Aranesp - instructions for use, dose, side effects, contraindications

Active substanceDarbepoetin alfaDarbepoetin alfa

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solution for injections

Dosage form: & nbspinjection

Composition:

Active substance in one pre-filled syringe pen (SureClickDarbepoetin alfa (recombinant): 20 μg (40 μg / ml), 40 μg (100 μg / ml), 60 μg (200 μg / ml), 80 μg (200 μg / ml), 100 μg (200 μg / ml), 150 μg (500 μg / ml), 300 μg (500 μg / ml), 500 μg (500 μg / ml)

Excipients in 1 ml of solution: sodium dihydrogen phosphate monohydrate - 2,118 mg, sodium hydrogen phosphate - 0,661 mg, sodium chloride - 8,182 mg, polysorbate 80 - 0,05 mg, water for injection - up to 1 ml.

Description:

A clear, colorless liquid.

Pharmacotherapeutic group:hematopoiesis stimulant

ATX: & nbsp

B.03.X.A Other stimulators of hemopoiesis

B.03.X.A.02 Darbepoetin alfa

Pharmacodynamics:

Darbepoetin alfa is produced using gene technology in Chinese hamster ovary cells (CHO-K1).

Darbepoetin alfa stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Darbepoetin alfa contains five N-linked carbohydrate chains, while endogenous hormone and recombinant human erythropoietins (rchEpo) have only three chains. The additional sugar residues, from the molecular point of view, do not differ from those present in endogenous hormone.Due to the high content of carbohydrates darbepoetin alfa has a longer half-life in comparison with p-epo, and, consequently, a greater activity in vivo. Despite these changes in the molecular structure darbepoetin alfa retains a very narrow specificity for the erythropoietin receptor.

Erythropoietin is a growth factor that basically stimulates the formation of red blood cells. Receptors to erythropoietin can be expressed on the surface of various tumor cells.

Patients with chronic renal insufficiency

In 2 clinical studies, it was found that in patients with CRF, the risk of death and serious cardiovascular adverse events is higher with the use of erythropoiesis stimulants to higher hemoglobin targets when compared with lower hemoglobin targets (135 g / L (8.4 mmol / L) ) against 113 g / l (7.1 mmol / l), 140 g / l (8.7 mmol / l) against 100 g / l (6.2 mmol / l).

In a randomized, double-blind, corrective study (n= 358) comparing dosing regimens once every two weeks and once a month in patients with chronic renal failure not on dialysis, the use of darbepoetin alfa to correct anemia once a month was no worse than once every two weeks.The mean time (1st Quarter, 3rd Quarter) of achieving hemoglobin correction (≥ 100 g / L and ≥ 10 g / L compared to baseline) was 5 weeks for both dosing regimens (3.7 weeks for dosing regimens once every two weeks and 3.9 weeks for the dosing regimen once a month). During the evaluation period (weeks 29-33), the mean (95% CI) of the equivalent dose was 0.20 (0.17, 0.24) μg / kg with a once-every-two-dose regimen and 0.27 (0, 23, 0.32) mkg / kg with the dosing regimen once a month.

In a randomized, double-blind, placebo-controlled study (TREAT), 4038 patients with chronic renal failure, type 2 diabetes, and hemoglobin ≤ 110 g / L not dialysis-treated received darbepoetin alfa with the goal of achieving a hemoglobin level of 130 g / l or a placebo (with the appointment of darbepoetin alfa with a lower hemoglobin level below 90 g / l). The study did not achieve the primary goal of reducing the risk of mortality for any reason or for cardiovascular morbidity (darbepoetin alfa vs placebo; risk ratio 1.05; 95% CI (0.94, 1.17), as well as the goal of reducing mortality for any reason and progressing to the terminal stage of renal failure (TSTP) (darbepoetin alfa vs placebo; risk ratio 1.06; 95% CI (0.95, 1.19).Analysis of the individual components of the composite endpoints showed the following risk ratio (95% CI): lethal outcome 1.05 (0.92, 1.21), chronic heart failure (CHF) 0.89 (0.74, 1.08), myocardial infarction (MI) 0.96 (0.75, 1.23), stroke 1.92 (1.38, 2.68), hospitalization in connection with myocardial ischemia 0.84 (0.55, 1.27) , TSPN 1.02 (0.87, 1.18).

Oncological patients receiving chemotherapy

Survival and progression of the tumor were studied in a total of 2,833 patients in five large controlled trials. Of these, four were double-blind and placebo-controlled, and one-open. Two studies included patients who had already undergone chemotherapy treatment. In two studies, the target level hemoglobin was set equal to and above 130 g / l, and in the other three - in the range from 120 to 140 g / l. In an open study, there was no difference in overall survival between the group receiving rhEPO treatment and control. In four placebo-controlled studies, risk indicators were in favor of control and ranged from 1.25 to 2.47. In these four studies, an unexplained statistically significant increase in mortality was found in comparison with control in patients with typical cancers and anemia, the treatment of which was performed with rCEPO.Comparison of the frequency of thromboses and other complications in the groups treated with rhEPO and control did not provide a satisfactory explanation for the reasons for this increase.

A systematic analysis of 57 studies, including a total of more than 9000 cancer patients, was conducted. In a meta-analysis of overall survival, the risk was 1.08 in favor of control (95% CI: 0.99-1.18, 8167 patients in 42 studies).

