Epoetin Beta

Pharmacological properties

epoetin beta - a glycoprotein, a factor in the stimulation of mitosis and the hormone of differentiation of cells, stimulates the formation of red blood cells from progenitor cells (stem cell class). The recombinant epoetin beta, obtained by genetic engineering, is identical in its amino acid and carbohydrate composition to erythropoietin, isolated from the urine of patients with anemia. epoetin beta has a high degree of purification, which corresponds to modern technological capabilities. in particular, in the active substance that is administered to a person, there are no residues of cell lines used to obtain the drug. epoetin beta after iv and SC administration increases the number of red blood cells, reticulocytes and the level of hemoglobin in the blood, as well as the rate of incorporation of 59fe into cells, does not affect leukopoiesis. the cytotoxic effect of erythropoietin on bone marrow or human skin cells was not detected.

Erythropoietin is a growth factor that primarily stimulates the production of red blood cells, but erythropoietin receptors can also be expressed on the surface of various tumors.

In very rare cases, during therapy with erythropoiesis stimulating agents, neutralizing antibodies to erythropoietin with or without true erythrocytic aplasia were observed.

Pharmacokinetics

Suction. With s / c administration of the drug to patients with uremia, prolonged absorption provides a plateau phase of the concentration of the drug in serum, and C_max achieved on average 12–28 hours after administration. The bioavailability of epoetin beta with sc administration is 23–42% compared with iv administration.

Distribution. The volume of distribution is equal to the volume of circulating blood plasma or 2 times greater than it.

Excretion: in healthy individuals and in patients with uremia T_½ epoetin beta for iv administration is 4–12 hours. In this case, the route of administration of T_½ in the terminal phase is longer than after intravenous administration, and averages 13–28 hours

Pharmacokinetics in special groups. The pharmacokinetics of epoetin beta have not been studied in patients with hepatic impairment.

Indications

Treatment for symptomatic anemia associated with chronic renal failure in adults and children;

prevention of anemia in premature infants born with a body weight of 750-1500 g before the 34th week of pregnancy;

treatment for symptomatic anemia in patients with non-myeloid malignant tumors receiving chemotherapy;

an increase in the volume of autologous blood intended for subsequent autotransfusion. The recorded risk of thromboembolic events must be taken into account. The use according to these indications is indicated only for patients with moderate anemia (hemoglobin level of 100–130 g / l (6.21–8.07 mmol / l) without iron deficiency), if blood preservation procedures are absent or insufficient, and planned extensive elective surgery may require a large volume of blood (≥4 units for women or ≥5 units for men).

Application

The drug is prescribed by a doctor with experience in the treatment of this pathology for use. since in some cases anaphylactoid reactions occur, the first dose of the drug must be administered under control.

Treatment for symptomatic anemia in adults and children with chronic renal failure. Symptoms and complications of anemia vary with age, gender, and nosology. A doctor needs to evaluate the clinical course of the disease and the general condition of the patient.

The drug is administered sc or iv in order to achieve a hemoglobin level that should not exceed 120 g / l (7.5 mmol / l).

In patients who do not require hemodialysis, s / c administration is preferred to avoid puncture of peripheral veins. With iv administration, the drug should be administered within 2 minutes, for example, patients undergoing hemodialysis through an arteriovenous shunt at the end of the dialysis session.

In connection with an individual feature, individual episodic changes in the hemoglobin level indicator are possible above and below the expected level. If the hemoglobin level changes, the dose of the drug should be corrected, bearing in mind the target hemoglobin range of 100–120 g / l (6.2–7.5 mmol / l). A sustained increase in hemoglobin levels above 120 g / l (7.5 mmol / l) should be avoided. Recommendations for dose adjustment at a hemoglobin level that exceeds 120 g / l (7.5 mmol / l) are given below.

