Aranesp solution for injection 30 µg 0.3ml syringe, 1pc

Composition

Active ingredient in one pre-filled syringe pen (SureClick™) Darbepoietin Alpha (recombinant):

30 mcg

Excipients in 1 ml of solution:

sodium dihydrogen phosphate monohydrate-2.118 mg,

sodium hydrophosphate-0.661 mg,

sodium chloride-8.182 mg,

polysorbate 80-0.05 mg,

water for injection-up to 1 ml

Pharmacological action

Pharmacodynamics

Darbepoietin alpha stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Darbepoietin alpha contains five N-linked carbohydrate chains, while endogenous hormone I recombinant human erythropoietins (rcEpo) have only three chains. 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, darbepoietin alpha has a longer half-life compared to RCHEPO, and therefore a greater activity in vivo.

Despite these changes in the molecular structure, darbepoietin alpha retains a very narrow specificity to the erythropoietin receptor.

Preclinical safety data.

In all studies in rats and dogs, the concentration of hemoglobin, hematocrit, red blood cells and reticulocytes significantly increased with the use of Aranespa, which corresponds to the expected pharmacological effect. Adverse events with the introduction of very high doses of the drug were considered as a consequence of increased pharmacological action (reduced tissue blood flow due to increased blood viscosity).

This category also included myelofibrosis and spleen hypertrophy, as well as the expansion of the QRS complex on the ECG in dogs, without cardiac arrhythmias and effects on the QT interval. Aranesp did not have any genotoxic potential and did not affect the proliferation of non-hematological cells either in vitro or in vivo. In chronic toxicity studies, no tumorogenic or unexpected mitogenic response was observed in any of the tissue types studied. In long-term animal studies, the carcinogenic potential of darbepoietin alpha has not been evaluated.

No clinically significant effects on pregnancy, fetal/fetal development, delivery, or postnatal development were observed in rat and rabbit trials. The level of drug penetration through the placenta was minimal. There were no changes in fertility.

Pharmacokinetics

Due to the increased carbohydrate content, the concentration of darbepoietin alpha circulating in the blood exceeds the minimum concentration required to stimulate erythropoiesis for a longer time compared to equivalent doses of rcEpo, which reduces the frequency of darbepoietin alpha use while maintaining an equivalent level of biological response.

Patients with chronic renal failure.

The pharmacokinetics of darbepoetin alfa were studied in patients with chronic renal failure after intravenous and subcutaneous use of the drug. Its half-life was 21 hours (standard deviation (CO) 7.5) when administered intravenously. The clearance of darbepoetin alfa was 1.9 ml / hr / kg (CO 0.56), and the volume of distribution (Odp) was approximately equivalent to that of plasma (50 ml/kg).

With subcutaneous use of the drug, its bioavailability corresponded to 37%. With monthly subcutaneous use of darbepoetin alfa at a dose of 0.6 to 2.1 mcg/kg, its half-life was 73 hours (CO 24). The longer half-life of darbopoietin alpha when administered subcutaneously, compared with intravenous, is due to the kinetics of absorption. In clinical studies, minimal accumulation of the drug was observed with any method of use. In preclinical studies, it was demonstrated that the renal clearance of darbepoetin is minimal (up to 2% of total clearance) and does not affect the half-life of the drug from serum. The method of use does not affect the dose of darbepoietin alpha required to maintain the achieved hemoglobin.

Cancer patients receiving chemotherapy.

After subcutaneous use of the drug at a dose of 2.25 mcg/kg to adult cancer patients, the average maximum concentrations of darbepoietin alpha, amounting to 10.6 ng / ml (CO 5.9), were established on average for 91 hours (CO 19.7). These parameters corresponded to linear pharmacokinetics of the dose in a wide range of values (from 0.5 to 8 mcg / kg for weekly use and from 3 to 9 mcg / kg for biweekly use).

Pharmacokinetic parameters did not change with repeated dosing for 12 weeks (weekly or biweekly use). There was an expected moderate increase (less than 2-fold) in the serum concentration of the drug upon reaching equilibrium, but no signs of its accumulation were detected upon repeated use. These studies were performed in patients with chemotherapy-induced anemia who received subcutaneous injections of darbepoietin alfa at a dose of 6.75 mcg/kg every three weeks in combination with chemotherapy. In this study, the mean (CO) half-life was 74 (CO 27) hours.

Indications

• treatment of anemia associated with chronic renal failure in adults and children 11 years and older;
• treatment of symptomatic anemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.

