Актемра®

General characteristics. Structure:

Active ingredient: 20 mg of a totsilizumab.

Excipients: polysorbate 80, sucrose, hydrophosphate sodium dodecahydrate, dihydrophosphate sodium a dihydrate, water for injections.

The first monoclone created for treatment of a pseudorheumatism.

Pharmacological properties:

Pharmacodynamics. Totsilizumab – the recombinant humanized monoclone to a human receptor interleykina-6 (IL-6) from a subclass of IgG1 immunoglobulins. Totsilizumab selectively communicates and suppresses both soluble, and membrane receptors of SILT-6 (sIL-6R and mIL-6R). SILT-6 is the multipurpose cytokine produced by various types of cells and also stimulation of a hemogenesis participates in paracrine regulation, system physiological and pathological processes, such as stimulation of secretion of Ig, activation of T-cells, stimulation of production of proteins of an acute phase in a liver. SILT-6 is involved in a pathogeny of various diseases, including inflammatory diseases, osteoporosis and new growths.

It is impossible to exclude probability of negative impact of a totsilizumab on antineoplastic and anti-infectious protection of an organism. The SILT-6 receptor inhibition role in development of tumors is not known.

Clinical performance at the pseudorheumatism (P). Efficiency of drug at the patients receiving тоцилизумаб both in monotherapy and in a combination with a methotrexate or basic antiinflammatory drugs (BPVP), did not depend on existence or lack of a rhematoid factor, age, sex, race, number of the previous courses of treatment or a stage of a disease. The response to therapy arose quickly (on the second week), further amplified and remained more than 3 years in the continuing open expanded researches.

At the patients receiving тоцилизумаб in a dose of 8 mg/kg the index of activity of a disease on DAS28 scale in comparison with the patients receiving placebo + BPVP significantly decreases. The number of the patients who reached clinical remission (DAS28 <2.6) on the 24th week, was much more in group of therapy totsilizumaby (28-34%) in comparison with control group (1-12%). By 52nd week of therapy number of the patients who reached DAS28 <2.6, increases to 47% in comparison with 33% on the 24th week of therapy.

The good or satisfactory answer by criteria of EULAR was noted more often at the patients who were receiving тоцилизумаб, than receiving placebo + BPVP.

In 2 years of therapy totsilizumabom/MT at 14% of patients the considerable clinical answer was observed (the ACRE 70 remained for 24 weeks and more).

Radiological assessment. At 83% of the patients receiving therapy totsilizumabom/MT within a year progressing of destruction of joints (change of a total index of Sharp is equal to zero or less) in comparison with 67% of the patients receiving placebo/MT is not registered. This result remained for 2 years of therapy. 93% of patients had no progressing of destruction of joints between 52 and 104 weeks of therapy.

Indicators of quality of life. At the patients receiving тоцилизумаб in a dose of 8 mg/kg (monotherapy or in combination with BPVP), in comparison with those who received MT/BPVP clinically significant improvement of functional activity (on the HAQ-DI index), decrease in fatigue (on a scale of functional assessment of therapy of chronic diseases on an indicator of fatigue of FACIT-Fatigue), and also improvement both indicators physical, and indicators of mental health on SF-36 questionnaire was observed.

Laboratory indicators. After introduction of a totsilizumab there is a bystry decrease in average values of ostrofazovy indicators, C-reactive protein, SOE and serumal amyloid A, decrease in number of thrombocytes within normal values, and also increase in hemoglobin (Hb) which was most observed at patients with the chronic anemia connected with RA.

Clinical performance at the patients with an early pseudorheumatism (RRA) who were earlier not receiving therapy of MT. At use of a totsilizumab in monotherapy in a dose of 8 mg/kg and a totsilizumaba in a dose of 4 or 8 mg/kg each 4 weeks in a combination with MT the index of activity of a disease on DAS28 scale significantly decreases in the groups receiving тоцилизумаб in a dose of 8 mg/kg in comparison with the patients receiving monotherapy of MT. The number of the patients who reached clinical remission (DAS28 <2.6) on the 24th week, are much more in the groups receiving тоцилизумаб (38.7-44.8%), in comparison with group of monotherapy of MT (15%). By 52nd week number of the patients who reached DAS28 <2.6 in groups of therapy totsilizumaby, increases to 39.4-49% in comparison with 19.5% in group of monotherapy of MT. The number of the patients who reached the answer the ACRE 20, 50, 70 are also significantly higher in groups of therapy totsilizumaby (70.2-74.5%; 47.6-56.9%; 30.1-38.6% on the 24th week and 63-67.2%; 49.3-55.9%; 36-43.1% on the 52nd week, respectively) in comparison with group of monotherapy of MT (65.2%; 43.2%; 25.4% on the 24th week and 57.1%; 40.8%; 28.9% on the 52nd week, respectively).

Radiological assessment. Lack of progressing of destruction of joints (change of a total index of Sharp is equal to zero or less) is observed at 82-83% of the patients receiving тоцилизумаб in a dose of 8 mg/kg as monotherapy or in a combination with MT in comparison with 73% of patients in group of monotherapy of MT.

Indicators of quality of life. Clinically significant improvement of functional activity on the HAQ-DI index is observed at the patients receiving тоцилизумаб in a dose of 8 mg/kg as monotherapy or a combination with MT in comparison with those who received monotherapy of MT.

At monotherapy totsilizumaby (in a dose of 8 mg/kg intravenously each 4 weeks at patients with RA, c intolerance of MT or at inexpediency of continuation of therapy of MT (including at the inadequate response to therapy of MT)) was observed more expressed statistically significant decrease of the activity of a disease on DAS28 scale in comparison with monotherapy adalimumaby (in a dose of 40 mg subcutaneously each 2 weeks). The number of the patients who answered therapy with DAS28 indicators <2.6 and DAS28 ≤3.2, was more at therapy totsilizumaby, than at therapy adalimumaby (39.9% against 10.5% and 51.5% against 19.8%, respectively). Answers the ACRE 20, 50, 70 were observed at 65%, 47.2%, 32.5% of the patients receiving тоцилизумаб in comparison with 49.4%, 27.8%, 17.9% of the patients receiving адалимумаб.

Clinical performance at polyarticulary juvenile idiopathic arthritis (pYuIA). Answers the ACRE 30, 50, 70, 90 were received at 89.4%, 83.0%, 62.2% and 26.1% of patients, respectively. The share of patients with the answer the ACRE 30, 50, 70 on the 40th week of therapy concerning indicators for the beginning of therapy made 74.4%, 73.2% and 64.6%, respectively.