Avoid increasing hemoglobin levels by more than 20 g / l (1.25 mmol / l) in 4 weeks. If such a phenomenon is observed, a dose adjustment of the drug is required. If the growth rate of the hemoglobin level exceeds 20 g / l (1.25 mmol / l) in 1 month or if the hemoglobin level rises and reaches 120 g / l (7.45 mmol / l), the dose should be reduced by about 25%. If the hemoglobin level continues to increase, treatment should be stopped until the hemoglobin level begins to decline. At this point, therapy should be resumed at a dose approximately 25% lower than the previous dose.

Patients must be carefully monitored to ensure that the lowest approved dose of Recormon is used to ensure adequate control of anemia symptoms.

In patients with hypertension, cardiovascular, cerebrovascular and peripheral vascular diseases, the weekly increase in hemoglobin level and the target hemoglobin level should be determined individually, depending on the clinical picture.

Treatment is carried out in two stages.

Stage of correction. With sc administration, the initial dose is 20 IU / kg body weight 3 times a week. With an insufficient increase in hemoglobin level (2.5 g / l / week), the dose can be increased every 4 weeks by 20 IU / kg 3 times a week. The total weekly dose of the drug can also be divided into daily doses at lower doses.

With iv administration, the initial dose is 40 IU / kg 3 times a week. After 4 weeks, the dose can be increased to 80 IU / kg 3 times a week. If it is necessary to further increase the dose, it should be increased by 20 IU / kg 3 times a week with a monthly interval.

Regardless of the method of administration, the maximum dose should not exceed 720 IU / kg / week.

Stage of maintenance therapy. To maintain hemoglobin at a level of 100-120 g / l, the dose should first be reduced by 2 times compared to the previous one. Subsequently, the maintenance dose is corrected individually, with an interval of 1 or 2 weeks (maintenance dose).

With s / c administration, the weekly dose can be administered as one injection per week or distribute this dose to 3 or 7 injections per week. When the condition stabilizes against a background of a single injection per week, you can switch to a single injection with a 2-week interval, in which case a dose increase may be required.

According to the results of clinical trials, as a rule, the smaller the child’s age, the higher doses of the drug are required. But, since it is impossible to predict an individual response to the drug, it is advisable to adhere to the recommended dosage regimen.

Treatment with Recormon is usually long. If necessary, it can be interrupted at any time. Data on a dosing schedule once a week is based on the results of clinical studies with a treatment duration of 24 weeks.

Prevention of anemia in premature infants. The drug is administered sc in a dose of 250 IU / kg body weight 3 times a week. Treatment with Recormon should begin as early as possible, preferably from the 3rd day of life, and continue for 6 weeks. In preterm infants who underwent transfusions before starting treatment with Recormon, the effect of therapy may be less pronounced than in preterm infants who did not undergo transfusions.

Treatment for symptomatic anemia induced by chemotherapy in patients with cancer.The drug is administered sc to patients with anemia (hemoglobin level ≤100 g / l (6.2 mmol / l)). Symptoms and complications of anemia vary with age, gender, and nosology. A doctor needs to evaluate the clinical course of the disease and the general condition of the patient.

The recommended initial dose is 30,000 IU / week (which approximately corresponds to 450 IU / kg / week, based on calculations based on patients with average body weight), a single or weekly dose can be divided into 3 or 7 injections.

In connection with an individual feature, individual episodic values ​​of hemoglobin levels above and below the desired level are possible. If the hemoglobin level changes, the dose of the drug should be corrected, bearing in mind the target hemoglobin range of 100–120 g / l (6.2–7.5 mmol / l). A sustained increase in hemoglobin levels above 120 g / l (7.5 mmol / l) should be avoided. Recommendations for dose adjustment for hemoglobin levels above 120 g / l (7.5 mmol / l) are given below.

With an increase in hemoglobin level of at least 10 g / l (0.62 mmol / l) after 4 weeks, therapy should be continued at the same dose. With an increase in hemoglobin level of less than 10 g / l (0.62 mmol / l) after 4 weeks, the dose must be doubled. If there is no increase in hemoglobin level by at least 10 g / l (0.62 mmol / l) after 8 weeks, treatment should be discontinued, since the response to therapy with Recormon is unlikely.

Treatment should be continued for 4 weeks after the end of chemotherapy.

