Simponi® (Simponi® )

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceGolimumabGolimumab
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  • Simponi®
    solution PC 
    MSD FARMASYUTIKALS, LLC     Russia
  • Simponi®
    solution PC 
    MSD FARMASYUTIKALS, LLC     Russia
    • Dosage form: & nbsphypodermic solution
    Composition:

    In 0.5 ml of solution contains:

    active substance: golimumab 50 mg;

    Excipients: sorbitol 20.5 mg, histidine 0.44 mg, polysorbate-80 0.075 mg, water for injection 0.5 ml.

    Description:Transparent or opalescent, colorless or light yellow solution.
    Pharmacotherapeutic group:antibodies monoclonal
    ATX: & nbsp

    L.04.A.B.06   Golimumab

    Pharmacodynamics:

    Golimumab is a human monoclonal antibody of the class IgG1k, which are produced by the mouse hybridoma cell line obtained using recombinant DNA technology.

    Mechanism of action

    Golimumab is a human monoclonal antibody that forms high affinity stable antigen-antibody complexes with both soluble and transmembrane bioactive forms of human tumor necrosis factor alpha (TNF-α), preventing the binding of TNF-α to its receptors. Increased expression of TNF-α is observed in chronic inflammatory diseases such as rheumatoid arthritis (RA), as well as in spondyloarthritis, including psoriatic arthritis (PsA) and axial spondylitis (ankylosing spondylitis (AS) and non-angiogenic axial spondylitis).TNF-α plays an important role in the development of inflammation and destruction of joints, which are typical for these diseases.

    Pharmacodynamic properties

    Binding of human TNF-α by gholimumab leads to inhibition (or suppression) of expression of adhesion molecules, including E-selectin, vascular cell adhesion molecules (VCAM-1) and intercellular adhesion molecules (ICAM-1), on the surface of endothelial cells. Besides, golimumab inhibits TNFα-induced secretion of interleukin IL-6, IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) by human endothelial cells. In vivo treatment with golimumab significantly delayed the appearance of clinical symptoms in mice with induced arthritis, and significantly inhibited the activity of pathological processes in the joints.

    Simponi ® has an effective modulating effect on inflammatory markers and bone metabolism in patients with various diseases. In particular, there was a decrease in the level of C-reactive protein (CRP) compared to the placebo group. The Simponi ® preparation caused a significant reduction in serum levels of IL-6, ICAM-1, matrix metalloproteinase-3 (MMP-3) and vascular endothelial growth factor (VEGF) compared to the control.In addition, there was a decrease in the level of TNF-α in patients with RA and AC and the concentration of IL-8 in patients with PsA. These changes were observed at the first examination (week 4) after the administration of the first dose of Simponi ® and remained until the 24th week. The use of the Simponi ® preparation with methotrexate (MT) or without it led to significant changes in serum levels of some markers of bone metabolism (an increase in the levels of osteocalcin and N-terminal propeptide of procollagen type I and a decrease in the level of deoxypyridinoline) at week 4. These changes in biomarkers are consistent with the improvement of the clinical course of the disease in the form of reducing inflammation, increasing bone growth and suppressing its resorption.

    Pharmacokinetics:

    Suction

    After a single subcutaneous administration of golimumab to healthy volunteers or patients with RA, the mean time to reach the maximum serum concentration (Tmax) was from 2 to 6 days. After subcutaneous administration of 50 mg of golimumab to healthy volunteers, the maximum serum concentration (Cmax) was 3.1 ± 1.4 μg / ml (mean ± standard deviation). After subcutaneous administration of Cmax and the area under the concentration-time curve (AUC) increased in proportion to the dose in the dose range of 50 to 400 mg.

    Absorption of golimumab was similar after a single injection of 100 mg under the skin of the shoulder, abdomen and thigh, and the average absolute bioavailability was 51%. Given the almost proportional dose of the pharmacokinetics of golimumab after subcutaneous administration, absolute biodegradationcThe treadmill dose of 50 mg or 200 mg of golimumab should be appropriate for a dose of 100 mg.

    Distribution

    After a single intravenous administration of the drug, the average volume of distribution amounted to 115 ± 10 ml / kg.

    Excretion

    The systemic clearance of golimumab was 6.9 ± 2.0 ml / day / kg. Half-life in healthy volunteers and patients with RA, PsA, AS or YaK (ulcerative colitis) was 12 ± 3 days.

    In patients with RA, PsA or AC, who received golimumab subcutaneously at a dose of 50 mg every 4 weeks, serum concentrations reached equilibrium levels at week 12. In the combined use of MT and subcutaneous administration of golimumab at a dose of 50 mg every 4 weeks, the median (± standard deviation) of the equilibrium minimum serum concentration was about 0.6 ± 0.4 μg / ml in patients with active RA, despite MT therapy, ,5 ± 0.4 μg / ml in patients with active PcA and about 0.8 ± 0.4 μg / ml in patients from AC. The minimum mean equilibrium serum concentration of golimumab in patients with non-radiographic axial spondylitis was comparable to that observed in patients with AS who received golimumab subcutaneously in dose 50 mg every 4 weeks.

