Simsia® (Simziya®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
Read on
Active substanceCervolizumab pegolCervolizumab pegol
Similar drugsTo uncover
  • Simsia®
    solution PC 
    YUSB Farma S.A.     Belgium
    • Dosage form: & nbspSolution for subcutaneous administration.
    Composition:

    per 1 ml of the drug

    active substance: cortolizumab pegol 200.0 mg;

    Excipients: sodium acetate 1.36 mg, sodium chloride 7.31 mg, water for injection up to 1.00 ml.

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

    L.04.A.B.05   Cervolizumab pegol

    Pharmacodynamics:

    Zertolizumab pegol is an inhibitor of tumor necrosis factor alpha (TNFa). TNFa is the main cytokine that supports the inflammatory process in rheumatoid arthritis, Crohn's disease, psoriatic arthritis and axial spondylitis. Cervolizumab pegol has a high specific activity against TNFα rights (IC90 is 4 ng / ml for inhibition of TNFα in vitro in the process of cytotoxic analysis of murine fibrosarcoma cells L929), it has no activity against lymphotoxin α (TNFβ).

    Shown, that cervolizumab pegol neutralizes the membrane bound and soluble human TNFα dose-dependent manner. Incubation of human monocytes with cerolizumab by patogol resulted in a dose-dependent inhibition of LPS (lipopolysaccharide) -induced TNF-α synthesis and interleukin-1 beta (IL-1β).

    Zertolizumab pegol does not contain a crystallizing fragment (Fc), which is usually contained in a complete antibody and therefore does not fix complement and does not lead to the development of antibody-dependent cellular cytotoxicity in vitro.

    CERTOLISUMABA PEGOL does not cause apoptosis in vitro monocytes and lymphocytes of human peripheral blood, and also does not lead to degranulation of neutrophils.

    Susceptibility of the tissue to cerolizumab pegola was studied in experiments ex vivo and in vitro, carried out on living tissue to assess the possible interaction between the preparation and cryosections of frozen normal human tissue. When using a standard set of human tissues, evidence of cross reactivity with cerolizumab pegol was not received.

    Pharmacodynamics

    The increased concentration of TNF-α is determined in the synovial fluid of patients with rheumatoid arthritis and plays an important role in the progression of inflammatory, proliferative and destructive changes in the joints, which is the main manifestation of the disease.
    The biological properties of TNF-α include activation of molecules of cell adhesion and chemokines, activation of class I and II molecules of the main histocompatibility complex and direct activation of leukocytes.TNF-α stimulates the formation of cellular mediators of inflammation, including IL-1, prostaglandins, platelet activating factor, nitric oxide. Increasing the concentration of TNFα plays a key role in the pathophysiological mechanisms of the development of Crohn's disease, rheumatoid arthritis, psoriatic arthritis and axial spondylitis. Cervolizumab pegol selectively binds to TNFα, suppressing its role as the main mediator of inflammation. In Crohn's disease, TNFα is defined in a significant concentration in the affected areas of the intestinal wall, and its concentration in the feces of patients with Crohn's disease reflects the clinical severity of the disease.
    After treatment of cortolizumab with patogol, a decrease in the concentration of C-reactive protein (CRP) in the blood was noted in patients with Crohn's disease. Against the backdrop of treatment with Symmasia® in patients who developed axial spondyloarthritis in adulthood, a marked decrease in the symptoms of inflammation was noted in the sacroiliac joints and in the intervertebral joints - both in the entire population of patients with axial spondyloarthritis and in subgroups of patients with ankylosing spondylitis and axial spondylitis without radiographic signs.
    The use of the Simia® drug was accompanied by a marked improvement in the main efficacy indicators, which included mobility of the spine and physical functions, intensity of pain, weakness and quality of life. Patients with active psoriatic arthritis who debuted in adulthood, showed a significant improvement in all major efficacy rates against the background of the use of the preparation of Sym- sia®. At 12 and 24 weeks of treatment with Symzia®, improvement in parameters characterizing the peripheral activity of the disease (for example, the number of swollen joints, the number of painful / chained joints, the severity of dactylitis and the prevalence of enthesitis) was observed in patients with psoriatic arthritis. Significant improvements in physical function, reduced arthritic pain, reduced fatigue compared with placebo were noted. Patients treated with Sym- sia® reported significant improvement in their quality of life.
    Pharmacokinetics:

    Suction: after subcutaneous administration, the maximum concentration of cerolizumab pegola in blood plasma is reached after 54-171 hours.The bioavailability of cerolizumab pegola is about 80% (from 76 to 88%).

    Distribution: In patients with rheumatoid arthritis and Crohn's disease, according to the population analysis of the parameters of pharmacokinetics of cerolizumab pegola, the equilibrium volume of distribution was estimated in the range of 6 to 8 liters.

    Metabolism: the metabolism of cerolizumab pegola in clinical studies has not been studied. In experimental studies in animals, it has been shown that the excretion of cerolizumab pegola is mainly carried out by the kidneys.

    Excretion: PEGylation (covalent attachment of polyethylene glycol (PEG) polymers to proteins) contributes to a delay in the removal of these compounds from the bloodstream due to various mechanisms, including decreased renal clearance, decreased proteolysis, and immunogenicity. Thus, conjugation with PEG of cerolizumab pegola, which is Fab-fragment of the antibody, promotes an increase in the half-life (T1/2) Fabfragment to a value comparable with T1/2 whole antibody. T1/2 cercolizumab pegola is about 14 days for all doses studied. In healthy individuals, the rate of excretion of cerolizumab pegola for intravenous administration is from 9.21 ml / h to 14.38 ml / h.In Crohn's disease, the clearance of cerolizumab pegola with subcutaneous administration was 17 ml / h according to population pharmacokinetic analysis.

    Similarly, in rheumatoid arthritis, the clearance of cerolizumab pegola with subcutaneous administration was 21.0 ml / h according to population pharmacokinetic analysis.

    When comparing patients with rheumatoid arthritis with different body weights, it was shown that in patients with a body weight of 70 kg the clearance of cerolizumab pegola is 29% lower and 38% higher than in patients weighing 40 kg and 120 kg, respectively.

