Actemra® (Actemra®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTocilizumabTocilizumab
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  • Actemra®
    concentrate d / infusion 
    Hoffmann-La Roche Ltd.     Switzerland
  • Actemra®
    solution PC 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbspconcentrate for solution for infusion
    Composition:

    1 ml of the preparation contains:

    active substance: tocilizumab - 20 mg;

    Excipients: polysorbate 80 - 0.5 mg, sucrose - 50.0 mg, sodium hydrophosphate dodecahydrate - q.s., sodium dihydrogen phosphate dihydrate - q.s., water for injections - q.s.

    Description:Transparent or opalescent colorless or light yellow liquid.
    Pharmacotherapeutic group:Antibodies monoclonal
    ATX: & nbsp

    L.04.A.C.07   Tocilizumab

    Pharmacodynamics:

    Mechanism of action

    Tocilizumab is a recombinant humanized monoclonal antibody to the human interleukin-6 receptor (IL-6) from a subclass of immunoglobulins IgG1. Tocilizumab selectively binds and inhibits both soluble and membrane IL-6 receptors (sIL-6R and mIL-6R). IL-6 is a multifunctional cytokine produced by various types of cells and participates in paracrine regulation, systemic physiological and pathological processes such as stimulation of secretion Ig, activation of T cells, stimulation of the production of acute phase proteins in the liver, and stimulation of hematopoiesis. IL-6 is involved in the pathogenesis of various diseases, including inflammatory diseases, osteoporosis and neoplasms.

    It is impossible to exclude the possibility of a negative effect of tocilizumab on antitumor and anti-infection protection of the body. The role of inhibition of the IL-6 receptor in the development of tumors is not known.

    Clinical efficacy in rheumatoid arthritis (RA)

    The effectiveness of the drug in patients who received tocilizumab both in monotherapy and in combination with methotrexate or basic anti-inflammatory drugs (DMAP), did not depend on the presence or absence of rheumatoid factor, age, sex, race, number of previous courses of treatment or stage of the disease. The response to therapy arose quickly (already in the second week), further intensified and persisted for more than 3 years in ongoing open expanded studies. In patients who received tocilizumab in a dose of 8 mg / kg, significantly reduced the index of disease activity on a scale DAS28 compared with patients receiving placebo + DMARD. Number of patients who achieved clinical remission (DAS28 <2.6) at week 24, was significantly higher in the treatment group of tocilizumab (28-34%) than in the control group (1-12%). By the 52nd week of therapy, the number of patients who reached DAS28 <2.6, increases to 47% compared with 33% at 24 weeks of therapy.

    A good or satisfactory response to the criteria EULAR was more common in patients who received tocilizumab, than those receiving placebo + DMARD.

    After 2 years of therapy with tocilizumab / MT, 14% of patients had a significant clinical response (AKR 70 persisted for 24 weeks or more).

    Radiographic evaluation

    In 83% of patients treated with tocilizumab / MT during the year, there was no progression of joint destruction (the change in the total Sharpe index was zero or less), compared with 67% of patients receiving placebo / MT. This result persisted for 2 years of therapy. In 93% of patients, there was no progression of joint destruction between 52 and 104 weeks of therapy.

    Quality of life indicators

    In patients who received tocilizumab in a dose of 8 mg / kg (monotherapy or in combination with DMARD), compared with those who received MT / DMAP, there was a clinically significant improvement in functional activity (by index HAQ-DI), decrease in fatigue (on the scale of functional evaluation of therapy of chronic diseases by fatigue index FACIT-Fatigue), and also improvement of both physical and mental health indicators according to the questionnaire SF-36.

    Laboratory indicators

    After the administration of tocilizumab, the average values ​​of acute phase parameters, C-reactive protein, ESR and serum amyloid A, a decrease in the number of platelets within the normal range, and an increase in hemoglobin (Hb), which was most pronounced in patients with chronic anemia associated with with RA.

    Clinical efficacy in patients with early rheumatoid arthritis (PPA) who had not previously received MT

    With the use of TOCILIZUMAB in monotherapy at a dose of 8 mg / kg and TOCILIZUMAB at a dose of 4 or 8 mg / kg every 4 weeks in combination with MT, the disease activity index on a scale DAS28 significantly reduced in the groups receiving tocilizumab in a dose of 8 mg / kg, compared with patients receiving monotherapy MT. Number of patients who achieved clinical remission (DAS28 <2.6) at 24 weeks, significantly more in the groups receiving tocilizumab (38.7-44.8%), compared with the MT (15%) monotherapy group. By week 52, the number of patients who reached DAS28 <2.6 in treatment groups with tocilizumab, increased to 39.4-49% compared with 19.5% in the MT monotherapy group.The number of patients who achieved the response of AKP to 20, 50, 70 was also significantly higher in the groups of therapy with tocilizumab (70.2-74.5%, 47.6-56.9%, 30.1-38.6% at 24 weeks and 63-67.2%, 49.3-55.9%, 36- 43.1% at week 52, respectively) compared with the MT monotherapy group (65.2%, 43.2%, 25.4% at 24 weeks and 57.1%, 40.8%, 28.9% at 52 weeks, respectively).

    Radiographic evaluation

    The lack of progression of joint destruction (the change in the total Sharpe index is zero or less) is observed in 82-83% of patients who received tocilizumab in a dose of 8 mg / kg as monotherapy or in combination with MT, compared with 73% of patients in the MT monotherapy group.

    Quality of life indicators

    Clinically significant improvement in functional activity by index HAQ-DI observed in patients who received tocilizumab in a dose of 8 mg / kg as a monotherapy or combination with MT, compared with those who received monotherapy MT. When monotherapy with tocilizumab (at a dose of 8 mg / kg intravenously every 4 weeks in patients with RA, with MT intolerance or in case of inexpediency of continuation of MT therapy (including an inadequate response to MT therapy)) there was a more pronounced statistically significant decrease in the activity of the disease on a scale DAS28 compared with monotherapy with adalimumab (40 mg subcutaneously every 2 weeks). The number of patients who responded to therapy with indicators DAS28 <2.6 and DAS28 <3.2, was greater with tocilizumab than with adalimumab (39.9% versus 10.5% and 51.5% versus 19.8%, respectively). The responses of AKP 20, 50, 70 were observed in 65%, 47.2%, 32.5% of patients receiving tocilizumab, compared with 49.4%, 27.8%, 17.9% of patients who received adalimumab.

