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Instruction for use: Aranesp

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Dosage form: solution for injections

Active substance: Darbaepoetinum alfa

ATX

B03XA02 Darbepoetin alfa

Pharmacological group

Hematopoiesis stimulant (anti-anemic agent) [Stimulators of hemopoiesis]

The nosological classification (ICD-10)

D63.0 Anemia in neoplasm: Anemia in chronic diseases; Anemia due to radiation damage; Radiation anemia; Anemia in patients with solid tumors; Pernicious anemia

D63.8 Anemia in other chronic diseases classified elsewhere: Anemia in chronic diseases; Anemia in immunological disorders; Anemia in peptic ulcer; Anemia in kidney diseases; Anemia with HIV treatment; Anemia in the background of chronic renal failure; Anemia in patients with myeloma; Symptomatic anemia; Symptomatic anemia of renal genesis; Anemia in HIV-infected patients; Renal anemia

N18.9 Chronic renal failure, unspecified: Edema of renal genesis

Composition

Injection solution - 1 pre-filled syringe

active substance: Darbepoetin alfa (recombinant) - 10 μg (25 μg / ml); 15 μg (40 μg / ml); 20 μg (40 μg / ml); 30 μg (100 μg / ml); 40 μg (100 μg / ml); 50 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)

Auxiliary substances in 1 ml of the 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

Description of dosage form

Transparent, colorless liquid.

Characteristic

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

Pharmachologic effect

Mode of action - Hematopoietic.

Pharmacodynamics

Darbepoetin alfa stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Darbepoetin alfa contains 5 N-linked carbohydrate chains, while endogenous hormone and recombinant human erythropoietin (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 increased carbohydrate content, darbepoetin alfa has a longer half-life in comparison with rchEPO, and therefore 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 target hemoglobin levels when compared with the lower 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, placebo-controlled trial (TREAT), 4038 patients with chronic renal failure, type 2 diabetes, and hemoglobin ≤110 g / l who were not on dialysis received darbepoetin alfa to reach a hemoglobin level of 130 g / L or placebo With the appointment of darbepoetin alfa with a lower hemoglobin level below 90 g / l). The study did not achieve the main goal of reducing the risk of death 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 In reducing mortality for any reason and progressing to the terminal stage of renal failure (dDPE) (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 relationship Risks (95% CI): death 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 hemoglobin level was set equal to and above 130 g / l, and in the other three - in the range from 120 to 140 g / l. In the open study, there was no difference in the overall survival between the group treated with rhEPO and the control group. In four placebo-controlled studies, risk indicators were in favor of the control group and ranged from 1.25 to 2.47. In these four studies, an unexplained statistically significant increase in mortality was found in comparison with the 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, does not provide a satisfactory explanation of 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 indicating 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.

Data were also analyzed for 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 the overall survival data revealed a risk ratio of 1.06 in favor of the control group (95% CI: 1, 1.12, 53 studies and 13 13933 patients), and for patients with malignant diseases receiving chemotherapy, the overall survival risk ratio was 1, 04 (95% CI: 0.97, 1.11, 38 studies and 10441 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 "Special instructions").

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 increased pharmacological action (reduction of tissue blood flow due to an increase in the viscosity of the blood). Here were included myelofibrosis and spleen hypertrophy, as well as the expansion of the QRS complex on the ECG in dogs, without disturbance of the heart rhythm and influence on the QT interval.

Darbepoetin alfa did not possess any genotoxic potential and did not affect the proliferation of non-hematological cells either in vitro or 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, compared with equivalent doses of rCEPO, which reduces the incidence of darbepoetin alfa with 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 IV and / or injection of the drug. Its half-life was 21 hours (standard deviation (CO 7.5) with IV injection.) The clearance of darbepoetin alfa was 1.9 ml / h / kg (CO 0.56), and the volume of distribution (Ors) was approximately equivalent to the volume (50 ml / kg), with a bioavailability of 37% at the time of the introduction of the drug.With a monthly infusion of darbepoetin alfa at a dose of 0.6 to 2.1 mkg / kg, its half-life was 73 h (CO 24 ) The longer half-life of darbepoetin alfa with p / k introduction, as compared with IV, is due to the absorption kinetics. Clinical studies, minimal accumulation of the drug was observed in 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 old) with chronic renal failure who are or are not on dialysis, with samples taken from the moment of a single SC or IV injection of the drug for up to one week (168 hours) after administration. Sampling periods were the same duration as in adults with chronic renal failure, and a comparison showed that the pharmacokinetics of darbepoetin alfa in adults and children with chronic renal insufficiency is similar. After intravenous administration, approximately 25% of the difference between adults and children was noted with respect to the area under the pharmacokinetic concentration-time curve from zero time to infinity (AUC0-∞); Nevertheless, this difference for children was less than twice the AUC0-∞ range. After SC administration of the drug, the AUC0-∞ value in adults and children was similar. Both after IV, and after SC administration, the half-life of the drug in children and adults with CRF was similar.