Use during pregnancy and lactation

Adequate and strictly controlled clinical studies on the safety of Aranesp use during pregnancy have not been conducted.

Pregnant women should be prescribed the drug with caution and after careful evaluation of the expected benefit of therapy for the mother and the potential risk to the fetus.

If it is necessary to prescribe Aranespa during lactation, breastfeeding should be discontinued.

Contraindications

Poorly controlled arterial hypertension; hypersensitivity to darbepoetin alfa, rcEPO, or any component of the drug.

Side effects

General provisions. Rare cases of potentially significant serious allergic reactions, including dyspnoea, skin rashes, and urticaria, have been reported in association with the use of darbepoietin alpha.

Patients with chronic renal failure.

Undesirable effects that develop during treatment with Aranesp include arterial hypertension and vascular access thrombosis. However, in the combined safety database, none of these events were associated with a change in hemoglobin (less than 120 vs. >120 g / l) or with a rate of increase in hemoglobin levels (less than 10,10 to less than 20,20 to less than 30, and >> 30 g/l of hemoglobin over 4 weeks).

Pain at the site of subcutaneous injection was recorded more often than with the use of RCHEPO.

Discomfort at the injection site was usually mild and temporary and developed mainly after the first injection. Undesirable effects that are considered to be associated with the use of Aranespa are as follows: :

Body System Frequency of detectingnegative reaction to the drug Central nervous system / Peripheral nervous system Frequently encountered (>1%, ≤10%)Headache of the cardiovascular system Frequently occurring (>1%, ≤10%)Hypertensivascular pathologyrequently occurring (>1%, ≤10%)Vascular access thrombosis at the injection site Frequently occurring (>1%, ≤10%)Pain at the injection site

Seizures have been reported in very rare cases in patients with chronic renal failure treated with Aranesp. In some cases, partial red cell aplasia (PCCA) caused by the neutralizing effect of anti-erythropoietin antibodies has been described in connection with the use of Aranesp.

All other treatment-related adverse events were observed with a 1% frequency and less frequently (not often or rarely occurring). Most of them had mild or moderate severity and corresponded to concomitant diseases in such patients.

Cancer patients.

The incidence of hypertension and cardiovascular events was comparable in cancer patients treated with placebo, rcEpo, or Aranesp when Aranesp was administered subcutaneously. In addition, such adverse events were not associated with either the hemoglobin content (less than 130 vs. >130 g / l) or the rate of increase in hemoglobin levels (>> 20 g/l over four weeks). Cancer patients treated with Aranesp had an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, compared to patients treated with placebo.

In general, the adverse events associated with the use of Aranespa in cancer patients receiving concomitant chemotherapy were consistent with the underlying disease and the chemotherapy used to treat it.

Undesirable effects that are considered to be associated with the use of Aranespa are as follows: :

Body system Frequency of detectingnegative reaction to the drug musculoskeletal system Frequently occurring (>1%, ≤10%)Arthralgia as a whole Frequently occurring (>1%, ≤10%)Peripheral edema at the injection site, often occurring (>1%, ≤10%)Injection site pain and vascular pathologyrequently occurring (>1%, ≤10%)Thromboembolic reactions

The most frequently reported adverse event considered to be associated with Aranespa (less than 5%) was pain at the injection site. Discomfort at the injection site was usually mild and temporary.

Interaction

The clinical data obtained so far do not contain any indications of the interaction of Aranespa with other substances.However, it is known that its interaction with drugs characterized by a high degree of affinity for red blood cells, such as cyclosporine, tacrolimus, is potentially possible.

When darbepoietin alfa is administered concomitantly with any similar medications, the level of their content in the blood serum should be monitored with a dose modification in case of an increase in the concentration of hemoglobin.

Since compatibility studies have not been conducted, Aranesp should not be mixed or infused with other medicinal products.

How to take, course of use and dosage

Treatment with Aranesp should be carried out by doctors who have experience in prescribing for the above-mentioned indications. Aranesp (SureClick) is delivered ready for use in pre-filled syringe pens. PSRS are intended only for subcutaneous injections. For instructions on how to use the product, how to handle it, and how to dispose of it, see Special Instructions for Use.

Treatment of anemia in patients with chronic renal failure. Aranesp can be administered subcutaneously or intravenously. Subcutaneous use is preferred in patients not receiving hemodialysis to prevent peripheral venous puncture. The goal of therapy is to increase the hemoglobin content to a level exceeding 110 g/l. Individual selection of the required hemoglobin above 110 g / l is required for each patient. Avoid increasing hemoglobin by more than 20 g / l in 4 weeks or by more than 140 g/l. Clinical studies have shown that individual patient responses may vary. However, at the initial stages, the following recommendations should be followed, both for adults and children, with subsequent optimization of therapy depending on the clinical indications. Treatment with Aranesp includes two stages-the correction phase and the maintenance phase:

Correction phase.