    Clinical efficacy in polyarticular juvenile idiopathic arthritis (pUIA)

    The responses of AKP 30, 50, 70, 90 were obtained in 89.4%, 83.0%, 62.2% and 26.1% of patients, respectively. The proportion of patients with AQR response of 30, 50, 70 at 40 weeks of therapy relative to the indices at the beginning of therapy was 74.4%, 73.2% and 64.6%, respectively.

    Clinical efficacy in systemic juvenile idiopathic arthritis CJUIA)

    The efficacy of tocilizumab for the treatment of active SUIA has been studied in a 12-week, randomized, double-blind, placebo-controlled study period with 2 parallel groups. At week 12, the proportion of patients who achieved an ACR response of 30, 50, 70, 90 with JIA was also greater in the TOCILIZUMAB group than in the placebo group: 90.7% versus 24.3%, 85.3% vs. 10.8%, 70.7% vs. 8.1% 37.3% against 5.4%, respectively (p <0.0001). The response to therapy persisted in the open extended period of the study.

    System Effects

    In 85% of patients who had a fever initially, fever was absent after 12 weeks of therapy with tocylizumab, compared with 21% of patients receiving placebo (p <0.0001). In addition, 64% of patients who had a rash initially had no rash after 12 weeks of therapy with tocylizumab, compared to 11% of patients receiving placebo (p = 0.0008). There was a significant decrease in the intensity of the pain syndrome in the treatment group with TOCILIZUMAB compared with placebo at week 12. The adjusted mean change in the pain score from the visual analogue scale (VAS) after 12 weeks of therapy with tocilizumab was 41 points (0 to 100 points) compared to 1 point in patients receiving placebo (p <0.0001). Systemic effects persisted in the ongoing open extended study period.

    Reducing the dose of glucocorticosteroids

    In 8 out of 31 patients in the placebo group and 48 out of 70 patients in the tocilizumab group who received glucocorticosteroids initially, AKR 70 was observed with JIA at 6 or 8 weeks, which reduced the dose of glucocorticosteroids. At the same time, 24% of patients in the group of tocilizumab and 3% of patients in the placebo group were ableto reduce the dose of glucocorticosteroids by at least 20% without a subsequent reduction in the frequency of response according to the criteria of AKP 30 with JIA (according to the criteria of the American College of Rheumatology, AKP) or the occurrence of systemic manifestations by week 12 (p = 0.028). A decrease in the dose of glucocorticosteroids continued, with 44 patients not receiving glucocorticosteroids at week 44, and the responses to AQR were unchanged.

    Quality of life indicators

    At week 12, the proportion of patients in the tocilizumab group demonstrating a minimal clinically significant improvement in the indicator score CHAQ-DI (defined as a decrease in the individual total score by> 0.13) was significantly higher than the proportion of patients in the placebo group - 77% versus 19%, respectively (p <0.0001). The answers were preserved in the ongoing open extended period of the study.

    Laboratory indicators

    Initially, in 67% of patients in the tocilizumab group, the Hb content was below the normal range. In 80% of these patients at week 12 there was an increase in Hb within the normal range, compared with 7% of patients in the placebo group (p <0.0001). In 88% of patients in the tocilizumab group who initially had a lower Hb content, their level increased by> 10 g / L by week 6, in the placebo group, the incidence rate was 3% (p<0,0001).

    The proportion of patients with baseline thrombocytosis who had a normal platelet count at week 12 was higher in the tocilizumab group than in the placebo group, 90% versus 4% (p<0,0001).

    After the administration of tocilizumab, the average values ​​of acute phase parameters rapidly decreased: C-reactive protein, ESR and serum amyloid A.

    Preclinical safety data

    Carcinogenicity: studies to study the carcinogenicity of tocilizumab were not conducted. The available preclinical data demonstrate the contribution of pleiotropic IL-6 to the progression of malignant neoplasms and resistance to apoptosis in various forms of cancer. These data do not suggest that treatment with TOCILIZUMAB leads to a significant risk of developing and progressing cancer.

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

    Influence on fertility: the available preclinical data do not imply the effect of analogues of tocilizumab on fertility. In studies on the study of chronic toxicity in Javanica monkeys and in female or male mice with IL-6 deficiency,Tocilizumab to the endocrine or reproductive organs was not detected.

    Teratogenicity: There was no direct or indirect adverse effect on pregnancy or intrauterine development with intravenous administration of tocilizumab to Javanese macaques in the early stages of the gestational period.

    Other: There was a slight increase in spontaneous miscarriage / intrauterine death of the fetus with a high level of systemic cumulative exposure (more than 100 times greater than that of humans) with a dose of 50 mg / kg / day compared with placebo or a lower level of doses administered. The incidence of miscarriage was within the historical control for Javanese macaques kept in captivity; individual miscarriages / fetal deaths did not show any relationship between these phenomena and the dose or duration of administration of tocilizumab. Despite the fact that IL-6 does not seem to play a decisive role in fetal development or immunological regulation of the mother-fetus system, the relationship of these phenomena with the administration of tocilizumab can not be ruled out.

    Excretion of the mouse analogue of tocilizumab in the milk of lactating mice was observed.The use of a mouse analogue of tocilizumab did not have a toxic effect on juvenile mice. In particular, there was no disturbance in the growth of the skeleton, immune function and sexual development.

    Pharmacokinetics:

    Rheumatoid arthritis

    The pharmacokinetic parameters of tocilizumab do not change with time. More than a dose-dependent increase in the area under the concentration-time curve (AUC) and minimum concentration (Cmin) is indicated for doses of 4 and 8 mg / kg every four weeks. The maximum concentration (CmOh) increases in direct proportion to the increase in dose. In the equilibrium state, the calculated AUC and Cmin were 2.7 and 6.5 times higher at a dose of 8 mg / kg compared to a dose of 4 mg / kg, respectively.