    In patients with RA, PsA or AC who did not receive concomitant MT therapy, the equilibrium minimum concentrations of golimumab were approximately 30% lower than those in patients receiving golimumab with MT. In population pharmacokinetic analysis in patients with RA it was also shown that the combined use of MT can lead to a decrease in the apparent clearance of golimumab by 36%. Nevertheless, the combined use of non-steroidal anti-inflammatory drugs, oral corticosteroids or sulfasalazine did not affect the apparent clearance of golimumab.

    After the administration of two induction doses (200 mg in Week 0, 100 mg in Week 2) and further supporting doses (50 mg or 100 mg every 4 weeks) in patients with YaK, serum concentrations of golimumab reached equilibrium at about the 14th week after initiation therapy.When using a 50 mg or 100 mg golimumab subcutaneously every 4 weeks during maintenance therapy minimum serum concentration at steady state was about 0.9 ± 0.5 mcg / mL and 1.8 ± 1.1 mcg / ml respectively.

    In patients with YaK who received golimumab subcutaneously at 50 mg or 100 mg every 4 weeks, sharing with immunosuppressants did not have a visible effect on minimal equilibrium concentrations of golimumab.

    The appearance of antibodies to golimumab is usually accompanied by a decrease in the minimum equilibrium serum concentrations of golimumab.

    Linearity

    In patients with RA, the pharmacokinetics of golimumab was proportional to the dose in the range of 0.1 to 10.0 mg / kg after a single intravenous administration. After a single subcutaneous administration of golimumab to healthy volunteers, the pharmacokinetic parameters were proportional to the dose in the dose range of 50 to 400 mg.

    Effect of body weight on pharmacokinetics

    With population pharmacokinetic analysis, there was a tendency to increase the apparent clearance of golimumab with an increase in body weight.

    Indications:

    Rheumatoid arthritis

    Preparation Simponi® in combination with MT is used according to the following indications:

    - treatment of active rheumatoid arthritis in adult patients in whom the response to therapy with basic anti-inflammatory drugs (MPA), including MT, was inadequate;

    - treatment of severe, active and progressive rheumatoid arthritis in adult patients who have not previously received MT.

    The use of Simponi ® in combination with MT delays the radiologic progression of structural damage and improves physical function. The Simponi ® preparation can be used in patients who previously received one or more TNF inhibitors.

    Psoriatic arthritis

    The Simponi ® preparation is used in the form of monotherapy or in combination with MT for the treatment of active and progressive psoriatic arthritis in adult patients in whom the response to therapy with DPOI was inadequate.

    The use of the Simponi® drug delays the radiologic progression of structural lesions in patients with symmetrical peripheral polyarthritis, and also improves the physical function.

    Axial spondylitis

    Ankylosing spondylitis

    Simponi ® is used to treat severe, active ankylosing spondylitis the Adult patients whose response to standard therapy was inadequate.

    Neretgenaboutgraphic axial spondylitis

    The Simponi ® preparation is used for the treatment of severe, active non-radiographic axial spondylitis with objective signs of inflammation, such as an increase in the concentration of CRP and / or the corresponding changes observed in magnetic resonance imaging (MRI) in adult patients in whom answer on therapy with non-steroidal anti-inflammatory drugs (NSAIDs) was inadequate, or in the presence of intolerance to NSAIDs.

    Ulcerative colitis

    Simponi ® is used for the treatment of moderate and severe active ulcerative colitis in adult patients whose response to standard therapy (using corticosteroids and 6-mercaptopurine or azathioprine) has been inadequate, or with intolerance or contraindications to standard therapy.

    Contraindications:

    - Hypersensitivity to the active substance or to any auxiliary substance;

    - active tuberculosis (TB) or other severe infectious processes, such as sepsis and opportunistic infections;

    - moderate or severe heart failure (III/IV class on NYHA);

    - pregnancy;

    - the period of breastfeeding;

    - children under 18 years of age (efficacy and safety not studied).

    Carefully:

    Infections

    Before prescribing the Simponi ® drug, during therapy and for 5 months after the end, patients should be carefully monitored for infection. In case of severe infection or sepsis, therapy should be discontinued (see section "Contraindications").

    The Simponi ® preparation should not be administered to patients with a clinically active infection. Care should be taken when using Symponi ® in patients with a chronic infection or a recurring infection in the anamnesis. Patients are advised to avoid exposure to potential risk factors for infection as much as possible.

    Patients receiving therapy with TNF inhibitors are at greater risk of developing the infectious process. There are reports of the development of bacterial (including sepsis and pneumonia), mycobacterial (tuberculosis),invasive fungal and opportunistic infections, including fatal cases, in patients receiving TNF inhibitors, including Simponi ®. In some cases, serious infections developed in patients receiving concomitant therapy with immunosuppressants, which, like the disease itself, predisposes to the development of infections. Patients with new cases of infectious diseases should be carefully examined. The use of the Simponi® drug should be discontinued in cases of severe infections or sepsis followed by the appointment of appropriate antibacterial or antifungal therapy, up to the control of the infectious process.

