Mirzer solution 75 µg/0.3ml 0.3ml syringe-tubes, 1pc

Composition

Active ingredient:

methoxypolyethylene glycol-epoetin beta;

Auxiliary substances:

L-methionine;

sodium sulfate anhydrous;

sodium dihydrogen phosphate monohydrate;

mannitol;

poloxamer 188;

hydrochloric acid diluted or sodium hydroxide solution;

water for injection

Pharmacological action

Mircera is a chemically synthesized representative of a new class of long-acting erythropoietin receptor activators.

Methoxypolyethylene Glycol-epoetin beta is a covalent conjugant of recombinant DNA protein and linear methoxypolyethylene glycol (PEG).

Methoxypolyethylene Glycol-epoetin beta differs from erythropoietin by the presence of an amide bond between the N-terminal amino group or e-amino group of lysine, mainly Lys52 and Lys45, and methoxypolyethylene glycolbutanoic acid. The molecular weight of methoxypolyethylene glycol-epoetin beta is approximately 60 kDa, including the 30 kDa molecular weight of PEG.

The drug Mircera has a different activity from erythropoietin at the receptor level and is characterized by a longer association with the receptor and faster dissociation from the receptor, reduced specific activity in vitro and increased activity in vivo, as well as an increased T_1/2, which allows you to administer the drug Mircera 1 time per month.

Mechanism of action. Mircera stimulates erythropoiesis by interacting with erythropoietin receptors on bone marrow progenitor cells.

Clinical efficacy. In 97.5% of patients with chronic kidney diseases who are not on dialysis, and in 93.3% of patients with chronic kidney diseases who are on dialysis, correction of anemia was noted during therapy with Mircera. In dialysis patients, the target hemoglobin (Hb) level remains stable when switching from darbepoietin alpha or epoetin therapy to Mircera therapy.

Pharmacokinetics

T_1/2 after intravenous use of Mircera is 15-20 times longer than with the use of recombinant human erythropoietin.

The clearance and volume of distribution of methoxypolyethylene glycol-epoetin beta do not depend on the dose.

Long-term use does not affect the clearance, volume of distribution, or bioavailability of methoxypolyethylene glycol-epoetin beta. The introduction of methoxypolyethylene glycol-epoetin beta 1 time in 4 weeks does not lead to significant accumulation of the drug, the accumulation coefficient is 1.03 when administered 1 time in 4 weeks and 1.12 — when administered 1 time in 2 weeks. There were no differences in the pharmacokinetics of the drug in patients receiving and not receiving dialysis. Hemodialysis does not affect the pharmacokinetics of methoxypolyethylene glycol-epoetin beta.

Pharmacokinetics, Pharmacodynamics and local tolerability do not depend on the site of subcutaneous injection of the drug (shoulder, anterior thigh, anterior abdominal wall).

Absorption after subcutaneous use. Time of achievement The_maximum concentration of methoxypolyethylene glycol-epoetin beta in serum after subcutaneous use is 72 hours.

The absolute bioavailability of methoxypolyethylene glycol-epoetin beta in dialysis patients and non-dialysis patients is 62% and 54%, respectively.

Distribution. The volume of distribution is 5 liters.

Excretion. T_1/2 of methoxypolyethylene glycol-epoetin beta with intravenous use is 134 hours (or 5.6 days), with subcutaneous use-139 hours (or 5.8 days), the total systemic clearance is 0.494 ml / h / kg.

Pharmacokinetics in special patient groups

Liver failure:  the pharmacokinetics of methoxypolyethylene glycol-epoetin beta in patients with severe hepatic insufficiency and in healthy patients do not differ.

Gender, race, and old age:  no adjustment of the initial dose of methoxypolyethylene glycol-epoetin beta is required.

Indications

Anemia in chronic renal failure (according to the NKF K/DOQI classification — in chronic kidney disease).

Use during pregnancy and lactation

The safety and efficacy of Mircera for these groups are poorly understood.

 During pregnancy and lactation, Mircera should only be prescribed if the intended benefit to the mother exceeds the potential risk to the fetus or child.

In animals, Mircera has no direct or indirect harmful effects on pregnancy, embryonic / fetal development, childbirth or postnatal development.

It is not known whether methoxypolyethylene glycol-epoetin beta is excreted in human breast milk.

Animal studies have shown that methoxypolyethylene glycol-epoetin beta is excreted in human milk.

Contraindications

• hypersensitivity to methoxypolyethylene glycol-epoetin beta or to any other component of the drug;
• uncontrolled arterial hypertension;
• children under 18 years of age (safety and efficacy have not been established).

With caution:

• pregnancy;
• breast-feeding period;
• hemoglobinopathies;
• epilepsy;
• thrombocytosis (platelet count >500 * 109/l).

Side effects

From the cardiovascular system:  arterial hypertension (common); shunt thrombosis (rare); hot flashes (very rare).

Nervous system disorders:  headache (rare), hypertensive encephalopathy (very rare).

From the immune system:  hypersensitivity reactions (very rare).

From the side of the skin and its appendages:  maculopapular rash (very rare).

Changes in laboratory parameters:  in 7.5% of patients treated with Mircera and 4.4% of patients treated with other erythropoiesis stimulators, thrombocytopenia was observed (platelet count 9/l).

Interaction

Interaction studies with other drugs have not been conducted.

The data obtained so far have not revealed any interactions of Mircera with other drugs.

The population analysis did not reveal any signs of the effect of other drugs on the pharmacokinetics and Pharmacodynamics of Mircera.

Do not mix methoxypolyethylene glycol-epoetin beta with other medications or injectable solutions.

How to take, course of use and dosage

Subcutaneously and intravenously.