Clinical performance at system juvenile idiopathic arthritis   (sYuIA). Efficiency of a totsilizumab for treatment of active sYuIA was studied in 12 weeks randomized, double blind placebo the controlled period of a research with 2 parallel groups. On the 12th week the share of the patients who reached the answer the ACRE 30, 50, 70, 90 at YuIA also was more in group of therapy totsilizumaby, than in group of placebo: 90.7% against 24.3%, 85.3% against 10.8%, 70.7% against 8.1%, 37.3% against 5.4%, respectively (р <0.0001). The response to therapy remained also in the open expanded period of a research.

System effects. At 85% of the patients who had initially fever in 12 weeks of therapy totsilizumaby fever was absent in comparison with 21% of the patients receiving placebo (р <0.0001). Besides, at 64% of the patients who had rash initially in 12 weeks of therapy totsilizumaby rash was absent in comparison with 11% of the patients receiving placebo (р =0.0008).

Significant decrease in intensity of a pain syndrome in group of therapy totsilizumaby in comparison with placebo on the 12th week was observed. The corrected average change of assessment of pain on the visual analog scale (VAS) after 12 weeks of therapy totsilizumaby corresponded to 41 points (from 0 to 100 points) in comparison with 1 point at the patients receiving placebo (р <0.0001). System effects remained also in the proceeding open expanded period of a research.

Dose decline of glucocorticosteroids. At 8 of 31 patients in group of placebo and at 48 of 70 patients in group of a totsilizumab receiving glucocorticosteroids initially the answer the ACRE 70 was observed at YuIA on the 6 or 8 week that allowed to lower a dose of glucocorticosteroids. At the same time 24% of patients in group of a totsilizumab and 3% of patients in group of placebo could lower a dose of glucocorticosteroids at least by 20% without the subsequent decrease in frequency of the answer by criteria the ACRE 30 at YuIA (by criteria of the American Board of Rheumatologists, the ACRE) or emergence of system manifestations by 12th week (р =0.028). The dose decline of glucocorticosteroids proceeded, at the same time 44 patients did not receive glucocorticosteroids on the 44th week, and answers the ACRE did not change.

Indicators of quality of life. On the 12th week the share of the patients in group of a totsilizumab showing the minimum clinically significant improvement of an indicator on CHAQ-DI questionnaire (defined as decrease in individual general point on ≥0.13) was much higher, than a share of patients in group of placebo – 77% against 19%, respectively (р <0.0001). Answers remained also in the proceeding open expanded period of a research.

Laboratory indicators. Initially 67% of patients from group of a totsilizumab had a maintenance of Hb below normal range. At 80% from these patients on the 12th week increase in Hb within normal range in comparison with 7% of patients in group of placebo was observed (р <0.0001). At 88% of the patients from group of a totsilizumab who had initially reduced maintenance of Hb, its level increased by ≥10 g/l by 6th week, in group of placebo the frequency of increase made 3% (р <0.0001).

The share of the patients who had initially a thrombocytosis and at which on the 12th week the normal number of thrombocytes was observed was higher in group of a totsilizumab in comparison with group of placebo – 90% against 4% (р <0.0001).

After introduction of a totsilizumab there was a bystry decrease in average values of ostrofazovy indicators: S-reactive protein, SOE and serumal amyloid A.

Preclinical these safety. Carcinogenicity: researches on studying of carcinogenicity of a totsilizumab were not conducted. The available preclinical data show a contribution of pleyotropny SILT-6 to progressing of malignant new growths and resistance to apoptosis at various forms of cancer. These data do not assume that treatment totsilizumaby results in essential risk of development and progressing of cancer.

Mutagenicity: standard genotoksichesky tests both in prokaryotic, and in eukaryotic cells were negative.

Influence on fertility: the available preclinical data do not assume influence of analogs of a totsilizumab on fertility. In researches on studying of chronic toxicity at the Javanese macaques and at females or males of mice with insufficiency of SILT-6 of negative influence of a totsilizumab on endocrine or reproductive organs it is not revealed.

Teratogenecity: the direct or mediated adverse influence on pregnancy or pre-natal development at intravenous administration of a totsilizumab to the Javanese macaques on early terms of the gestational period is not revealed.

Other: insignificant increase in cases of a spontaneous abortion / pre-natal death of a fruit was noted at the high level of system cumulative influence (more than by 100 times exceeding that at the person) at introduction of a dose of 50 mg/kg/days in comparison with placebo or smaller level of the entered doses. Frequency of an abortion was within historical control for the Javanese macaques who are contained in bondage; separate cases of an abortion / did not show to pre-natal death any interrelation between these phenomena and a dose or duration of introduction of a totsilizumab.

In spite of the fact that SILT-6, apparently, does not play a crucial role in fetation or immunological regulation of system mother fruit, the interrelation of these phenomena with introduction of a totsilizumab cannot be excluded.

Excretion of a mouse analog of a totsilizumab in milk of the lactating mice was observed.

Use of a mouse analog of a totsilizumab had no toxic effect on juvenile mice. In particular, the growth disorder of a skeleton, immune function and sexual development was not observed.

Pharmacokinetics. Pseudorheumatism. Pharmacokinetic parameters of a totsilizumab do not change eventually. More than dozozavisimy increase in the area under a curve "concentration time" (AUC) and the minimum concentration (Cmin) is noted for doses of 4 and 8 mg/kg each four weeks. The maximum concentration (Cmax) increases in direct ratio to increase in a dose. In an equilibrium state settlement AUC and Cmin were in 2.7 and 6.5 times is higher at a dose of 8 mg/kg in comparison with a dose of 4 mg/kg, respectively.

Indicators of AUC, Cmin and Cmax increase at increase in body weight. At the body weight of ≥100 kg settlement average (± a standard deviation) AUC in an equilibrium state made 55500±14100 mkg x h/ml, Cmin and Cmax of 19.0±12.0 mkg/ml and 269±57 mkg/ml, respectively. As these indicators exceed average values of exposure in population of patients, increase in a dose of drug higher than 800 mg on one infusion at patients with the body weight of ≥100 kg is not recommended (see the section "Route of Administration and Doses").