In patients treated with rhEPO, there was an increase in the relative risk of thromboembolic events (RR = 1.67, CI 95%: 1.35-2.06, 6769 patients in 35 studies). Thus, there is a sufficient amount of data that indicates the potential for significant harm in the treatment of cancer patients with EPO. It is unclear to what extent this applies to the appointment of recombinant human erythropoietins to achieve a target hemoglobin level of less than 130 g / l in patients with oncological diseases who receive chemotherapy, as there was a small number of patients with such characteristics in the data analyzed.

Also, data were analyzed in more than 13,900 patients with malignant diseases (chemotherapy, radiation therapy, chemotherapy and radiation therapy or lack of therapy),included in 53 controlled clinical trials of several epoetins. A meta-analysis of data on overall survival revealed a risk ratio of 1.06 in favor of the control group (95% CI: 1.00, 1.12, 53 studies and 13,933 patients), and for patients with malignant diseases receiving chemotherapy, The survival rate was 1.04 (95% CI: 0.97, 1.11, 38 studies and 10,441 patients). Meta-analysis also indicates a significant increase in the relative risk of thromboembolic events in patients with malignancies receiving recombinant human erythropoietin (see section "Specific guidance").

Preclinical safety data

In all studies in rats and dogs, the concentration of hemoglobin, hematocrit, erythrocytes and reticulocytes significantly increased with the use of darbepoetin alfa, 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 the enhanced pharmacological action (reduction of tissue blood flow due to an increase in the viscosity of the blood).Here were referred myelofibrosis and spleen hypertrophy, as well as the expansion of the complex QRS on ECG in dogs, without disturbance of heart rate and influence on the interval QT.

Darbepoetin alfa did not possess any genotoxic potential and did not affect the proliferation of non-hematological cells in vitro, nor in vivo. In studies on chronic toxicity, there was no tumorogenic or unexpected mitogenic response in any of the tissues studied. In long-term animal studies, the carcinogenic potential of darbepoetin alfa has not been evaluated.

In trials conducted on rats and rabbits, there was no clinically significant effect on pregnancy, embryonic / fetal development, childbirth, or postnatal development. The level of penetration of the drug through the placenta was minimal. There were no changes in fertility.

Pharmacokinetics:

Due to the high carbohydrate content, the concentration of darbepoetin alfa circulating in the blood exceeds the minimum concentration necessary to stimulate erythropoiesis for a longer time in comparison with equivalent doses of pentopoietin,which reduces the frequency of darbepoetin alfa administration while maintaining an equivalent level of biological response.

Patients with chronic renal insufficiency

The pharmacokinetics of darbepoetin alfa has been studied in patients with chronic renal failure with intravenous and subcutaneous administration of the drug. Its half-life was 21 hours (standard deviation (CO) 7.5) with intravenous administration. The clearance of darbepoetin alfa was 1.9 ml / h / kg (CO 0.56), and the volume of distribution (O_pc) was approximately equivalent to the plasma volume (50 ml / kg). With subcutaneous administration of the drug, its bioavailability was 37%. With a monthly subcutaneous injection of darbepoetin alfa at a dose of 0.6 to 2.1 μg / kg, its half-life was 73 hours (CO 24). A longer half-life of darbepoetin alfa with subcutaneous administration, compared with intravenous, is due to absorption kinetics. In clinical trials, minimal accumulation of the drug was observed with any method of administration. In preclinical studies, it was demonstrated that the renal clearance of darbepoetin is minimal (up to 2% of the total clearance) and does not affect the half-life of the drug from the serum.

The pharmacokinetics of darbepoetin alfa has been studied in children (3-16 years) with CRF who are or are not on dialysis, with samples taken from the moment of a single subcutaneous or intravenous injection of the drug for up to one week (168 hours) after administration. Sampling periods were the same duration as in adults with CRF, and a comparison showed that the pharmacokinetics of darbepoetin alfa in adults and children with CRF is similar. After intravenous administration, approximately 25% of the difference between adults and children was noted for the area under the pharmacokinetic concentration-time curve from zero time to infinity (AUC[0-∞]); However, this difference for children was less than a two-fold range AUC[0-∞]. After subcutaneous administration of the drug, the value AUC[0-∞] in adults and children was similar. Both after intravenous and after subcutaneous administration of the drug, the half-life of the drug in children and adults with CRF was similar.

Oncological patients receiving chemotherapy

After subcutaneous administration of the drug at a dose of 2.25 μg / kg to adult oncological patients, the mean maximum concentrations of darbepoetin alfa, 10.6 ng / ml (CO 5.9), were established on average for 91 hours (CO 19.7).These parameters corresponded to the linear pharmacokinetics of the dose over a wide range of values (0.5 to 8 μg / kg with weekly administration and 3 to 9 μg / kg once every two weeks). Pharmacokinetic parameters did not change with multiple dosing for 12 weeks (weekly or biweekly administration). There was an expected moderate increase (<2-fold) of the serum concentration of the drug when the equilibrium state was reached, but there was no evidence of its accumulation with a repeated appointment. Pharmacokinetics studies were performed involving patients with chemotherapy-induced anemia who, in combination with chemotherapy, subcutaneously received darbepoetin alpha injections at a dose of 6.75 μg / kg every three weeks. In this study, the mean (CO) value of the half-life was 74 (CO 27) hours.

Indications:

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

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

Contraindications:

Hypersensitivity to darbepoetin alfa, rchEpo or to any component of the drug.

Uncontrolled arterial hypertension.

Carefully:

Diseases of the liver; sickle-cell anemia; epilepsy.

Pregnancy and lactation:

Full-fledged, controlled studies of Aranesp the pregnant women not conducted.

In animal experiments, no direct damaging effects of the drug on during pregnancy, on embryonic / fetal development, delivery or postnatal development. There were no effects on fertility. When prescribing the drug to pregnant women women should be careful.