The maximum dose of the drug should not exceed 60,000 IU / week.

Upon reaching the required level of hemoglobin, individual for each patient, the dose should be reduced by 25-50%, maintaining hemoglobin at this level. Keep in mind the appropriate dose titration.

If the hemoglobin level exceeded 120 g / l (7.5 mmol / l), the dose should be reduced by about 25-50%. If the hemoglobin level exceeds 130 g / l (8.1 mmol / l), the drug Recormon must be temporarily discontinued. If the hemoglobin level is reduced to 120 g / l (7.5 mmol / l) or lower, treatment should be restored at a dose less than about 25% of the previous dose.

If the hemoglobin level increases by more than 20 g / l (1.3 mmol / l) after 4 weeks, the dose should be reduced by 25-50%.

Patients should be carefully monitored to ensure that the lowest approved dose of Recormon is used to ensure adequate control of anemia symptoms.

Preparation of patients for autologous blood sampling for subsequent autohemotransfusion. The drug is administered iv (for about 2 minutes) or s / c 2 times a week for 4 weeks. In cases where the patient’s hematocrit index (≥33%) allows blood sampling, Recormon is administered at the end of the procedure. During the entire course of treatment, the hematocrit should not exceed 48%.

The dose of the drug is determined by the surgical team individually for each patient, depending on how much blood will be taken from the patient, and on his erythrocyte reserve:

1. The amount of blood that will be taken from the patient depends on the expected blood loss, on the available methods of blood preservation and the general condition of the patient; it should be sufficient to avoid a blood transfusion from another donor. The volume of blood that will be taken from the patient is expressed in units (1 unit is equivalent to 180 ml of red blood cells).

2. The possibility of donation depends mainly on the blood volume of the patient and the initial hematocrit. Both indicators determine the endogenous red blood cell reserve, which can be calculated by the following formula:

Endogenous erythrocyte reserve = blood volume [ml] × (hematocrit - 33): 100.

Women: blood volume [ml] = 41 [ml / kg] × body weight [kg] + 1200 [ml].

Men: blood volume [ml] = 44 [ml / kg] × body weight [kg] + 1600 [ml] (with body weight ≥45 kg).

Indications for use of the drug Recormon and its single dose are determined by nomograms, based on the required volume of donated blood and endogenous red blood cell reserve.

A single dose, determined in this way, is administered 2 times a week for 4 weeks. The maximum dose should not exceed 1600 IU / kg / week for iv administration and 1200 IU / kg / week for s / c administration.

Instructions for use syringe tube. The syringe tube with the drug Recormon is ready for use.It should be used only colorless, transparent or slightly opalescent solution, which practically does not contain visible inclusions. Recormon in a syringe tube is sterile, but does not contain preservatives. In no case should you enter more than one dose on a syringe tube.

Wash hands before injection.

1. Remove 1 syringe tube from the package and make sure that the solution is transparent, colorless and contains virtually no visible impurities. Remove the cap from the syringe.

2. Remove one needle from the packaging, place it on the syringe and remove the protective cap from the needle.

3. Remove air from the syringe and needle by holding the syringe vertically and carefully moving the piston up. Press the piston until the required dose of Recormon remains in the syringe.

4. Wipe the skin at the injection site with cotton wool moistened with alcohol. Use thumb and forefinger to fold the skin. Holding the syringe body closer to the needle, insert it under the skin. Introduce the solution of the drug Recormon. Quickly remove the needle and squeeze the injection site with sterile dry cotton wool.

The syringe tube is for single use only. Any unused product or waste should be disposed of in accordance with local requirements.

Contraindications

Hypersensitivity to epoetin beta or other components of the drug, uncontrolled ag; myocardial infarction or stroke suffered during the previous month, unstable angina or an increased risk of deep vein thrombosis (with a history of venous thromboembolism) - when prescribed to increase the volume of autologous blood for autohemotransfusion.

