Мирцера®

General characteristics. Structure:

Active ingredient: - 50 mkg, 100 mkg, 200 mkg, 300 mkg, 400 mkg, 600 mkg, 1000 mkg metoksipolietilenglikol-epoetin a beta in 1 ml of solution in a bottle;

- 30 mkg, 40 mkg, 50 mkg, 60 mkg, 75 mkg, 100 mkg, 120 mkg, 150 mkg, 200 mkg, 250 mkg metoksipolietilenglikol-epoetin a beta in 0,3 ml of solution in an unit-dose syringe;

- 360 mkg, 400 mkg, 600 mkg, 800 mkg metoksipolietilenglikol-epoetin a beta in 0,6 ml of solution in an unit-dose syringe.

Excipients: L-methionine, sodium sulfate anhydrous, dihydrophosphate sodium monohydrate, Mannitolum, half-oxameasures 188, Acidum hydrochloricum diluted or solution of sodium of hydroxide (q.s. to рН 6.2), water for injections.

Drug of the last generation for treatment of nephrogenic anemia.

Pharmacological properties:

Pharmacodynamics. The drug Mirtsera® - chemically synthesized representative of a new class of activators of receptors of erythropoetin of long action. Metoksipolietilenglikol-epoetin a beta is a covalent conjugant of the protein received by method of recombinant DNA and linear метоксиполиэтиленгликоля (PEG). Metoksipolietilenglikol-epoetin a beta differs from erythropoetin in existence of amide communication between a N-trailer amino group or an e-amino group of a lysine, Lys52 and Lys45, and metoksipolietilenglikolbutanovy acid is preferential. Molecular weight metoksipolietilen-glycol-epoetin a beta makes about 60 kd, including 30 kd the molecular mass of PEG.

The drug Mirtsera® has activity, other than erythropoetin, at the level of a receptor and is characterized by longer association with a receptor and more bystry dissociation from a receptor, reduced specific activity of in vitro and a superactivity of in vivo, and also the increased elimination half-life that allows to administer the drug Mirtsera® once a month.

Action mechanism. The drug Mirtsera® stimulates an erythrogenesis at interaction with eritropoetinovy receptors on marrow progenitors.

Being the major factor of growth necessary for maturing of erythrocytes, natural erythropoetin is produced by kidneys and released in a blood channel in response to a hypoxia. In response to a hypoxia erythropoetin interacts with progenitors of erythrocytes and leads to increase in formation of erythrocytes.

Clinical performance. Correction of anemia is noted at 97.5% and 94.1% of the patients with the chronic disease of kidneys (CDK) who are not on dialysis at therapy by the drug Мирцера® 1 of times in 2 weeks and once a month, respectively. In the first 8 weeks of therapy hemoglobin (Hb) exceeded 130 g/l at 11.4% of the patients receiving the drug Мирцера® 1 of times in 2 weeks and at 34% of the patients receiving дарбэпоэтин an alpha and exceeded 120 g/l at 25.8% of the patients receiving the drug Mirtsera® once a month and at 47.7% of the patients receiving дарбэпоэтин an alpha.

At 93.3% of patients from HBP which are on dialysis at therapy the drug Mirtsera® noted correction of anemia. At the patients who are on dialysis at transfer from therapy darbepoetiny the alpha or epoetiny on therapy by the drug Mirtsera® remains stable target Hb.

In group of a maintenance therapy the drug Mirtsera®, once a month, the share of patients from HBP which are on a hemodialysis with the response to therapy was much higher in comparison with group of a maintenance therapy darbepoetiny an alpha, once a month (р <0.0001).

Pharmacokinetics. Pharmacokinetic and pharmacological parameters allow to administer the drug Мирцера® 1 of times month in connection with the increased elimination half-life.

The elimination half-life (T1/2) after the drug Mirtsera®, intravenous (in/in) introductions, is 15-20 times more long, than at administration of recombinant human erythropoetin.