    Before starting treatment with Sympony®, patients who have visited or lived in regions endemic for invasive mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis, the possible benefits and risks of Simponi® treatment should be carefully weighed.

    Tuberculosis

    There have been reports of the development of active tuberculosis in patients treated with Simponi ®. Most cases of tuberculosis were with extrapulmonary localization in the form of both local and disseminated disease.

    Before starting therapy with Sympony®, the patient should be closely monitored for both active and latent tuberculosis. The examination should include a careful history, including whether the patient had had a TB disease in the past, had contacts with tuberculosis patients, and whether immunosuppressant therapy had been or was being conducted. It is necessary to conduct the necessary screening tests (chest x-ray, tuberculin test). In this case, it should be taken into account that in patients with severe illness and in patients with immunosuppression, a false-negative tuberculin test can be obtained.

    When diagnosing active tuberculosis therapy with Simponi ® can not be started (see the section "Contraindications").

    If suspicion of latent tuberculosis should be consulted phthisiatrician. In all cases described below, the possible risk and expected benefit of the Simponi® therapy should be carefully evaluated.

    When diagnosing latent tuberculosis, appropriate therapy should be started before the initiation of therapy with the Simponi® preparation.

    In patients with multiple or significant risk factors for developing tuberculosis, but whose latent tuberculosis is not confirmed by the test, consideration should be given to the need for antituberculous therapy before initiating therapy with Simponi®. Consideration should be given to the need for the use of antituberculosis therapy prior to the initiation of therapy with the Simponi ® drug in patients with active or latent tuberculosis in history, for which an adequate course of therapy can not be confirmed.

    There have been reports of the development of active tuberculosis in patients treated with Simponi ® during and after the treatment of latent tuberculosis. Patients receiving Simponi® therapy, including patients with negative latency tuberculosis test results, patients receiving latent tuberculosis therapy, and patients who had previously been treated for tuberculosis, require careful monitoring for signs and symptoms of active tuberculosis.

    Patients should consult a doctor if signs or symptoms of tuberculosis appear (persistent cough, weight loss / weight loss, subfebrile fever) during or after therapy with Simponi®.

    Reactivation of the hepatitis B virus

    As with other immunosuppressants, therapy with TNF-α inhibitors was accompanied by the reactivation of hepatitis B virus in chronic carriers of the virus (with a positive surface antigen test), including with the development of a lethal outcome. All patients before the start of therapy should be examined for the exclusion of viral hepatitis B. Chronic carriers of the hepatitis B virus must be careful monitoring before the start of treatment, during treatment and for several months after discontinuation of treatment with Simponi ®.

    Data on the effectiveness of the combined use of antiviral therapy and TNF-α inhibitors in patients - chronic virus carriers are not available.

    With the reactivation of a viral infection, treatment with Simponi® should be stopped and appropriate antiviral therapy is prescribed.

    Malignant tumors

    The possible role of therapy with TNF-α inhibitors in the development of malignant tumors has not been established, however, based on current data, the risk of developing lymphomas, leukemias and other malignant tumors against anti-TNF-α therapy can not be ruled out.Caution should be exercised when prescribing TNF inhibitors in patients with a history of malignant tumors or with continued therapy in the event of a malignant tumor.

    Malignant tumors in children

    During the postmarketing studies, cases of the formation of malignant tumors, some fatal, among children, adolescents and adult young people (under the age of 22 years) who received inhibitors of TNF (initiation of therapy at the age of ≤18 years) were reported. Approximately half of the cases reported lymphomas. Other cases are represented by a number of different malignant tumors, including malignant tumors that are not usually seen in children and adolescents. Most patients received concomitant therapy with immunosuppressants, such as methotrexate, azathioprine or 6-mercaptopurine. The role of TNF inhibitors in the development of malignant tumors in children and adolescents remains unclear.

    Lymphoma and leukemia

    In controlled clinical trials of therapy with all TNF inhibitors, including the Simponi® drug, lymphoma cases were recorded more often in patients treated with TNF inhibitors than in the control group.In clinical studies 2b and 3 phases, the frequency of lymphoma in patients treated with the Simponi ® preparation was higher than the expected frequency in the general population.

    In the course of post-marketing use of TNF inhibitors, cases of development of leukemia were reported. Since the risk of developing lymphoma and leukemia is elevated in patients with rheumatoid arthritis with a protracted, highly active inflammatory disease, risk assessment is difficult.

    In the post-marketing period, rare cases of hepatolienal T-cell lymphoma were reported in the treatment with TNF inhibitors. This rare type of T-cell lymphoma is characterized by a very aggressive course of the disease and usually ends in a lethal outcome. Almost all cases have been reported in patients with Crohn's disease or in patients with ulcerative colitis, most of which have been reported in adolescents or young adult men. Almost all of these patients received azathioprine or 6-mercaptopurine therapy together with a TNF inhibitor during or before the diagnosis. A possible risk of simultaneous use of azathioprine or 6-mercaptopurine and Simponi® should be carefully evaluated.It is impossible to exclude the risk of developing hepatolienneal lymphoma in patients receiving TNF inhibitors.