Side effects

Based on the results of clinical studies, which included 1725 patients, the occurrence of side effects during treatment with the drug can be expected in approximately 8% of patients. The following categories were used to describe the frequency of adverse reactions: very often (10%), often (1%, 10%), sometimes (0.1%, 1%), rarely (0.01%, 0.1%), very rarely (0.01%).

Patients with anemia associated with chronic renal failure. The most common adverse reactions during the use of the drug Rekormon are an increase in blood pressure or a worsening of the course of existing hypertension, especially with a rapid increase in hematocrit (see SPECIAL INSTRUCTIONS). Hypertensive crises with manifestations of encephalopathy (headache, confusion, sensorimotor disorders such as speech impairment, gait, up to tonic-clonic seizures) may occur in some patients with normal or low blood pressure (see SPECIAL INSTRUCTIONS).

Shunt thrombosis may occur, especially in people with a tendency to hypotension or in patients who have complications from arteriovenous fistula (stenosis, aneurysm) (see SPECIAL INSTRUCTIONS). In most cases, simultaneously with an increase in hematocrit, the concentration of ferritin in the blood serum decreases (see SPECIAL INSTRUCTIONS). In some cases, a short-term increase in the level of potassium and phosphate in the blood serum was noted (see SPECIAL INSTRUCTIONS).

Separate cases of true erythrocyte aplasia with the detection of neutralizing antibodies to erythropoietin associated with therapy with Recormon have been reported. It is not recommended to transfer patients to therapy with Recormon when establishing a diagnosis of true red blood cell aplasia, mediated by the presence of neutralizing antibodies to erythropoietin (see SPECIAL INSTRUCTIONS).

The frequency of side effects in clinical studies that were considered to be related to treatment with Recormon:

vascular disorders: sometimes - hypertensive crisis; often - AH.

Violation of the nervous system: often - headache.

Violations of the blood system and lymphatic system: rarely - shunt thrombosis; very rarely - thrombocytosis.

Oncological patients.Headache and hypertension associated with treatment with epoetin beta, which can be treated with medication, are common.

In some patients, a decrease in the levels of iron in serum was noted (see SPECIAL INSTRUCTIONS). In clinical studies, a higher incidence of thromboembolism was recorded in patients with tumors who received treatment with epoetin beta (7%) compared with the untreated control group (4%). Moreover, in the group taking epoetin beta, there was no increase in mortality from thromboembolism compared with the control group.

The frequency of side effects in clinical studies that were considered to be related to treatment with Recormon:

vascular disorders: often - hypertension.

Disorders from the blood system and lymphatic system: often - thromboembolic complications.

Disorders from the nervous system: often - headache.

Patients who have been assigned an autologous blood donation. Patients who were prescribed autologous donor blood sampling showed a higher incidence of thromboembolic events. However, a clear causal relationship with the drug Recormon has not been established.

In placebo-controlled studies, iron deficiency was more pronounced in patients treated with Recormon than in the placebo group (see SPECIAL INSTRUCTIONS).

The frequency of side effects in clinical studies that were considered to be related to treatment with Recormon:

disorders of the nervous system: often - headache.

Preterm infants: very often (10%) there was a decrease in serum ferritin levels (see SPECIAL INSTRUCTIONS).

All indications for use

Changes in the skin and its derivatives: rarely - rash, itching, urticaria, reactions at the injection site.

Anaphylactoid reactions have been very rarely reported. However, in controlled clinical trials, there was no increase in the frequency of hypersensitivity reactions.

Very rarely, especially at the beginning of therapy, flu-like symptoms associated with treatment with epoetin beta have been reported, such as fever, chills, headache, limb pain, malaise and / or bone pain. These reactions were mild or moderate and disappeared after a few hours or several days.

According to data from controlled clinical trials of epoetin alfa or darbepoetin alfa, stroke was reported at a frequency of ≥1 / 100 to 1/10.

special instructions

Caution must be exercised when prescribing the drug Recormon to patients with refractory anemia in the presence of blast-transformed cells, patients with thrombocytosis, epilepsy, and chronic liver failure. before starting treatment with epoetin beta, a deficiency of vitamin B12 and folic acid should be excluded, since their insufficiency reduces the effectiveness of the drug recormon.