Pharmacokinetic parameters of drug were studied at healthy volunteers and at the patients with anemia and HBP who are and not being on dialysis.

At patients with HBP the clearance and volume of distribution of a metoksipolietilenglikol-epoetin a beta do not depend on a dose.

The pharmacokinetics of the drug Mirtsera® was studied at patients with HBP after single introduction on the 9th week and 19 or 21 week. Repeated introduction does not influence clearance, volume of distribution and bioavailability of a metoksipolietilenglikol-epoetin a beta. The beta of 1 times in 4 weeks to patients with HBP does not lead introduction of a metoksipolietilenglikol-epoetin to significant cumulation of drug, the coefficient of cumulation is equal 1.03 at introduction of 1 times to 4 weeks. The cumulation coefficient at introduction of 1 times to 2 weeks is equal to 1.12. Results of comparison of serumal concentration of a metoksipolietilenglikol-epoetin a beta before carrying out a hemodialysis at patients with HBP showed that the hemodialysis does not exert impact on drug pharmacokinetics. At patients from the HBP which are receiving and not receiving dialysis, distinctions in pharmacokinetics were absent.  

The pharmacokinetics, pharmacodynamics and local portability do not depend on the place hypodermic (п / to) drug injections (a shoulder, the front surface of a hip, a front abdominal wall) that is confirmed by results of the research conducted on healthy volunteers. On the basis of these results these places equally approach for п / to administration of the drug Mirtsera®.

Absorption after hypodermic introduction. Time of achievement of the maximum serumal concentration metoksipolietilen-glycol-epoetina a beta at п / to introduction to patients with HBP which is on dialysis - 72 hours (median) and 95 hours after introduction to the patients who are not on dialysis.

Absolute bioavailability of a metoksipolietilenglikol-epoetin a beta at the patients who are on dialysis and at the patients who are not on dialysis makes 62% and 54%, respectively.

Distribution. At patients with HBP the volume of distribution makes 5 liters.

Excretion. T1/2 of a metoksipolietilenglikol-epoetin a beta at in introduction 134 hours (or 5.6 days), and full system clearance of 0.494 ml/h/kg. Drug T1/2 at п / to introduction - 139 hours at the patients who are on dialysis and 142 hours, at the patients who are not on dialysis.

Pharmacokinetics at special groups of patients. Liver failure: the pharmacokinetics of a metoksipolietilenglikol-epoetin a beta at patients with a heavy liver failure and at healthy volunteers does not differ (see the section "Route of Administration and Doses", the subsection "Dosing in Special Cases").
Other special groups of patients: to correction of an initial dose of a metoksipolietilenglikol-epoetin a beta depending on a floor, race, age is not required.

Patients have 65 years and change of an initial dose is more senior it is not required.

At the patients who are and not being on dialysis, distinctions in pharmacokinetics of drug are absent.

Preclinical data on safety. Carcinogenicity: long-term researches on studying of carcinogenicity at animals were not conducted. The drug Mirtsera® did not cause the proliferative answer of in vitro, at the same time binding of the drug Mirtsera® was observed only in target cells (progenitors in marrow).

Fertility disturbance: researches on animals did not reveal any negative influence of drug on fertility.

Indications to use:

Anemia at a chronic renal failure (on NKF K/DOQI classification - at a chronic disease of kidneys).

Route of administration and doses:

Considering longer elimination half-life, the drug Mirtsera® has to be administered less than other stimulators of an erythrogenesis. Treatment by the drug Mirtsera® needs to be begun only under observation of the specialist.

Rules of storage of solution in out-patient and stationary conditions. Solution of the drug Mirtsera® is sterile and does not contain preservatives. It is only necessary to apply transparent colourless or slightly yellowish color the solution which is not containing visible impurity. Before introduction solution is brought to room temperature if drug was stored in the refrigerator.

The unit-dose syringe can be stored within 1 month at the room temperature (not above 30 °C) and has to be used within this month.