It is not known whether Aranesp is excreted into breast milk. Therefore, there is a risk for the child when breastfeeding. The decision to stop breastfeeding or stop / stop treatment with Aranesp should be taken considering the benefits of breastfeeding for the baby and the benefits of treatment for the mother.

Dosing and Administration:

Treatment with Aranesp should be performed by physicians with experience in prescribing for the above indications.

Aranesp is supplied ready for use in pre-filled syringes (PZH). Instructions on the use of the drug, handling it and the procedure for its destruction are given in the section "Specific instructions for use".

Therapy of symptomatic anemia in combination with chronic renal failure (CRF) in adults and children

Symptoms of anemia and consequences may vary depending on the age of the patients, their sex and the severity of the disease; in each case, an analysis of the patient's individual clinical data is required by the attending physician.

Aranesp can be administered subcutaneously or intravenously to increase the hemoglobin level, but not higher than 120 g / l. In patients who are not on dialysis, the subcutaneous route of administration is preferred because it avoids puncture of the peripheral veins.

The level of hemoglobin in patients is subject to individual fluctuations, including sometimes higher or lower than the desired target values. If the hemoglobin level deviates beyond the target values, a dose modification is performed, with the target value being the range from 100 to 120 g / l.It is necessary to avoid a persistent increase in hemoglobin level above 120 g / l, instructions for modifying the dose for hemoglobin values above 120 g / l are given below. Also, increase hemoglobin levels by more than 20 g / l over a 4-week period should be avoided. In this case, a dose adjustment is also necessary.

Treatment with Aranesp includes two stages - the correction phase and the supporting phase. Recommendations for use and dosing in adults and children are given in the instructions separately. Application in children less than 1 year old has not been studied.

Adult patients with chronic renal insufficiency

Correction phase

The initial dose for subcutaneous or intravenous administration should be 0.45 μg / kg of body weight with a single weekly administration. Alternatively, for patients not receiving dialysis, the following initial doses of the drug may also be administered subcutaneously: 0.75 μg / kg body weight every two weeks or 1.5 μg / kg body weight once a month. If the increase in hemoglobin concentration is insufficient (less than 10 g / L for 4 weeks), the dose of the drug increases by approximately 25%. An increase in the dose of the drug should not be carried out more often than once every four weeks.

If the increase in hemoglobin exceeds 20 g / L for 4 weeks, the dose should be reduced by approximately 25%. In the case where the hemoglobin level exceeds 120 g / l, the possibility of reducing the dose of the drug should be considered. If the hemoglobin content continues to increase, the dose should be reduced by about 25%. If after a dose reduction, hemoglobin continues to increase, it is necessary to temporarily stop the drug before the hemoglobin level begins to decrease, after which it is possible to resume therapy, and the dose of the drug should be reduced by approximately 25% of the previous dose.

Hemoglobin should be measured weekly or biweekly before stabilization.

In the future, the intervals between hemoglobin measurements can be increased.

Supporting phase

In patients on dialysis, you can continue to administer Aranesp once a week or go on an injection once every two weeks. When transferring patients who are on dialysis, from weekly injections to the mode of administration once every two weeks, the initial dose should be twice the dose administered once a week.For patients who do not receive dialysis, you can continue to administer Aranesp once a week or once every two weeks or once a month. For patients receiving Aranesp once every two weeks, after achieving the required hemoglobin concentration, its subcutaneous administration can then be performed once a month using the original dose twice the previous dose, administered bi-weekly.

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

If the optimization of the Aranesp dose is necessary to maintain the required hemoglobin, it is recommended to increase it by approximately 25%.

If the hemoglobin is increased more than 20 g / l in 4 weeks, the dose should be reduced by approximately 25%, depending on the rate of increase. If the hemoglobin content exceeds 120 g / l, the possibility of reducing the dosage of the drug should be considered. If the hemoglobin content continues to increase, the dose should be reduced by about 25%. If after a dose reduction, hemoglobin continues to rise,it is necessary to temporarily stop the use of the drug before the hemoglobin level begins to decrease, after which it is possible to resume therapy, and the dosage of the drug should be reduced by approximately 25% of the previous dose.

Careful monitoring of patients should be performed to ensure adequate correction of anemia using the minimum approved doses of Aranesp.

After any change in dose or mode of administration, the hemoglobin content should be monitored every 1 or 2 weeks. The dose change during the maintenance phase should not be performed more than once every two weeks.

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

Adult patients who receive one, two or three injections of rhepoepy on a weekly basis can be transferred to the once-weekly Aranesp administration or its administration once every two weeks. The initial weekly dose of Aranesp (μg / week) is determined by dividing the total weekly dose of pseudo (IU / week) by 200. The initial dose of Aranesp (μg / two weeks) with a once-weekly regimenare determined by dividing the total cumulative dose of pentopoin, introduced over a two-week period, by 200. In view of the known individual variability, it may be necessary to titrate doses for individual patients to obtain the optimal therapeutic effect. When replacing pHoPo with Aranesp, measurement of hemoglobin should be performed at least once a week or two weeks, and the route of administration should remain unchanged.

Children with chronic renal insufficiency

Correction phase

For children aged 11 years and older, the initial dose for subcutaneous or intravenous administration of the drug is 0.45 μg / kg of body weight as a single injection once a week. In patients who do not receive dialysis, an initial dose of 0.75 μg / kg can be administered subcutaneously once every two weeks. If the increase in hemoglobin is insufficient (less than 10 g / L for a 4-week period), it is necessary to increase the dose of the drug by approximately 25%. The dose should be increased no more than once every four weeks.