Polyarticulary juvenile idiopathic arthritis. The following indicators are characteristic of patients with the body weight of ≥30 kg receiving тоцилизумаб in a dose of 8 mg/kg each 4 weeks: settlement average (± a standard deviation) Auc4ned, Cmax and Cmin of a totsilizumab made 29500±8660 mkg x h/ml, 182±37 mkg/ml and 7.49±8.2 mkg/ml, respectively.

With body weight <30 kg receiving тоцилизумаб in a dose of 10 mg/kg each 4 weeks are characteristic of patients the following indicators: settlement average (± a standard deviation) Auc4ned, Cmax and Cmin of a totsilizumab made 23200±6100 mkg x h/ml, 175±32 mkg/ml and 2.35±3.59 mkg/ml, respectively.

The coefficient of cumulation made 1.05 and 1.16 for Auc4ned and 1.43 and 2.22 for Cmin in a dose of 10 mg/kg (for patients with the body weight <30 kg) and 8 mg/kg (for patients weighing ≥30 kg), respectively. Cumulation for Cmax was not observed. 

System juvenile idiopathic arthritis. The following indicators are characteristic: settlement average (± a standard deviation) Auc2ned – 32200±9960 mkg x h/ml, Cmax and Cmin – 245±57.2 mkg/ml and 57.2±23.3 mkg/ml, respectively. Cumulation coefficient for Cmin (12 weeks / 2 week) – 3.2±1.3. Cmin of a totsilizumab was stabilized after the 12th week. Settlement average values of exposure of a totsilizumab did not differ in group of patients with the body weight of ≥30 kg and in group of patients with body weight <30 kg.

Distribution. After intravenous administration тоцилизумаб undergoes two-phase removal from a system blood-groove. At patients with RA distribution volume in the central camera makes 3.5 l, in the peripheral camera – 2.9 l, and distribution volume in an equilibrium state makes 6.4 l.

At children with pYuIA distribution volume in the central camera makes 1.98 l, in the peripheral camera – 2.1 l, and distribution volume in an equilibrium state makes 4.08 l. At children with sYuIA distribution volume in the central camera makes 0.94 l, in the peripheral camera – 1.6 l, and distribution volume in an equilibrium state makes 2.54 l.

Removal. The general clearance of a totsilizumab depends on concentration and represents the sum of linear and nonlinear clearance. The linear clearance makes 12.5 ml/h at patients with RA, children have 5.8 ml/h from pYuIA and 7.1 ml/h at children with sYuIA. The nonlinear clearance depending on concentration has the greatest value at low concentration of a totsilizumab. At higher concentration of a totsilizumab the linear clearance in connection with saturation of a way of nonlinear clearance prevails.

The elimination half-life (t1/2) depends on concentration at RA. At RA once in 4 weeks makes the dependent on concentration seeming t1/2 for a totsilizumab in a dose of 4 mg/kg up to 11 days, and for a totsilizumab in a dose of 8 mg/kg once in 4 weeks – up to 13 days.

At pYuIA t1/2 for a totsilizumab (in a dose of 8 mg/kg for children with the body weight of ≥30 kg and in a dose of 10 mg/kg for children with body weight <30 kg in an equilibrium state) makes up to 16 days.

At sYuIA t1/2 for a totsilizumab (in a dose of 8 mg/kg for children with the body weight of ≥30 kg and in a dose of 12 mg/kg for children with the body weight <30 kg) on the 12th week makes up to 23 days.

Pharmacokinetics at special groups of patients. Patients with a liver failure. The pharmacokinetics of a totsilizumab at patients with a liver failure was not studied.

Patients with a renal failure. Special researches on patients with a renal failure were not conducted. The majority of the sick RA considered in the population pharmacokinetic analysis had a normal function of kidneys or a renal failure of easy severity (clearance of creatinine on Kokrofta-Gault's formula <80 ml/min. and ≥50 ml/min.) which did not influence pharmacokinetics of a totsilizumab. Dose adjustment of a totsilizumab is not required to patients with a renal failure of easy severity.

Floor, race, advanced age. The population pharmacokinetic analysis at adult patients with RA showed that age, sex and race do not influence pharmacokinetics of a totsilizumab. Dose adjustment of a totsilizumab is not required.

Indications to use:

Pseudorheumatism. A pseudorheumatism with an average or high degree of activity at adults both in the form of monotherapy, and in a combination with a methotrexate (MT) and/or with other basic antiinflammatory drugs (BPVP), including for braking radiological the proved destruction of joints.

Polyarticulary juvenile idiopathic arthritis.

Active polyarticulary juvenile idiopathic arthritis at patients at the age of 2 years is also more senior both in the form of monotherapy, and in a combination with MT.

System juvenile idiopathic arthritis.

Active system juvenile idiopathic arthritis at patients at the age of 2 years is also more senior both in the form of monotherapy, and in a combination with MT.

Route of administration and doses:

Standard mode of dosing. The drug Aktemra® has to get divorced the doctor or the nurse of sterile 0.9% chloride sodium solution in aseptic conditions. It is recommended to enter intravenously kapelno during, at least, 1 h.

Pseudorheumatism. Intravenously kapelno in a dose of 8 mg/kg of 1 times in four weeks.
The drug Aktemra® can be used both in monotherapy, and in a combination with MT and/or BPVP.

Increase in a dose over 800 mg on one infusion is not recommended to patients with body weight higher than 100 kg (see the section "Pharmacological Action", the subsection "Pharmacokinetics").

Solution preparation:
1. To calculate the amount of drug necessary for introduction for the patient (at the rate of 0.4 ml on 1 kg of body weight (0.4 ml/kg)).
2. In aseptic conditions from an infusional bottle (package) containing 100 ml of 0.9% of solution of sodium of chloride (solution has to be sterile and depyrogenized) to select the one-time sterile syringe the number of 0.9% of solution of sodium of chloride equal to the amount of the drug Aktemra® calculated for introduction.
3. Other one-time sterile syringe in aseptic conditions from a bottle with the drug Aktemra® to select the calculated amount of drug and to enter it into an infusional bottle (package) from 0.9% chloride sodium solution; as a result the volume of the prepared solution has to be equal 100 ml.
4. For hashing it is accurate to turn a bottle (package) in order to avoid foaming.

Before introduction it is necessary to examine the prepared solution regarding lack of foreign particles or change of coloring.
It is necessary to enter only transparent or opalescent colourless or light yellow solution without visible foreign particles.