    Non-lymphocytic malignant tumors

    In controlled clinical trials of the Simponi® 2b and 3 phases in patients with RA, PcA, AC and YaK, the frequency of other malignant tumors (with the exception of non-melanoma skin cancer) was similar in the Simponi® group and in the control group.

    In a clinical study evaluating the use of the Simponi® drug in patients with severe persistent asthma, malignant tumors in patients treated with the Simponi® drug were more common than in the control group (see "Side effect" section). The significance of this fact is not established.

    In a clinical trial using a different inhibitor of TNF-α, infliximab, a large incidence of lung, head and neck tumors in the TNF inhibitor group was observed in patients with moderate to severe chronic obstructive pulmonary disease (COPD) compared with the control group. Caution should be exercised in prescribing TNF inhibitors in patients with COPD, as well as in high-risk patients, such as chronic smokers.

    Dysplasia / colorectal cancer

    It is not known whether therapy with Simponi ® influences the risk of developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk for developing dysplasia or colon cancer (for example, patients with prolonged ulcerative colitis or primary sclerosing cholangitis) and patients with dysplasia or colon cancer in the anamnesis should be screened regularly (before and during therapy) for the appearance of dysplasia. The examination should include a colonoscopy and a biopsy, depending on local recommendations. Patients taking the Simponi ® preparation with newly diagnosed dysplasia should carefully evaluate the possible risk and expected benefit of Simponi ® therapy and decide whether to continue or discontinue therapy.

    Malignant neoplasm of skin

    Patients receiving TNF-α blockers, including Simponi®, reported cases of melanoma development. There have been reports of the development of Merkel's carcinoma in patients receiving other TNF-α (not golimumab). It is recommended to conduct periodic examination of skin in patients,especially in patients with risk factors for the development of malignant skin tumors.

    Chronic heart failure (XCH)

    In the treatment of TNF inhibitors, there have been cases of growth or development of chronic heart failure, including when treated with Simponi ®. In clinical studies using other TNF inhibitors, progression of heart failure and increased mortality due to CHF were observed.

    The effect of the Simponi ® preparation has not been studied in patients with CHF. The Simponi ® drug should be used with caution in patients with mild heart failure (I/II class on NYHA). Patients should be monitored, and if there is a new or worsening of the existing signs of heart failure, therapy with Simponi® should be discontinued (see "Contraindications").

    Neurological disorders

    The use of TNF inhibitors, including the Simponi ® preparation, was rarely accompanied by the appearance or increase in clinical and / or radiographic signs of demyelinating diseases of the central nervous system (including multiple sclerosis) and the peripheral nervous system.In patients with existing or newly emerging demyelinating diseases, the use and risk of treatment with TNF inhibitors should be weighed carefully before the appointment of the Simponi ® preparation. In the case of the development of such diseases, therapy with Simponi® should be discontinued.

    Surgery

    Data on the safety of the use of Simponi ® in patients receiving surgical treatment, including arthroplasty, are limited. When planning operations, it is necessary to take into account the long half-life. When performing operations, patients receiving therapy with the Simponi ® drug need careful monitoring of infections and timely therapy if they occur.

    Immunosuppression

    There is a potential likelihood of exposure to TNF inhibitors, including the Simponi® preparation, on immunity against infections and tumors associated with blockade of inflammation and modulation of the cellular response mediated via TNF-α.

    Autoimmune processes

    The relative deficiency of TNF-α on the background of therapy with TNF inhibitors can lead to the development of autoimmune processes.With the appearance of clinical symptoms of lupus-like syndrome and positive tests for antibodies to double-stranded DNA, therapy with Simponi® should be discontinued.

    Combined use of the Simponi ® preparation and anakinra preparation

    The combined use of anakinra and another TNF inhibitor, etanercept, in clinical studies was accompanied by the development of serious infections and neutropenia and did not lead to an additional clinical effect. Given the nature of the side effects observed with this combination therapy, it can be assumed that similar types of toxicity can occur with combined drug therapy anakinra and other TNF inhibitors. In this regard, the combined use of the drug Simponi ® and anakinros is not recommended.

    Combined application of Simponi® and the drug abatacept

    In clinical studies, the combined use of TNF and abatacept inhibitors was associated with an increased risk of infection, including serious infections, compared with the use of only TNF inhibitors, without increasing clinical benefit.Due to the nature of the side effects observed with combined therapy with TNF inhibitors and abatacept, the combination of Simponi® and abatacept is not recommended.

    Joint application with other biological preparations

    There is insufficient data on the joint use of the Simponi ® preparation and other biological preparations intended for use under the same indications. The joint use of the Simponi ® preparation with these drugs is not recommended in view of a possible increase in the risk of infection.