The initial dose for subcutaneous or intravenous use should be 0.45 mcg/kg of body weight with a single weekly use. Alternatively, for patients who do not receive dialysis, subcutaneous use of the drug is allowed at an initial dose of 0.75 mcg/kg of body weight every two weeks. If the increase in hemoglobin concentration is insufficient (less than 10 g / l in 4 weeks), the dose of the drug is increased by approximately 25%. Increasing the dose of the drug should not be carried out more often than once every four weeks.

If the hemoglobin concentration increases by more than 25 g / l in four weeks, the dose of Aranespa should be reduced by 25-50%, depending on the rate of increase in hemoglobin. If the hemoglobin content exceeds 140 g / l, therapy should be interrupted until the hemoglobin level drops below 130 g / l, and then the drug should be resumed at a dose reduced by about 25% relative to the previous one. Hemoglobin should be measured weekly or biweekly until it stabilizes. Subsequently, hemoglobin can be evaluated periodically.

Maintenance phase.

During the maintenance phase, you can continue a single weekly use of Aranesp or switch to use every two weeks. When transferring patients on dialysis from weekly injections to a single-dose biweekly regimen, the initial dose should be twice as high as the once-weekly dose. For patients who do not receive dialysis, after reaching the required hemoglobin concentration against the background of prescribing the drug every two weeks, its subcutaneous use can be performed once a month using an initial dose twice as high as the previous dose administered every two weeks.

Titration of the dose to maintain the required hemoglobin concentration should be performed as often as necessary.

Individual selection of the required hemoglobin above 110 g / l is required for each patient. If optimization of the Aranespa dose is necessary to maintain the required hemoglobin, it is recommended to increase it by approximately 25%. If there is an increase in hemoglobin of more than 20 g / l in 4 weeks, the dose of the drug should be reduced by approximately 25%, depending on the rate of increase. If the hemoglobin content exceeds 140 g/l, therapy should be interrupted until the concentration decreases below 130 g/l, and then resume the drug use at a dose that is approximately 25% less than the previous one. After any change in the dose or mode of use, the hemoglobin content should be monitored every 1 or 2 weeks. Dose changes during the maintenance phase should be made no more than once every two weeks.

When changing the route of use of the drug, the same doses of the drug should be used and the hemoglobin concentration should be monitored every 1-2 weeks in order to maintain the required hemoglobin level.

Patients receiving one, two, or three weekly injections of RCHEPO can be switched to a single weekly Aranespa or bi-weekly Aranespa regimen. The initial weekly dose of Aranespa (mcg / week) is determined by dividing the total weekly dose of rcEpo (IU/week) by 200. The initial dose of Aranespa (mcg/ biweekly) for a biweekly regimen is determined by dividing the total cumulative dose of rcEpo administered over a two-week period by 200. Due to the known individual variability, individual patients may need to titrate the doses until the optimal therapeutic effect is obtained.

When replacing RCHEPO with Aranesp., the hemoglobin level should be measured at least once a week or every two weeks, and the method of use of the drug should remain unchanged.

Treatment of symptomatic anemia in cancer patients.

Aranesp should be administered subcutaneously to patients with anemia (at a hemoglobin concentration of less than 110 g / l).

The recommended starting dose is 500 mcg (6.75 mcg / kg) given once every three weeks. If the clinical response after nine weeks is inadequate (fatigue, hemoglobin content), further therapy may not be effective.

Alternatively, the drug can be administered once a week at a dose of 2.25 mcg/kg of body weight.

Aranespa is discontinued approximately four weeks after the end of chemotherapy. The hemoglobin content should not exceed 130 g / l.

After reaching the target hemoglobin, the dose of the drug should be reduced by 25-50% to maintain hemoglobin at the appropriate level. If necessary, further dose reduction is allowed to prevent an increase in the hemoglobin concentration of more than 130 g/l.

If the rate of increase in hemoglobin exceeds 20 g / l for 4 weeks, the dose of the drug should be reduced by 25-50%.

Overdose

The limits of the therapeutic dose of Aranesp are very wide. Even with a very high concentration of the drug in the blood serum, no symptoms of overdose were observed.

If polycythemia is detected, Aranespa should be temporarily discontinued (see section Dosage and use). If there are clinical indications, phlebotomy can be performed.