    Indicators AUC, FROMmin and CmOh increase with increasing body weight. With body weight ≥100 kg calculated mean (± standard deviation) AUC in the equilibrium state was 55500±14100 mcg x h / ml, Cmin and CmOh 19.0±12.0 μg / ml and 269±57 μg / ml, respectively. Since these values ​​exceed the average exposure values ​​in the patient population, it is not recommended to increase the dose of the drug above 800 mg per infusion in patients with body weight ≥100 kg (see section "Method of administration and dose") /

    Polyarticular Juvenile Idiopathic Arthritis

    For patients with body weight ≥30 kg receiving tocilizumab in a dose 8 mg / kg every 4 weeks, characterized by the following indicators: the estimated average (± standard deviation) A UFROM4 weeks,

    Cmin and CmOh tocilizumab was 29500±8660 μg x h / ml, 182±37 μg / ml and 7.49±8.2 μg / ml, respectively.

    For patients with body weight <30 kg receiving tocilizumab in a dose 10 mg / kg every 4 weeks, the following indicators are characteristic: the calculated mean (± standard deviation) A UFROM4 weeks,

    Cmin and CmOh tocilizumab was 23200±6100 μg x h / ml, 175±32 μg / ml and 2.35±3.59 μg / ml, respectively.

    The cumulative coefficient was 1.05 and 1.16 for A UFROM4 weeks and 1.43 and 2.22 for Cmin in a dose of 10 mg / kg (for patients with a body weight <30 kg) and 8 mg / kg (for patients with a mass> 30 kg), respectively. Cumulation for FROMmOh was not observed.

    Systemic juvenile idiopathic arthritis

    The following indicators are characteristic: the calculated mean (± standard deviation) AUC2week - 32200 ± 9960 μg x h / ml, CmOh and Cmin - 245 ± 57.2 μg / ml and 57.2 ± 23.3 μg / ml, respectively. The cumulative coefficient for Cmin (12 weeks / 2 weeks) - 3.2 ± 1.3. Cmin TOCILIZUMAB stabilized after 12 weeks.The estimated mean exposure indices of tocilizumab did not differ in the group of patients with body weight ≥30 kg and in the group of patients with a body weight <30 kg.

    Distribution

    After intravenous administration tocilizumab undergoes a two-phase excretion from the systemic blood flow. In patients with RA, the volume of distribution in the central chamber is 3.5 liters, in the peripheral chamber it is 2.9 liters, and the volume of distribution in the equilibrium state is 6.4 liters.

    In children with pUIA, the volume of distribution in the central chamber is 1.98 liters, in the peripheral chamber 2.1 liters, and the volume of distribution in the equilibrium state is 4.08 liters. In children with SUIA, the volume of distribution in the central chamber is 0.94 liters, in the peripheral chamber 1.6 liters, and the volume of distribution in the equilibrium state is 2.54 liters.

    Excretion

    The total clearance of tocilizumab depends on the concentration and is the sum of the linear and non-linear clearance. The linear clearance is 12.5 ml / h in patients with RA, 5.8 ml / h in children with pUIA and 7.1 ml / h in children with SJUA. Non-linear clearance, depending on the concentration, has the greatest value at low concentrations of tocilizumab. At higher concentrations of tocilizumab, linear clearance predominates due to saturation of the nonlinear clearance pathway.

    Half-life (t1/2) depends on the concentration of RA. In RA, the concentration-dependent apparent t1/2 for tocilizumab at a dose of 4 mg / kg once every 4 weeks is up to 11 days, and for tocilizumab at a dose of 8 mg / kg once every 4 weeks - up to 13 days. With pUIA t1/2 for tocilizumab (at a dose of 8 mg / kg for children with a body weight> 30 kg and at a dose of 10 mg / kg for children with a body weight <30 kg in equilibrium) is up to 16 days. With SJUIA t1/2 for tocilizumab (at a dose of 8 mg / kg for children with a body weight> 30 kg and at a dose of 12 mg / kg for children weighing <30 kg) at week 12 is up to 23 days.

    Pharmacokinetics in specific patient groups

    Patients with hepatic insufficiency

    The pharmacokinetics of tocilizumab in patients with hepatic impairment have not been studied.

    Patients with renal insufficiency

    Special studies on patients with kidney failure have not been conducted. Most RA patients considered in the population pharmacokinetic analysis had a normal renal function or a mild kidney function disorder (creatinine clearance by Cockcroft-Gault formula <80 ml / min and ≥50 ml / min), which did not affect the pharmacokinetics of tocilizumab. Correction of the dose of tocilizumab to patients with impaired renal function of mild severity is not required.

    Sex, race, advanced age

    Population pharmacokinetic analysis in adult patients with RA showed that age, sex and race do not affect the pharmacokinetics of tocilizumab. Correction of the dose of tocilizumab is not required.

    Indications:

    Rheumatoid arthritis

    Rheumatoid arthritis with moderate to high activity in adults both in monotherapy and in combination with methotrexate (MT) and / or with other basic anti-inflammatory drugs (CPAP), including for inhibition of radiological evidence of joint destruction.

    Polyarticular Juvenile Idiopathic Arthritis

    Active polyarticular juvenile idiopathic arthritis in patients aged 2 years and older both in monotherapy and in combination with MT.

    Systemic Juvenile Idiopathic Arthritis

    Active systemic juvenile idiopathic arthritis in patients aged 2 years and older both in monotherapy and in combination with MT.

    Contraindications:
    Hypersensitivity to tocilizumab, any component of the drug in history; active infectious diseases (including tuberculosis).
    Children under 2 years old for patients with polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis. Children under 18 years of age for patients with rheumatoid arthritis.
    Combination with TNF-alpha inhibitors or the use of anti-TNF antibodies for 1 month after treatment.
    Carefully:

    In the patient's medical records, the trade name of the drug (Actemra®) should be indicated.

    For all indications

    Infections: in patients receiving immunosuppressants (including the drug Actemra®), serious cases of infectious diseases (sometimes with a lethal outcome) were observed (see the "Side effect" section). Do not begin treatment with the drug Actemra® to patients with active infectious diseases. With the development of serious infections, therapy with Actemra® should be discontinued until infection is eliminated. Care should be taken when using the drug Actemra® in patients with recurrent infectious diseases in the anamnesis, as well as with concomitant diseases predisposing to the development of infections (for example, with diverticulitis, diabetes mellitus).

    Care should be taken with a view to early detection of serious infectious diseases in patients with moderate and high activity RA or in patients with pYuIA or SJIIA receiving biological agents,because the signs or symptoms of acute inflammation can be erased in connection with the suppression of the reaction of the acute phase. Patients and parents / guardians of children with pYuIA or SJUIA should be instructed to seek immediate medical attention for any symptoms that indicate infection, in order to timely diagnose and prescribe the necessary treatment.