    Transfer from another biological preparation

    Care should be taken when transferring from one biological product to another, as cross-biological activity may increase the risk of infection.

    Hematologic reactions

    In the post-marketing study, there have been reports of pancytopenia, leukopenia, neutropenia, and thrombocytopenia in patients receiving TNF inhibitors, including Simponi®. Caution should be exercised when treating Simponi ® with patients with cytopenia or with a history of serious history of cytopenia.Patients with development of signs of hematologic disorders (persistent fever, bruising, bleeding, pallor) should be immediately examined. In the case of severe hematologic abnormalities, therapy with Simponi® should be discontinued.

    Allergic reactions

    In the post-marketing study of Simponi®, serious systemic hypersensitivity reactions, including anaphylactic ones, are described. Some cases are described after the first administration of the drug. In cases of development of anaphylactic reactions or other serious allergic reactions, the use of the Simponi® drug should be discontinued and appropriate therapy prescribed.

    Pregnancy and lactation:

    Women of childbearing age, when taking treatment with goilitum and for at least 6 months after the end, should use reliable contraceptive methods.

    Pregnancy

    Data on the use of golimumab in pregnant women is not enough. In connection with the inhibition of TNF, golimumab can lead to a violation of the immune response in the newborn. In pre-clinical studies, the drug did not have a direct or indirect adverse effect on the course of pregnancy,embryo / fetus development, labor activity or postnatal development. Use of golimumab in pregnant women is not recommended (see section "Contraindications").

    Golimumab penetrates the placenta. Monoclonal antibodies, TNF inhibitors, were determined for up to 6 months in serum in children born to women who received therapy with TNF inhibitors during pregnancy. As a consequence, such children may have an increased risk of developing infections, and administering live vaccines is not recommended within 6 months from the last administration of mother's golimumab.

    Breastfeeding period

    It is not known whether golimumab with milk from people and whether it is absorbed after ingestion. Golimumab was detected in milk in monkeys, and since human immunoglobulins are excreted in breast milk, the use of the Simponi® preparation When breastfeeding for at least 6 months after the last injection of golimumab is contraindicated.

    Impact on fertility

    Studies on the effect of golimumab on fertility have not been conducted. A study in mice using a similar antibody that inhibited murine TNF-α did not reveal an effect on fertility.

    Dosing and Administration:

    Subcutaneously.

    Treatment with Simponi ® should be started and carried out under the supervision of qualified doctors with experience in the diagnosis and treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondylitis or ulcerative colitis.

    After training in the hypodermic injection technique, patients can themselves administer the Simponi® preparation if the doctor considers this possible. In this case, the doctor should continue to monitor the patient.

    Patients should be instructed that they should be given the entire volume of the Simponi ® preparation, according to the instructions for medical use. If you want to do several injections at the same time, the drug is injected into various parts of the body.

    Adults (≥18 years old)

    Rheumatoid arthritis

    The Simponi ® preparation 50 mg is administered subcutaneously monthly on the same day of the month.

    The drug Simponi ® is used in combination with methotrexate.

    Psoriatic arthritis, ankylosing spondylitis or non-radiographic axial spondylitis

    The Simponi ® preparation 50 mg is administered subcutaneously monthly on the same day of the month. For of all the above indications the data at the current time indicate the development of a clinical response between 12-14 weeks of therapy (3-4 injections). In the absence of effect during this period, it is necessary to evaluate the appropriateness of further use of the drug.

    Patients with a body weight of more than 100 kg

    For all of the above indications, patients with RA, PsA, AC or non-radiographic axial spondylitis with a body weight of more than 100 kg in the absence of an adequate response after 3-4 injections, it is possible to consider increasing the dosage of nolimumab up to 100 mg monthly, taking into account the possible increase in the risk of serious adverse reactions associated with an increase in the dose. In the absence of effect after 3-4 injections of 100 mg golimumab, it is necessary to re-evaluate the appropriateness of further use.

    Ulcerative colitis

    Patients weighing less than 80 kg

    The first dose of Simponi ® is 200 mg subcutaneously, then 100 mg after 2 weeks, and then 50 mg every 4 weeks.

    Patients with a body weight of 80 kg and more

    The first dose of Simponi ® is 200 mg subcutaneously, then 100 mg after 2 weeks, and then 100 mg every 4 weeks.

    During maintenance treatment, it is possible to gradually reduce the dose of corticosteroids in accordance with current clinical guidelines.Data for the current time indicate the development of a clinical response between 12-14 weeks of therapy (through 4 injections). In the absence of effect during this period, it is necessary to evaluate the appropriateness of further use of the drug.

    Injection skip

    If the injection was not performed on the scheduled date, the next injection should be as soon as possible. In case of self-administration of the Simponi ® drug, the patient should not increase the dose in order to compensate for the missed injection.

    If less than 2 weeks have elapsed since the planned date of injection, the next injection should be performed at the same dose as usual, and then the therapy is continued in accordance with the previous regimen.

    If more than 2 weeks have passed since the planned date of injection, the next injection should be performed at the same dose as usual, and then the therapy is continued in a new mode.