Oncological patients receiving chemotherapy

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

Indication of the drug Aranesp

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.

With caution: liver disease; Sickle-cell anemia.

Application of pregnancy and breastfeeding

Clinical data on the use of Aranesp during pregnancy are absent.

In animal studies, no direct damaging effect of the drug on pregnancy, fetal / fetal development, delivery or postnatal development has been demonstrated. When prescribing the drug, pregnant women should be careful.

Due to the lack of clinical experience in women during lactation, Aranesp should not be given during breastfeeding. In the presence of absolute indications for the use of Aranesp, breastfeeding should be discontinued.

Side effects

General Provisions

Reported the development of serious allergic reactions, including anaphylactic manifestations, angioedema, dyspnoea, rash and urticaria associated with darbepoetin alfa.

Data obtained in controlled trials

Patients with chronic renal failure. In controlled studies of 1,357 patients, 766 patients received Aranesp and 591 patients recombinant human erythropoietin, 83% were on dialysis, 17% were not.

With the introduction of Aranesp, pain was reported at the site of injection as associated with the use of the drug and more often recorded in the darbepoetin group than in the group receiving recombinant human erythropoietin. Discomfort at the injection site, as a rule, was insignificant and transient and was noted mainly after the first injection.

The incidence of adverse reactions assessed as related to treatment with Aranespom in controlled clinical trials was as follows (Table 1):

Table 1

MedDRA Body System Frequency of occurrence Undesirable reaction to the drug
From the heart Very often (≥1 / 10) Increased blood pressure
From the skin and subcutaneous tissue Often (≥1 / 100 to <1/10) Rash / erythema
From the side of the vessels Rarely (≥1 / 1000 to <1/100) Thromboembolism
From the nervous system Often (≥1 / 100 to <1/10) Stroke
From the body as a whole, including local reactions Often (≥1 / 100 to <1/10) Pain at the injection site
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 adverse effects assessed as related to treatment with Aranespom, in controlled clinical trials, is as follows (Table 2):

Table 2

MedDRA Body System Frequency of occurrence Undesirable reaction to the drug
From the skin and subcutaneous tissue Often (≥1 / 100 to <1/10) Rash / erythema
From the cardiovascular system Often (≥1 / 100 to <1/10) Thromboembolism, including pulmonary embolism
From the body as a whole, including local reactions Very often (≥1 / 10) Edema
Often (≥1 / 100 to <1/10) Pain at the injection site

Data of post-registration security monitoring

During the application of Aranesp in routine clinical practice, the following adverse reactions were reported:

- partial red cell aplasia. In some cases, in connection with Aranespum therapy, neutralizing antibodies to erythropoietin, mediating PKAA, have been reported. Mostly, these reports were received for patients with chronic renal failure who received the drug p / k. If the PKAA is confirmed, Aranespum therapy should be discontinued and patients must be transferred to another recombinant erythropoietin;

- Allergic reactions, including anaphylactic reactions, angioedema, skin rash and hives. Frequency is unknown, (cannot be estimated based on available data);

- convulsions. Frequency is unknown, (cannot be estimated based on available data);

- Increased blood pressure. The frequency is unknown (cannot be estimated from the available data).

Interaction

Interaction with other drugs and other types of 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 cyclosporin, tacrolimus, is potentially possible. With the simultaneous appointment of Aranesp with any such drugs, the level of serum levels in the blood serum should be monitored with a dose modification in case of an increase in the hemoglobin concentration.

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

Dosing and Administration

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

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

Therapy of symptomatic anemia in combination with chronic renal failure 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 individual clinical data of the patient by the attending physician is necessary.