 

Increase in activity of "hepatic" enzymes:

Value of an indicator	Treatment correction
Exceeding of VGN * in> 1-3 times	If necessary to carry out dose adjustment of at the same time appointed BPVP. At steady increase in activity of transaminases in this range to lower a drug Aktemra® dose to 4 mg/kg or to interrupt treatment with drug before normalization of indicators of alaninaminotranspherase (ALT) or aspartate aminotransferase (nuclear heating plant). To resume treatment by drug in a dose of 4 mg/kg or 8 mg/kg according to clinical need.
Exceeding of VGN in> 3-5 times	To interrupt treatment with the drug Aktemra® before decrease in an indicator to level less than by 3 times of the exceeding VGN; further to follow recommendations for exceeding of VGN in> 1-3 times (see above). To stop treatment by the drug Aktemra® at the steady increase in an indicator exceeding VGN more than by 3 times (confirmed at a repeated research, see the section "Special Instructions").
Exceeding of VGN more than by 5 times	To stop treatment by the drug Aktemra®.

VGN * - the upper bound of norm

Low absolute number of neutrophils (ANN):

Value of an indicator (number of cells x 109/l)	Treatment correction
ACHN> 1	Not to change a dose.
ACHN 0.5-1	To interrupt treatment with the drug Aktemra®. At increase in an indicator to> 1 x 109/l to resume treatment by drug in a dose of 4 mg/kg and to increase a dose to 8 mg/kg according to clinical need.
ACHN <0.5	To stop treatment by the drug Aktemra®.

Low number of thrombocytes:

Value of an indicator (number of cells x 103/mkl)	Treatment correction
50-100	To interrupt treatment with the drug Aktemra®. At increase in an indicator> 100 x 103/mkl to resume treatment by drug in a dose of 4 mg/kg and to increase a dose to 8 mg/kg according to clinical need.
<50	To stop treatment by the drug Aktemra®.

Polyarticulary juvenile idiopathic arthritis. Intravenously kapelno 1 time in four weeks in a dose:
·        to patients with body weight <30 kg – 10 mg/kg;
·        to patients with the body weight of ≥30 kg – 8 mg/kg.
Change of a dose is possible only in case of permanent change of body weight of the patient. The drug Aktemra® can be used both in monotherapy, and in a combination with MT.

Solution preparation. Patients with the body weight of ≥30 kg:
1. To calculate the amount of drug necessary for introduction for the patient (at the rate of 0.4 ml on 1 kg of body weight (0.4 ml/kg)).
2. In aseptic conditions from an infusional bottle (package) containing 100 ml of 0.9% of solution of sodium of chloride (solution has to be sterile and depyrogenized) to select the one-time sterile syringe the number of 0.9% of solution of sodium of chloride equal to the amount of the drug Aktemra® calculated for introduction.
3. Other one-time sterile syringe in aseptic conditions from a bottle with the drug Aktemra® to select the calculated amount of drug and to enter it into an infusional bottle (package) from 0.9% chloride sodium solution; as a result the volume of the prepared solution has to be equal 100 ml.
4. For hashing it is accurate to turn a bottle (package) in order to avoid foaming.

Patients with body weight <30 kg:
1. To calculate the amount of drug necessary for introduction for the patient (at the rate of 0.5 ml on 1 kg of body weight (0.5 ml/kg)).
2. In aseptic conditions from an infusional bottle (package) containing 50 ml of 0.9% of solution of sodium of chloride (solution has to be sterile and depyrogenized) to select the one-time sterile syringe the number of 0.9% of solution of sodium of chloride equal to the quantity calculated for administration of the drug Aktemra®.
3. Other one-time sterile syringe in aseptic conditions from a bottle with the drug Aktemra® to select the calculated amount of drug and to enter it into an infusional bottle (package) from 0.9% chloride sodium solution; as a result the volume of the prepared solution has to be equal 50 ml.                                   
4. For hashing it is accurate to turn a bottle (package) in order to avoid foaming.

System juvenile idiopathic arthritis. Intravenously kapelno 1 every two weeks in a dose:
·        to patients with body weight <30 kg – 12 mg/kg;
·        to patients with the body weight of ≥30 kg – 8 mg/kg.
Change of a dose is possible only in case of permanent change of body weight of the patient. The drug Aktemra® can be used both in monotherapy, and in a combination with MT.

Solution preparation. Patients with the body weight of ≥30 kg:
1. To calculate the amount of drug necessary for introduction for the patient (at the rate of 0.4 ml on 1 kg of body weight (0.4 ml/kg)).
2. In aseptic conditions from an infusional bottle (package) containing 100 ml of 0.9% of solution of sodium of chloride (solution has to be sterile and depyrogenized) to select the one-time sterile syringe the number of 0.9% of solution of sodium of chloride equal to the amount of the drug Aktemra® calculated for introduction.
3. Other one-time sterile syringe in aseptic conditions from a bottle with the drug Aktemra® to select the calculated amount of drug and to enter it into an infusional bottle (package) from 0.9% chloride sodium solution; as a result the volume of the prepared solution has to be equal 100 ml.
4. For hashing it is accurate to turn a bottle (package) in order to avoid foaming.

Patients with body weight <30 kg:
1. To calculate the amount of drug necessary for introduction for the patient (at the rate of 0.6 ml on 1 kg of body weight (0.6 ml/kg)).
2. In aseptic conditions from an infusional bottle (package) containing 50 ml of 0.9% of solution of sodium of chloride (solution has to be sterile and depyrogenized) to select the one-time sterile syringe the number of 0.9% of solution of sodium of chloride equal to the amount of the drug Aktemra® calculated for introduction.
3. Other one-time sterile syringe in aseptic conditions from a bottle with the drug Aktemra® to select the calculated amount of drug and to enter it into an infusional bottle (package) from 0.9% chloride sodium solution; as a result the volume of the prepared solution has to be equal 50 ml.
4. For hashing it is accurate to turn a bottle (package) in order to avoid foaming.

Before introduction it is necessary to examine the prepared solution regarding lack of foreign particles or change of coloring.

It is necessary to enter only transparent or opalescent colourless or light yellow solution without visible foreign particles.

Recommendations about dose adjustment at change of laboratory indicators at patients with pYuIA and sYuIA. The dose decline of the drug Aktemra® was not studied at patients with pYuIA and sYuIA. Breaks in administration of drug at patients with pYuIA or sYuIA in case of changes of laboratory indicators are recommended in the same situations which are listed above for patients with RA (see also sections "Special Instructions", "With Care"). If necessary it is necessary to change a dose of at the same time accepted MT and/or other accompanying drugs or to stop their reception, and also to take a break in administration of the drug Aktemra® to an explanation of a clinical situation. At patients from pYuIA or sYuIA the decision on the therapy termination has to be made by the drug Aktemra® at emergence of changes in laboratory indicators depending on an individual clinical situation.