    Complications of diverticulitis: patients with RA reported cases of perforation of the diverticulum as a complication of diverticulitis. Caution should be used when using the drug Actemra® in patients with ulcerative lesions of the gastrointestinal tract (GI tract) or diverticulitis in the anamnesis. Patients with signs possibly indicating a complicated diverticulitis (abdominal pain) should be immediately examined for the purpose of early detection of gastrointestinal perforation.

    Tuberculosis: prior to the appointment of the drug Actemra®, as with the appointment of other biological agents for the treatment of RA, PNIA or SJUIA, a preliminary examination of patients for the presence of latent tuberculosis should be conducted. When detecting latent tuberculosis, a standard course of antimycobacterial therapy should be performed before starting treatment with Actemra®.

    Immunization: It should not be immunized with live and live attenuated vaccines concurrently with therapy with Actemra®, since the safety of such a combination is not established. There is no data on secondary transmission of infection from patients receiving live vaccines to patients receiving tocilizumab. In patients with RA receiving treatment with tocilizumab / MT, the response to the 23-valent pneumococcal polysaccharide vaccine and tetanus toxoid was comparable to that of patients receiving MT monotherapy.

    It is recommended that before the initiation of treatment with Actemra®, all patients, especially patients with pYuIA and SJUIA, are vaccinated in accordance with the national vaccination calendar. The interval (in accordance with current immunization recommendations) in patients receiving immunosuppressive therapy should be observed between immunization with live vaccines and initiation of therapy with Actemra®.

    Hypersensitivity reactions: during the infusion of the drug Actemra, severe hypersensitivity reactions were observed (see the "Side effect" section). In the post-marketing application, severe hypersensitivity and anaphylaxis occurred in patients,received different doses of Actemra® regardless of the presence of concomitant therapy for the treatment of rheumatoid arthritis, premedication and / or hypersensitivity reactions in the anamnesis. In the postmarketing use of the drug Actemra® for intravenous administration, fatal cases have been reported. These phenomena occurred already during the first infusion of the drug (see the sections "Contraindications" and "Side effect").

    With the intravenous administration of the drug Actemra®, a set of necessary measures should be envisaged to treat a possible anaphylactic reaction.

    If an anaphylactic reaction or other serious hypersensitivity reaction occurs, the administration of Actemra® should be stopped immediately and the drug should not be reopened.

    Active liver disease and liver failure: therapy with Actemra®, especially simultaneously with MT, may be associated with an increase in the activity of "liver" transaminases, so caution should be exercised in patients with active liver disease or liver failure (see.sections "Application during pregnancy and during breastfeeding", "Side effect").

    Reactivation of viral infections: In patients with RA who received therapy with biological agents, cases of reactivation of a viral infection (for example, viral hepatitis B) were observed. Patients who had a positive screening test for hepatitis were not included in the clinical trials of Actemra®.

    Demyelinating diseases: care should be taken with a view to early detection of symptoms, possibly indicating the development of demyelinating diseases of the central nervous system (CNS). At present, the ability of TOCILIZUMAB to cause a demyelinating disease of the CNS is not known.

    Pregnancy and lactation:

    Pregnancy and the period of breastfeeding

    The safety and effectiveness of the use of the drug Actemra® during pregnancy have not been adequately studied. Studies in monkeys have not detected a dysmorphogenetic potential of the drug Actemra®. However, when the drug was administered in high doses, an increased risk of spontaneous miscarriage / intrauterine death was detected. The meaning of this information for people is not known (see.section "Pharmacological action", subsection "Pharmacodynamics").

    Do not use tocilizumab during pregnancy, except when there is an obvious clinical need.

    It is not known whether the drug Actemra® with human breast milk. Despite the isolation of endogenous IgG in breast milk, systemic absorption of the drug during breastfeeding is unlikely in connection with the rapid proteolytic degradation of such proteins in the digestive system.

    When deciding whether to continue / interrupt breastfeeding or continue / cancel therapy with Tocilizumab, the benefits of breastfeeding for the baby and the benefit of continuing therapy for the mother should be taken into account.

    Children

    The safety and effectiveness of the use of tocilizumab in children have not been established, except for systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis (children under 2 years old have not been studied).

    Dosing and Administration:

    Standard dosing regimen

    The drug Actemra® should be diluted by a doctor or nurse sterile

    - 9% solution of sodium chloride in aseptic conditions.It is recommended to administer intravenously drip for at least 1 hour.

    Rheumatoid arthritis

    Intravenously drip in a dose of 8 mg / kg once every four weeks.

    The drug Actemra® can be used both in monotherapy, and in combination with MT and / or DPO.

    Not recommended increasing the dose above 800 mg per infusion patients weighing more than 100 kg (see. The section "Pharmacological effect", subsection "Pharmacokinetics").

    Preparation of the solution

    - Calculate the amount of preparation needed for administration to the patient (0.4 ml per 1 kg of body weight (0.4 ml / kg)).

    - Under aseptic conditions, from an infusion bottle (package) containing 100 ml of 0.9% sodium chloride solution (the solution should be sterile and pyrogen-free) to select the number of disposable sterile syringe 0.9% sodium chloride solution equal to the calculated injection quantity Aktemra® preparation.

    - Another disposable sterile syringe aseptically from the vial with the drug Aktemra® away calculated amount of formulation and introduce it into the infusion bottle (package) with 0.9% sodium chloride solution; as a result, the volume of the prepared solution should be equal to 100 ml.

    4.For mixing, gently flip the vial (packet) to avoid foaming.

    Before introduction, it is necessary to inspect the prepared solution for the absence of foreign particles or discoloration.

    It is necessary to introduce only a transparent or opalescent colorless or light yellow solution without visible foreign particles.

    Recommendations for correcting the dose when changing laboratory indicators (see section "Special instructions").

    Increased activity of "liver" enzymes:

    Indicator value

    Correction of treatment

    Excess of VGN * in> 1-3 times

    If necessary, adjust the dose of the concomitant DMAP.

    With a stable increase in the activity of transaminases in this range, reduce the dose of Actemra® to 4 mg / kg or interrupt treatment with the drug before normalizing the parameters of alanine aminotransferase (ALT) or aspartate aminotransferase (ACT).

    Resume drug treatment at a dose of 4 mg / kg or 8 mg / kg according to clinical need.