    FabThe fragment is a protein compound that degrades to simple proteins and amino acids during proteolysis. Deconjugated PEG is rapidly removed from the plasma, but the volume excreted by the kidneys is not established. The concentration of cerolizumab pegola in blood plasma is definitely proportional to the dose value.

    Parameters of pharmacokinetics in patients with rheumatoid arthritis and disease

    Crohns do not differ from the corresponding indicators in healthy

    volunteers.

    Special patient groups

    Patients with impaired renal function

    It is assumed that in patients with renal insufficiency, clearancecerolizumab pegola is reduced; However, no special clinical studies have been performed to assess the effect of renal failure on the pharmacokinetics of cerolizumab pegola, therefore, there is insufficient data to recommend a special dosage regimen for renal failure of moderate to severe severity.

    Patients with impaired liver function

    Special clinical studies to study the pharmacokinetics of cerolizumab pegola in patients with impaired liver function were not performed.

    Elderly patients (>65 years)

    The results of population pharmacokinetic analysis did not show any correlation with the age of patients.

    Floor

    The sex of the patients had no effect on the parameters of the pharmacokinetics of pterola. As the clearance decreases with a decrease in body weight, a somewhat larger systemic exposure of cel- tolyzumab pegola can be observed in women.

    The concomitant use of methotrexate and other biological agents, as well as the racial affiliation of patients, did not affect the pharmacokinetics of cerolizumab pegola in patients with Crohn's disease and rheumatoid arthritis.

    Only the body weight and the presence of antibodies to cerolizumab pegol had a significant effect on the pharmacokinetics of the drug. Nevertheless, the results of pharmacodynamic analysis did not confirm the therapeutic advantage of the use of dose regimens calculated by body weight of patients. The presence of antibodies to cerolizumab pegol increased the clearance of the drug 3.6 times.

    Indications:

    Rheumatoid arthritis

    Treatment of rheumatoid arthritis of moderate to high degree of activity in adults (from 18 years of age):

    - in combination with methotrexate in case of insufficient response to treatment with basic anti-inflammatory drugs (DMAP), including methotrexate, or

    - as monotherapy for intolerance or inexpediency of further treatment with methotrexate.

    It has been shown that, when combined with methotrexate, Sympression® reduces the progression of joint damage, assessed by radiography, and improves physical function.

    Crohn's disease

    Treatment of Crohn's disease with a moderate and high degree of disease activity in adults with ineffective treatment with BPD.

    Axial Spondyloarthritis

    Symsia® is indicated for the treatment of severe active axial spondylitis in adults, including:

    Ankylosing spondylitis (AS)

    Severe active ankylosing spondylitis with insufficient response to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or with their intolerance in adults.

    Axial spondylitis without x-ray signs of ankylosing spondylitis

    Severe active axial spondyloarthritis without X-ray signs of AS, but with objective signs of inflammation, manifested in an increase in the concentration of CRP and / or with appropriate changes in magnetic resonance imaging (MRI), with insufficient response to NSAID therapy or with their intolerance.

    Psoriatic arthritis

    Treatment of active psoriatic arthritis in adults:

    - in combination with methotrexate in case of insufficient response to therapy with DMARD;

    - as a monotherapy in case of intolerance or inexpediency of further treatment with methotrexate.

    Contraindications:
    - Hypersensitivity to cortolizumab pegola or other components that make up the drug;
    - sepsis or the risk of sepsis, as well as severe chronic or localized infections in the active stage (including tuberculosis, abscess, other opportunistic infections, including fungal infections (histoplasmosis, candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, nocardiosis, listeriosis, etc.) pneumocystis and viral infections, including viral hepatitis B in the reactivation stage;
    - heart failure of III-IV functional class according to NYHA (classification of the New York Association of Cardiology);
    - children's age (up to 18 years);
    - simultaneous application of anakinra, abatacept and etanercept.
    Pregnancy and lactation:
    Women of reproductive age should use reliable contraceptive methods during treatment and for at least 10 weeks after the end.
    Active transplacental transfer of immunoglobulins (IgG) occurs due to the binding of the Fc fragment of the antibody to the neonatal Fc receptor (FcRn). Cervolizumab pegol consists only of the Fab fragment of the antibody and does not contain an Fc fragment. In a study of reproductive performance in rats, it was shown that during pregnancy, TN3 γl (the total surrogate antibody to the cetolizumab pegol, including the Fc fragment) was transferred to the fetus.However TN3 PF (surrogate antibody Fab fragment to certolizumab pegolu without Fc fragment) was transferred to the fetus in minor or unmeasurable amounts in comparison with the concentration in plasma Fc fragment maternal blood, suggesting an important role in the Fc fragment transplacental transfer.
    In addition, the data confirming these observations were obtained in vitro using the closed loop model of human placental transport. It was shown that the concentration of celolizumab in the fetal contour was lower or near the lower limit of its quantitative determination.
    Within the framework of an independent clinical study in 10 patients with Crohn's disease treated with the drug during pregnancy Simziya®, measured the concentration of certolizumab pegola in maternal blood, umbilical cord blood, as well as in the blood of newborns (n ​​= 12) on the day of delivery. The concentration of pterola cortolizum was very low in cord blood (<0.41-1.66 μg / ml) and in neonatal blood (<0.41 - 1.58 μg / ml) compared with the concentration in maternal blood (1.87 - 59.57 μg / ml). The concentration of PEG (polyethylene glycol) was below the limit of detection in all samples of cord blood and newborn blood.
    Preclinical and clinical data allow one to judge the absence of active FcRn-dependent transplacental transfer of cerolizumab pegola.
    Since there are no well-controlled studies of the preparation of Sym- zia® in pregnant women, it should not be used during pregnancy, except in cases of obvious need.
    In connection with the inhibition of tumor necrosis factor (TNF-α), the preparation of Symzia®, used during pregnancy, can affect the parameters of the normal immune response of the newborn. Although the concentration of cortolizumab pegola in the blood of infants is low, the clinical significance of these data is not clear.
    The risk / benefit ratio when using live vaccines during the first 12 weeks of life of an infant should be evaluated by pediatricians. However, the Simia® preparation does not suppress the humoral immune response when using inanimate vaccines in adults.
    In male rodents, a decrease in the motility of spermatozoa and a tendency to decrease in their numbers without a visible effect on the fertility of animals were found.
    In a clinical study evaluating the effects of cervolizumab pegola on the quality of semen (sperm volume,number and concentration of spermatozoa, progressive mobility, percentage of total mobility, viability and morphology of spermatozoa), 20 healthy men were randomized to receive a single subcutaneous injection of 400 mg of cepolizumab pegola or placebo. During the 14 weeks of follow-up, there was no evidence of the effect of cerolizumab pegola on qualitative sperm counts compared with placebo.
    It is not established whether the cervolizumab pegol with breast milk. However, it is known that immunoglobulins are able to penetrate into breast milk, so the risk to a child who is breastfed can not be eliminated. If treatment with Symmasia® is necessary during lactation, breastfeeding should be discontinued.
    Dosing and Administration:

    Subcutaneously.

    Treatment should be appointed and monitored by a physician with experience in the diagnosis and treatment of diseases in which the use of the preparation Symmy® is indicated.

    After the patient has been properly trained in the technique of administering the drug, the physician can allow the drug to be administered alone (see further instructions

    on the introduction) with appropriate medical supervision.

    Symphony® is used as a ready-to-use solution for injections at a dosage of 200 mg (a disposable syringe containing 1.0 ml of cerolizumab pegola).

    Induction dose

    The recommended induction dose of Symma® for adult patients is 400 mg in the form of two subcutaneous injections of 200 mg on the first day of treatment, at the second and fourth week of treatment.

    Maintenance dose

    Crohn's disease

    After the induction dose, the recommended maintenance dose of Symzyme® for adult patients is 400 mg once every 4 weeks.

    Rheumatoid arthritis

    After the induction dose, the recommended maintenance dose of Symmia® for adult patients is 200 mg once every 2 weeks. For the maintenance of the disease, it is possible to use an alternative dosing regimen of 400 mg once every 4 weeks.

    Axial Spondyloarthritis

    Ankylosing spondylitis

    After the induction dose, the recommended maintenance dose of Symmasia® for adult patients is 200 mg once every 2 weeks or 400 mg once every 4 weeks.

    Axial spondylitis without x-ray signs of ankylosing spondylitis

    After the induction dose, the recommended maintenance dose of the drug

    Symphony® for adult patients is 200 mg once every 2 weeks or 400 mg once every 4 weeks.

    Psoriatic arthritis

    After the induction dose, the recommended maintenance dose of Symmia® for adult patients is 200 mg once every 2 weeks. After the response to therapy, it is possible to use an alternative dosing regimen of 400 mg once every 4 weeks.

    The data obtained in studies of rheumatoid arthritis, axial spondylitis and psoriatic arthritis indicate that a clinical response is usually achieved within 12 weeks of treatment. The decision to continue treatment of patients whose therapeutic effect did not develop during the first 12 weeks of therapy should be carefully weighed.

    Missing dose

    Patients who missed the next dose should be advised to enter a missed dose of Symmy® as soon as they remembered, and then continue to administer subsequent doses according to the initial treatment plan.

    Elderly patients (65 years and older)Correction of the dose is not required.

    Instruction on the technique of subcutaneous injection

    Preparation for injection

    Before you enter the preparation of Symmasia® in a pre-filled syringe, you need to make sure of the following:

    - on the package and syringe, the name of the preparation is given. Simia®,

    - the shelf life of the drug has not expired,

    - the integrity of the drug package is not broken, the protective labels are stored on the bottom and top side of the cardboard bundle,

    - the drug in the syringe was not frozen and was not exposed to direct sunlight,

    - the contents of the pre-filled syringe are a clear opalescent colorless or yellow solution in which there are no visible particles.

    The drug can not be used if at least one of the listed requirements is not met!

    Each package of the Symzia® product contains a disposable syringe equipped with a needle and two individually packaged alcohol swabs.

    For each injections use 1 syringe and 1 alcohol swab (Fig. 1):


    Fig. 1



    It is also necessary to additionally have 1 clean cotton swab (not included in the Simia® product) and a protective container for used needles and syringes, which protects from getting a piercing injury when working with needles (Figure 2).


    Fig. 2



    Each pre-filled syringe contains a dose sufficient for one injection (200 mg). In accordance with the prescription of the doctor, you may need to enter the drug more than once. If the preparation Symzia® is prescribed at a dose of 400 mg, then two subcutaneous injections (200 mg x 2 times) should be performed. The drug is injected under the skin in the abdomen or thigh. If you need to enter the drug twice, it should be injected into anatomically different areas (for example, the right and left side, or the abdomen and thigh).


    Remove 1 or 2 pre-filled syringes with Symmy® and alcohol tampons from the refrigerator and place them on a clean, level surface. Before the injection, let the syringe and the preparation warm up to room temperature. This will require

    approximately 30 minutes.


    Selection and preparation of the injection site


    Wash your hands thoroughly with soap and water (Figure 3).


    Fig. 3


    Determine the place (s) for injection (s), considering the need for the drug to be administered in different anatomical areas. The distance from the previously used injection site should be at least 3 cm (injection sites should be noted). Do not inject the drug into areas with hemorrhages, in areas where the skin has hardened or reddened, as well as in the area of ​​scars or striae.If you have chosen a stomach area, you should not inject the drug within a 5 cm radius from the navel. Alternate the injection site between the abdomen and thighs to avoid the risk of local skin reactions (Figure 4).


    Fig. 4


    Use an alcohol sponge to treat the injection site. Do not touch the treated skin before injection.


    Use of pre-filled syringes with Simsia®


    Make sure that the drug in the syringe is a colorless or pale yellow solution that does not contain visible mechanical particles. You can see the air bubbles. This is normal. No need to remove air bubbles before injection. Subcutaneous administration of a solution containing air bubbles is safe.

    Remove the cap from the needle by pulling it up behind the plastic ring. Be careful not to touch the needle. Set the needle cap aside. Do not bend the needle. Give the injection immediately. (Figure 5).