Rules of storage of the prepared solution. The prepared infusion solution of the drug Aktemra® physically is also chemically stable in 0.9% chloride sodium solution during 24 h at a temperature of 30 °C.

From the microbiological point of view the prepared solution has to be used immediately.

If drug is not used at once, then time and storage conditions of the prepared solution are responsibility of the user and should not exceed 24 h at a temperature from 2 °C to 8 °C (to store in the refrigerator) and only if preparation of solution was carried out in controlled and validiruyemy aseptic conditions.

The instruction for destruction of unused drug, and also after a period of validity. Hit of medicines together with waste 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.

Dosing in special cases. Elderly patients. Dose adjustment is not required from elderly patients (≥65 years).

Patients with a renal failure. Dose adjustment with a renal failure of easy severity is not required from patients (see the section "Pharmacological Action", the subsection "Pharmokokinetika at Special Groups of Patients"). Use of a totsilizumab for patients with a moderate and heavy renal failure was not studied.

Patients with a liver failure. Safety and efficiency of a totsilizumab at patients with a liver failure was not studied (see the section "Special Instructions").

Features of use:

System juvenile idiopathic arthritis. The syndrome of activation of macrophages is a serious zhizneugrozhayushchy state which can develop at patients with sYuIA. Efficiency and safety of the drug Aktemra® during emergence of a syndrome of activation of macrophages were not studied.

Changes of laboratory indicators. For all indications. Neutropenia: therapy by the drug Aktemra® was associated with higher frequency of development of a neutropenia and was not associated with development of serious infections. It is necessary to show care at purpose of the drug Aktemra® to patients with a neutropenia, i.e. at AChN <2.0 x 109/l. At AChN <0.5 x 109/l treatment by the drug Aktemra® are not recommended.

At RA it is necessary to monitorirovat number of neutrophils in day of performing the 2nd or 3rd infusion, and further according to clinical practice. Recommendations about a drug dosing depending on AChN are presented in the section "Route of Administration and Doses".

At pYuIA and sYuIA the number of neutrophils should be controlled in day of performing the 2nd infusion, and further according to clinical practice (see the section "Route of Administration and Doses").

Thrombocytopenia: therapy by the drug Aktemra® was associated with decrease in number of thrombocytes and was not associated with serious cases of bleedings. It is necessary to be careful at the solution of a question of the beginning of therapy by the drug Aktemra® at number of thrombocytes lower than 100 x 103/mkl. Treatment is not recommended at number of thrombocytes <50 x 103/mkl.

At RA it is necessary to monitorirovat number of thrombocytes in day of performing the 2nd or 3rd infusion, and further according to clinical practice. Recommendations about a drug dosing depending on number of thrombocytes are presented in the section "Route of Administration and Doses".

At pYuIA and sYuIA the number of thrombocytes should be controlled in day of performing the 2nd infusion, and further according to clinical practice (see the section "Route of Administration and Doses").

Increase in activity of "hepatic" transaminases: easy or moderate increase in activity of "hepatic" transaminases without symptoms of a liver failure was observed (see the section "Side effect"). Frequency of emergence of similar changes increased when using the drug Aktemra® together with the drugs possessing a potential hepatotoxic action (for example, MT). It is necessary to be careful at the solution of a question of the beginning of therapy by the drug Aktemra® at patients with an indicator of ALT or nuclear heating plant exceeding VGN more than by 1.5 times. Therapy by the drug Aktemra® is not recommended at the indicator of ALT or nuclear heating plant exceeding VGN more than by 5 times.

At RA it is necessary to monitorirovat ALT and nuclear heating plant in day of performing the 2nd or 3rd infusion, and further according to clinical practice. Recommendations about a drug dosing depending on activity of "hepatic" transaminases are presented in the section "Route of Administration and Doses".

At pYuIA and sYuIA ALT and nuclear Heating Plant it is necessary to control in day of performing the 2nd infusion, and further according to clinical practice.

Change of indicators of lipidic exchange: increase in indicators of lipidic exchange (the general cholesterol, LPNP, triglycerides) was observed.

At RA it is necessary to estimate indicators of lipidic exchange in day of performing the 2nd or 3rd infusion of the drug Aktemra®, and at pYuIA and sYuIA – in day of performing the 3rd, 4th or 5th infusion. When maintaining patients it is necessary to be guided by national recommendations about treatment of a lipidemia.

Features of effect of medicine at the first reception or at its cancellation. Researches on studying of a possibility of the drug Aktemra® to cause dependence were not conducted. Proceeding from the available data, the drug Aktemra® does not possess such action.

Pregnancy and period of breastfeeding. Safety and efficiency of use of the drug Aktemra® at pregnancy are studied insufficiently. Researches did not find the dismorfogenetichesky potential of the drug Aktemra® in monkeys. However at administration of drug in high doses the increased risk of a spontaneous abortion / pre-natal death is found. Value of this information for people is not known (see the section "Pharmacological Action", the subsection "Pharmacodynamics").

It is not necessary to apply тоцилизумаб during pregnancy unless there is an obvious clinical need.

It is unknown whether the drug Aktemra® with breast milk at the person is removed. Despite allocation of endogenous IgG in breast milk, system absorption of drug when breastfeeding is improbable in connection with bystry proteolytic degradation of such proteins in system of digestion.

At making decision on feeding continuation/interruption by a breast or therapy continuation/cancellation totsilizumaby it is necessary to take into account advantage of breastfeeding for the child and advantage of continuation of therapy for mother.

Children. Safety and efficiency of use of a totsilizumab for children are not established, except for system juvenile idiopathic arthritis and polyarticulary juvenile idiopathic arthritis (children up to 2 years were not investigated).

Influence on ability to manage vehicles, mechanisms. Researches on studying of influence of drug on ability to manage vehicles and mechanisms were not conducted. However, considering the fact that at therapy the drug Aktemra® often observed dizziness, the patients experiencing this undesirable reaction should not recommend to manage vehicles and mechanisms until dizziness does not stop.