The bottle can be stored within 7 days at the room temperature (not above 25 °C) and has to be used during these 7 days.

Unused solution has to be destroyed. Each bottle or an unit-dose syringe can be used only once. Not to stir up.

Route of administration. The drug can be administered as п / to, and in/in, depending on clinical preferences. The drug should be administered п / to the area of a shoulder, the front surface of a hip or a front abdominal wall. All above-stated areas of introduction equally approach for п / to injections. It is necessary to control the maintenance of Hb 1 time in 2 weeks before its stabilization and periodically after stabilization.

Standard mode of dosing. The patients who are not receiving an erythrogenesis stimulator now.

The patients who are not on dialysis. The recommended initial dose: 1.2 mkg/kg п / to once a month, target Hb> 110 g/l (6.83 mmol/l). The alternative mode of a drug dosing Mirtsera® in an initial dose of 0.6 mkg/kg in/in or п / to 1 time in 2 weeks, target Hb> 110 g/l (6.83 mmol/l) is possible.

The patients who are on dialysis. The recommended initial dose: 0.6 mkg/kg in/in or п / to 1 time in 2 weeks, target Hb> 110 g/l (6.83 mmol/l).

The dose of the drug Mirtsera® can be increased by 25-50% from previous if a month later increase in Hb makes less than 10 g/l (0.621 mmol/l). Further increase in a dose approximately for 25-50% can be carried out bucketed before achievement of individual target Hb once a month.

The dose of the drug Mirtsera® is reduced by 25-50% from previous if a month later increase in Hb makes more than 20 g/l (1.24 mmol/l). If Hb exceeds 130 g/l (8.07 mmol/l), then therapy needs to be interrupted before decrease in Hb less than 130 g/l (8.07 mmol/l) and then to renew, in a dose of 50% of previous. At target Hb of 120 g/l the dose of drug changes for 25%.

After the termination of therapy of Hb decreases approximately by 3.5 g/l (0.22 mmol/l) a week. At achievement of target Hb> 110 g/l (6.83 mmol/l) of the patients receiving therapy by the drug Мирцера® 1 of times in 2 weeks can be transferred to the mode of administration of drug in the dose exceeding previous twice once a month. Dose adjustment of drug is carried out not more often than 1 time a month.

The patients receiving an erythrogenesis stimulator now. The patients receiving other stimulator of an erythrogenesis can be transferred to therapy by the drug Mirtsera® with the introduction mode once a month or 1 time in 2 weeks п / to or in / century.

Initial dose: depends on a week dose of earlier administered drug - a darbepoetin an alpha or an epoetina (an alpha or a beta) (see Tables 1 and 2). The first injection of the drug Mirtsera® is carried out in day of the following planned injection of earlier applied darbepoetin by an alpha or an epoetina (an alpha or a beta).

Table 1. Transition from an epoetin (alpha or beta)

The previous week dose of an epoetin (PIECE/week)	Drug Mirtsera® dose
	Once a month (mkg/month)	1 time in 2 weeks (mkg / 2 weeks)
<8000	120	60
8000 - 16000	200	100
> 16000	360	180

 Table 2. Transition from a darbepoetin alpha

The previous week dose of a darbepoetin an alpha (mkg/week)	Drug Mirtsera® dose
	Once a month (mkg/month)	1 time in 2 weeks (mkg / 2 weeks)
<40	120	60
40 - 80	200	100
> 80	360	180

If for maintenance of target Hb higher than 110 g/l (6.83 mmol/l) are required dose adjustment, then the monthly dose can be changed to 25%. 

The dose of the drug Mirtsera® is reduced by 25-50% from previous if a month later increase in Hb makes more than 20 g/l (1.24 mmol/l). If Hb exceeds 130 g/l (8.07 mmol/l), then therapy needs to be interrupted before decrease in Hb to level less than 130 g/l (8.07 mmol/l) and then to renew, in a dose of 50% of previous.