    Fig. 5


    Hold the syringe with the needle down. Do not touch the needle with your fingers or rest it against other surfaces. Hold the syringe in one hand, the other hand gently gather the skin fold of the pre-treated area of ​​the skin and hold it firmly.Position the needle at an angle of 45 ° to the surface of the skin and in one quick short motion, insert the needle all over the thickness of the skin fold. (Figure 6).


    Fig. 6


    While holding the syringe, slowly pull the piston back. If blood appears in the syringe, it means that you have entered a blood vessel. Do not administer Symmy ®. Remove the needle and discard the pre-filled syringe and needle in a protective container.


    Do not use this syringe again!


    If blood does not appear in the syringe, inject the entire solution under the skin, pressing the piston. (Figure 7).


    Fig. 7


    After the drug is not left in the syringe, gently pull the needle out of the skin at the same angle at which it was inserted, and then squeeze the injection site with a clean cotton swab for 10 seconds. Do not wipe the injection site. There may be a slight bleeding, to stop it, you can apply a small pressure bandage to the injection site, if necessary.


    Repeat the above steps if you are assigned a second injection (total dose of 400 mg).


    Recycling


    Never use the syringe and needle again, do not put the cap on the needle. Used syringes and needles are to be disposed of, they are placed in a special protective container for subsequent destruction.When filling the container with 2/3 parts, it is sealed and sent for destruction in accordance with the doctor's recommendations (Fig. 8).


    Fig. 8


    Special instructions and precautions


    Infections


    Patients should be carefully screened for infections, including chronic and local foci of infection, prior to the prescription of Symmy®, during and after treatment. Taking into account the long half-life of the Symzia® preparation, patient monitoring should be carried out throughout this period.

    Patients with a newly diagnosed infection on the background of treatment with Symmy® should be closely monitored. When TNF antagonists, including Sym- sitia, were used, sepsis, tuberculosis and other severe infections with bacterial, mycobacterial, invasive fungal, viral and / or parasitic pathogens were reported.

    Among opportunistic infections, the most frequently reported histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, nocardiosis, listeriosis and pneumocystis.

    If severe infection develops, treatment with Symmy® should be discontinued.

    Prior to the appointment of Symmy®, the relationship between the benefits and risks of this therapy should be carefully evaluated in patients with chronic or recurrent or opportunistic infections in the anamnesis; in patients undergoing concomitant immunosuppressive therapy; at conditions of patients predisposing to the development of infections, as well as when changing places of residence or traveling to areas with high incidence of tuberculosis, mycoses, histoplasmosis and other infections.

    In patients with rheumatoid arthritis, the symptoms of an infectious disease can be worn out. Therefore, early detection of any infectious disease, especially atypical clinical manifestations of severe infection, is extremely important for the timely diagnosis and immediate start of treatment.

    Tuberculosis

    As with the use of other TNF-α inhibitors in the treatment with the Symzia® drug, there have been cases of reactivation of tuberculosis or new cases of tuberculosis (including miliary pulmonary tuberculosis, extrapulmonary tuberculosis and disseminated form of the disease).Prior to the appointment of the Symzia® drug, it is necessary to assess the benefit-risk ratio of this therapy in consideration of the risk factors for developing tuberculosis. Before starting treatment with Symmasia®, all patients should be examined to exclude active or latent (latent) tuberculosis. This examination should include a detailed examination of the patient's history in order to exclude the previous tuberculosis, to identify possible contacts with patients with tuberculosis, and to obtain data on ongoing or ongoing immunosuppressive therapy. All patients undergo appropriate screening tests, for example, a tuberculin skin test (or another study to identify latent tuberculosis) and chest radiography. It should be taken into account that in some cases it is possible to obtain a false-negative result of the tuberculin test, especially in patients with a severe clinical condition and a decreased immune status. When carrying out a tuberculin test, the papule size of 5 mm or more is considered positive, even if BCG vaccination was previously performed (Calmette-Guérin's bacillus).Consideration should be given to the need for a prophylactic course of treatment for tuberculosis prior to the prescription of Symmyso® in those patients who, with evidence of previously transmitted tuberculosis or signs of latent flow, confirm previous adequate antituberculous therapy, as well as in patients with risk factors for developing tuberculosis, despite the negative test result for the detection of latent tuberculosis. To address the need for