If the increase in hemoglobin exceeds 20 g / L for 4 weeks, the dose should be reduced by approximately 25%, depending on the degree of increase in hemoglobin.In the case where the hemoglobin level exceeds 120 g / l, the possibility of reducing the dose of the drug should be considered. If the hemoglobin content continues to increase, the dose should be reduced by about 25%. If after a dose reduction, hemoglobin continues to increase, it is necessary to temporarily stop the drug before the hemoglobin level begins to decrease, after which it is possible to resume therapy, and the dose of the drug should be reduced by approximately 25% of the previous dose.

Hemoglobin should be measured weekly or biweekly before stabilization.

In the future, the intervals between hemoglobin measurements can be increased.

Treatment of anemia with Aranesp in the phase of correction in children in the dosing regimen once a month has not been studied.

Recommendations for correcting the level of hemoglobin in children aged 1 to 10 years are not present.

Supporting phase

In children 11 years of age and older in the supporting phase of therapy, Aranesp can be continued once a week or once every two weeks. Patients on dialysis, when transferring them from the Aranesp dosage regimen once a week to the once-weekly regimen, should initially receive a dose equivalent to twice the once-weekly mode of administration.If the patient is not on dialysis, once the target hemoglobin level has been reached in the dosing regimen of the drug once every two weeks, Aranesp can be administered subcutaneously once a month, with the initial dosage being twice the dose that was used in mode 1 once in two weeks.

For children aged 1 to 18 years, clinical data showed that patients receiving rhEPo two or three times a week can be transferred to Aranesp administered once a week, and patients receiving rhEPO once a week can be transferred to mode of administration once every two weeks. The initial Aranesp dosage for children (μg / week) administered weekly can be determined by dividing the total weekly dose of rEpoPo (IU / week) by 240. The initial Aranesp dosage when administered every 2 weeks (μg / every 2 weeks) can be determined by dividing of the total dose of rhEPO over a two-week period of 240. Because of individual differences, the selection of the optimal therapeutic dose is required for individual patients. When replacing arterioscopy with Aranesp, the hemoglobin level should be monitored every 1-2 weeks, and the same route of administration should be used.

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

If the optimization of the Aranesp dose is necessary to maintain the required hemoglobin, it is recommended to increase it by approximately 25%.

If the increase in hemoglobin exceeds 20 g / L for 4 weeks, the dose should be reduced by approximately 25%, depending on the degree of increase in hemoglobin. In the case where the hemoglobin level exceeds 120 g / l, the possibility of reducing the dose of the drug should be considered. If the hemoglobin content continues to increase, the dose should be reduced by about 25%. If after a dose reduction, hemoglobin continues to increase, it is necessary to temporarily stop the drug before the hemoglobin level begins to decrease, after which it is possible to resume therapy, and the dose of the drug should be reduced by approximately 25% of the previous dose.

Patients should be monitored carefully to ensure that the minimum approved doses of Aranesp provide adequate control of the symptoms of anemia.

After any change in dose or mode of administration, the hemoglobin content should be monitored every 1 or 2 weeks.The dose change during the maintenance phase should not be performed more than once every two weeks.

Treatment of symptomatic anemia induced by chemotherapy in patients with oncological diseases

In patients with anemia (eg hemoglobin concentration equal to or below 100 g / l), Aranesp can be administered subcutaneously to increase hemoglobin levels, but not more than 120 g / l. Symptoms and consequences of anemia depend on the age of the patients, their sex and the severity of the disease. In each case, an analysis of the individual clinical data of the patient by the treating physician is necessary.

Since the hemoglobin content in the blood is an individual indicator, for which a marked diversity is characteristic, in some patients its content may both exceed the target level, and be less than it. In this case, correction of the dosage of the drug helps, taking into account the fact that the target hemoglobin level is from 100 g / l to 120 g / l.Avoid increasing the hemoglobin concentration by more than 120 g / l; The guidance on dose adjustment is given below if the hemoglobin content exceeds 120 g / l.

The recommended initial dose of the drug is 500 μg (6.75 μg / kg) once every 3 weeks or 2.25 μg / kg once a week. If the clinical response (fatigue, hemoglobin content) after nine weeks is inadequate, further therapy may not be effective. The use of Aranesp is discontinued approximately four weeks after completion of chemotherapy.

After reaching the target hemoglobin level, the dosage of the drug should be reduced by 25-50%, to adequately control the symptoms of anemia using the minimum approved doses of Aranesp. Titration of the dose between 500 μg, 300 μg and 150 μg is possible.

Careful monitoring of the patients' condition should be made. If the patient's hemoglobin level exceeds 120 g / l, the dose should be reduced by 25-50%. If the hemoglobin content exceeds 130, careful monitoring of the patients' condition should be made. If the patient's hemoglobin level exceeds 120 g / l, Aranesp should be temporarily discontinued.After lowering the hemoglobin level to 120 g / l or lower, therapy can be resumed, the dosage of the drug should be approximately 25% less than the previous one.

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

Side effects:

General Provisions

Identified undesirable reactions, associated with taking Aranesp, include hypertension, stroke, thromboembolism, seizures, allergic reactions, rash / erythema and partial red cell aplasia (PKAA).

Pain at the injection site was reported to be associated with treatment in studies in which Aranesp was administered as a subcutaneous injection. The discomfort at the injection site was generally mild and transient and developed mainly after the first injection.

The frequency of development of adverse reactions is indicated by the class of organ system and frequency of occurrence.

The frequency of occurrence is defined as follows: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000), is unknown (can not be estimated from available data).