Given the longer T_1/2, Mircera should be administered less frequently than other erythropoiesis stimulants.

Treatment with Mircera should be started only under the supervision of a specialist.

Rules for storing the solution in outpatient and inpatient settings

The Mircera solution is sterile and does not contain preservatives. Use only a clear, colorless or slightly yellowish solution that does not contain visible impurities. Before use, the solution is brought to room temperature, if the solution was stored in the refrigerator.

The syringe tube can be stored for 1 month at room temperature (no higher than 25 °C) and must be used within a month.

The bottle can be stored for 7 days at room temperature (no higher than 25 °C) and must be used within 7 days.

The unused solution must be destroyed. Each bottle or syringe tube can only be used once. Do not shake.

Method of application. The drug should be administered subcutaneously in the shoulder area, the anterior surface of the thigh, or the anterior abdominal wall.

The Hb content should be monitored once every 2 weeks before its stabilization and periodically after stabilization.

Standard dosage regimen

Patients not currently receiving an erythropoiesis stimulator. The recommended initial dose is 0.6 mcg/kg IV or subcutaneous 1 time in 2 weeks, the target hemoglobin value is >110 g / l (6.83 mmol/l).

The dose of Mircera can be increased by 25-50% from the previous one, if after 1 month the increase in Hb is

The dose of Mircera is reduced by 25-50% from the previous one, if after 1 month the increase in Hb is >20 g / l (1.24 mmol/l). If Hb exceeds 130 g / l (8.07 mmol / L), then therapy should be interrupted until Hb decreases

After discontinuation of therapy, Hb decreases by approximately 3.5 g / l (0.22 mmol / l) per week.

Dose adjustment of the drug is carried out no more than once a month.

Patients currently receiving an erythropoiesis stimulator. Patients receiving another erythropoiesis stimulator can be transferred to therapy with Mircera with a regimen of use 1 time a month or 1 time in 2 weeks subcutaneously or iv.

If a dose adjustment is required to maintain the target Hb above 110 g / l (6.83 mmol / L), then the monthly dose can be changed by 25%.

The dose of Mircera is reduced by 25-50% from the previous one, if after 1 month the increase in Hb is more than 20 g/l (1.24 mmol/l). If Hb exceeds 130 g / l (8.07 mmol/L), then therapy should be interrupted until Hb decreases to less than 130 g/L (8.07 mmol/L) and then resumed at a dose of 50% of the previous one.

At the target Hb of 120 g / l, the dose of the drug changes by 25%.

After discontinuation of therapy, Hb decreases by approximately 3.5 g / l (0.22 mmol / l) per week.

Dose adjustment of the drug is carried out no more than once a month.

Break in treatment. Treatment of anemia, including Mircera therapy, is usually long-term. However, if necessary, therapy with Mircera can be interrupted at any time.

Missed dose. A missed single injection of Mircera should be administered as soon as possible and then administered at the prescribed dosage frequency.

Dosage in special cases

In patients with hepatic insufficiency of any severity, no adjustment of the initial dose of the drug and the dosage regimen is required.

In the elderly (over 65 years of age) correction of the initial dose of the drug is not required.

Overdose

Symptoms: excessive pharmacodynamic response, i. e. excessive erythropoiesis, is possible.

Treatment: if the hemoglobin level is high, it is necessary to temporarily interrupt therapy with Mircera.

If necessary, a phlebotomy can be performed.

Special instructions

Iron deficiency should be excluded before and during treatment with Mircera.

Additional iron therapy is recommended if the serum ferritin content is below 100 mcg / l or the transferrin iron saturation is below 20%.

No effect: the most common causes of incomplete response to treatment with erythropoiesis-stimulating agents are iron deficiency, inflammation, chronic blood loss, bone marrow fibrosis, a sharp increase in aluminum concentration due to hemodialysis, folic acid or vitamin_{B12 deficiency}, and hemolysis.

If all these conditions are excluded and the patient has a sudden decrease in hemoglobin, reticulocytopenia, and antibodies to erythropoietin are detected, it is necessary to conduct a bone marrow study to exclude partial red cell aplasia (PCCA).

If PCA develops, Mircera therapy should be discontinued and patients should not be transferred to therapy with other erythropoiesis stimulators.

Cases of PCA caused by antibodies to erythropoietin have been reported during therapy with erythropoiesis stimulators. Antibodies have a cross-reaction with all stimulators of erythropoiesis. It is not recommended to transfer patients with confirmed or suspected erythropoietin antibodies to Mircera therapy.

Arterial hypertension: Blood pressure should be monitored before and during treatment with Mircera, as with other erythropoiesis stimulants. If If blood pressure cannot be controlled by medication, it is necessary to reduce the dose or suspend therapy with Mircera (see “Dosage and use”).

Effect on tumor growth: Mircera, like other drugs that stimulate erythropoiesis, is a growth factor that mainly stimulates the formation of red blood cells. Erythropoietin receptors can be present on the surface of various tumor cells. It is possible that agents that stimulate erythropoiesis can stimulate the growth of any type of malignancy.

In clinical studies in which epoetins were used in patients with various malignant tumors, including head and neck, breast, there was an increase in mortality, the causes of which are unclear.

Influence on the ability to drive a car and work with mechanisms. Studies on the effect of the drug on the ability to drive a car and work with mechanisms have not been conducted. Based on the mechanism of action and safety profile, Mircera does not have such an effect.

Form of production

Solution for intravenous and subcutaneous use

Storage conditions

Store in a dark place, at a temperature of 2-8 °C (do not freeze)

Shelf life

2 years

Active ingredient

Methoxypolyethylene Glycol-epoetin beta

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection and infusion