Aranesp can be used SC or IV in order to increase the level of hemoglobin, but not higher than 120 g / l. In patients who are not on dialysis, the subcutaneous route of administration is preferred, because Allows to avoid punctures of peripheral veins.

The level of hemoglobin in patients is subject to individual fluctuations, incl. Sometimes higher or lower than the desired target values. If the hemoglobin level deviates beyond the target values, dose modification is carried out, while the target value should be considered an interval 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 a SC or IV dose should be 0.45 μg / kg of body weight with a single weekly injection. Alternatively, for patients who do not receive dialysis, the administration of the drug at an initial dose of 0.75 μg / kg of body weight every two weeks is permissible. 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 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 when the level of hemoglobin 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 should be reduced by approximately 25% of the previous dose.

Hemoglobin should be measured weekly or bi-weekly, before stabilization.

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

Supporting phase. In the maintenance phase of treatment, 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, after reaching the required hemoglobin concentration against the background of the appointment of the drug every two weeks, its SC administration can be performed once a month using the initial dose twice the previous dose, which was administered every two weeks.

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 level, it is recommended to increase it by approximately 25%.

If there is an increase in hemoglobin level of more than 20 g / l for 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 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 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 2 weeks.

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

Adult patients who receive weekly 1, 2 or 3 injections of rhEPO can be switched to the once-weekly Aranesp administration or its administration once every two weeks. The initial weekly dose of Aranesp (mkg / week) is determined by dividing the total weekly dose of rCHEPO (IU / wk) by 200. The initial dose of Aranesp (μg / 2 weeks) with the biweekly administration regimen is determined by dividing the cumulative cumulative dose of rhEPO, Administered over a 2-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 rCHEPO 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 with a p / c or IV injection of the drug is 0.45 mkg / kg of body weight as a single injection once a week. In patients who do not receive dialysis, an initial dose of 0.75 mkg / kg, once every two weeks, can be used. If the increase in hemoglobin level is not enough (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 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%, depending on the degree of hemoglobin increase. In the case when the level of hemoglobin 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 should be reduced by approximately 25% of the previous dose.

Hemoglobin should be measured weekly or every 2 weeks before stabilization.

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

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

Supporting phase. In children 11 years of age and older in the maintenance 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 given once a month, with the initial dosage being twice the dose from that used in Mode once every 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 may be Translated into the 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 rEPEPO (IU / week) by 240. The initial Aranesp dosage when administered every 2 weeks (mkg / every 2 weeks) can be determined by dividing Of the total dose of rhEPO over a two-week period of 240. Due to individual differences, an optimal therapeutic dose is required for individual patients. When replacing rCEPO 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 level, 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 when the level of hemoglobin 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 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 2 weeks.

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

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

In patients with anemia (for example, with a hemoglobin concentration equal to or below 100 g / l), Aranesp can be used to increase hemoglobin levels (but not higher 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, the analysis of the individual clinical data of the patient by the attending 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 that the target hemoglobin level is from 100 g / l to 120 g / l. It is necessary to 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 mkg (6.75 mkg / kg) once every 3 weeks or 2.25 mkg / kg once a week. If the clinical response (fatigue, hemoglobin content) after 9 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 mkg, 300 mkg and 150 mkg is possible.

Careful monitoring of the patient's 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 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%.

Overdose

Darbepoetin alfa is a drug with a wide therapeutic range. Even with a very high concentration of the drug in the blood serum, no symptoms of overdose were observed.

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

Special instructions

Impact on the ability to drive and handle machinery. It was not revealed.

General Provisions

It is necessary to monitor BP in all patients, especially at the beginning of Aranespom therapy. If there is no adequate control of blood pressure by standard methods, the concentration of hemoglobin can be reduced by reducing the dose and canceling Aranesp (see "Method of administration and dose").

When treating Aranesp with patients with CRF, there was a development of severe form of 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 aim of prescribing additional iron therapy if necessary.

The lack of a response to the use of Aranesp should serve as an incentive for identifying causal factors. Efficacy of erythropoiesis stimulant 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 blood loss, 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 picture of the bone marrow corresponds to the picture of the PKAA, it is recommended to perform a test for the presence of antibodies to erythropoietin.