Data are presented separately for patients with CRF and oncological patients and reflect the profile of adverse reactions in these populations.

Patients with chronic renal insufficiency

In controlled trials of 1,357 patients, 766 patients received Aranesp and 591 patients received recombinant human erythropoietin. 83% were on dialysis, 17% were not. Stroke was identified as an unwanted reaction in an additional clinical study (TREAT).

The frequency of adverse reactions assessed as related to treatment with Aranespom is:

The system of MedDRA	Frequency of occurrence	Unwanted reaction
On the part of the blood and lymphatic system	Unknown *	Partial red cell aplasia
From the side immune systems	Often*	Hypersensitivity
From the side nervous systems	Often	Stroke
From the side nervous systems	Nechasto *	Convulsions
From the heart	Often	Increase arterial pressures
From the side of the vessels	Rarely	Thromboembolism
From the skin and subcutaneous tissue	Often	Rash / Erythema
From the side organism in whole, including local reactions	Hasto	Pain at the injection site

*cm. description of the noted undesirable reactions.

Oncological patients

Adverse reactions were determined from pooled data from seven randomized, double-blind, placebo-controlled Aranesp studies that included 2112 patients (Aranesp 1200, placebo 912).Clinical trials included patients with solid tumors (eg, lung, breast, colon, ovaries) and lymphoid malignancies (eg, lymphoma, multiple myeloma).

The frequency of undesirable effects, regarded as related to the treatment of Aranespum, is:

The system of MedDRA	Frequency of occurrence	Unwanted reaction
From the immune systems	Often*	Hypersensitivity
From the nervous side systems	Infrequently*	Convulsions
From the heart	Often*	Hypertension
From the side of the vessels	Often	Thromboembolism, including thromboembolism pulmonary artery
From the skin and subcutaneous tissue	Often	Rash / Erythema
From the side of the body in whole, including local reactions	Often	Edema
	Often	Pain at the injection site

*cm. description of the noted undesirable reactions.

Description of the noted undesirable reactions

Patients with chronic renal insufficiency

Stroke has been reported as a common unwanted reaction in patients with CRF in a TREAT study.

In some cases, neutralizing antibodies to erythropoietin have been reported,mediating partial red cell aplasia (PKAA) associated with Aranespom therapy, mainly in patients with CRF who received the drug subcutaneously. If confirmation of the diagnosis of PKA is confirmed, Aranespum therapy should be discontinued, and patients should not be transferred to another recombinant erythropoietin.

The frequency of hypersensitivity reactions was evaluated on the basis of clinical trials as "very often" in patients with CRF. There have been reports of the development of serious hypersensitivity reactions, including anaphylactic reactions, angioedema, allergic bronchospasm, skin rashes and hives associated with darbepoetin alfa.

There have been reports of seizures in patients receiving darbepoetin alfa. Frequency was assessed on the basis of clinical trials as "infrequent" in patients with HNP.

Oncological patients

When used in routine clinical practice, hypertension was observed in cancer patients. Frequency was evaluated on the basis of clinical research data as "often" in cancer patients and was also often found in groups receiving a placebo.

When used in routine clinical practice, hypersensitivity reactions were observed in cancer patients. The frequency of hypersensitivity reactions was evaluated on the basis of clinical trials as "very often" in cancer patients. Also, hypersensitivity reactions were very common in groups receiving a placebo. There have been reports of the development of severe hypersensitivity reactions, including anaphylactic reactions, angioedema, allergic bronchospasm, skin rashes and hives associated with darbepoetin alfa.

When used in routine clinical practice in patients receiving darbepoetin alfa, reported on convulsions. The frequency was estimated on the basis of clinical research data as "infrequent" in cancer patients. Seizures often occurred in groups receiving a placebo.

Children with chronic renal insufficiency

There are limited data on the safety of Aranesp in children.

Aranesp's safety was evaluated in a clinical trial in children with chronic renal failure (1 to 18 years of age) receiving dialysis that was stable with epoetin alfa and then transferred to Aranesp to maintain hemoglobin levels.There were no additional adverse reactions in children, compared to those previously recorded in adult patients.

Overdose:

The maximum amount of Aranesp, safe for administration as a single or multiple dose, was not determined. In case of insufficient control of hemoglobin level and titration dose, Aranespum therapy can lead to polycythemia. After an overdose of Aranespum, severe hypertension was observed.

In the case of polycythemia, the introduction of Aranesp should be temporarily discontinued (see section "Method of administration and dose"). In the presence of clinical indications, phlebotomy can be performed.

Interaction:

Clinical data obtained to date do not contain indications of the interaction of darbepoetin alfa with other substances. However, it is known that its interaction with drugs characterized by a high degree of affinity for erythrocytes, such as ciclosporin, tacrolimus. With the simultaneous appointment of Aranesp with any such drugs, the level of serum levels should be monitored, with a dose modification in case of increased hemoglobin concentration.

Because compatibility studies have not been conducted, Aranesp should not be mixed or administered as an infusion along with other medications.

Special instructions:

General Provisions

It is necessary to monitor blood pressure in all patients, especially at the beginning of Aranespum therapy. If blood pressure is not adequately controlled by standard methods, the concentration of hemoglobin can be reduced by decreasing the dosage and canceling Aranesp (see section "Dosage and Administration").

When treating Aranesp with patients with CRF, there was a development of severe hypertension, including hypertensive crisis, hypertensive encephalopathy and convulsive seizures.

In order to confirm the effectiveness of erythropoiesis, all patients should determine the iron content before and during treatment with the purpose of prescribing, if necessary, additional iron therapy.

The lack of a response to the use of Aranesp should serve as an incentive for identifying causal factors.

