Mirsera - instructions for use, doses, side effects, contraindications

Active substanceEpoetin beta [methoxypolyethylene glycol]Epoetin beta [methoxypolyethylene glycol]

Similar drugsTo uncover

Mircera®

solution in / in PC

Hoffmann-La Roche Ltd. Switzerland

Mircera®

solution in / in PC

Hoffmann-La Roche Ltd. Switzerland

Dosage form: & nbspsolution for intravenous and subcutaneous administration

Composition:

One bottle (1 ml) contains:

active substance: methoxypolyethylene glycol-epoetin beta 50 μg, 100 μg, 200 μg, 300 μg, 400 μg, 600 μg, 1000 μg;

Excipients: L-methionine - 1.49 mg, sodium sulfate anhydrous 5.68 mg, sodium dihydrogen phosphate monohydrate 1.38 mg mannitol 30.00 mg poloxamer 188 0.10 mg hydrochloric acid diluted or sodium hydroxide solution (q.s. up to pH 6.2), water for injection.

One syringe tube (0.3 ml) contains:

active substance: methoxy polyethylene glycol-epoetin beta 30 μg, 40 μg, 50 μg, 60 μg, 75 μg, 100 μg, 120 μg, 150 μg, 200 μg, 250 μg

Excipients: L-methionine 0.447 mg, sodium sulfate anhydrous -1.704 mg, sodium dihydrogen phosphate monohydrate 0.414 mg, mannitol 9,000 mg, poloxamer 188 0.030 mg, hydrochloric acid diluted or sodium hydroxide solution (q.s. up to pH 6.2), water for injection.

One syringe tube (0.6 ml) contains:

active substance: methoxy-polyethylene glycol-epoetin beta 360 μg, 400 μg, 600 μg, 800 μg

Excipients: LMethionine - 0.894 mg, sodium sulfate anhydrous - 3.408 mg, sodium dihydrogen phosphate monohydrate - 0.828 mg, mannitol -18.000 mg, poloxamer 188 - 0.060 mg, hydrochloric acid diluted or sodium hydroxide solution (q.s. up to pH 6.2), water for injection.

Description:

Transparent colorless or slightly yellowish liquid.

Pharmacotherapeutic group:Other anti-anemic drugs

ATX: & nbsp

B.03.X.A.03 Methoxy-polyethylene glycol epoetin beta

Pharmacodynamics:

Mircera® is a chemically synthesized representative of a new class of activators of erythropoietin receptors for long-term action. Methoxypolyethylene glycol- epoetin beta is a covalent conjugate of a recombinant DNA protein and linear methoxy polyethylene glycol (PEG). Methoxypolyethylene glycol epoetin beta differs from erythropoietin by the presence of an amide bond between N- terminal amino group or s-amino group of lysine, advantageously Lys⁵² and Lys⁴⁵, and methoxy polyethylene glycol butanoic acid. The molecular weight of methoxypolyethylene glycol-epoetin beta is about 60 kDa, including the 30 kDa molecular weight of PEG.

Mircera® has an activity different from erythropoietin at the level of the receptor 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 extended half-life, which allows the administration of Mircera® once a month.

Mechanism of action

Mircera® stimulates erythropoiesis upon interaction with erythropoietin receptors on bone marrow precursor cells.

As the main growth factor necessary for the maturation of red blood cells, natural erythropoietin is produced by the kidneys and released into the bloodstream in response to hypoxia. In response to hypoxia, erythropoietin interacts with cells and urea precursors and leads to increased erythrocyte formation.

Clinical efficacy

Correction of anemia was noted in 97.5% and 94.1% of patients with chronic kidney disease (CKD) not on dialysis, when treated with Mircera® once a 2 weeks and once a month, respectively. In the first 8 weeks of therapy, hemoglobin (Hb) exceeded 130 g / L in 11.4% of patients who received Mircera® once every 2 weeks, and 34% of patients who received darbepoetin alfa, and exceeded 120 g / L in 25.8% of patients who received Mircera® once a month, and 47.7% of patients who received darbepoetin alfa.

In 93.3% of patients with CKD who are on dialysis, with treatment with Mirtsera®, correction of anemia was noted.In patients on dialysis, when transferring from therapy with darbepoetin alfa or epoetin to Mircera® therapy, a stable target Hb remains.

In the Mircera® maintenance group, once a month, the proportion of patients with CKD on hemodialysis who responded to therapy was significantly higher compared with the maintenance group of darbepoetin alfa, once a month (p <0.0001).