With care. It is necessary to specify the trade name of drug (Актемра®) in medical documentation of the patient. For all indications. Infections: at the patients receiving immunosuppressants (including the drug Aktemra®) serious cases of developing of infectious diseases were observed (sometimes with a lethal outcome) (see the section "Side effect"). It is not necessary to begin treatment with the drug Aktemra® to patients with active infectious diseases. At development of serious infections therapy by the drug Aktemra® has to be interrupted before elimination of an infection. It is necessary to be careful when using the drug Aktemra® at patients with recurrent infectious diseases in the anamnesis, and also at the associated diseases contributing to development of infections (for example, at a diverticulitis, a diabetes mellitus).

It is necessary to show extra care for the purpose of early detection of serious infectious diseases at patients with RA of average and high activity or at patients from pYuIA or sYuIA receiving biological drugs as signs or symptoms of an acute inflammation can be erased in connection with suppression of reaction of an acute phase. Patients and parents/trustees of children with pYuIA or sYuIA need to be instructed about the immediate address to the doctor at any symptoms testimonial of emergence of an infection, for the purpose of timely diagnosis and purpose of necessary treatment.

Diverticulitis complications: at patients with RA cases of perforation of a diverticulum as diverticulitis complications were reported. It is necessary to be careful at use of the drug Aktemra® for patients with a canker of bodies of the digestive tract (DT) or a diverticulitis in the anamnesis. Patients with the signs which are perhaps indicating the complicated diverticulitis (abdominal pain) have to be immediately inspected for the purpose of early identification of perforation of a GIT.

Tuberculosis: before purpose of the drug Aktemra®, as well as at purpose of other biological drugs for treatment of RA, pYuIA or sYuIA, it is necessary to conduct preliminary survey of patients on existence of latent tuberculosis. At detection of latent tuberculosis it is necessary to conduct a standard course of antimikobakterialny therapy before an initiation of treatment the drug Aktemra®.

Immunization: it is not necessary to carry out immunization by live and live attenuated vaccines along with therapy by the drug Aktemra® as safety of a similar combination is not established. There are no data on secondary transmission of infection from the patients receiving live vaccines to the patients receiving тоцилизумаб. At patients from RA receiving therapy totsilizumabom/MT the answer to a 23-valent pneumococcal polisakharidny vaccine and tetanic anatoxin was comparable to that at the patients receiving monotherapy of MT.

It is recommended that prior to treatment by the drug Aktemra® all patients, especially patients with pYuIA and sYuIA, underwent vaccination according to a national calendar of inoculations. It is necessary to observe an interval (according to the existing recommendations about immunization) at the patients receiving therapy by immunosuppressive drugs between immunization by live vaccines and the beginning of therapy by the drug Aktemra®.

Hypersensitivity reactions: at infusion of the drug Aktemra® serious reactions of hypersensitivity were observed (see the section "Side effect"). At post-marketing use the serious phenomena of hypersensitivity and an anaphylaxis arose at the patients receiving various doses of the drug Aktemra® irrespective of existence of the accompanying therapy for treatment of a pseudorheumatism, premedication and/or reactions of hypersensitivity in the anamnesis. At post-marketing use of the drug Aktemra® for intravenous administration cases from the death were registered. These phenomena arose already during the first infusion of drug (see sections of "Contraindication" and "Side effect").

At intravenous administration of the drug Aktemra® the complex of necessary actions for treatment of possible anaphylactic reaction has to be provided.

At emergence of anaphylactic reaction or other serious reaction of hypersensitivity administration of the drug Aktemra® it is necessary to stop and not to resume immediately therapy by drug further.

Active diseases of a liver and liver failure: therapy by the drug Aktemra®, especially along with MT, can be associated with increase in activity of "hepatic" transaminases therefore it is necessary to show care at patients with an active disease of a liver or a liver failure (see the sections "Use During Pregnancy and During Breastfeeding", "Side effect").

Reactivation of viral infections: at patients from RA receiving therapy by biological drugs cases of reactivation of a viral infection were observed (for example, a viral hepatitis In). The patients who had a positive take at a screening on hepatitis did not join in clinical trials of the drug Aktemra®.

Demyelinating diseases: it is necessary to show extra care for the purpose of early identification of the symptoms which are perhaps indicating development of demyelinating diseases of the central nervous system (CNS). Now ability of a totsilizumab to cause demyelinating diseases of TsNS is not known.

Side effects:

Pseudorheumatism. For the description of frequency of undesirable reactions the following categories are used: very often (≥1/10), it is frequent (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100), is rare (≥1/10000 and <1/1000), is very rare (<1/10000, including separate cases).

The undesirable reactions given below are listed as the clinical importance for the patient.

Table 1. The generalized data on the undesirable reactions registered at the sick RA receiving the drug Aktemra® as monotherapy or in a combination with MT or others BPVP*.

System Body Class	Very often	Often	Infrequently
Infections	upper respiratory tract infections	the infections caused by Herpes simplex of 1 type and Herpes zoster	diverticulitis
From system of digestion		abdominal pains, ulcers of an oral cavity, gastritis	stomatitis, stomach ulcer, perforation of a GIT
From skin and its appendages		rash, itch, urticaria, phlegmon
From a nervous system		headache, dizziness
Changes of laboratory indicators		increase in activity of "hepatic" transaminases, increase in body weight	increase in the general bilirubin
From cardiovascular system		increase in the arterial pressure (AP)
From blood and lymphatic system		leukopenia, neutropenia
From a metabolism		hypercholesterolemia	gipertriglitseridemiya
From an organism in general and reactions in an injection site		peripheral hypostases
From respiratory system		cough, short wind
From an organ of sight		conjunctivitis
From an urinary system			nephrolithiasis
From endocrine system			hypothyroidism
From immune system		hypersensitivity reactions	anaphylactic reactions

* all controlled population - all patients who were taking part in the double blind period of each basic research from the moment of randomization before the first change of the mode of treatment or at achievement of 2 years.
 
The undesirable phenomena at patients with pYuIA were similar observed at patients with RA and sYuIA.

We will compare the profile of safety of a totsilizumab investigated at patients with RRA of an average and high degree of activity who did not receive therapy of MT and therapy by biological drugs earlier with the known profile of safety of a totsilizumab.

Below additional information on separate undesirable reactions is provided.

Infections: the following serious infectious diseases were registered: the pneumonia, phlegmon, infections caused by Herpes zoster, a gastroenteritis, a diverticulitis, sepsis, bacterial arthritis some of them were followed by a lethal outcome. Cases of developing of opportunistic infections were reported.