Efficacy of erythropoiesis stimulating drugs (ESP) decreases with a deficiency in the body of iron, folic acid or vitamin B₁₂, as a result of which the level of their content needs to be adjusted.

The erythropoietic response can also be weakened by the presence of concomitant infectious diseases, symptoms of inflammation or trauma, latent hemorrhage, hemolysis, severe aluminum intoxication, concomitant hematologic diseases or bone marrow fibrosis.

The number of reticulocytes should be considered as one of the parameters of the evaluation. If the typical reasons for the absence of a response are excluded, and the patient is diagnosed with reticulocytopenia, a bone marrow examination should be performed. If the bone marrow pattern corresponds to the picture of the PKAA, it is recommended to perform a test for the presence of antibodies to erythropoietin.

PACA was described, caused by the neutralizing effect of anti-EPSO antibodies associated with the use of ESP, including Aranesp. More often than not, such reports relate to patients with CRF who received the drug subcutaneously. It was shown that these antibodies cross-react with all erythropoietic proteins. In the case of a diagnosis of PKA. treatment with Aranesp should be stopped without further transfer of the patient to a therapeutic regimen,including another recombinant erythropoietic protein (see the "Side effect" section).

The paradoxical reduction in hemoglobin and the development of severe anemia with low reticulocyte counts should lead to the immediate withdrawal of epoetin and the test for the presence of antibodies to erythropoietin. Such cases have been described in patients with hepatitis C who received interferon and ribavirin therapy in combination with epoetins. The use of epoetins in the treatment of anemia in hepatitis C is not approved.

In all studies of Aranesp the exclusion criteria were active liver diseases, therefore data on the use of the drug in patients with impaired liver function are absent. Since the liver is considered the main way to eliminate darbepoetin alfa and rchEpo, patients with liver pathology should be given these drugs with caution.

Abuse Aranespum 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 cap of the PZH needle consists of natural dehydrated rubber (latex derivative), which can cause an allergic reaction.

When maintaining hemoglobin levels in patients with chronic renal failure, its concentration should not exceed the upper limit specified in the section "Method of administration and dose". In clinical trials, when the target hemoglobin level reaches more than 120 g / l against the background of the use of ESP. patients had an increased risk of death, development of serious complications from the cardiovascular system or disorders of the cerebral circulation, including stroke and thrombosis of vascular access.

In controlled clinical trials, it has not been possible to identify significant benefits from the use of epoetins, if the hemoglobin concentration exceeds the level needed to control the symptoms of anemia and eliminate the need for blood transfusions.

Aranesp should be used with caution in patients with epilepsy. There are reports of seizures in patients receiving Aranesp.

Patients with chronic renal insufficiency

In patients with chronic renal failure, maintaining hemoglobin concentrations should not exceed the upper limit of the target hemoglobin concentration, recommended in the section "Method of administration and dose".In clinical trials, there were increased risks of death, serious cardiovascular complications or cerebrovascular accidents, including stroke, and thrombosis of vascular access in appointing ESPs to achieve hemoglobin levels above 120 g / l (7.5 mmol / l).

Conducted controlled clinical trials have not shown significant advantages in the appointment of epoetins, when the hemoglobin concentration rises above the level required to treat the symptoms of anemia and to avoid blood transfusions.

All patients with a serum ferritin level below 100 mcg / l or those with transferrin saturation below 20% are recommended additional iron therapy.

During the application of Aranesp, the serum potassium content should be monitored regularly. An increase in potassium concentration has been reported in several patients receiving Aranesp, but no causal relationship has been established. If an increased or increasing potassium concentration is detected, Aranesp should be discontinued before it is normalized.

Oncological patients

Influence on tumor growth

Epoetins are growth factors which, mainly, stimulate the production of red blood cells. Receptors to erythropoietin can be expressed on the surface of various tumor cells. As with any growth factor, there is a suggestion that erythropoietins can stimulate tumor growth.

In a number of controlled clinical trials in cancer patients receiving chemotherapy, the use of epoetins did not increase the overall life span or reduce the risk of tumor progression in patients with anemia associated with oncological disease.

In controlled clinical studies of Aranesp and other ESPs, it was demonstrated:

- Reducing the time to progression in patients with advanced head and neck cancer receiving radiotherapy, with the corrective appointment of epoetin to achieve a target hemoglobin value higher than 140 g / l, ESP are not shown in this group of patients.

- Decrease in the overall life expectancy and increase in mortality associated with the progression of the disease for 4 months in patients with metastatic breast cancer receiving chemotherapy, with the corrective appointment of epoetin to achieve the target hemoglobin value of 120-140 g / l.

- An increase in the risk of death with a corrective appointment of epoetin to achieve a target hemoglobin value of 120 g / l in patients with active malignant tumors, who received no chemotherapy or radiation therapy. Erythropoiesis-stimulating agents are not shown in this group of patients.

In accordance with the above, in some clinical situations, blood transfusion should be used to treat anemia in patients with oncological diseases. The decision to prescribe recombinant erythropoietins should be taken based on an assessment of the benefit / risk ratio for each individual patient, taking into account the particular clinical situation. It is necessary to consider the following factors: the type and stage of the tumor process; the degree of anemia; life expectancy; The situation in which the patient will undergo treatment; and the wishes of the patient himself (see the section "Pharmacodynamics").

In patients with solid tumors or with lymphoproliferative malignancies, when the hemoglobin level is higher than 120 g / l, the dose adjustment scheme described in the Application and Dose section should be strictly followed in order to minimize the potential risk of 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. One syringe should not be administered more than one dose of the drug. Any amount of medicinal product remaining in the pre-filled syringe is subject to destruction.