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

After the termination of therapy of Hb decreases approximately by 3.5 g/l (0.22 mmol/l) a week. Dose adjustment of drug is carried out not more often than 1 time a month.

Having rummaged in treatment. Treatment of anemia including therapy by the drug Mirtsera®, usually happens long-term. But if necessary therapy by the drug Mirtsera® can be interrupted at any time.

The passed dose. The passed single injection of the drug Mirtsera® needs to be entered as soon as possible and further to administer the drug with the ordered dosing frequency.

Dosing in special cases. Liver failure: correction of an initial dose of drug and the mode of dosing is not required from patients with a liver failure of any severity (see the section "Pharmacological Action", the subsection "Pharmacokinetics at Special Groups of Patients").

Advanced age (65 years are also more senior): correction of an initial dose of drug is not required (see the section "Pharmacological Action", subsection "Pharmacokinetics from special groups of patients).

Children: use of the drug Mirtsera® for children up to 18 years is not recommended, in connection with insufficient data on safety and efficiency of drug at this category of patients.

The instruction on the address about the syringe tube
1. To take out a transparent blister strip packaging with medicine from a cardboard pack, without opening a protective film.
2. To carefully wash up hands warm water with soap.
3. To remove a protective film from a blister strip packaging, to get an unit-dose syringe and a transparent plastic container with a needle.
4. Holding a container with a needle, to disconnect a cap, having made rotary motion clockwise. To remove a cap from an upper part of a container with a needle.

 1. Holding an unit-dose syringe, to remove a rubber tip, previously having bent and having pulled.

 1. Holding a transparent container with a needle, to densely insert a needle into an unit-dose syringe.

 Preparation and carrying out injection
1. For administration of medicine to choose one of the recommended places: a front abdominal wall, excepting area around a navel, a front surface of the middle of a hip or the outside surface of a shoulder. Not to administer medicine in birthmarks, fabrics of hems, hematomas or in a navel, to places with consolidations and/or reaction after the previous injections. It is necessary to change every time drug injection sites. To avoid sites which can be exposed to irritation a belt or a belt of clothes.

2. To carefully process leather in the place of an injection the tampon moistened with alcohol. To wait still processed site will dry up.

3. Accurately holding an unit-dose syringe, not pressing the piston, to carefully remove a transparent container from a needle.
4. To collect by two fingers skin pleated in the place of an estimated injection. To enter a needle into a skin fold at right angle.

5. To slowly administer all medicine, smoothly pressing on the piston.

Do not stop pressing the syringe tube on the piston you will not take a needle from skin yet!

6. After introduction of all dose to take out a needle from skin, without releasing the piston the syringe tube.

7. Having released the piston, the protection device will be released and will close a needle.

8. To press a cotton plug a medicine injection site. If necessary to stick the place of an injection with a plaster.

Features of use:

Prior to the beginning of and during treatment by the drug Mirtsera® it is necessary to exclude deficit of iron. Additional therapy by iron is recommended if the content of ferritin in blood serum is lower than 100 mkg/l or saturation of transferrin iron lower than 20%.

Lack of effect: the most frequent reasons of the incomplete response to treatment by the means stimulating an erythrogenesis are deficit of iron, an inflammation, and also chronic blood loss, marrow fibrosis, the sharp increase in concentration of aluminum caused by a hemodialysis, deficit of folic acid or B12 vitamin, hemolysis. If all listed states are excluded and at the patient sudden decrease in Hb, a reticulocytopenia is observed and antibodies to erythropoetin are found, it is necessary to conduct a marrow research for PKKA exception. At development of PKKA therapy by the drug Mirtsera® needs to be stopped and patients should not be transferred to therapy by other stimulators of an erythrogenesis.