In order to ensure effective erythropoiesis, iron deficiency should be excluded before starting treatment with Recormon, as well as during the entire period of therapy in all patients. If necessary, iron therapy may be prescribed in accordance with clinical recommendations.

Severe aluminum overload as a result of treating renal failure can reduce the effectiveness of Recormon.

The decision to use the drug Recormon in patients with nephrosclerosis who are not receiving dialysis must be taken individually, since the possibility of accelerating the progression of renal failure cannot be completely ruled out.

True erythrocyte aplasia caused by neutralizing antibodies to erythropoietin may be associated with erythropoietin therapy, including Recormon. These antibodies cross-react with all erythropoietic proteins.It is not recommended to transfer patients to therapy with Rekormon if there is a suspicion of presence or confirmed presence of neutralizing antibodies to erythropoietin (see ADVERSE EFFECTS).

With a paradoxical decrease in hemoglobin and the development of severe anemia associated with a low number of reticulocytes, treatment with epoetin beta should be discontinued and antibodies to erythropoietin should be determined. Such cases have been reported in patients with hepatitis C receiving concurrent treatment with interferon, ribavirin and epoetins. Epoetins are not approved for use in the treatment of anemia associated with hepatitis C.

Patients with chronic renal failure may experience episodes of increased blood pressure or worsening the course of existing hypertension, especially with an increase in hematocrit. An increase in blood pressure can be corrected medically. In the absence of the effect of drug therapy, a temporary break in therapy with Recormon is necessary. It is recommended to regularly monitor blood pressure (especially at the beginning of treatment), including between dialysis sessions.

Hypertensive crisis may occur with the phenomena of encephalopathy, which requires immediate medical advice and intensive medical care. Particular attention is required in the event of a sudden acute migraine-like headache.

In patients with chronic renal failure during treatment with the drug Recormon, especially with iv administration of the drug, a dose-dependent moderate increase in the number of platelets within the normal range is possible, followed by an independent return to normal. Therefore, regular monitoring of platelets is required during the first 8 weeks of treatment.

Hemoglobin concentration. In patients with chronic renal failure, the maintenance concentration of hemoglobin should not exceed the upper limit of the target hemoglobin level - 120 g / l (7.5 mmol / l). In clinical studies, an increased risk of death and the occurrence of serious cardiovascular complications and cerebrovascular complications, including stroke, was noted when erythropoiesis stimulants were used to achieve a hemoglobin level exceeding 120 g / l (7.5 mmol / l).

In controlled clinical trials, significant advantages of using epoetin were not obtained when the hemoglobin level exceeded the level necessary to control the symptoms of anemia and avoid blood transfusion.

In preterm infants, a slight increase in the number of platelets is possible, especially on the 12-14th day of life, therefore, platelet count should be monitored regularly.

Effect on tumor growth. Epoetins are growth factors that mainly stimulate red blood cell production. Erythropoietin receptors can be expressed on the surface of cells of various tumors. Therefore, like other growth factors, epoetins can stimulate tumor growth. Several controlled studies have not found that epoetins improve overall survival or reduce the risk of tumor progression in patients with tumor-associated anemia.

In controlled clinical trials with the use of the drug Recormon and other drugs that stimulate erythropoiesis, it is shown:

reduction of time to tumor progression in patients with advanced head and neck cancer treated with radiation therapy, when the hemoglobin level is higher than 140 g / l (8.7 mmol / l);

a decrease in overall survival and an increase in mortality due to disease progression after 4 months in patients with metastatic breast cancer treated with chemotherapy, with a hemoglobin level of 120–140 g / l (7.5–8.7 mmol / l);

increased risk of death when a hemoglobin level of 120 g / l (7.5 mmol / l) is reached in patients with active malignant disease who have not received chemo or radiation therapy. Erythropoiesis stimulants are not indicated for use in this patient population.