    course of anti-tuberculosis therapy for each individual patient requires consultation of a phthisiatrician.
    Patients should be closely monitored, paying attention to symptoms such as persistent cough, sputum, weight loss, subfebrile fever, which may indicate tuberculosis. If active tuberculosis is diagnosed before or during therapy, do not start or continue treatment with Symmy®, and appropriate antituberculosis therapy should be started.
    Reactivation of viral hepatitis B (HBV)
    There have been reports of reactivation of viral hepatitis B in patients who are chronic carriers of this virus (including those with a positive surface antigen) who received TNFα inhibitors, including the Simia® preparation. In some cases, the disease was fatal. Prior to the appointment of Symmy®, patients should be screened for hepatitis B virus. Patients with positive hepatitis B virus test results should be advised to consult a specialist in the treatment of hepatitis B.
    Hepatitis B virus carriers, who are treated with Sym- sia®, should be under constant surveillance to detect signs and symptoms of active HBV infection in time for the entire course of therapy and in the next few months after the end of treatment. Appropriate data on the treatment of patients with HBV infection by antiviral drugs concomitantly with TNF antagonists for preventing the reactivation of HBV have not been obtained.
    If patients develop symptoms of hepatitis B virus reactivation, discontinue use of Symmy ® and prescribe effective antiviral and appropriate maintenance therapy.
    Vaccination
    Vaccination of patients receiving treatment with Symmy ® is allowed, except for the use of live or live attenuated vaccines.
    There is no evidence of a response to vaccination or secondary transmission of infection through live vaccine to patients receiving the preparation of Sym- sia®. Live vaccines and live attenuated vaccines are not recommended for administration against the background of treatment with the preparation of Sym- sia®. All necessary vaccination measures should be carried out in accordance with the current national immunization schedule, if possible, before the start of treatment with the Simia® preparation. Sym- sia® does not inhibit the humoral immune response to the pneumococcal polysaccharide vaccine or the influenza vaccine.
    Malignant and lymphoproliferative diseases
    In clinical studies, lymphoma and malignant neoplasms were more common in patients who received the Sym- sia® drug than in the placebo group. However, a limited number of patients in the control group and a short time of their treatment do not allow making unequivocal conclusions. There have been no studies in which patients with a malignant neoplasm in history, or studies,in which the treatment with Symmasia® would be continued after the detection of malignant neoplasms. Therefore, in this group of patients, treatment with Symmy® is recommended with caution. In patients with rheumatoid arthritis, especially in a subgroup with very high disease activity, the risk of developing lymphoma is elevated.
    In patients with Crohn's disease and other diseases in which prolonged immunosuppressive therapy is prescribed, the risk of developing lymphoma, in comparison with the whole patient population, can also be increased, even if therapy with TNFα inhibitors is not performed. Cases of acute and chronic leukemia have been reported with the use of TNF-α inhibitors in rheumatoid arthritis and other indications. Even in the absence of therapy with TNFα inhibitors, the risk of developing leukemia in patients with rheumatoid arthritis is higher (about 2 times) than in the population as a whole. There are reports of malignant neoplasms, including fatalities, in adults and children treated with TNF-α inhibitors (at the start of treatment before the age of 18, inclusive). Approximately half of these cases have been diagnosed with lymphomas (including Hodgkin's lymphoma and non-Hodgkin's lymphomas).The remaining cases included various malignant neoplasms, including rare ones, which, as a rule, were associated with immunosuppressant therapy. Malignant neoplasms developed on average after 30 months of treatment (from 1 to 84 months). Most patients received concomitant therapy with immunosuppressants. These cases were published in the postmarketing period and were obtained from various sources of security information, including registers and spontaneous post-marketing messages.
    During post-marketing follow-up, cases of hepatic-splenic T-cell lymphoma (hepatosplenic T-cell lymphoma - HSTCL), a rare type of T-cell lymphoma with extremely aggressive course of the disease and, as a rule, fatal Exodus. Most cases associated with the use of TNF antagonists have been observed in adolescents and young men with Crohn's disease and ulcerative colitis. Almost all of these patients were treated with immunosuppressants, azathioprine and / or 6-mercaptopurine, in combination with TNF inhibitors at or before the diagnosis.
    Skin cancer
    With the use of TNF inhibitors, including the Symzia® preparation, melanoma and carcinoma from Merkel cells have been reported. It is recommended to periodically inspect the skin of all patients, and especially those patients who have risk factors for skin cancer.
    Chronic obstructive pulmonary disease (COPD)
    A study of another drug from the group of TNFα inhibitors in patients with moderate and severe COPD showed an increased risk of malignant neoplasms (mainly with localization in the lungs, as well as in the head and neck) in the group of patients treated with the TNFα inhibitor compared to the control group . All patients were active smokers. In this regard, caution should be exercised when treating with inhibitors of TNFa in patients with COPD, as well as patients with an increased risk of developing malignant tumors due to active smoking.
    Chronic heart failure (CHF)
    In the treatment of TNF-α inhibitors, including the Symzia® preparation, there have been reports of cases of the development of chronic heart failure (CHF) and its progression.It should be used with caution in patients with CHF I-II functional class according to the NYHA classification.
    The preparation of Symzia® should be discontinued with the first diagnosed CHF or the detection of symptoms of its progression. It is recommended to prescribe symptomatic therapy.
    Hypersensitivity reactions
    The following symptoms, which may resemble hypersensitivity reactions, have been observed in patients in rare cases after the administration of Symmy®: angioedema, shortness of breath, lowering of blood pressure, skin rash, serum sickness and urticaria.
    Some of these reactions were noted after the first use of the preparation of Simsia®.
    If the above reactions occur, the introduction of the Simia® drug should be stopped immediately and appropriate treatment started.
    Neurological disorders
    The use of TNF antagonists in rare cases was associated with a new development or an increase in the severity of already existing clinical symptoms and / or radiologic signs of demyelinating disease, including multiple sclerosis.
    In patients with an existing or newly emerging demyelinating disease, the risk / benefit ratio should be carefully weighed before starting therapy with Symmy®. Rare cases of neurological diseases, including convulsive disorders, neuritis and peripheral neuropathies were noted in the treatment with the preparation of Symmy.
    Immunosuppression
    Due to the fact that TNF-α is a mediator of the inflammation process and modulates the cellular immune response, when treating with Symmasia®, one can not exclude the possibility of suppressing the body's immune system and reducing the body's resistance to infections and malignant tumors.
    The formation of antibodies
    Treatment with Symmasia® can be accompanied by the formation of antinuclear antibodies (AHA) and, infrequently, the development of "lupus-like" syndrome.
    If, against the backdrop of treatment with Symmasia®, the patient develops symptoms similar to the "lupus-like" syndrome, treatment should be discontinued. The effect of prolonged therapy with Symmasia® on the development of autoimmune diseases is unknown. Special studies of the preparation of Simia® with systemic lupus erythematosus have not been performed.
    Hematologic reactions
    There have been reports of rare cases of pancytopenia and very rare cases of aplastic anemia with the use of TNFα inhibitors. Caution should be exercised in prescribing Symmy® to patients who have a history of marked changes in blood test results. All patients and their relatives should be aware of the need for immediate medical attention if the patient develops symptoms and symptoms characteristic of hematologic disorders or infection (eg, prolonged fever, sore throat, bruising, bleeding, pallor skin integument). Such patients are recommended to conduct a medical examination, including a detailed clinical blood test. When confirming the diagnosis of pancytopenia or other significant hematologic disorders, treatment with the drug should be discontinued.
    Combination Therapy
    Reports of severe infections and neutropenia have been reported in clinical trials with the combined use of Symmy® with other TNFα inhibitors: an anakin (interleukin-1 antagonist) or abatacept (modulator of C28 activity on the T cell surface), as well as with etanercept.The simultaneous use of Symma® with these drugs or with other biological DMARDs showed no additional clinical benefit and, therefore, is not recommended.
    Elderly patients
    In clinical studies, a higher incidence of infectious diseases has been observed in patients aged 65 years and older than younger patients, although this data is limited. It is advisable to use caution when using Symmy ® in elderly patients, special attention is required by patients of this group with regard to the possible development of infection.
    Effect on blood coagulability
    Against the backdrop of the use of the Symzyme® preparation, a false positive increase in APTT (activated partial thromboplastin time) is possible in patients who do not have coagulation disorders. The increase in APTT was observed with the use of various methods, including a test with lupus anticoagulant. No evidence has been obtained of the effect of treatment with the preparation of Simsia® on blood coagulation in vivo.
    In patients receiving treatment with Symmy ®, special attention should be paid to the interpretation of blood coagulation indicators that go beyond normal values, regardless of the analytical method.
    Influences on other parameters of blood coagulability (thrombin time, prothrombin time, etc.) are not established.
    Surgical interventions
    There are limited data on the safety of surgical procedures in patients receiving the preparation of Sym- sia®. When planning a surgical operation, it is necessary to take into account that the half-life of celitholizumab pegola is 14 days. If during the treatment with Symmasia® the patient needs surgical intervention, it is necessary to ensure constant monitoring of the patient for the timely detection of signs of infections and taking appropriate measures.
    Side effects:
    Rheumatoid arthritis