Pharmacokinetics:

Pharmacokinetic and pharmacological parameters allow the administration of MIRCER® once a month in connection with an increased half-life.

The half-life (T1/2) after intravenous (iv) administration of MIRCER® is 15-20 times longer than when recombinant human erythropoietin is administered.

Pharmacokinetic parameters of the drug were studied in healthy volunteers and in patients with anemia and CKD who are not on dialysis.

In patients with CKD, the clearance and volume distribution of methoxypolyethylene glycol-epoetin beta are dose independent.

The pharmacokinetics of the MIRCER® preparation was studied in patients with CKD after a single administration at week 9 and on week 19 or 21.Multiple administration does not affect the clearance, the volume of distribution and bioavailability of methoxypolyethylene glycol-epoetin beta. The administration of methoxypolyethylene glycol-epoetin beta 1 every 4 weeks to patients with CKD does not lead to significant cumulation of the drug, the cumulation factor is 1.03 with the introduction of 1 every 4 weeks. The cumulation factor when administered once every 2 weeks is 1.12. The results of comparison of serum concentrations of methoxy-polyethylene glycol-epoetin beta before and after hemodialysis in patients with CKD showed that hemodialysis does not affect the pharmacokinetics of the drug. In patients with CKD receiving and not receiving dialysis, there was no difference in pharmacokinetics.

Pharmacokinetics, pharmacodynamics and local tolerance do not depend on the site of subcutaneous (SC) injection of the drug (shoulder, anterior surface of the thigh, anterior abdominal wall), which is confirmed by the results of a study conducted on healthy volunteers. On the basis of these results, these sites are equally suitable for the administration of Mircera®.

Absorption after subcutaneous administration

Time to reach the maximum serum concentration of methoxypolyethylene glycol-epoetin beta atSC administration to patients with CKD on dialysis is 72 hours (median) and 95 hours after administration to patients not on dialysis. The absolute bioavailability of methoxy-polyethylene glycol-epoetin beta in dialysis patients and in patients not on dialysis is 62% and 54%, respectively.

Distribution

In patients with CKD, the volume of distribution is 5 liters.

Excretion

T1/2 methoxypolyethylene glycol-epoetin beta with an iv injection of 134 hours (or 5.6 days), and a total system clearance of 0.494 ml / h / kg. Thy drug with SC administration is 139 hours in patients on dialysis and 142 hours in patients not on dialysis.

Pharmacokinetics in special patient groups

Liver failure: the pharmacokinetics of methoxy-polyethylene glycol-epoetin beta in patients with severe hepatic insufficiency and in healthy volunteers does not differ (see the "Method of administration and dosage", subsection "Dosage in special cases").

Other special patient groups: correction of the initial dose of methoxypolyethylene glycol epoetin beta, depending on sex, race, age not required.

In patients 65 years of age and older, a change in the initial dose is not required.

In patients who are not on dialysis, there are no differences in the pharmacokinetics of the drug.

Preclinical safety data

Carcinogenicity: Long-term studies on the study of carcinogenicity in animals have not been conducted. Mircera® did not elicit a proliferative response in vitro, while the binding of MIRCER® was observed only in target cells (precursor cells in the bone marrow).

Fertility disorder: Studies in animals have not revealed any negative effect of the drug on fertility.

Indications:

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

Contraindications:

Hypersensitivity to methoxy polyethylene glycol-epoetin beta or to any other component of the drug.

Uncontrolled hypertension.

Carefully:

Pregnancy, the period of breastfeeding, hemoglobinopathy, epilepsy, thrombocytosis (the number of platelets is more than 500 x 10⁹/ l), since the safety and efficacy of Mircera® for these groups have not been adequately studied.

Pregnancy and lactation:

The safety and efficacy of MIRCERA in pregnant women have not been adequately studied.

The results of animal studies suggest that MIRCER® does not have a direct or indirect adverse effect on pregnancy, embryonic / fetal development, childbirth or postnatal development. Care should be taken when prescribing Mircera® to pregnant women. It is not known whether methoxypolyethylene glycol-epoetin beta is excreted in human breast milk. An animal study showed that methoxy-polyethylene glycol-epoetin beta is excreted in human milk. The question of stopping breastfeeding or abolishing therapy should be decided depending on the importance of treatment for mother and breastfeeding for the child.

Dosing and Administration:

Given a longer half-life, the Mircera® preparation should be administered less frequently than other erythropoiesis stimulants.