    Elderly patients (≥65 years of age)

    Correction of dose in elderly patients is not required.

    Children (≤18 years)

    Due to the lack of data on efficacy and safety in this age group, the use of the Simponi ® preparation in children and adolescents under 18 years of age is contraindicated (see.section "Contraindications").

    Patients with impaired renal and / or liver function

    The effect of Simponi ® was not studied in such patients. Give any special recommendations for dosing can not.

    Instructions for the administration of the drug Simponi® using a pre-filled syringe

    If you want to administer Sympony® alone, you must be trained to prepare for injection and self-administered by a qualified technician. If you have not completed the training, please contact behind consultation with a specialist.

    Step 1: Preparation for use of the pre-filled syringe

    The figure below shows the appearance of the pre-filled syringe (see Fig. 1).

    Hold the pre-filled syringe behind the body

    - Do not hold a pre-filled syringe behind the piston tip, piston, needle fuse wings or needle protective cap.

    - Never pull the piston.

    - Never shake the pre-filled syringe.

    - Do not remove the protective cap of the needle from the pre-filled syringe until you are ready to administer the drug - see step 3.

    - Do not touch the needle fuse activation clips (marked with "*" in the first figure) to prevent the needle from closing prematurely with a fuse.

    Calculate the number of syringes needed

    - Make sure that the correct number of syringes is used.

    - If you need 50 mg, take 1 pre-filled syringe with 50 mg golimumab.

    - If you need to inject 100 mg, take 2 pre-filled syringes with 50 mg golumumab (2 injections will be necessary), for the 2 injections select different sites (for example, the first injection in the right thigh, the second injection in the left thigh). Injections are done one after another.

    - If you need to enter 200 mg, take 4 pre-filled syringes with 50 mg of gholimumab (you will need to make 4 injections). To conduct these injections, select different sites. Injections are done one after another.

    Check expiration date

    - Check the expiry date (marked as "YEAR BEFORE") on the label, looking through the inspection window located in the body of the pre-filled syringe.

    - If you can not see the expiration date through the inspection window, take the pre-filled syringe for its housing and rotate the protective cap of the needle so that the position of the expiration date in the viewing window is aligned.

    - You can also check the expiry date printed on a cardboard box.

    - He Use a pre-filled syringe if its expiration date has expired. Expiration date is the last day of the month indicated on the packaging. Consult your doctor or pharmacist (see Figure 2).

    Wait 30 minutes for the syringe to reach room temperature

    - To perform the injection properly, remove the syringe from the carton and leave it for 30 minutes at room temperature in a place inaccessible to children.

    - Do not heat the syringe in another way (for example, in a microwave oven or hot water).

    - Do not remove the cap from the syringe at room temperature.

    Prepare additional materials

    - Prepare additional materials that will be required to perform the injection (an alcohol sponge, a cotton ball or gauze and a container for sharp objects).

    Check the solution in a pre-filled syringe

    - Take the pre-filled syringe by the body, pointing the needle cap down.

    - Look at the solution through the sight glass of the pre-filled syringe to make sure that the solution is clear or slightly opalescent, colorless or light yellow. It is acceptable to use a solution containing several small translucent or white protein particles.

    - If you can not see the solution through the inspection window, take the pre-filled syringe for its housing and rotate the protective cap of the needle so that the solution position in the viewing window is leveled.

    - You can also notice an air bubble. This is normal.

    - Do not use a syringe if the solution has a different color, cloudy or contains large particles. In this case, consult a doctor or pharmacist.

    STEP 2: Selection and preparation of injection site

    - Usually, the injection site is the middle part of the front surface of the thighs.

    - You can also inject the drug into the lower abdomen under the navel, with the exception of an area of ​​about 5 cm directly below the navel.

    - Do not administer the drug to areas of the skin where there is soreness, bruising, redness, peeling or condensation. Avoid areas where there are scars or stretch marks.

    - If several injections are required at the same time, the drug should be administered to various parts of the body (see Figure 3).

    - If the injection is performed by another person, the drug can be injected into the upper part of the outer surface of the shoulder (see Figure 4).

    - Injection is allowed to be carried out in any of the indicated places, regardless of weight and physique.

    Preparation of injection site

    - Wash your hands thoroughly with warm water and soap.

    - Wipe the injection site with an alcoholic napkin.

    - Wait until the skin has dried. Do not blow on a prepared clean patch of skin.

    - Before the injection, do not touch this area any more.

    ETAP 3: Introduction preparation

    - Do not remove the cap until you are ready to administer the drug. The drug should be administered within 5 minutes after removing the cap.

    Remove the protective cap of the needle

    - When you are ready to perform the injection, take the pre-filled syringe by the body with one hand and immediately remove the protective cap of the needle with the other hand, without touching the piston.

    - Discard the protective cap of the needle after injection.

    - You can notice an air bubble in the pre-filled syringe. You do not need to remove the air bubble.

    - You can also see a droplet of liquid on the tip of the needle. This is normal (see Figure 5).