    The most frequent adverse events related to the "infections and invasions" group were observed in 14.4% of the patients receiving the Symzia® preparation and 8.0% of the placebo group, "general disorders and reactions at the site of administration" in 8.8 % of patients receiving the preparation of Symzia®, and 7.4% of placebo, as well as "skin and subcutaneous tissue disorders" in 7.0% of patients who received the preparation of Sym- sia® and 2.4% of placebo.

    Therapy was discontinued due to the development of adverse events in 4.4% of patients receiving the preparation of Sym- sia® and 2.7% of patients who did not receive the drug (placebo group).

    Crohn's disease

    In patients with Crohn's disease in controlled trials, serious adverse events were noted in 10.8% of cases treated with Symmy®, and in the placebo group at 8.6%.

    The most frequent adverse reactions were rhinopharyngitis (11.1% and 6.7%, respectively), nausea (8% and 6.7%, respectively), infections of the urinary system (5.1% and 4.4%, respectively) , abdominal pain (9.3% and 8.8%, respectively), arthralgia (6.7% and 3,9%, respectively), headache (14.8% and 13.8%, respectively).

    Because of adverse reactions, 11.3% of patients who received the Sym- sia® drug discontinued therapy, and 12,6% - receiving a placebo. The most frequent adverse reactions that led to the withdrawal of the Symzia® drug were: diarrhea (0.5% and 0,2%, respectively), abdominal pain (0.9% and 0.4%, respectively) and nausea (0.4% and 0.2%, respectively).

    Axial Spondyloarthritis

    In a placebo-controlled study, a safety profile was evaluated in 325 patients with active axial spondylitis, who received the preparation of Symzyme ® for up to 30 months. The profile of the safety of the preparation Symma® when used in patients with axial spondylitis was similar to that in patients with rheumatoid arthritis and the previous experience with the drug.

    Psoriatic arthritis

    In a placebo-controlled study, a safety profile was evaluated in 409 patients with psoriatic arthritis, who received the preparation of Symzyme ® for up to 30 months.

    The safety profile of the preparation Symma® when used in patients with psoriatic arthritis corresponded to that in patients with rheumatoid arthritis and the previous experience of using the drug.

    Adverse reactions are grouped according to the frequency of occurrence: very often (>1/10); often (>1/100, <1/10); infrequently (>1/1000, <1/100); rarely (>1/10 000, <1/1000); very rarely (<1/10 000); frequency is not established (it is impossible to estimate from available data).

    Infectious and parasitic diseases: often - bacterial infections (including abscess), viral infections (including those caused by the herpes virus, influenza, papillomavirus); infrequently - sepsis (including multiple organ failure and septic shock), tuberculosis, fungal infections (including opportunistic infections).

    Benign tumors, malignant neoplasms and unspecified neoplasms (including cysts and polyps): infrequently - malignant diseases of the blood and lymphatic system, including lymphoma and leukemia,solid neoplasms, malignant neoplasms of the skin that do not include melanoma, pre-tumoral lesions (leukoplakia of the oral mucosa, melanocytic nevus), benign tumors and cysts (including papilloma of the skin); rarely - neoplasms of the gastrointestinal tract, melanoma.

    Disturbances from the blood and lymphatic system: often - eosinophilia, eosinopenia, leukopenia (lymphopenia and neutropenia); infrequently - Anemia, thrombocytopenia, lymphadenopathy, thrombocytosis; rarely - pancytopenia, splenomegaly, erythrocytosis, morphological changes in leukocytes.

    Disorders from the immune system: infrequently - vasculitis, SLE (systemic lupus erythematosus), increased drug sensitivity, psoriasis and related diseases, allergic disorders, a positive reaction to autoantibodies; rarely - angioedema, sarcoidosis, serum sickness, panniculitis (including erythema nodosum).

    Disorders from the endocrine system: rarely - Thyroid dysfunction.

    Disorders from the metabolism and nutrition: infrequently - Electrolyte disorders, dyslipidemia, anorexia, weight loss; rarely - change in the concentration of glucose in the blood plasma, hypoalbuminemia, hypoproteinemia, hemosiderosis.