Perforation of a GIT: mainly cases of perforation of a GIT were reported as a complication of a diverticulitis and included diffuse purulent peritonitis, perforation of lower parts of a GIT, fistula and abscess.

Infusional reactions: episodes of increase in the ABP were undesirable reactions which were most often noted during administration of drug. Undesirable reactions which were noted during 24 h after the end of administration of drug were the headache and reactions from integuments (rash, urticaria). These reactions did not lead to therapy restriction.

Frequency of an anaphylaxis was several times higher at the patients receiving drug in a dose of 4 mg/kg than at the patients receiving drug in a dose of 8 mg/kg. Clinically significant reactions of hypersensitivity caused by administration of the drug Aktemra® and which demanded the treatment termination were noted at 0.3% of patients. These reactions were observed, as a rule, during the period between the second and fifth infusion of the drug Aktemra® (see the section "With Care").

Immunogenicity: antibodies to a totsilizumab were revealed at 1.6% of the inspected patients. At 5 of them clinically significant reactions of hypersensitivity were noted that led to full cancellation of treatment. At 1.1% of patients neutralized antibodies are revealed (see above Table 1).

Polyarticulary juvenile idiopathic arthritis. Infections: the nasopharyngitis and upper respiratory tract infections were the most often found infections. Frequency of heavy infections, and also the infections leading to the temporary termination of use of a totsilizumab is much higher at patients with body weight <30 kg receiving тоцилизумаб in a dose of 10 mg/kg in comparison with patients whose body weight was ≥30 kg receiving тоцилизумаб in a dose of 8 mg/kg.

Infusional reactions: the reactions connected with infusion at patients decided on pYuIA as any phenomenon arising in time or during 24 h after infusion. At 5.9% of the patients receiving тоцилизумаб infusional reactions were noted directly during infusion, at 20.2% of patients infusional reactions were noted within 24 hours after infusion. Undesirable reactions at patients about pYuIA noted during infusion or within 24 hours after infusion, in character did not differ from that, observed at patients with RA and sYuIA (see the section "Side effect").

Immunogenicity: antibodies to a totsilizumab without development of reaction of hypersensitivity were revealed at one patient with body weight <30 kg, the totsilizumab receiving 10 mg/kg and which afterwards stopped treatment.

System juvenile idiopathic arthritis. Generally undesirable reactions at patients with sYuIA in character do not differ from that, observed at patients with RA (see the section "Side effect" above).

Infections: the registered serious infections did not differ from those at patients with RA, except for chicken pox and average otitis.

Infusional reactions: the reactions connected with infusion at patients decided on sYuIA as any phenomenon arising in time or during 24 h after infusion. At the patients receiving тоцилизумаб the undesirable phenomena were: rash, urticaria (the serious phenomenon), diarrhea, discomfort in epigastriums, an arthralgia, a headache, etc.

At <1% of the patients receiving тоцилизумаб registered clinically significant reaction of hypersensitivity connected with therapy and which demanded its cancellation.

Immunogenicity: antibodies to a totsilizumab were revealed at 2 of 112 inspected patients. At one of them hypersensitivity reaction developed that led to treatment cancellation.

Changes from laboratory indicators. Hematologic disturbances. Neutrophils. Pseudorheumatism. Decrease in number of neutrophils is lower 1 x 109/l it was noted at 3.4% of patients to whom the drug Aktemra® was administered in a dose 8 mg/kg in a combination with BPVP, in comparison less than from 0.1% of the patients receiving placebo in a combination with BPVP. Approximately in half of cases decrease in AChN is lower 1 x 109/l arose within 8 weeks after an initiation of treatment. Decrease in number of neutrophils is lower 0.5 x 109/l was reported at 0.3% of the patients receiving the drug Aktemra® in a dose of 8 mg/kg in a combination with BPVP (see the sections "Route of Administration and Doses", "With Care", "Special Instructions").

Is lower than accurate communication between decrease in number of neutrophils 1 x 109/l and development of serious infectious diseases did not note.

Polyarticulary juvenile idiopathic arthritis. At routine monitoring of laboratory indicators decrease in number of neutrophils is lower 1 x 109/l it was noted at 3.7% of the patients receiving the drug Aktemra®.

Communication between decrease in number of neutrophils lower than 1 x 109/l and development of serious infectious diseases was not noted.

System juvenile idiopathic arthritis. At routine monitoring of laboratory indicators within 12 weeks of therapy decrease in number of neutrophils is lower 1 x 109/l arose at 7% of the patients receiving the drug Aktemra® and was absent at the patients receiving placebo.

In the subsequent period of observation decrease in number of neutrophils is lower 1 x 109/l is registered at 15% of the patients receiving the drug Aktemra®.

Is lower than accurate communication between decrease in number of neutrophils 1 x 109/l and development of serious infectious diseases did not note.

Thrombocytes. Pseudorheumatism. Decrease in number of thrombocytes is lower 100 x 103/mkl it was noted at 1.7% of the patients receiving the drug Aktemra® in a dose of 8 mg/kg in a combination with BPVP and was not followed by development of episodes of bleeding.

Polyarticulary juvenile idiopathic arthritis. At routine monitoring of laboratory indicators decrease in number of thrombocytes ≤50 x 103/mkl arose at 1% of the patients receiving the drug Aktemra®. These changes were not followed by development of episodes of bleeding.

System juvenile idiopathic arthritis. At routine monitoring of laboratory indicators within 12 weeks of therapy decrease in number of thrombocytes ≤100 x 103/mkl arose at 1% of patients, in the subsequent period of observation decrease in number of thrombocytes is lower 100 x 103/mkl is registered at 3% of the patients receiving the drug Aktemra®. These changes were not followed by development of episodes of bleeding.

Increase in activity of "hepatic" transaminases. Pseudorheumatism. Accession to monotherapy totsilizumaby the drugs possessing a potential hepatotoxic action (for example, MT), led to increase in frequency of cases of increase in activity of transaminases. Increase in activity of "hepatic" transaminases was not followed by clinically significant increase in concentration of direct bilirubin, and also clinical displays of hepatitis or liver failure. At the patients receiving тоцилизумаб in a dose of 8 mg/kg in a combination with BPVP, the frequency of exceeding of the upper bound of norm of an indirect bilirubin made 6.2%. The Tranzitorny increase in activity of ALT (more than by 3 times the exceeding VGN) observed at adult patients with RRA of an average or high degree of activity (average duration of a disease of ≥6 months) which did not receive therapy of MT earlier had more expressed return tendency to normal values in comparison with population of patients with RA.