    - He Touch the needle and do not touch the surface with any needle.

    - Do not use a pre-filled syringe if you dropped it with the protective cap removed. In this case, consult a doctor or pharmacist.

    Arrange the syringe and perform the injection

    - Take the body of the pre-filled syringe with one hand between the middle and index fingers and place the thumb on top of the piston tip. Use another hand to gently collect the previously cleansed skin into the crease. Hold it tightly.

    - Place the needle at an angle of about 45 degrees to the compressed skin. One quick movement Insert the needle through the skin as deep as it can enter (see Figure 6).

    - Insert the product completely, pressing the piston until the piston tip is completely located between the needle fuse wings (see Figure 7).

    - When the piston moves to the stop, continue pressing on the tip of the piston, remove the needle from the skin and stop squeezing the skin.

    - Slowly remove the thumb from the piston tip so that the empty syringe goes up until the needle is completely closed with a fuse, as shown in the figure (see Figure 8).

    STAGE 4: After injection

    Use a ball of cotton or gauze

    - At the injection site, a small amount of blood or fluid can be observed. This is normal.

    - You can press a cotton ball or gauze onto the injection site for 10 seconds.

    - If necessary, the injection site can be sealed with a small piece of the plaster.

    - Do not rub the injection site.

    Disposal of an empty syringe

    - Immediately place the empty syringe in the sharps container. For your safety and health and for the safety of others, needles and empty syringes should not be reused.

    - Dispose of the sharps container in accordance with local regulations (see Figure 9).

    Instructions for the administration of the drug Simponi® with using an autoinjector / pre-filled syringe pen

    If you want to administer the drug Simponi® on your own, you should undergo training but preparation for injection and its independent implementation from a competent specialist. If you are not trained, please consult a specialist.

    Step 1: Preparation for use of the pre-filled syringe pen

    The figure below shows the appearance of the pre-filled syringe handle (see Figure 10).

    - Never shake the syringe pen.

    - Do not remove the cap from the syringe pen until you are ready to administer the drug - see step 3.

    Calculate the number of syringes needed

    - Make sure that the correct amount of syringes is used.

    - If you need to enter 50 mg, take 1 pre-filled syringe pen with 50 mg golimumab.

    - If you need to inject 100 mg, take 2 pre-filled syringe pens with 50 mg golimumab (you will need to make 2 injections). For 2 Injections select different areas (for example, the first injection in the right thigh, the second injection in the left thigh). Injections are done one after another.

    - If you need to enter 200 mg, take 4 pre-filled syringe pens with 50 mg golimumab (you will need to make 4 injections).To conduct these injections, select different sites. Injections are done one after another.

    Check expiration date

    - Check the expiry date (marked as "YEAR BEFORE") on the syringe pen.

    - You can also check the expiry date printed on a cardboard box.

    - Do not use a syringe pen if its expiration date has expired. Expiration date is the last day of the month indicated on the packaging. Consult a physician or pharmacist for advice.

    Check the protective film

    - Check the protective film around the cap of the syringe pen.

    - If the protective film is damaged, do not use a syringe pen. Consult a physician or pharmacist for advice.

    Wait 30 minutes for the syringe pen to warm up to room temperature

    - To perform the injection properly, remove the syringe pen from the cardboard pack and leave it at room temperature for 30 minutes out of the reach of children place.

    - Do not heat the syringe handle in another way (for example, in a microwave oven or hot water).

    - Do not remove the cap from the syringe at room temperature.

    Prepare additional materials

    - Prepare additional materials that will be required to perform the injection (an alcohol sponge, a cotton ball or gauze and a container for sharp objects).

    Check the solution in the syringe pen

    - Look at the solution through the inspection window of the pen syringe to make sure that the solution is clear or slightly opalescent, colorless or light yellow. It is acceptable to use a solution containing several small translucent or white protein particles.

    - You can also notice an air bubble. This is normal.

    - Do not use a syringe pen if the solution is of a different color, cloudy or contains large particles. In this case, consult a doctor or pharmacist.

    STEP 2: Selection and preparation of injection site

    Choose the injection site

    - Usually, the injection site is the middle part of the front surface of the thighs.

    - You can also inject the drug into the lower abdomen under the navel, with the exception of an area of ​​about 5 cm directly below the navel.

    - Do not administer the drug to areas of the skin where there is soreness, bruising, redness, peeling or condensation. Avoid areas where there are scars or stretch marks.

    - If you need to do several injections at the same time, you should inject the drug into different parts of the body.

    - If the injection is performed by another person, then the drug can be administered at upper part of the outer surface of the shoulder.

    - Injection is allowed to be carried out in any of the indicated places, regardless of weight and physique.

    Preparation of injection site

    - Wash your hands thoroughly with warm water and soap.

    - Wipe the injection site with an alcoholic napkin.

    - Wait until the skin has dried. Do not blow on a prepared clean patch of skin.

    - Before the injection, do not touch this area any more.