Before administration, the Aranesp solution should be monitored for the presence of visible particles. It is allowed to use only a colorless, transparent or slightly opalescent solution. The solution should not be shaken. Before the introduction, wait until the PZH is warmed to room temperature.

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

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

TECHNIQUE FOR THE PROCEDURE OF INJECTION OF ARANESPAN PREPARATION IN PRE-FILLED SYRINGES OR IN PRE-FILLED SYRINGES WITH A PROTECTIVE DEVICE FOR NEEDLE

This section describes the procedure for injecting Aranesp, which you can do yourself. Before using the drug in pre-filled syringes and pre-filled syringes with a needle protector, please first read the "General Recommendations" below (section 1) and then, with the recommendations for the appropriate release form (section 2 in the case of a pre- filled syringes and section 3 in the case of pre-filled syringes with a needle guard).

Section 1. General recommendations

It is very important that you do not inject yourself until your doctor, nurse or pharmacist teaches you. If you have any questions, consult your doctor, nurse.

Before the injection

Carefully read all the recommendations before administering the drug.

How do you, or someone who makes you this injection, use PZH?

Your doctor has appointed you Aranesp PZH for subcutaneous injections. Your doctor, nurse or pharmacist will tell you how much of the drug and how often you need to enter.

Equipment

For self-injection you will need:

- one PZH / PZSH with a protective device for the needle with the preparation Aranesp; and

- alcohol-soaked tampons or similar materials.

Before the injection

1. Take the syringe out of the refrigerator. To remove the pre-filled syringe from the bundle, grasp the center of the transparent needle guard (see Figure 1).

Do not take the PZS for the piston rod, gray cap or antennae of the needle guard. This can damage the device or activate the needle protector.

2. Leave the PZH at room temperature for about 30 minutes. This will make the injection more comfortable.

3. Please pay attention to the following instructions:

a. Do not preheat the pre-filled syringe in hot water or in a microwave oven.

b. Do not leave a pre-filled syringe in direct sunlight.

c. Do not use a pre-filled syringe for the piston rod, gray needle cap, or barb of the needle guard.

d. Do not shake the PZS.

e. Do not remove the gray cap of the pre-filled syringe until you are ready to inject.

f. Do not attempt to activate the pre-filled syringe before injection.

g. Do not attempt to remove the transparent needle guard from the pre-filled syringe.

h. He Try to remove the tear-off label from the pre-filled syringe before injection.

Store pre-filled syringes in a place inaccessible to children.

4. Before use, check the following:

a. You use that drug and dose, which you appointed a doctor.

b. Shelf life on the label of the pre-filled syringe (YEAR BEFORE :). Not Use the PGS if the last day of the specified month has expired.

c. Description preparation Aranesp. The solution should be clear, colorless or light yellow. If the solution is cloudy or contains particles, the drug should not be used.

d. You can notice small air bubbles in the pre-filled syringe. You do not need to remove air bubbles before the injection. The introduction of a solution with air bubbles is safe.

5. Wash hands thoroughly.

6. Choose a comfortable, well-lit place and a clean surface, it is convenient to arrange all the necessary materials.

How to choose an injection site?

It is best to inject in the upper part of the hip and in the abdomen.If the injection makes you someone else, you can use the outer surface of the shoulder (see. Fig. 2).

If the area where you are going to inject, reddened or swollen, you should choose a different injection site.

Section 2. Recommendations for the introduction of Aranesp in a pre-filled syringe

How to prepare for an injection?

Before the injection, you must do the following:

1. To avoid bending the needle, gently pull the cap off the needle immediately, without twisting, as shown in Figure 3 (see Figure 3).

2. Do not touch the needle or press the plunger.

3. Now you can use a pre-filled syringe.

How to administer the drug?

1. Disinfect injection space via moistened with alcohol swab, and a skin clamp (without squeezing) the thumb and forefinger.

2. Insert the needle into the skin completely as indicated by the doctor or nurse.

3. Enter the prescribed dose subcutaneously, as your doctor or nurse indicated.

4. Slowly and continuously apply pressure on the piston, thus compressing the skin fold and not release it until the syringe is empty.

5. Remove the needle and release the skin fold.

6. If the blood came, gently wipe it with a cotton ball or tissue, DO NOT rub the injection site.If necessary, you can glue it with adhesive tape.

7. One pre-filled syringe is designed for single use. Do not use the drug Aranesp left in the syringe.

Remember: In case of difficulties, seek help or advice from a doctor or nurse.

Section 3. Recommendations for the introduction of the drug Aranesp in a pre-filled syringe with a protective device for the needle

To reduce the risk of accidental injury, each PZS is equipped with a needle guard that is automatically activated to close the needle after the injection is completed.

Pre-filled syringe with a transparent needle guard (see Figure 4).

It can be used if the transparent protective device for the needle looks as shown below - see Fig. 5.

Can not be used if the transparent protective device for the needle looks activated (the spring is stretched) - see Fig. 6.

Do NOT attempt to activate the transparent fuse filled syringe before injection.

Do not touch the barbels of the needle guard - see Fig. 7.

DO NOT use PZS if the gray cap has been removed. or a transparent needle guard has been activated (needle coating).

The CYL cylinder contains a tear-off label, which can be removed after the injection. This label is used by the doctor to fill the patient's card.

How to administer the drug?

1. Cleanse the skin with an alcohol-soaked tampon.

2. To avoid bending the needle, gently pull the gray cap off the needle immediately. Do not touch the needle and do not press the plunger (see figure 8).