Special instructions

General provisions.

In order to confirm the effectiveness of erythropoiesis, all patients should be assessed for iron content before and during treatment, with a view to prescribing, if necessary, additional therapy with iron preparations.

The lack of response to the use of Aranespa should serve as an incentive to identify causal factors. The effectiveness of substances that stimulate erythropoiesis decreases when there is a lack of iron, folic acid or vitamin B12 in the body, as a result of which the level of their content must be adjusted. The erythropoietic response may also be weakened in the presence of concomitant infectious diseases, inflammatory symptoms, or cases of trauma, latent blood loss, hemolysis, severe aluminum intoxication, concomitant hematological diseases, or bone marrow fibrosis. The number of reticulocytes should be considered as one of the evaluation parameters. If the typical reasons for the lack of response are excluded, and the patient has reticulocytopenia, a bone marrow examination should be performed. If the bone marrow picture corresponds to the PCA picture, it is recommended to perform a test for the presence of antibodies to erythropoietin.

PCA caused by the neutralizing effect of anti-erythropoietin antibodies has been described in connection with the use of recombinant erythropoietic proteins, including darbepoietin alpha. These antibodies have been shown to cross-react with all erythropoietic proteins. If a diagnosis of PCA is made, treatment with Aranesp should be discontinued without further transfer of the patient to a therapeutic regimen that includes another recombinant erythropoietic protein (see the section Side effects).

In all studies of Aranespa, the exclusion criterion was active liver disease, so there are no data on the use of the drug in patients with impaired liver function. Since the liver is considered the main route of elimination of Aranespa and RCHEPO, patients with liver pathology should be prescribed these drugs with caution.

Abuse of Aranesp in healthy individuals can lead to an excessive increase in hematocrit, such phenomena can be associated with life-threatening complications from the cardiovascular system.

The protective cap of the needle on the PSHR contains natural dehydrated rubber (a latex derivative), which can cause an allergic reaction.

Patients with chronic renal failure.

The use of additional iron therapy is recommended for all patients whose serum ferritin concentration does not exceed 100 mcg/l or transferrin saturation level is below 20%, Blood pressure should be monitored in all patients, especially at the beginning of Aranespa use.Patients should be made aware of the importance of following the recommendations for the use of antihypertensive drugs and dietary restrictions. If blood pressure is poorly controlled during appropriate procedures, you can reduce the hemoglobin content by reducing the dose of Aranespa or temporarily stopping its use (see the section Dosage and use).

In patients with chronic renal failure and clinical symptoms of coronary heart 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 pectoris) requires a different solution.

During the use of Aranespa, the serum potassium content should be regularly monitored. Increased potassium concentrations have been reported in several patients receiving Aranesp, but no causal relationship has been established. If an increased or rising potassium concentration is detected, the use of Aranespa should be stopped until it returns to normal.

Patients with epilepsy should be prescribed Aranesp with caution, as there have been reports of seizures in patients with chronic renal failure treated with Aranesp.

Cancer patients

Influence on tumor growth.

Erythropoietins are growth factors that mainly stimulate the production of red blood cells. Erythropoietin receptors can be expressed on the surface of various tumor cells. As with all growth factors, there is an assumption that erythropoietins can stimulate the growth of malignancies of any type. Two controlled clinical trials on the use of erythropoietins in patients with various forms of cancer, including head and neck cancer and breast cancer, showed an unexplained increase in the mortality rate.

In patients with solid tumors or with lymphoproliferative malignancies, if the hemoglobin level increases above 130 g/l, the dose adjustment scheme described in the section Dosage and use should be strictly observed in order to minimize the potential risk of developing thromboembolic events. It is also necessary to regularly monitor the number of platelets and the concentration of hemoglobin in the blood. Special instructions for use

Aranesp is a sterile product made without preservatives. No more than one dose of the drug should be administered with a single syringe handle. Any amount of medication remaining in the pre-filled syringe pen must be disposed of.

Before use, the solution of Aranesp should be checked for the presence of visible particles. Only a colorless, transparent, or slightly opalescent solution can be used. The solution must not be shaken. Before use, you should wait for the PSHR to warm up to room temperature.

To avoid discomfort at the injection site, it is necessary to change the injection site of the drug.

Any quantities of unused product or its waste must be disposed of in accordance with local regulations.

Form of production

Aranesp solution for injection.

Storage conditions

Store in a dark place, at a temperature of 2 °C to 8 °C.

Shelf life

2 years

Active ingredient

Darbepoietin alpha

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

For adults as directed by your doctor

Indications

Anemia