Darbestim^® (Solution) Instructions for Use

Marketing Authorization Holder

Biocad, JSC (Russia)

ATC Code

B03XA02 (Darbepoetin alfa)

Active Substance

Darbepoetin alfa (Rec.INN registered by WHO)

Dosage Forms

	Darbestim®	Solution for injection 10 mcg/0.4 ml: syringes 1 or 4 pcs.
		Solution for injection 15 mcg/0.375 ml: syringes 1 or 4 pcs.
		Solution for injection 20 mcg/0.5 ml: syringes 1 or 4 pcs.
		Solution for injection 30 mcg/0.3 ml: syringes 1 or 4 pcs.
		Solution for injection 40 mcg/0.4 ml: syringes 1 or 4 pcs.
		Solution for injection 50 mcg/0.5 ml: syringes 1 or 4 pcs.
		Solution for injection 60 mcg/0.3 ml: syringes 1 or 4 pcs.
		Solution for injection 80 mcg/0.4 ml: syringes 1 or 4 pcs.
		Solution for injection 100 mcg/0.5 ml: syringes 1 or 4 pcs.
		Solution for injection 150 mcg/0.3 ml: syringes 1 or 4 pcs.
		Solution for injection 300 mcg/0.6 ml: syringe
		Solution for injection 500 mcg/1 ml: syringe

Dosage Form, Packaging, and Composition

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.4 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.4 ml – glass syringes (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.
0.4 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.4 ml – glass syringes with needle protection system (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.375 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.375 ml – glass syringes (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.
0.375 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.375 ml – glass syringes with needle protection system (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.5 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.5 ml – glass syringes (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.
0.5 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.5 ml – glass syringes with needle protection system (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.3 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.3 ml – glass syringes (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.
0.3 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.3 ml – glass syringes with needle protection system (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.4 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.4 ml – glass syringes (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.
0.4 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.4 ml – glass syringes with needle protection system (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.5 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.5 ml – glass syringes (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.
0.5 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.5 ml – glass syringes with needle protection system (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.3 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.3 ml – glass syringes (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.
0.3 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.3 ml – glass syringes with needle protection system (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.4 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.4 ml – glass syringes (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.
0.4 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.4 ml – glass syringes with needle protection system (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.5 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.5 ml – glass syringes (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.
0.5 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.5 ml – glass syringes with needle protection system (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.3 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.3 ml – glass syringes (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.
0.3 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.3 ml – glass syringes with needle protection system (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

0.6 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
0.6 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.

Solution for injection transparent, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 2.118 mg, disodium hydrogen phosphate – 0.661 mg, sodium chloride – 8.812 mg, polysorbate 80 – 0.05 mg, water for injections – up to 1 ml.

1 ml – glass syringes (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.
1 ml – glass syringes with needle protection system (1) – contour cell packaging (1) complete with alcohol wipes (1 pc.) – cardboard packs.

Clinical-Pharmacological Group

Erythropoiesis stimulant

Pharmacotherapeutic Group

Hematopoiesis stimulant (anti-anemic agent)

Pharmacological Action

Hematopoiesis stimulator, anti-anemic 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 half-life 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 may 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 half-life 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 volume of distribution was approximately equivalent to the plasma volume (50 ml/kg). After subcutaneous administration of the drug, the bioavailability was 37%.

With monthly subcutaneous administration of darbepoetin alfa at doses from 0.6 to 2.1 mcg/kg, the half-life was 73 h (SD 24). The longer half-life of darbepoetin alfa after subcutaneous administration, compared to intravenous, is due to absorption kinetics. During clinical studies, minimal accumulation of the drug was observed with any route of administration.

Preclinical studies have demonstrated that renal clearance of darbepoetin is minimal (up to 2% of total clearance) and does not affect the serum half-life 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 half-life 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 reached 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 administration or administration every two weeks). 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 half-life 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 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.

Cardiovascular system very common – increased blood pressure.

Dermatological reactions common – rash, erythema.

Hematopoietic system thromboembolism.

Local reactions pain at the injection site.

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

Contraindications

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

Use in Pregnancy and Lactation

No adequate and well-controlled clinical studies on the safety of use during pregnancy have been conducted. Darbepoetin alfa may be used with caution in pregnant women after a thorough assessment of the expected therapy benefit for the mother and the potential risk to the fetus.

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

Special Precautions

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

Blood pressure monitoring 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 darbepoetin alfa, the cause should be identified. The effectiveness of erythropoiesis-stimulating agents is reduced in case of iron, folic acid, or vitamin B₁₂ deficiency; consequently, their levels must be corrected. The erythropoietic response may also be weakened in the presence of concomitant infectious diseases, inflammatory symptoms, or cases of trauma, occult blood loss, hemolysis, severe aluminum intoxication, concomitant hematological diseases, or bone marrow fibrosis. The reticulocyte count should be considered as one of the evaluation parameters. If typical causes of no response are excluded and the patient has reticulocytopenia, a bone marrow examination should be performed. If the bone marrow picture corresponds to Pure Red Cell Aplasia (PRCA), it is recommended to test for the presence of anti-erythropoietin antibodies.

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 receiving the drug subcutaneously. These antibodies have been shown to cross-react with all erythropoietins. If PRCA is diagnosed, treatment with darbepoetin should be discontinued without subsequently transferring the patient to a therapeutic regimen involving another recombinant erythropoietin.

Data on use in patients with impaired liver function are not available. Since the liver is considered the main route of elimination for darbepoetin alfa and rHuEpo, use in patients with liver pathology should be conducted 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 during the use of erythropoiesis-stimulating drugs, patients had an increased risk of mortality and the development of serious cardiovascular complications. Controlled clinical studies have failed to identify significant benefits from the use of epoetins when the hemoglobin concentration exceeds the level necessary to control anemia symptoms 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 µg/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 (e.g., angina) requires a different decision.

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 may be expressed on the surface of various tumor cells. As with any growth factors, there is a suggestion that erythropoietins may 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

• A reduction in the time to progression in patients with advanced head and neck cancer receiving radiation therapy when epoetin was administered correctively to achieve a target hemoglobin level of more than 140 g/L. The use of erythropoiesis-stimulating drugs in such patients is not indicated;
• A reduction in overall survival and an increase in mortality associated with disease progression over 4 months in patients with metastatic breast cancer receiving chemotherapy when epoetin was administered correctively to achieve a target hemoglobin value of 120-140 g/L;
• An increased risk of death when epoetin was administered correctively to achieve a target hemoglobin value of 120 g/L in patients with active malignant tumor who were not receiving 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 specifics of the clinical situation. The following factors must be considered: the type and stage of the tumor process; the 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 malignant diseases, when the hemoglobin level increases above 120 g/L, the recommended dose adjustment regimen should be strictly followed to minimize the potential risk of thromboembolic events. Platelet count and hemoglobin concentration in the blood should also be regularly monitored.

Drug Interactions

It is known that darbepoetin alfa may interact with drugs characterized by a high degree of affinity for red blood cells, such as cyclosporine and tacrolimus. When darbepoetin alfa is used concomitantly with any such medicines, their serum levels should be monitored with dose modification in case of an increase in 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.