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

Rules for storage of solution in outpatient and inpatient settings The solution of Mirsera is sterile and does not contain preservatives.Apply only a clear, colorless or slightly yellowish solution that does not contain visible impurities. Before administration, the solution is brought to room temperature if the drug is stored in the refrigerator.

Syringe tube can be stored for 1 month at room temperature (no higher than 30 ° C) and should be used during this month.

Bottle can be stored for 7 days at room temperature (not above 25 ° C) and should be used during these 7 days.

Unused solution must be disposed of. Each vial or syringe-tube can be used only once. Do not shake.

Vials and syringe-tubes should be stored in a cardboard box in accordance with storage requirements (see section "Storage conditions").

Mode of application

The drug can be administered as a s / c, and / in, depending on clinical preferences. The drug should be injected s / c into the shoulder area, the front of the thigh or the front abdominal wall. All of the above areas of administration are equally suitable for injections.

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

Standard dosing regimen

Patents not receiving the stimulant of erythropoiesis at the present time Patients not on dialysis

Recommended initial dose: 1.2 mcg / kg po 1 time per month, target Hb> 110 g / l (6.83 mmol / l). An alternative dosing regimen of Mircera® is possible at an initial dose of 0.6 mcg / kg iv or p / c once every 2 weeks, with a target Hb> 110 g / l (6.83 mmol / l).

Patients on dialysis

Recommended initial dose: 0.6 mcg / kg iv or c / 1 every 2 weeks, the target Hb > 110 g / l (6.83 mmol / l).

The dose of Mircera® can be increased by 25-50% from the previous one, if after a month the increase in Hb is less than 10 g / l (0.621 mmol / l). A further increase in the dose by about 25-50% can be carried out at intervals of 1 time per month until an individual target Hb is reached.

The dose of Mircera® is reduced by 25-50% from the previous one, if after a 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 to reduce Hb less than 130 g / l (8.07 mmol / l) and then resume, at a dose of 50% of the previous. With a target Hb of 120 g / l, the dose of the drug is changed by 25%.

After discontinuation of therapy, Hb decreases by approximately 3.5 g / L (0.22 mmol / L) per week. When the target Hb> 110 g / l (6.83 mmol / l) is reached,receiving therapy with Mertsera ® once in 2 weeks, can be transferred to the mode of administration of the drug once a month in a dose twice as high as the previous one. Correction of the dose of the drug is carried out no more than 1 time per month.

Patents receiving the erythropoiesis stimulant are currently Patients receiving another stimulant of erythropoiesis can be transferred to Mircera® therapy with a regimen of once a month or once in two weeks after or after IV. Initial dose: depends on the weekly dose of the previously administered drug - darbepoetin alfa or epoetin (alpha or beta) (see Fig. Tables 1 and 2). The first injection of Mircera® is carried out on the day of the next scheduled injection of the previously used darbepoetin alfa or epoetin (alpha or beta).

Table 1. Transition from epoetin (alpha or beta)

The previous weekly dose of epoetin (ED / week)	The dose of Mirtsera®
The previous weekly dose of epoetin (ED / week)	1 time per month (mcg / month)	1 time in 2 weeks (mcg / 2 weeks)
<8000	120	60
8000- 16000	200	100
>16000	360	180

Table 2. Transition from darbepoetin alfa

The previous weekly dose of darbepoetin alfa (μg / week)	The dose of Mirtsera®
The previous weekly dose of darbepoetin alfa (μg / week)	1 time per month (mcg / month)	1 time in 2 weeks (mcg / 2 weeks)
<40	120	60
40-80	200	100
>80	360	180

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

The dose of Mircera® is reduced by 25-50% from the previous one, if after a 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 to a level of less than 130 g / l (8.07 mmol / l) before HD and then resumed at a dose of 50% of the previous one.

With a target Hb of 120 g / l, the dose of the drug is changed by 25%.

After discontinuation of therapy, Hb decreases by approximately 3.5 g / L (0.22 mmol / L) per week. Correction of the dose of the drug is carried out no more than 1 time per month.

Interruption in treatment

Treatment of anemia, including therapy with Mirtsera®, is usually long-term. But if necessary, therapy with Mircera® can be interrupted at any time.

Missing dose

A missed single injection of MIRCER® should be administered as soon as possible and then administered with the prescribed dosage frequency.

Dosing in special cases

Liver failure: there is no need to correct the initial dose of the drug and the dosing regimen in patients with hepatic insufficiency of any severity (see section "Pharmacological action", subsection "Pharmacokinetics in special patient groups").