Against the background of therapy by erythrogenesis stimulators, including at drug Mirtsera® use, it was reported about cases of development of PKKA caused by antibodies to erythropoetin. Antibodies possess cross-reaction with all stimulators of an erythrogenesis. It is not necessary to transfer to therapy by the drug Mirtsera® of patients with the confirmed antibodies to erythropoetin or suspicion on their existence.

Increase in arterial pressure: prior to the beginning of and during treatment by the drug Mirtsera®, as well as other stimulators of an erythrogenesis, it is necessary to control arterial pressure. If arterial pressure does not manage to be controlled medicamentally, it is necessary to lower a dose or to suspend therapy by the drug Mirtsera® (see the section "Route of Administration and Doses").

Effect on tumoral growth: the drug Mirtsera®, as well as other medicines stimulating an erythrogenesis is a growth factor which generally stimulates formation of erythrocytes. Eritropoetinovy receptors can be present at a surface of various tumor cells. It is possible that the means stimulating an erythrogenesis (as well as other growth factors), can stimulate growth of a malignancy of any type.

At use of epoetin for patients with various malignant tumors, including the heads and necks, a mammary gland, increase in a lethality which reasons are not clear was observed.

It is necessary to show care at use of the drug Mirtsera® for patients with hemoglobinopathies, epilepsy, a thrombocytosis (number of thrombocytes more than 500 x 109/l) as safety and efficiency of drug for these groups are not studied.

Hit of medicines to the environment has to be minimized. It is not necessary to utilize drug by means of sewage or together with household waste. It is whenever possible necessary to use special systems for utilization of medicines.
 
Influence on ability to driving of transport and work with cars and mechanisms. Researches on studying of influence of drug on ability to manage vehicles and to be engaged in other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions were not conducted. Proceeding from the mechanism of action and a profile of safety, the drug Mirtsera® does not possess such action.

Safety and efficiency of use of the drug Mirtsera® for pregnant women are studied insufficiently. Results of the researches conducted on animals demonstrate that the drug Mirtsera® has no direct or indirect harmful effect concerning pregnancy, embryonic/fetalis development, childbirth or post-natal development. It is necessary to be careful at purpose of the drug Mirtsera® to pregnant women.

It is unknown whether the beta with breast milk at the person is removed metoksipolietilenglikol-epoetin. In a research on animals it is shown that metoksipolietilenglikol-epoetin the beta is removed with maternal milk. The question of the feeding termination by a breast or cancellation of therapy has to be solved depending on importance of treatment for mother and breastfeeding for the child.

Side effects:

Clinical trials. At ^{drug Mirtsera®} use emergence of undesirable reactions is possible approximately at 6% of patients. The most frequent of them is increase in arterial pressure (often).

For the description of frequency of undesirable reactions the following categories are used: often (³1/100 and <1/10), infrequently (³1/1000 and <1/100) and it is rare (³1/10000 and <1/1000).

Table 3. The undesirable reactions connected with therapy ^{by the drug Mirtsera®}, registered in controlled clinical trials at patients with HBP.

System Body Class	Frequency	Undesirable reaction
From cardiovascular system	often	increase in arterial pressure
	seldom	"inflows"
Injuries, poisonings and complications of procedures	infrequently	shunt thrombosis
From a nervous system	infrequently	headache
	seldom	hypertensive encephalopathy
From immune system	seldom	hypersensitivity reactions
From skin and a hypodermic fatty tissue	seldom	rash (makulopapulezny, serious undesirable reaction)

All other undesirable reactions connected with therapy ^{by the drug Mirtsera®} were reported seldom and in most cases were easy or moderate severity. These undesirable reactions can be caused by associated diseases.

Changes of laboratory indicators. In clinical trials during therapy ^{the drug Mirtsera®} observed insignificant decrease in number of thrombocytes within normal values.

At 7.5% of the patients receiving therapy ^{by the drug Mirtsera®} and at 4.4% of the patients receiving therapy by other stimulators of an erythrogenesis thrombocytopenia was observed (quantity of thrombocytes <^{100 x 109/l}).