    Exceeding VGN in> 3-5 times

    Abort treatment with Actemra® before the decrease to less than 3 times that of UHN; further follow the recommendations for exceeding the IGN> 1-3 times (see Fig.above).

    Stop treatment with the drug Actemra® with a steady increase in the index, exceeding the VGN by more than 3 times (confirmed during the re-examination, see the section "Special instructions").

    Excess of VGN more than 5 times

    Discontinue treatment with Actemra®.

    VGN * - the upper limit of the norm

    Low absolute number of neutrophils (ASC):

    Indicator value

    Correction of treatment


    (number of cells x 109/ l)



    ASC> 1

    Do not change the dose.


    ASC 0.5-1

    Discontinue treatment with Actemra®. If the index is increased to> 1 x 109 / l, resume treatment with the drug at a dose of 4 mg / kg and increase the dose to 8 mg / kg according to the clinical need.


    АЧН <0.5

    Discontinue treatment with Actemra®.


    Low platelet count:

    The value of the indicator (the number of cells x 103/ μl)

    Correction of treatment

    50-100

    Discontinue treatment with Actemra®.

    With an increase of> 100 x 10 / μL, resume treatment with the drug at a dose of 4 mg / kg and increase the dose to 8 mg / kg according to the clinical need.

    <50

    Discontinue treatment with Actemra®.




    Polyarticular Juvenile Idiopathic Arthritis

    Intravenously drip once every four weeks in a dose:

    - patients with a body weight <30 kg - 10 mg / kg;

    - patients with body weight ≥30 kg - 8 mg / kg.

    A dose change is possible only in the case of a persistent change in the patient's body weight. The drug Actemra® can be used both in monotherapy and in combination with MT.

    Preparation of the solution

    Patients with body weight ≥30 kg

    - Calculate the amount of preparation needed for administration to the patient (0.4 ml per 1 kg of body weight (0.4 ml / kg)).

    - Under aseptic conditions, from an infusion bottle (package) containing 100 ml of 0.9% sodium chloride solution (the solution should be sterile and pyrogen-free) to select the number of disposable sterile syringe 0.9% sodium chloride solution equal to the calculated injection quantity Aktemra® preparation.

    Another single-use sterile syringe in aseptic conditions from a vial of Actemra® is to take the calculated amount of the drug and insert it into the infusion bottle (bag) with 0.9% sodium chloride solution; as a result, the volume of the prepared solution should be equal to 100 ml.

    4. For mixing, gently flip the vial (sachet) to prevent froth Patients with a body weight <30 kg

    - Calculate the amount of preparation needed for administration to the patient (0.5 ml per 1 kg of body weight (0.5 ml / kg)).

    - In aseptic conditions from the infusion bottle (package) containing 50 ml of 0.9% sodium chloride solution (the solution must be sterile and pyrogen-free), take a 0.9% sodium chloride solution equal to the amount calculated for the administration of Actemra® with a disposable sterile syringe.

    - Another single-use sterile syringe in aseptic conditions from a vial of Actemra® is to take the calculated amount of the drug and insert it into the infusion bottle (bag) with 0.9% sodium chloride solution; as a result, the volume of the prepared solution should be equal to 50 ml.

    - For mixing, gently flip the vial (sachet) to prevent foaming.

    Systemic juvenile idiopathic arthritis Intravenously drip once every two weeks in a dose:

    - patients with a body weight <30 kg - 12 mg / kg;

    - patients with a body weight> 30 kg - 8 mg / kg.

    A change in the dose is possible only in the event of a persistent change in the patient's body weight. The drug Actemra® can be used both in monotherapy and in combination with MT.

    Preparation of the solution

    Patients with body weight ≥30 kg

    1. Calculate the amount of preparation needed for administration to the patient (0.4 ml per 1 kg of body weight (0.4 ml / kg)).

    2. Under aseptic conditions, from an infusion bottle (package) containing 100 ml of 0.9% sodium chloride solution (the solution should be sterile and pyrogen-free) to select the number of disposable sterile syringe 0.9% sodium chloride solution equal to the calculated injection quantity Aktemra® preparation.

    3. Another disposable sterile syringe aseptically from the vial with the drug Aktemra® away calculated amount of formulation and introduce it into the infusion bottle (package) with 0.9% sodium chloride solution; as a result, the volume of the prepared solution should be equal to 100 ml.

    4. For mixing, gently flip the vial (packet) to avoid foaming.

    Patients with a body weight <30 kg

    - Calculate the amount of preparation necessary for administration to the patient (0.6 ml per 1 kg of body weight (0.6 ml / kg)).

    - In aseptic conditions from the infusion bottle (package) containing 50 ml of a 0.9% solution of sodium chloride (the solution must be sterile and pyrogen-free), take a 0.9% sodium chloride solution equal to the amount of the drug Actemra® calculated for administration with a disposable sterile syringe.

    - Another disposable sterile syringe aseptically from the vial with the drug Aktemra® away calculated amount of formulation and introduce it into the infusion bottle (package) with 0.9% sodium chloride solution; as a result, the volume of the prepared solution should be equal to 50 ml.

    - For mixing, gently flip the vial (packet) to avoid foaming.

    - Before introduction, it is necessary to inspect the prepared solution for the absence of foreign particles or discoloration.

    It is necessary to introduce only a transparent or opalescent colorless or light yellow solution without visible foreign particles.

    Recommendations for correcting the dose when changing laboratory parameters in patients with pUIA and SJUIA

    The dose reduction of Actemra® was not studied in patients with pYuIA and SJUIA. Breaks in the administration of the drug in patients with pYuIA or sIIA in case of changes in laboratory parameters are recommended in the same situations that are listed for patients with RA above (see also the sections "Special instructions", "With caution"). If necessary, the dose of concomitant MT and / or other concomitant medications should be changed or discontinuedreception, and also to take a break in the introduction of the drug Actemra® before explaining the clinical situation. In patients with pYuIA or SJUIA, the decision to discontinue therapy with Actemra® should occur with changes in laboratory indicators depending on the individual clinical situation.

    Rules for storing the prepared solution

    The prepared infusion solution of Actemra® is physically and chemically stable in a 0.9% solution of sodium chloride for 24 hours at a temperature of 30 ° C. From the microbiological point of view, the prepared solution should be used immediately.