    Disorders of the psyche: infrequently - anxiety (including mental stress), mood changes (and related symptoms); rarely - suicidal attempts, delirium, reduction of mental activity, aggression. Disturbances from the nervous system: often - headache (including migraine), sensitivity disorders; infrequently - peripheral neuropathy, dizziness, tremor, optic neuritis; rarely - demyelinating diseases, including neuritis of the cranial nerve, convulsive attack, extrapyramidal disorders, neuralgia of the trigeminal nerve, impaired coordination of movements and sense of balance, dysphonia, masky facial expression, sleep disturbance. Disorders from the side of the organ of vision: infrequently - impaired visual perception (including reduced visual acuity), uveitis and blepharitis, dacryoadenitis and dacryocystitis. Hearing disorders and labyrinthine disturbances: infrequently - vertigo, noise in the ears; rarely hearing loss. Disorders from the cardiovascular system: often - increased blood pressure; infrequently - cardiomyopathy, heart failure, ischemic heart disease, arrhythmias (including atrial fibrillation (atrial fibrillation)), palpitations, hemorrhages, bleeding, venous thromboembolism (PE, thrombophlebitis), syncope, lowering blood pressure, swelling (face, limbs), ecchymoses hematomas, petechiae); rarely - pericarditis, atrioventricular blockade, shock, stroke, atherosclerosis, Reynaud's syndrome, reticular ledo, telangiectasia. Disturbances from the respiratory system, chest and mediastinal organs: infrequently - pleural effusion (and associated symptoms), bronchial asthma and its manifestations, dyspnea, congestive and inflammatory changes in the lungs, coughing; rarely - interstitial lung diseases, pneumonitis, ulceration of the nasal mucosa. Disturbances from the gastrointestinal tract: often - nausea, vomiting; infrequently - ascites, symptoms of Crohn's disease (stenosis), ulcerative lesions and perforation (various parts of the gastrointestinal tract), inflammation of the mucous membrane of the digestive tract, dyspepsia, stomatitis, bloating, dryness of the oral and pharyngeal mucosa; rarely - intestinal obstruction, painful swallowing, anal fissures, increased intestinal motility. Disorders from the liver and biliary tract: often - hepatitis, increased activity of "hepatic" enzymes; infrequently - liver disease, including liver cirrhosis, cholestasis, increased bilirubin concentration in blood plasma; rarely - cholelithiasis. Disturbances from the skin and subcutaneous tissues: often - a rash; infrequently - alopecia, the onset of psoriasis or weighting of its symptoms, dermatitis, eczema, impaired sweat gland function, skin ulceration, increased photosensitivity, acne, skin pigmentation disorders, dry skin, nail plate lesions and nail bed; rarely - Acute febrile neutrophilic dermatosis, exfoliation and skin desquamation, bullous dermatitis, skin ulceration, pink lichen, striae, rosacea, hair structure disorder. Disorders from the musculoskeletal system: infrequently - arthritis, muscle function disorder; rarely - violation of the function of tendons. Disorders from the urinary system: infrequently - impaired renal function, hematuria, nephrolithiasis, urethritis, cystitis; rarely - nephropathy, nephritis. Disorders from the reproductive system and the breast: infrequently - disorders of the menstrual cycle, uterine bleeding, amenorrhea, dysfunction of the mammary glands, azoospermia; rarely premature birth, vaginal discharge, sexual dysfunction, balanitis. General disorders and reactions at the site of administration: often - Hyperthermia, pain (unspecified localization), asthenia, pruritus (unspecified localization), reactions at the injection site; infrequently - formation of fistulas (without specification of localization), chills, flu-like syndrome, violation of temperature sensitivity, night sweats, "hot flashes"; damage to the skin, slow healing of wounds. Laboratory and instrumental data: infrequently - increased activity of creatinine phosphokinase (CK), alkaline phosphatase, total bilirubin, increased blood coagulation time, changes in general urine analysis; rarely - increased concentration of uric acid in the blood. The following adverse reactions are associated with the use of drugs from the class of antagonists of TNFa: carcinoma from Merkel cells, multiple sclerosis, Guillain-Barre syndrome,but the incidence of their occurrence with the use of the preparation Symzyma ® is unknown.

    Infections

    In controlled trials in patients rheumatoid arthritis

    new cases of infectious diseases were observed at a frequency of 1.03

    patients per year treated with Symmy® and with a frequency of 0.92 patients per year in those receiving placebo. Infections were mainly due to diseases of the upper and lower respiratory tract, diseases of the urinary system and viral herpetic diseases.

    In controlled studies, serious cases of infectious diseases in the group treated with drug Simziya® longer observed (0,07 patients per year) than in the placebo group (0.02 patients per year). The most frequent serious infectious diseases were pneumonia and tuberculosis. There is no evidence of an increased risk of infection with an increase in the duration of the use of Symmy®.

    The incidence of infections in controlled studies in patients Crohn's disease was 38.6% in patients treated with Symmy ® and 30.6% in patients receiving placebo. Infectious diseases of the respiratory tract were mainly observed (18.9% in the patients treated with the Symzia® and 12.4% in the placebo group).The incidence of clinically significant serious infections during controlled trials was 2.6% of patients per year among those treated with Symmy ® and 1.3% in placebo. Serious infections included both bacterial and viral diseases, pneumonia and pyelonephritis.

    Tuberculosis

    The use of drugs from the group of TNFα inhibitors can be accompanied by the development of active tuberculosis. There are reports of severe and lethal cases of tuberculosis in the background of treatment with the preparation Simsia®. In completed and ongoing clinical trials of all known indications, among 5,118 patients who received treatment with Symmy®, the incidence of tuberculosis was approximately 0.61 per 100 patients per year. The greatest number of cases was observed in countries, endemic for tuberculosis. The reports included cases of pulmonary and disseminated tuberculosis and, in rare cases, opportunistic infections. There were rare cases of death in patients with tuberculosis and opportunistic infections.

    Malignant and lymphoproliferative diseases

    In controlled trials of TNFα inhibitors, there are more cases of malignantneoplasms and lymphomas were recorded in the group of patients receiving the preparation of Sym- sia®, compared with the control group.

    Of the 4,049 patients rheumatoid arthritis, who received the preparation of Sym- sia®, lymphoma was diagnosed in 5 patients. In patients with rheumatoid arthritis, especially with severe disease activity, the risk of developing lymphoma is increased.

    Of the 2657 patients who received the Crohn's disease, 1 patient is diagnosed with lymphoma; also 1 case of lymphoma was observed in the control group of patients, including 1319 people. The incidence of malignant tumors and lymphoma in clinical studies of the Simia® drug can not be compared with the results of studies of other TNFα inhibitors and can not serve as a basis for predicting the incidence of these diseases with the use of the Sym- sia® drug in a broader patient population. In patients with Crohn's disease who require long-term therapy with immunosuppressants, increased risk of developing lymphoma, compared with the population as a whole, even if they are not treated with TNFα inhibitors.