Therefore, in some clinical situations for the treatment of anemia in patients with malignant neoplasms, it is necessary to give the advantage of blood transfusion. The decision to prescribe recombinant erythropoietin should be based on an assessment of the benefit / risk ratio for each patient. In this case, factors such as the clinical situation, the type of tumor and its stage, the degree of anemia, the average probable life expectancy, the environment in which the patient receives treatment, and what the patient prefers, should be taken into account.

An increase in blood pressure is possible, which can be corrected medically. Therefore, monitoring of blood pressure is recommended, especially in the initial phase of treatment of patients with malignant tumors.

People with cancer should also regularly monitor platelet count and hemoglobin levels at regular intervals.

Patients preparing for blood donation for subsequent autotransfusion may have an increased platelet count, mainly within normal limits. Therefore, such patients should have at least a weekly monitoring of platelet counts. With their increase by more than 150 10⁹/ l compared with the initial value or higher than normal, the drug Recormon should be discontinued.

Patients with chronic renal failure often require an increase in the dose of heparin during a hemodialysis session due to an increase in hematocrit. Possible dialysis system occlusion with inadequate heparinization.

Early revision of the shunt and timely prophylaxis of thrombosis (for example, acetylsalicylic acid) in patients with chronic renal failure with a risk of shunt thrombosis is recommended.

During treatment, Recormon should periodically monitor the level of potassium and phosphate in the blood serum. An increase in potassium levels has been reported in several patients with uremia receiving Recormon, although a causal relationship has not been established. If the potassium level is elevated or increasing, consideration should be given to temporarily discontinuing the drug Recormon until the normalization of potassium concentration.

If Recormon is prescribed before the collection of autologous donor blood, the recommendations on the donation procedure should be followed:

blood can be taken only in patients with a hematocrit ≥33% (hemoglobin level of at least 110 g / l (6.83 mmol l));

special care should be observed in relation to patients with a body weight of 50 kg;

the volume of blood taken simultaneously, should not exceed 12% of the estimated blood volume of the patient.

Treatment with Recormon is indicated only for patients who are most important to avoid homologous blood transfusion, given the risk / benefit ratio for homologous transfusion.

Improper use by medical professionals can lead to an excessive increase in hematocrit, which, in turn, can lead to life-threatening cardiovascular complications.

Each syringe tube contains up to 0.3 mg of phenylalanine. This should be considered for patients with severe forms of phenylketonuria.

Each syringe tube contains up to 1 mmol of sodium (23 mg), that is, it is believed that the drug does not contain sodium.

In order to improve tracking of erythropoiesis stimulating agents, the name of the erythropoiesis stimulating agent should be clearly indicated in the patient’s medical records.

Use during pregnancy and lactation. There are no clinical data on the use of epoetin beta in pregnant women. During pregnancy, the drug should be prescribed with caution. The results of animal studies showed the absence of direct and indirect harmful effects during pregnancy, the development of the embryo / fetus, childbirth, postnatal development.

There is only limited experience with the use of epoetin beta in humans during lactation. Endogenous erythropoietin is secreted into breast milk and is completely absorbed in the digestive tract of the newborn.The choice between continuing breastfeeding or continuing therapy with Recormon is made taking into account the ratio of the benefits of therapy for the mother and the benefits of breastfeeding for the baby.

Children. Treatment for symptomatic anemia associated with chronic renal failure in children.

Prevention of anemia in premature infants born with a body weight of 750-1500 g until the 34th week of pregnancy.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. The drug does not affect the ability to drive vehicles or the ability to work with mechanisms.

Interactions

The data obtained to date have not revealed any interactions of epoetin beta with other drugs.

In experimental animal studies, epoetin beta did not increase the myelotoxicity of cytostatic drugs such as etoposide, cisplatin, cyclophosphamide, fluorouracil.

Overdose

The therapeutic index of the drug recormon is very wide. even with very high concentrations of the drug in the blood serum, no intoxication symptoms were noted.

Storage conditions

At a temperature of 2–8 ° C (in the refrigerator). if transportation is necessary, a temporary change in the temperature regime (up to 25 ° C) is allowed, but not more than 3 days.