    If the drug is not used immediately, then the time and conditions for storing the prepared racesare not the responsibility of the user and should not exceed 24 hours at a temperature of 2 ° C to 8 ° C (refrigerated) and only if the preparation of the solution is carried out under controlled and validated aseptic conditions.

    Instructions for the destruction of an unused preparation, and also after the expiration date

    The presence of medicinal products together with waste 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.

    Dosing in special cases

    Elderly patients

    Dose adjustments in elderly patients (≥65 years) is not required.

    Patients with renal insufficiency

    Dose adjustment in patients with mild renal insufficiency is not required (see section "Pharmacological action", subsection "Pharmacokinetics in special patient groups"). The use of tocilizumab in patients with moderate and severe renal failure has not been studied.

    Patients with hepatic insufficiency

    The safety and effectiveness of TOCILIZUMAB in patients with hepatic insufficiency has not been studied (see section "Specific guidance").

    Side effects:

    Rheumatoid arthritis

    The following categories are used to describe the frequency of undesired reactions: very often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10000 and <1/1000), very rarely (<1/10000, including individual cases).

    The undesirable reactions listed below are listed in the order of clinical significance for the patient.

    Table 1.Generalized data on adverse reactions recorded in RA patients treated with Actemra® as monotherapy or in combination with MT or other DMARDs.

    System Organ Class

    Often

    Often

    Infrequently

    Infections

    upper respiratory tract infection

    infections caused by Herpes simplex 1 type and Herpes zoster

    diverticulitis

    From the side of the digestive system


    pain in the abdomen, mouth ulcers, gastritis

    stomatitis, stomach ulcer, perforation of the gastrointestinal tract

    From the skin and its appendages


    rash, itching, urticaria, phlegmon


    From the nervous system


    headache, dizziness


    Changes in laboratory indicators


    an increase in the activity of "hepatic" transaminases, an increase in body weight

    increase in total bilirubin

    From the side of the cardiovascular system


    increase in blood pressure

    (HELL)


    On the part of the blood and lymphatic system


    leukopenia, neutropenia


    From the side of metabolism


    hypercholesterolemia

    hypertriglyceridemia

    From the body as a whole and the reaction at the site of administration


    peripheral edema


    From the respiratory system


    cough, dyspnea


    From the side of the organ of vision


    conjunctivitis


    From the side of the urinary system



    nephrolithiasis

    From the endocrine system



    hypothyroidism

    From the immune


    hypersensitivity reactions

    anaphylactic

    systems


    vigilance

    reactions






    * the entire controlled population - all patients who participated in the double-blind period of each baseline study, from the time of randomization to the first change in the treatment regimen or at the age of 2 years.

    Adverse events in patients with pUIA were similar to those observed in patients with RA and SJUIA. The safety profile of tocilizumab, investigated in patients with moderate to high-grade PPA who had not received previous MT therapy and biological therapy, is comparable to the known safety profile of TOCILIZUMAB.

    Additional information on individual adverse reactions is provided below.

    Infections: the following serious infectious diseases were registered: pneumonia, phlegmon, infections caused by Her­pes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis, some of which were fatal. Cases of opportunistic infections have been reported.

    Perforation of the gastrointestinal tract: Most cases of perforation of the gastrointestinal tract were reported as complications of diverticulitis and included diffuse purulent peritonitis, perforation of the lower gastrointestinal tract, fistula and abscess.

    Infusion reactions: The undesirable reactions that were most frequently observed during the administration of the drug were episodes of increased blood pressure. Unwanted reactions that occurred within 24 hours after the end of the drug administration were headache and reactions from the skin (rash, urticaria). These reactions did not lead to restriction of therapy. The incidence of anaphylaxis was several times higher in patients receiving the drug at a dose of 4 mg / kg than in patients receiving the drug at a dose of 8 mg / kg. Clinically significant hypersensitivity reactions due to the administration of Actemra® and requiring discontinuation of treatment were noted in 0.3% of patients. These reactions were observed, as a rule, between the second and fifth infusions of the drug Actemra® (see the section "With caution"). Immunogenicity: antibodies to tocilizumab were detected in 1.6% of the examined patients. In 5 of them, clinically significant hypersensitivity reactions were noted, which led to a complete withdrawal of treatment.Neutralizing antibodies were detected in 1.1% of patients (see Table 1 above).

    Polyarticular Juvenile Idiopathic Arthritis

    Infections: The most common infections were nasopharyngitis and upper respiratory tract infections. The incidence of severe infections, as well as infections leading to the temporary cessation of the use of tocilizumab, is significantly higher in patients with a body weight <30 kg who received tocilizumab in a dose of 10 mg / kg, compared with patients whose body weight was ≥30 kg who received tocilizumab in a dose of 8 mg / kg.

    Infusion reactions: reactions associated with infusion in patients with pUIAS were defined as any phenomenon occurring during or within 24 hours after infusion. In 5.9% of patients who received tocilizumab, infusion reactions were noted directly during infusion, 20.2% patients infusion reactions were noted within 24 hours after infusion. Undesirable reactions in patients with pUIA, noted during infusion or within 24 hours after infusion, did not differ in nature from those observed in patients with RA and SJUIA (see the section "Side effect"),

    Immunogenicity: antibodies to tocilizumab without developing a hypersensitivity reaction were detected in one patient with a body weight <30 kg receiving 10 mg / kg of tocilizumab, and subsequently discontinued treatment.

    Systemic juvenile idiopathic arthritis

    In general, adverse reactions in patients with SJUA do not differ in character from those observed in patients with RA (see the section "Side effects" above).

    Infections: The reported serious infections did not differ from those in patients with RA, except for chicken pox and otitis media.

    Infusion reactions: reactions associated with infusion in patients with SJIA were defined as any phenomenon occurring during or within 24 hours after infusion. In patients who received tocilizumab, undesirable phenomena were: a rash, urticaria (a serious phenomenon), diarrhea, epigastric discomfort, arthralgia, headache, etc.

    <1% of patients who received tocilizumab, a clinically significant hypersensitivity reaction associated with therapy was registered and required its cancellation.

    Immunogenicity: antibodies to tocilizumab were detected in 2 of 112 patients examined.One of them developed a hypersensitivity reaction, which led to the cancellation of treatment.