Elderly (65 years and over): no correction of the initial dose of the drug is required (see the section "Pharmacological action", subsection "Pharmacokinetics in special patient groups").

Children: the use of Mirtsera ® in children under 18 years is not recommended, due to insufficient data on the safety and efficacy of the drug in this category of patients.

Instructions for handling a syringe tube

1. Remove the transparent contour mesh package with the drug from the cardboard bundle without opening the protective film.

2. Wash hands thoroughly with warm water and soap.

3. Remove the protective film from the outline of the cell package, remove the syringe and a transparent plastic container with a needle.

4. While holding the container with the needle, detach the cap by turning it clockwise, as shown in the figure. Remove the cap from the top of the container with the needle.

5. While holding the syringe tube, remove the rubber tip, pre-bending and pulling, as shown in the figure.

6. While holding the transparent container with the needle, firmly insert the needle into the syringe tube, as shown in the figure.

Preparation and injection

1. For the introduction of the drug, choose one of the recommended places: the anterior abdominal wall, excluding the area around the navel, the front surface of the middle of the thigh or the outer surface of the shoulder. Do not inject the medication into birthmarks, scar tissue, hematoma or in the navel, in places with seals and / or reaction after previous injections. Each time the injection site should be changed. Avoid areas that can be irritated by a belt or belt of clothing.

2. Thoroughly treat the skin at the injection site with a swab dampened with alcohol. Wait until the treated area dries.

3. Gently holding the syringe-tube, without pressing the piston, carefully remove the transparent container from the needle.

4. With two fingers, put the skin in a crease at the site of the proposed injection. Insert the needle into the skin fold at a right angle.

5. Slowly introduce the entire medication, gently pressing on the piston. Do not stop squeezing the syringe until the needle is removed from the skin!

6. After the entire dose is administered, remove the needle from the skin without releasing the plunger of the syringe tube, as shown in the figure.

7. Having released the piston, the protective device will be released and the needle will be closed.

8. Press the swab with the cotton swab. If necessary, seal the injection site with a patch.

Side effects:

Clinical researches

When MIRCER® is used, the appearance of undesirable reactions is possible at approximately 6% patients. The most common of these is the increase in blood pressure (often).

To describe the frequency of unwanted reactions, the following categories are used: often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100) and rarely (> 1/10000 and <1/1000).

Table 3. Undesirable reactions associated with therapy with Mircera®, registered in controlled clinical trials in patients with CKD.

System Organ Class	Frequency	Unwanted reaction
From the side of the cardiovascular system	often	increase in blood pressure
From the side of the cardiovascular system	rarely	"tides"
Injury, poisoning and complications of procedures	infrequently	thrombosis of the shunt
From the nervous system	infrequently	headache
From the nervous system	rarely	hypertensive encephalopathy
From the immune system	rarely	hypersensitivity reactions
From the skin and subcutaneous fat	rarely	Rash (maculopapular, serious unwanted reaction)

All other unwanted reactions associated with therapy with Mircera® were rarely reported and in most cases were mild or moderate. These adverse reactions may be due to concomitant diseases.

Changes in laboratory indicators

In clinical studies during the treatment with Mirtsera®, there was a slight decrease in the number of platelets within the normal range.

7.5% of patients treated with Mircera® and 4.4% of patients treated with other erythropoiesis stimulants had thrombocytopenia (platelet count <100 x 10⁹/ l).

Postmarketing observations

With the use of the Mircera® preparation, partial red cell aplasia (PKAA) has been reported, caused by the formation of neutralizing antibodies to erythropoietin (see section "Special instructions"). Otherwise, the safety profile of the drug corresponded to undesirable reactions recorded with the application of MIRCER® in clinical studies (see section "Special instructions" and section "Pharmacological action", subsection "Clinical Efficiency").

Overdose:

Mircera® has a wide therapeutic range, when initiating therapy, individual response to therapy should be considered. An excessive pharmacodynamic response is possible, i. E. excessive erythropoiesis. At a high level of Hb, it is necessary to temporarily interrupt therapy with Mircera® (see the section "Dosage and Administration"). If necessary, phlebotomy can be performed.

Interaction:

Studies on the interaction with other drugs have not been conducted. The data obtained so far have not revealed any interactions of Mircera® with other drugs, as well as evidence of the effect of other drugs on the pharmacokinetics and pharmacodynamics of MIRCER®. Do not mix methoxypolyethylene glycol-epoetin beta with other drugs or injectable solutions.