Polyarticulary juvenile idiopathic arthritis. At routine monitoring of laboratory indicators increase in activity of ALT or nuclear heating plant by ≥3 times the exceeding VGN is registered at 3.7% and <1% of patients, respectively.

System juvenile idiopathic arthritis. At routine monitoring of laboratory indicators in the 12 weeks period of treatment increase in activity of ALT or nuclear heating plant by ≥3 times the exceeding VGN is registered at 5% and 3% of the patients receiving тоцилизумаб, respectively. In the subsequent period of observation increase in activity of ALT or nuclear heating plant by ≥3 times the exceeding VGN is registered at 12% and 4% of the patients receiving тоцилизумаб, respectively.

Change of indicators of lipidic exchange. Pseudorheumatism. At therapy the drug Aktemra® observed increase in indicators of lipidic exchange (the general cholesterol, triglycerides, LPVP, LPNP). Permanent increase in an indicator of the general cholesterol> 6.2 mmol/l (240 mg/dl) was observed at 24% of patients, and permanent increase in an indicator of LPNP of ≥4.1 mmol/l (160 mg/dl) – at 15% of patients. At most of patients the index of an aterogennost did not raise, and increase in concentration of the general cholesterol korrigirovatsya effectively by hypolipidemic drugs.

Polyarticulary juvenile idiopathic arthritis. At routine monitoring of laboratory indicators increase in an indicator of the general cholesterol> 1.5khvgn - 2hVGN it was noted at one patient (0.5%) receiving the drug Aktemra®. Increase in an indicator of LPNP> 1.5khvgn - 2hVGN was noted only at one patient (0.5%) receiving the drug Aktemra®.

System juvenile idiopathic arthritis. Increase in an indicator of the general cholesterol> 1.5khvgn - 2hVGN arose at 1.5% of the patients receiving the drug Aktemra®. Increase in an indicator of LPNP> 1.5khvgn - 2hVGN arose at 1.9% of the patients receiving the drug Aktemra®.

Post-marketing observation. The profile of safety of drug at post-marketing use will be coordinated with data of clinical trials, except for the cases of development of a fatal anaphylaxis registered at drug Aktemra® use (see sections of "Contraindication", "With Care"). During post-marketing use Stephens-Johnson's syndrome was observed.

Interaction with other medicines:

The population pharmacokinetic analysis of clinical trials did not reveal any impact of MT, non-steroidal anti-inflammatory drugs or glucocorticosteroids on clearance of a totsilizumab.

Pharmacokinetic parameters of a totsilizumab remain invariable at simultaneous use of other drugs for treatment of a pseudorheumatism (such as antimalarial drugs (chlorquinine and its derivatives), immunosuppressants (Azathioprinum, лефлуномид), folic acid and its derivatives, cyclooxygenase-2 inhibitors (целекоксиб) and analgetics (paracetamol, трамадол, codeine and their derivatives)).

Simultaneous single introduction of a totsilizumab in a dose of 10 mg/kg and MT in a dose of 10-25 mg once a week did not exert clinically significant impact on exposure of MT.

Researches on studying of the combined use of a totsilizumab with other biological BPVP were not conducted.

As the expression of hepatic isoenzymes of CYP450 is suppressed under the influence of cytokines (for example, SILT-6 which stimulates a chronic inflammation), when performing therapy with the means inhibiting effect of cytokines (for example, тоцилизумаб), the expression of isoenzymes of CYP450 can be broken.

In the researches in vitro conducted on culture of hepatocytes of the person it was shown that SILT-6 causes decrease in an expression of isoenzymes of CYP1A2, CYP2C9, CYP2C19 and CYP3A4. Use of a totsilizumab normalizes an expression of these isoenzymes.

Influence of the drug Aktemra® on CYP isoenzymes (except CYP2C19 and CYP2D6) has clinical value for the drugs which are CYP450 substrates with a narrow therapeutic index and/or for which doses are selected individually.

At patients with RA concentration of a simvastatin (CYP3A4 substrate) in 1 week after single introduction of a totsilizumab decreased by 57%, i.e. healthy volunteers had a little raised or similar that.

At the beginning or at end of a course of therapy by the drug Aktemra® it is necessary to watch carefully the patients receiving medicines in individually picked up doses and which are metabolized by means of isoenzymes of CYP450 3A4, 1A2 or 2C9 (for example, аторвастатин, blockers of "slow" calcium channels, theophylline, warfarin, Phenytoinum, cyclosporine or benzodiazepines). Ensuring therapeutic effect of these drugs perhaps will require increase in their dose. Considering long t1/2 of the drug Aktemra®, its action on activity of CYP450 of enzymes can remain within several weeks after the therapy termination.

Contraindications:

Hypersensitivity to a totsilizumab, any component of drug in the anamnesis; active infectious diseases (including tuberculosis).

Children's age up to 2 years for patients with polyarticulary juvenile idiopathic arthritis and system juvenile idiopathic arthritis.

Children's age up to 18 years for patients with a pseudorheumatism.

Combination with inhibitors the FNO-alpha or use within 1 month after ANTI-FNO'S treatment by antibodies.

Overdose:

Available data on overdose of the drug Aktemra® are limited. In one case of inadvertent overdose of drug in a dose of 40 mg/kg at the patient with a multiple myeloma of undesirable reactions it is noted. Also serious undesirable reactions at healthy volunteers who received once the drug Aktemra® in a dose to 28 mg/kg were not noted though the neutropenia demanding a dose decline was observed.

Storage conditions:

Period of validity 2 years 6 months. 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. Period of validity. 2 years 6 months. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for infusions of 20 mg/ml. On 4 ml (80 mg / 4 ml), 10 ml (200 mg / 10 ml) or 20 ml (400 mg / 20 ml) drug in the bottles made of colourless glass (a hydrolytic class 1 EF), corked by a cover from butyl rubber, which are pressed out by aluminum caps and closed by plastic covers; color of a cap and cover corresponds to color which allocated a drug dosage on the label of a bottle and on a pack. 1 or 4 bottles together with the application instruction place in a cardboard pack with cardboard inserts (partitions) inside. On a pack there is an opening control.

Packaging on JSC Pharmstandart-UFAVITA: 1 or 4 bottles place in the plastic pallet or in a cardboard insert which together with the instruction on a medical use is placed in a pack from a cardboard import.

For the purpose of control of the first opening on a pack paste self-adhesive round stickers with a text "opening control".