Post-marketing observations. At use ^{of the drug Mirtsera®} it was reported about a partial krasnokletochny aplasia (PKKA) caused by formation of neutralized antibodies to erythropoetin (see the section "Special Instructions"). For the rest the profile of safety of drug corresponded to the undesirable reactions registered at use ^{of the drug Mirtsera®} in clinical trials (see the section "Special Instructions" and the section "Pharmacological Action", the subsection "Clinical performance").

Interaction with other medicines:

Researches on studying of interaction with other medicines were not conducted. The data obtained so far did not reveal any interactions of the drug Mirtsera® with other drugs, and also signs of influence of other drugs on pharmacokinetics and a pharmacodynamics of the drug Mirtsera®. It is not necessary to mix metoksipolietilenglikol-epoetin a beta with other medicines or injection solutions.

Contraindications:

Hypersensitivity to a metoksipolietilenglikol-epoetin a beta or to any other component of drug. Uncontrollable arterial hypertension.                                                                                         
 
With care. Pregnancy, the feeding period a breast, hemoglobinopathies, epilepsy, a thrombocytosis (number of thrombocytes more than 500 x 109/l) as safety and efficiency of the drug Mirtsera® for these groups are studied insufficiently.

Overdose:

The drug Mirtsera® has broad therapeutic range, at initiation of therapy it is necessary to take the individual response to therapy into account. The excessive pharmakodinamichesky answer, i.e. an excessive erythrogenesis is possible. At the high Hb level it is necessary to interrupt temporarily therapy with the drug Mirtsera® (see the section "Route of Administration and Doses"). If necessary the phlebotomy can be carried out.

Storage conditions:

Period of validity Bottles – 1 year. The syringe tubes – 3 years. Drug should not be used after the period of validity specified on packaging.

To store at a temperature of 2-8 °C in the place protected from light. Not to freeze. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for hypodermic and intravenous administration, bottles. On 50 mkg / 1 ml, 100 mkg / 1 ml, 200 mkg / 1 ml, 300 mkg / 1 ml, 400 mkg / 1 ml, 600 mkg / 1 ml, 1000 mkg / 1 drug ml in the bottles made of colourless glass (a hydrolytic class 1 on EF), corked by a cover from butyl rubber, which are pressed out by an aluminum cap and closed by a plastic cover; color of a cover corresponds to color which allocated a drug dosage on the label of a bottle and on a pack.

Each bottle together with the application instruction is placed in a cardboard pack; on a pack there is a control of opening of packaging with the indication of the place of opening.
Solution for hypodermic and intravenous administration, the syringe tubes.

On 30 mkg / 0.3 ml, 40 mkg / 0.3 ml, 50 mkg / 0.3 ml, 60 mkg / 0.3 ml, 75 mkg / 0.3 ml, 100 mkg / 0.3 ml, 120 mkg / 0.3 ml, 150 mkg / 0.3 ml, 200 mkg / 0.3 ml, 250 mkg / 0.3 ml, 360 mkg / 0.6 ml, 400 mkg / 0.6 ml, 600 mkg / 0.6 ml, 800 mkg / 0.6 ml in the syringe tubes which case is manufactured of glass (a hydrolytic class 1 on EF), the piston – from plastic, with a stopper from the butyl rubber laminated by a ftorpolimer. Color of the piston corresponds to color which allocated a drug dosage on the label the syringe tube and on a pack. On the round handle of the piston there is a logo r. On the other hand the syringe tubes are corked by a tip from the butyl rubber laminated by a ftorpolimer.

The unit-dose syringe is placed in a transparent protective plastic container with a spring. 1 sterile injection cannula is placed in hermetically corked plastic container with opening control.

1 unit-dose syringe together with a container with an injection cannula is placed in the transparent blister strip packaging which is hermetically corked. The blister strip packaging together with the application instruction is placed in a cardboard pack.