Special instructions:

Before and during treatment with Mircera®, iron deficiency should be eliminated.

Additional iron therapy It is recommended if serum ferritin levels are below 100 μg / L or iron transferrin is less than 20% saturated.

Lack of effect: the most frequent reasons for the incomplete response to treatment with agents stimulating erythropoiesis are iron deficiency, inflammation, as well as chronic blood loss, bone marrow fibrosis, a sharp increase in the concentration of aluminum due to hemodialysis, a deficiency of folic acid or vitamin B12, hemolysis. If all listed conditions are excluded and the patient has a sudden decrease in Hb, reticulocytopenia and antibodies to erythropoietin are detected, it is necessary to conduct a bone marrow examination to exclude PKAA.

With the development of PKAA therapy with Mircera® should be stopped and patients should not be transferred to therapy with other stimulants of erythropoiesis.

Against the background of therapy with stimulants of erythropoiesis, including with the use of Mirtsera®, cases of development of PKA caused by antibodies to erythropoietin were reported. Antibodies have a cross-reaction with all stimulants of erythropoiesis. Do not transfer to Mircera® therapy for patients with confirmed antibodies to erythropoietin or suspected of their presence.

Increase in blood pressure: before and during treatment with Mertsera, as well as other stimulants of erythropoiesis, it is necessary to control blood pressure.If blood pressure can not be monitored medically, it is necessary to lower the dose or suspend therapy with Mircera® (see the section "Dosage and Administration").

The effect on tumor growth: the Mircera® preparation, like other drugs that stimulate erythropoiesis, is a growth factor, which mainly stimulates the formation of erythrocytes. Erythropoietin receptors may be present on the surface of various tumor cells. It is possible that drugs that stimulate erythropoiesis (like other growth factors) can stimulate the growth of any type of malignant formation.

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

Caution should be exercised when using Mircera® in patients with hemoglobinopathies, epilepsy, thrombocytosis (platelets more than 500 x 109/ l), since the safety and efficacy of the drug for these groups have not been studied.

The presence of drugs in the environment should be minimized.Do not dispose of the product with sewage or with household waste. If possible, it is necessary to use special systems for the disposal of medicinal products.

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

Studies to study the effect of the drug on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions have not been carried out. Based on the mechanism of action and safety profile, Mircera® does not have this effect.

Form release / dosage:Solution for subcutaneous and intravenous administration.

Packaging:

Bottles

50 μg / 1 ml, 100 μg / 1 ml, 200 μg / 1 ml, 300 μg / 1 ml, 400 μg / 1 ml, 600 μg / 1 ml, 1000 μg / 1 ml of the drug into vials made of colorless glass (hydrolytic class 1 according to EF), sealed with a lid of butyl rubber, crimped with an aluminum cap and covered with a plastic lid; the color of the lid corresponds to the color by which the dosage of the drug is allocated on the label of the vial and on the pack.

Each bottle together with the instruction for use is placed in a cardboard box; on the packet there is a control of the opening of the package indicating the location of the opening.

Syringe Tubes

30 μg / 0.3 ml, 40 μg / 0.3 ml, 50 μg / 0.3 ml, 60 μg / 0.3 ml, 75 μg / 0.3 ml, 100 μg / 0.3 ml, 120 μg / 0.3 ml, 150 μg / 0.3 ml, 200 μg / 0.3 ml μg / 0.3 ml, 250 μg / 0.3 ml, 360 μg / 0.6 ml, 400 μg / 0.6 ml, 600 μg / 0.6 ml, 800 μg / 0.6 ml in syringe tubes, the body of which is made of glass (hydrolytic class 1 according to the EF ), the piston is made of plastic, with a plug of butyl rubber laminated with fluoropolymer. The color of the piston corresponds to the color by which the dosage of the drug is marked on the label of the syringe and on the pack. On the round handle of the piston there is a logo <Roche>. On the other hand, the syringe tubes are sealed with a tip of butyl rubber laminated with fluoropolymer.

The syringe tube is placed in a transparent protective plastic container with a spring.

1 sterile needle for injection is placed in a hermetically sealed plastic container with opening control.

1 a syringe tube together with a container with an injection needle is placed in a transparent contour mesh package, hermetically sealed. The contourcell pack together with the instructions for use is placed in a cardboard box.

Storage conditions:

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

Shelf life:

Vials -1 year.

Syringe tubes - 3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-002182/08

Date of registration:28.03.2008

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

F.Hoffmann-La Roche, Ltd. Switzerland