    Changes in laboratory indicators

    Hematologic disorders

    Neutrophils

    Rheumatoid arthritis

    A decrease in the number of neutrophils below 1 x 10% was noted in 3.4% of patients who received Actemra® at a dose of 8 mg / kg in combination with DMARD, compared with less than 0.1% of patients receiving placebo in combination with HDL. In about half of the cases, a decrease in AFN below 1 x 10% occurred within 8 weeks after initiation of treatment. A decrease in the number of neutrophils below 0.5 x 10% was reported in 0.3% of patients who received Actemra® at a dose of 8 mg / kg in combination with DMARD (see the section on "Dosage and Administration", "Precautions", "Special Guidelines"). A clear connection between a decrease in the number of neutrophils below 1 x 10% and the development of serious infectious diseases has not been noted.

    Polyarticular Juvenile Idiopathic Arthritis

    With routine monitoring of laboratory parameters, a decrease in the number of neutrophils below 1 x 10% was noted in 3.7% of patients receiving the drug Actemra®. There was no connection between a decrease in the number of neutrophils below 1 x 10% and the development of serious infectious diseases.

    Systemic Juvenile Idiopathic Arthritis

    At routine monitoring of laboratory parameters for 12 weeks of therapy, a decrease in the number of neutrophils below 1 x 10% occurred in 7% of patients receiving the drug Actemra ®, and was absent in patients receiving placebo. In the subsequent follow-up period, a decrease in the number of neutrophils below 1 x 10% was recorded in 15% of patients receiving the drug Actemra®. A clear connection between a decrease in the number of neutrophils below 1 x 10% and the development of serious infectious diseases has not been noted.

    Platelets

    Rheumatoid arthritis

    Decreased platelet count below 100 x 103/ μl was observed in 1.7% of patients who received Actemra® at a dose of 8 mg / kg in combination with DMARD and did not experience any bleeding episodes (see "Dosage and Administration", "Precautions," "Specific Instructions" ).

    Polyarticular Juvenile Idiopathic Arthritis

    With routine monitoring of laboratory parameters, a decrease in the number of platelets <50 x 103/ ml occurred in 1% of patients receiving the drug Actemra®. These changes were not accompanied by the development of episodes of bleeding.

    Systemic Juvenile Idiopathic Arthritis

    With routine monitoring of laboratory parameters for 12 weeks of therapy, a decrease in the number of platelets <100 x 103/ ml occurred in 1% of patients, in the subsequent period of observation, a decrease in the number of platelets below 100 x 103/ μL was recorded in 3% of patients receiving the drug Actemra®. These changes were not accompanied by the development of episodes of bleeding.

    Increased activity of "liver" transaminases

    Rheumatoid arthritis The addition of drugs with potential hepatotoxic effects (eg, MT) to monotherapy with tocilizumab resulted in an increase in the incidence of increased transaminase activity. Increased activity of "liver" transaminases was not accompanied by a clinically significant increase in the concentration of direct bilirubin, as well as clinical manifestations of hepatitis or liver failure.

    In patients who received tocilizumab in a dose of 8 mg / kg in combination with DMARD, the frequency of exceeding the upper limit of the norm of indirect bilirubin was 6.2%. Transient increase in ALT activity (more than 3 times higher than UGN) observed in adult patients with moderate or high activity ppA (mean duration of the disease> 6 months) who had not previously received MT therapy,had a more pronounced tendency to return to normal values ​​in comparison with the population of patients with RA.

    Polyarticular Juvenile Idiopathic Arthritis

    With routine monitoring of laboratory parameters, increased ALT activity or ACT at ≥3 times higher than ULN recorded in 3.7% and <1% of patients, respectively.

    Systemic Juvenile Idiopathic Arthritis

    With routine monitoring of laboratory parameters in the 12-week treatment period, increased ALT activity or ACT at ≥3 times higher than ULN was recorded in 5% and 3% of patients receiving tocilizumab, respectively. In the subsequent follow-up period, an increase in ALT activity or ACT > 3 times higher than ULN recorded in 12% and 4% of patients who received tocilizumab, respectively.

    Change in lipid metabolism

    Rheumatoid arthritis

    When therapy with the drug Actemra®, there was an increase in lipid metabolism (total cholesterol, triglycerides, HDL, LDL). A persistent increase in total cholesterol> 6.2 mmol / l (240 mg / dL) was observed in 24% of patients, and a persistent increase in LDL> 4.1 mmol / L (160 mg / dl) in 15% of patients.In most patients, the atherogenicity index did not increase, and the increase in total cholesterol concentration was effectively corrected by hypolipidemic drugs.

    Polyarticular Juvenile Idiopathic Arthritis

    With routine monitoring of laboratory parameters, an increase in the total cholesterol> 1.5xVGN - 2xVGN was observed in one patient (0.5%) who received the drug Actemra®. An increase in LDL> 1.5xVGN-2xVHN was noted in only one patient (0.5%) who received the drug Actemra®.

    Systemic Juvenile Idiopathic Arthritis

    An increase in the total cholesterol> 1.5xVGN-2xVHN occurred in 1.5% of patients receiving the drug Actemra®. An increase in LDL> 1.5xVGN-2xVGN occurred in 1.9% of patients receiving the drug Actemra®.

    Postmarketing surveillance

    The safety profile of the drug in the post-marketing application is consistent with the data of clinical studies, except for cases of the development of fatal anaphylaxis registered with the drug Actemra® (see the sections "Contraindications", "With caution"). During the post-marketing application, Stevens-Johnson syndrome was observed.