PACA has been described, caused by the neutralizing effect of anti-EPSO antibodies associated with the use of ESP, including Aranesp. Most often, such reports relate to patients with CRF who received the drug p / k. It was shown that these antibodies cross-react with all erythropoietic proteins. In case of diagnosis of PKAA, treatment with Aranesp should be stopped without further transfer of the patient to a therapeutic regimen including another recombinant erythropoietic protein (see "Side effects").

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 criterion for exclusion was active liver disease, 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 and rchEPO, patients with liver pathology should be prescribed with caution.

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

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

While maintaining the hemoglobin level 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 reached more than 120 g / l against the background of the use of ESP, the patients had an increased risk of mortality, development of serious cardiovascular complications or cerebrovascular disorders, including stroke and thrombosis of vascular access.

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

Caution is necessary when prescribing the drug to patients with epilepsy. There are reports of seizures in patients receiving Aranesp.

Patients with chronic renal insufficiency

In patients with chronic renal insufficiency, maintenance concentrations of hemoglobin 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 cerebral circulatory disorders, 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 serum ferritin levels below 100 μg / 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 that 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 are capable of stimulating tumor growth.

In a number of controlled clinical trials in oncological 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:

- Reduction of the time to progression in patients with advanced head and neck cancer receiving radiation therapy, 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 corrective prescription of epoetin to achieve a target hemoglobin value of 120-140 g / l;

- an increased risk of death with a corrective appointment of epoetin to achieve a target hemoglobin value of 120 g / l in patients with active cancer, who have not received chemotherapy or radiation therapy, erythropoiesis stimulating agents are not indicated in this group of patients.

In accordance with the foregoing, 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 made on the basis of 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 be treated; And wishes of the patient.

In patients with solid tumors or lymphoproliferative malignancies, when the hemoglobin level is higher than 120 g / l, the dose adjustment scheme described in the section "Method of administration and dose" should be strictly observed 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, you should wait for the PZH to warm up 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.

The technique of the Aranesp injection procedure in pre-filled syringes or pre-filled syringes with a needle guard

This section describes the procedure for injecting Aranesp, which the patient can perform on his own. Before using the drug in pre-filled syringes and pre-filled syringes with a needle protector, first read the "General Recommendations" below (section 1) and then, with recommendations for the appropriate release form (section 2 for 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 the patient does not do the injection himself until the attending physician, nurse or pharmacist teaches him. If the patient has questions, then it is necessary to consult a doctor, a nurse.

Before the injection

Carefully read all the recommendations before administering the drug.

How to use the FPGA?

If a doctor has appointed Aranesp PZH for a patient's injection, the attending physician, nurse or pharmacist should tell the patient how much of the drug and how often it is necessary to inject.

Equipment

For self-contained injections, you will need:

- a new PZH / PZSH with a protective device for a needle with a drug Aranesp;

- alcohol-soaked tampons or similar materials.

What needs to be done prior to the self-administration of Aranesp subcutaneously?

1. Remove the syringe from the refrigerator. Do not take the PZS for the piston or protective cap. This may damage the device.

2. Leave the PZH at room temperature for about 30 minutes, for better injection tolerability. Do not heat the syringe in any other way (for example in a microwave oven or in hot water). Do not expose the syringe to direct sunlight.

3. Do not shake the PZS.

4. Do not remove the cap from the PZH until everything is ready for injection.

5. Check that the dose indicated on the label corresponds to that prescribed by the doctor.

6. Check the expiration date on the label (Good to :). Do not use the PGS if the last day of the specified month has expired.

7. Check the appearance of the preparation Aranesp. The liquid should be transparent or slightly "pearl". If the solution is cloudy or contains particles, the drug should not be used.

8. Wash hands thoroughly.

9. Choose a comfortable, well-lit place and a clean surface where you can place all the necessary materials in such a way that they are easily accessible.

How to choose an injection site?

It is best to inject in the upper part of the hips and abdomen. If the injection is performed by another person, then you can also use the back surface of the hands to administer the drug. If the area where the injection is scheduled, blushed or swollen, you should choose another 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 need to do the following:

1. In order not to bend the needle, carefully remove the cap from it - do not unscrew it.

2. Do not touch the needle and do not press the plunger of the syringe.

3. If air bubbles are visible inside the PZH, it is not necessary to remove them before injection. The introduction of a solution with air bubbles will not cause harm.

3. Now the syringe is ready for use.

How to administer the drug?

1. To disinfect the skin, without pressing, using a tampon soaked in alcohol, and take the skin (without squeezing) into the fold with a thumb and index finger.