    In a clinical study, one patient with psoriatic arthritis was diagnosed with lymphoma.

    Chronic heart failure

    Against the backdrop of treatment with the drug Symzia®, both new cases of CHF and the progression of earlier symptoms of CHF were noted. Most of these cases were mild or moderate in severity and were diagnosed during the first year of treatment with the drug.

    Immunogenicity

    Rheumatoid arthritis

    Total number of patients rheumatoid arthritis with antibodies to the preparation of Symmy ®, which were determined at least once, was 9.6% in placebo-controlled trials of the drug. In about 1/3 of these patients, antibodies exhibited neutralizing activity in vitro. In patients who simultaneously took immunosuppressants (methotrexate), the rate of antibody formation was lower than in patients who did not receive them initially. The formation of antibodies was associated with a lower concentration of the Symzyme ® drug in the blood plasma, and in some patients - with its lower efficacy.

    Crohn's disease

    When Crohn's disease In 8% of patients who received long-term treatment with Sym- sia®, antibodies to the drug were detected, approximately 6% of them were neutralized in vitro. There is no apparent relationship between the formation of antibodies and the efficacy of the preparation Symzyma®. In patients who simultaneously took immunosuppressants, the level of antibody production was lower than in patients who did not take them (3% and 11%, respectively).

    Psoriatic arthritis

    Total number of patients with psoriatic arthritis in a placebo-controlled study in which antibodies to Simzia® were detected at least once for 24 weeks were 11.7%. The formation of antibodies was associated with a lower concentration of the drug in the blood plasma. The number of patients with antibodies to the Simsia® preparation was not sufficient to provide a definite assessment of the relationship between the antibody titre and the efficacy of the drug.

    Axial Spondyloarthritis

    In a placebo-controlled study with axial spondylitis the total number of patients who had antibodies to the Simsia® preparation at least once for 24 weeks was 4.4%. The formation of antibodies was associated with a lower concentration of the drug in the blood plasma.The number of patients with antibodies to the drug was not enough to give a definite assessment of the relationship between the antibody titre and the efficacy of the drug.

    The formation of antibodies

    In clinical trials, 4% of patients with Crohn's disease, and 2% of patients receiving placebo received antinuclear antibody production (AHA). In studies of drugs inhibitors of TNF-α, including the preparation of Sym- sia®, in some patients with rheumatoid arthritis, antinuclear antibodies (AHA). In clinical studies of the Symzyme® drug in rheumatoid arthritis and Crohn's disease, some patients developed symptoms similar to those of the lupus-like syndrome. The effect of prolonged treatment with Symmasia® on the development of an autoimmune process has not been established.

    Hypersensitivity reactions

    The following symptoms, which are similar to hypersensitivity reactions, were rarely observed after the administration of Symmy® to patients: angioedema, allergic dermatitis, itching rash, dyspnea, hot flashes, lowering blood pressure, reactions at the injection site,feeling of malaise, hyperthermia, rash, serum sickness and fainting.

    Reactions at the injection site

    In some patients, the following reactions were observed at the site of administration of the drug SymiSia®: erythema, pruritus, subcutaneous hematoma, pain, swelling, or bruising.

    There were no cases of drug withdrawal due to the development of local reactions.

    Increase in activity of creatine phosphokinase (CK)

    The incidence of increased CK activity in patients with axial spondylitis (ACA) was generally higher than in the population of patients with rheumatoid arthritis (RA). This frequency was higher in patients with ASA and RA who received placebo, respectively, 2.8% and 0.4%, and against the background of treatment with the preparation of Symmy ®, respectively, 4.7% and 0.8%.

    The increase in activity of CK in patients with ASA in most cases was transient, clinically insignificant, and did not cause the termination of participation in the study of any patient.

    Overdose:Within the framework of clinical studies, the relationship between toxicity and dose of the drug has not been documented. When subcutaneous injection of the preparation of Symsia® to 800 mg and intravenous administration of 20 mg / kg of symptoms of overdose was not noted.In case of symptoms of overdose, careful monitoring of the patient's condition and symptomatic therapy are necessary.
    Interaction:
    Simultaneous application of the preparation of Simia® with glucocorticosteroids, non-steroidal anti-inflammatory drugs drugs (NSAIDs), analgesics, salicylates, antibacterial, antiviral drugs, as well as immunosuppressants (azathioprine, mercaptopurine, methotrexate) did not affect the pharmacokinetics parameters of the drug.

    Effect on the ability to drive transp. cf. and fur:After the introduction of the Symzia®, dizziness, visual impairment and fatigue may occur, which may have an adverse effect on the ability to carry out activities requiring concentration and high speed of psychomotor reactions. Therefore, when these symptoms appear, one should refrain from managing vehicles and complex mechanisms.
    Form release / dosage:
    A solution for subcutaneous administration of 200 mg / ml.
    Packaging:
    By 1.0 ml of the drug in single-dose syringes of transparent colorless borosilicate glass (type I) with an asymmetrical finger rest and a piston rod with a rubber seal,equipped with a 25G x 1/2 "stainless steel injection needle with a rubber protective cap and an outer polypropylene cap equipped with a ring for easy opening.
    2 syringes are placed in a contour pack of sheet plastic (correx).
    1 Correx complete with 2 individually packaged napkins, isopropanol impregnated with 70%, together with the instruction for use, is placed in a cardboard package of the "Wallet" type.
    Storage conditions:
    In the dark place at a temperature of 2 to 8 ° C. Do not freeze.
    Keep out of the reach of children.
    Shelf life:
    2 years. Do not use after the expiration date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:PL 000008
    The owner of the registration certificate: YUSB Farma S.A. YUSB Farma S.A. Belgium
    Manufacturer: & nbsp
    Representation: & nbspYUSB FARMA LLC YUSB FARMA LLC Russia
    Information update date: & nbsp18.10.2015
    Illustrated instructions
    Instructions
    Up