the hemoglobin level rises above 120 g/l, the recommended dose adjustment regimen should be strictly followed to minimize the potential risk of thromboembolic events. It is also necessary to regularly monitor platelet count and hemoglobin concentration in the blood.

Drug Interactions

It is known that interaction of darbepoetin alfa with drugs characterized by a high degree of affinity for erythrocytes, such as cyclosporine, tacrolimus, is possible. When darbepoetin alfa is used concomitantly with any such drugs, their serum levels should be monitored with dose modification in case of increased hemoglobin concentration.

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.