3. Hold the skin (do not squeeze) with your thumb and forefinger. Insert the needle into the skin.

4. Press down on the piston with light continuous pressure.

Push the piston until the syringe is empty. The transparent needle guard will not work until the pre-filled syringe is empty (see Figure 9).

5. While the piston is depressed, remove the needle from the skin, release the plunger and allow the syringe to rise upward until the entire needle is covered with a transparent needle guard (see Figure 10).

If the needle protector is not activated, it is possible that you did not complete the injection completely. Call your doctor if you think you have not received the full dose.

DO NOT put the gray cap back on the needle.

6.If blood comes out, gently wipe it with a cotton ball or cloth. Do not rub the injection site. If necessary, you can glue the injection site with a patch.

Do not use the drug Aranesp left in the syringe.

Remember: Use one PZH for only one injection.

In case of difficulties, seek help or advice from a doctor or nurse.

Destruction of used PSS

Do not put a gray cap back on used syringes. You can accidentally get hurt.

- Store used syringes in a place that is protected from children.

- Dispose of the used PZS / PZH with the needle protector in accordance with local regulations. Ask the pharmacist how to destroy the drug if it is no longer needed. These measures will help protect the environment.

The following information is only for medical personnel:

How to remove a tear-off label from a pre-filled width with a needle guard

Pre-filled syringes with a needle guard have a tear-off label that can be removed and placed on the patient's card.

Note: follow these instructions after performing the injection and when the transparent protective device covers the needle.

1. Hold the syringe as shown in the figure (see. Fig. 11), and is believed to plug yourself in such a way that you see a window with a label without opening the window, as shown below.

2. Slightly turn the plunger away from you until the label appears from the window, as shown below (see Figure 12).

3. Pull the label and then tear off the perforation as shown below (see Figure 13).

Effect on the ability to drive transp. cf. and fur:

The effect of the preparation Aranesp on the ability to drive a car and the handling of machinery was not revealed.

Form release / dosage:Injection, 10 μg, 15 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 80 μg, 100 μg, 150 μg, 300 μg, 500 μg.

Packaging:

Pre-filled syringes (PZSH) consist of a cylinder with built-in needle, the elastomeric cap is closed, the piston and the elastomeric plunger laminated fluoropolymer or of a cylinder with built-in needle, the elastomeric cap closed with the additional polypropylene cap, and an elastomeric piston plunger laminated fluoropolymer. Also, the PZS can be equipped with an automatic protective device for the needle.

The cap of the PZH needle consists of natural dehydrated rubber (latex derivative).

Pre-filled syringes

For 0.4 ml of the solution (25 μg / ml) 10 μg or 0.375 ml of the solution (40 μg / ml) 15 μg or 0.5 ml of the solution (40 μg / ml) 20 μg or 0.3 ml (100 μg / ml) 30 μg or 0.4 ml of the solution (100 μg / ml) 40 μg or 0.5 ml of the solution (100 μg / ml) 50 μg or 0.3 ml of the solution 200 μg / ml) - 60 μg, or 0.4 ml of the solution (200 μg / ml) - 80 μg, or 0.5 ml of the solution (200 μg / ml) - 100 μg, or 0.3 ml of the solution (500 μg / ml) - 150 μg or 0.6 ml solution (500 μg / ml) - 300 μg, or 1.0 ml solution (500 μg / ml) - 500 μg into syringes of glass I of hydrolytic class with stainless steel needles (27G).

1. One pre-filled syringe (10 μg, 15 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 80 μg, 100 μg, 150 μg, 300 μg, 500 μg) is placed in a cardboard box equipped with a cardboard fixative, together with instructions for use.

Each pack is glued with a transparent protective label-control of the first opening, which has a longitudinal color strip.

2. 1 pre-filled syringe is placed in a contour mesh package. One contoured cell package (doses of 300 μg, 500 μg) or 4 contiguous cell packs (doses of 10 μg, 15 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 80 μg, 100 μg, 150 μg) are placed together with instructions for use in a cardboard box.

Pre-filled syringes with needle guard

For 0.5 ml of the solution (40 μg / ml) 20 μg or 0.3 ml of the solution (100 μg / ml) 30 μg or 0.4 ml of the solution (100 μg / ml) 40 μg or 0, 5 ml of the solution (100 μg / ml) 50 μg or 0.3 ml of the solution (200 μg / ml) 60 μg or 0.4 ml of the solution (200 μg / ml) 80 μg or 0.5 ml (200 μg / ml) 100 μg, or 0.3 ml solution (500 μg / ml) 150 μg or 0.6 ml solution (500 μg / ml) 300 μg, or 1.0 ml solution (500 μg / ml) μg / ml) - 500 μg into syringes of glass I of hydrolytic class with stainless steel needles (27G).

One pre-filled syringe with a needle guard is placed in a contour mesh package. One out-of-the-box cell package (20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 80 μg, 100 μg, 150 μg, 300 μg, 500 μg) or 4 cell contiguous packs (20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 80 μg, 100 μg, 150 μg) are placed together with the instructions for use in a cardboard pack.

Storage conditions:

Store in a dark place at a temperature of 2 to 8 ° C. Do not freeze. Keep out of the reach of children.

Special instructions on the condition of storage

Before out-patient use, Aranesp can be moved from storage to a room temperature (up to 25 ° C) for a maximum period of 7 days.

Once removed from the refrigerator and reached room temperature (up to 25 ° C), the syringe should be used within 7 days or destroyed.

Shelf life:

3 years.

Do not use at the end of the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-001710/07

Date of registration:26.07.2007 / 19.11.2014

Expiration Date:Unlimited