    Overdose:Available data on an overdose of Actemra® are limited. In one case, an unintentional overdose of the drug at a dose of 40 mg / kg in a patient with multiple myeloma of adverse reactions was not noted. There were also no serious adverse reactions in healthy volunteers who received a single dose of Actemra® at a dose of up to 28 mg / kg, although there was neutropenia requiring a dose reduction.
    Interaction:
    Population pharmacokinetic analysis of clinical studies did not reveal any effect of MT, non-steroidal anti-inflammatory drugs or glucocorticosteroids on the clearance of TOCILIZUMAB.
    The pharmacokinetic parameters of tocilizumab remain unchanged with the simultaneous use of other drugs for the treatment of rheumatoid arthritis (such as antimalarial drugs (chlorohrinin and its derivatives), immunosuppressants (azathioprine, leflunomide), folic acid and its derivatives, inhibitors of cyclooxygenase-2 (celecoxib) and analgesics (paracetamol, tramadol, codeine and their derivatives)). Simultaneous single administration of tocilizumab at a dose of 10 mg / kg and MT at a dose of 10-25 mg once a week had no clinically significant effect on MT exposure.Studies to study the combined use of tocilizumab with other biological BPDs have not been conducted.
    Since the expression of the hepatic isoenzymes of CYP450 is suppressed by the action of cytokines (for example, IL-6, which stimulates chronic inflammation), during therapy with agents that inhibit the action of cytokines (for example, tocilizumab), the expression of CYP450 isoenzymes may be impaired.
    In in vitro studies conducted on human hepatocyte culture, IL-6 has been shown to decrease the expression of isoenzymes CYP1A2, CYP2C9, CYP2C19 and CYP3A4. The use of tocilizumab normalizes the expression of these isoenzymes. The effect of Actemra® on CYP isoenzymes (other than CYP2C19 and CYP2D6) is of clinical relevance for preparations that are substrates of CYP450, with a narrow therapeutic index and / or for which the doses are individually selected. In patients with RA, the concentration of simvastatin (substrate CYP3A4) 1 week after a single injection of tocilizumab decreased by 57%, i.e. was slightly elevated or similar to that of healthy volunteers.
    At the beginning or at the conclusion of the course of therapy with the drug Actemra ® should carefully monitor patients receiving drugs in individually selected doses,and which are metabolized by the CYP450 3A4, 1A2 or 2C9 isoenzymes (eg, atorvastatin, blockers of "slow" calcium channels, theophylline, warfarin, phenytoin, ciclosporin or benzodiazepines). To ensure the therapeutic effect of these drugs may need to increase their dose. Given the long t1/2 of the drug Actemra®, its effect on the activity of CYP450 enzymes may persist for several weeks after discontinuation of therapy.
    Special instructions:

    Systemic juvenile idiopathic arthritis

    The macrophage activation syndrome is a serious life threatening condition that can develop in patients with SJIA. The efficacy and safety of Actemra® during the onset of the macrophage activation syndrome have not been studied.

    Changes in laboratory indicators

    For all indications

    Neutropenia: The therapy with Actemra® was associated with a higher incidence of neutropenia and was not associated with the development of serious infections. Caution should be exercised when administering Actemra® to patients with neutropenia, i.e. with an ACH <2.0 x 109 / l. At an ACH <0.5 x 109/ l treatment with the drug Actemra® is not recommended.

    When RA should monitor the number of neutrophils on the day of the second or third infusion, and in future in accordance with clinical practice. Recommendations for the dosage of the drug depending on the ACN are presented in the section "Method of administration and dose".

    With pYuIA and sIIA, the number of neutrophils should be monitored on the day of the 2nd infusion, and subsequently in accordance with clinical practice (see section "Dosing and Administration").

    Thrombocytopenia: therapy with Actemra® was associated with a decrease in the number of platelets and was not associated with serious cases of bleeding. Caution should be exercised when deciding whether to initiate therapy with Actemra® with a platelet count below 100 x 103/ μl. Treatment is not recommended with platelet count <50 x 103/ μl.

    When RA should monitor the number of platelets on the day of the second or third infusion, and in future in accordance with clinical practice. Recommendations for dosing the drug depending on the number of platelets are presented in the section "Method of administration and dose".

    With pYuIA and sIIA, the number of platelets should be monitored on the day of the 2nd infusion,and further in accordance with clinical practice (see section "Method of administration and dose").

    Increased activity of "liver" transaminases: there was an easy or moderate increase in the activity of "liver" transaminases without signs of hepatic insufficiency (see the "Side effect" section). The incidence of such changes increased with the use of the drug Actemra® together with drugs that have a potential hepatotoxic effect (for example, MT). Caution should be exercised when deciding whether to initiate therapy with Actemra® in patients with ALT or ACT, exceeding the VGN by more than 1.5 times. Therapy with Actemra® is not recommended for ALT or ACT, exceeding the VGN by more than 5 times.

    When RA should monitor ALT and ACT the day of the second or third infusion, and in the future in accordance with clinical practice. Recommendations for dosing the drug depending on the activity of "liver" transaminases are presented in the section "Method of administration and dose".

    With pUIA and SJAAA ALT and ACT should be monitored on the day of the second infusion, and in the future in accordance with clinical practice (see.See section "Dosing and Administration").

    Change in lipid metabolism: an increase in lipid metabolism (total cholesterol, LDL, triglyceride) was observed (see section "Side effect"). In RA, lipid metabolism should be assessed on the day of the 2nd or 3rd infusion with Actemra®, and with pYuIA and sIIA on the day of the 3rd, 4th or 5th infusion. The management of patients should be guided by national guidelines for the treatment of hyperlipidemia.

    Features of the drug during the first admission or when it is canceled Studies to study the possibility of the drug Actemra® did not lead to dependence. Based on the available data, the drug Actemra® does not have this effect.

    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 mechanisms were not conducted. However, given the fact that dizziness has often been experienced with therapy with Actemra®, patients who experience this undesirable reaction should be advised not to drive vehicles and mechanisms until dizziness stops.
    Form release / dosage:

    Concentrate for the preparation of a solution for infusions of 20 mg / ml.

    Packaging:

    4 ml (80 mg / 4 ml), 10 ml (200 mg / 10 ml) or 20 ml (400 mg / 20 ml) of the drug in vials made of colorless glass (hydrolytic class 1 EF), sealed with a lid of butyl rubber, Crimped with aluminum caps and covered with plastic caps; the color of the cap and lid corresponds to the color by which the dosage of the drug is allocated on the label of the vial and on the pack. 1 bottle together with the instruction for use is placed in a cardboard box with cardboard inserts (partitions) inside. On the pack there is an autopsy control.

    Packing at OJSC "Pharmstandard-UfaVITA": 1 bottle is placed in a plastic pallet or in a cardboard insert, which, together with the instruction for medical use, is placed in a pack of imported cardboard.

    For the purpose of controlling the first opening, a self-adhesive round sticker with an inscription "autopsy control" is applied to the pack.

    Storage conditions:
    Store at 2-8 ° C in a dark place. Do not freeze.
    Keep out of the reach of children.
    Shelf life:2 years and 6 months. Do not use after the expiration date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LSR-003012/09
    Date of registration:16.04.2009 / 05.12.2016
    Expiration Date:Unlimited
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp01.07.2017
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