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

3. Gently pull the plunger of the syringe to make sure that there is no puncture of the vessel. If blood appears inside the syringe, remove the needle and insert it into another place.

4. Slowly and continuously push the piston, while compressing the skin fold and do not let it go until the syringe is empty.

5. Remove the needle and release the fold of the skin.

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

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

Section 3. Recommendations for the introduction of 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 activated automatically to close the needle after the injection is completed.

Do not try to disassemble the PES before injection.

Do not use the PZS if the cap has been removed, or the needle guard has been activated (covering the needle).

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.

Do not attempt to remove the tear-off label from the PZH cylinder prior to injection.

How to administer the drug?

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

2. To avoid bending the needle, carefully remove the cap from the needle immediately, without twisting, as shown in the figure. Do not touch the needle or press the plunger.

3. If small bubbles of air are visible inside the PZH, it is not necessary to remove them before injection. The introduction of a solution with air bubbles is safe.

4. Hold the skin (not squeezing) between the thumb and forefinger. Insert the needle into the skin completely, as a doctor or nurse showed.

5. Gently pull the plunger to make sure that there is no puncture of the blood vessel. If blood appears inside the syringe, remove the needle and put it in another place after pre-disinfecting the skin.

6. Slowly push the piston with continuous pressure, while compressing the skin fold. Press on the piston until the syringe is empty. The needle guard will not work until the syringe is empty.

7. While the piston is lowered, remove the needle from the skin, then release the piston and allow the syringe to rise up until the whole needle is covered with the needle guard. The needle guard may not be activated if the injection is not completed. You should call your doctor if the patient thinks that you have not received the full dose.

8. Do not put the cap back on the needle.

9. 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.

10. Use one PZH for only one injection. Do not use the drug remaining in the syringe Aranesp.

It is necessary to remember: In case of problems, you should seek help or advice from a doctor or nurse.

Destruction of used PSS

Do not put the cap back on the used needles - you can accidentally get hurt.

Keep used syringes in a place protected from children.

Dispose of used PZS / PZH with a needle protector in accordance with local regulations. It is necessary to 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 syringe with a needle protector?

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

Note: It is necessary to follow this instruction after the injection and when the protective device covers the needle.

1. Take the syringe as shown in the picture and turn the plunger towards you so that the window with the label is visible, without opening the window, as shown below.

2. Slightly turn the plunger away from yourself until the label appears from the window, as shown below.

3. Pull the shortcut and then tear off the perforation as shown below.

Tear off perforations.

Release form

Prefilled syringes consist of a cylinder with a built-in needle, closed elastomeric cap, piston and elastomer plunger laminated with fluoropolymer or from a cylinder with a built-in needle closed by an elastomeric cap with an additional outer polypropylene cap, piston and elastomeric plunger laminated with 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 (PZH)

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 ml solution (500 μg / ml) - 500 μg into syringes of hydrolytic glass I with stainless steel needles (27G).

1. 1 PZH (doses of 10 mcg, 15 mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg, 60 mcg, 80 mcg, 100 mcg, 150 mcg, 300 mcg, 500 mcg) are placed in a cardboard box equipped with a cardboard Fixative.

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

2. 1 PZH 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 In a cardboard box.

Pre-filled syringes with a protective device for the needle.

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 of the solution (500 μg / ml) 150 μg or 0.6 ml of the solution (500 μg / ml) 300 μg or 1.0 ml of the solution 500 Μg / ml) - 500 μg into syringes of glass I of hydrolytic class with stainless steel needles (27G).

1 PZHH with a protective device for the needle is placed in a contour mesh package. One out-of-the-box cell pack (doses of 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) is placed in a cardboard pack.

Manufacturer

Amgen Europe BV

Minervum, 7061, NL-4817, ZK Breda, The Netherlands.

In the case of packaging on the Russian production site,

Packed: LLC "Dobrolek", 115446, Moscow

For more information on Aranesp, please contact

Representative in Russia: Amgen LLC.

123317, Moscow

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Aranesp

In the dark place at a temperature of 2-8 C (do not freeze). Before out-patient use, it can be moved from storage to room temperature (up to 25 C) for a maximum 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.

Keep out of the reach of children.

Shelf life of the drug Aranesp

3 years.

Do not use after the expiry date printed on the package.

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