    STEP 3: Administration of the drug

    - Do not remove the cap until you are ready to administer the drug. The drug should be administered within 5 minutes after removing the cap.

    Remove the cap

    - When you are ready to perform the injection, slightly turn the cap to open the protective film.

    - Remove the cap and discard it after injection (see Figure 11)

    - Do not put the cap back on, as this may damage the needle inside the pen syringe.

    - Do not use a syringe pen if you dropped it with the cap removed. In this case, consult a doctor or pharmacist.

    Press firmly syringe pen to skin

    - Take the syringe-pen so that it is convenient for you to hold it and the arm. Do not press the button.

    - You should choose one of 2 methods of administration. It is recommended to inject the drug without making a skin fold. But if you want to make a skin fold to create a denser surface during the injection, then this is permissible.

    - Without pressing the button, firmly press the open end of the pen syringe to the skin at an angle of 90 degrees until the safety sleeve completely appears in the transparent section (see Fig. 12,13).

    Click on the button to enter the drug

    - Continuing to tightly press the syringe pen against the skin, press the front raised part of the button. You can press the button only if the syringe pen is tightly pressed against the skin, and the safety sleeve is inside the transparent section.

    - After pressing the button, it remains in the pressed position, so you do not need to continue pressing it (Fig. 14).

    - You will hear a loud "click". The first loud "click" means that the needle was inserted and the injection started. In this case, you can feel or not feel the needle prick.

    - Do not remove the syringe pen from the skin.If you take the pen syringe from the skin, then not the entire dose of the drug can be administered.

    Wait for the second "click"

    - Continue to press the syringe pen against the skin until you hear a second "click" (usually it takes about 3-6 seconds, but it can take up to 15 seconds).

    - The second "click" means that the injection is completed and the needle is drawn back into the syringe pen. If you have a weakened hearing, count 15 seconds from the time you pressed the button, and then take the pen syringe away from the injection site.

    - Remove the syringe from the injection site (see Figure 15).

    STAGE 4: After injection

    Use a ball of cotton or gauze

    - At the injection site, a small amount of blood or fluid can be observed. This is normal.

    - You can press a cotton ball or gauze 10 seconds into the injection site.

    - If necessary, the injection site can be sealed with a small piece of the plaster.

    - Do not rub the injection site.

    Check the viewing window - yellow indicator confirms, that the syringe-pen worked correctly.

    - The yellow indicator is connected to the plunger of a disposable syringe. If the yellow indicator does not appear in the viewing window, then the plunger has not moved sufficiently and the injection has not occurred.

    - The yellow indicator can occupy about half the viewing window. This is normal.

    - If you do not see the yellow indicator in the viewing window or you think that the dose was not administered, ask your doctor or pharmacist for help. Do not administer a second dose without consulting your physician (see Figure 16).

    Disposal of the syringe pen

    - Immediately place the syringe pen in the sharps container.

    - Dispose of the sharps container in accordance with local regulations.

    Compatibility studies have not been conducted, so this drug should not be confused with other drugs. Unused product or waste should be disposed of in accordance with applicable regulations.

    Side effects:

    In the controlled period of basic clinical trials of patients with RA, PsA, AS, non-radiographic axial spondylitis and YaK, the most frequent adverse reaction was upper respiratory tract infection (in the golimumab group, the frequency was 12.6% compared to 11.0% in the control groups) . Among serious adverse reactions, severe infections (including sepsis, pneumonia, TB, invasive fungal and opportunistic infections) have been observed.demyelinating diseases, lymphoma, reactivation of viral hepatitis B, chronic heart failure, autoimmune diseases (lupus-like syndrome) and hematologic disorders (see the section "With caution").

    The undesirable reactions observed in clinical trials and the post-registration period of use of the Simponi® preparation are listed in Table 1. They are distributed according to the system-organ classes and frequency based on the following criteria: very frequent (≥ 10%), frequent (≥1% and <10 %), infrequent (≥0,1% and <1%), rare (≥0,01% and <0,1%), very rare (less than 0,01%), unknown (can not be estimated based on available data).

    Table 1. Undesirable reactions

    Infectious and parasitic diseases

    Very Frequent:

    Infection of the upper respiratory tract (nasopharyngitis, pharyngitis, laryngitis, rhinitis)

    Frequent:

    Bacterial infections (such as phlegmon), lower respiratory infections (such as pneumonia), viral infections (such as influenza and herpes), bronchitis, sinusitis, superficial fungal infections, abscess

    Infrequent:

    Sepsis, including septic shock, pyelonephritis

    Rare:

    Tuberculosis, opportunistic infections (invasive fungal infections [histoplasmosis, coccidioidomycosis, pneumocystosis], bacterial, atypical mycobacterial and protozoal infections), bacterial arthritis, infectious bursitis

    Benign, malignant tumors and unspecified neoplasms

    Infrequent:

    Tumors (such as skin cancer, squamous cell carcinoma and myelocytic nevus)

    Rare:

    Lymphoma, leukemia, melanoma

    Unknown:

    Hepatolienne T-cell lymphoma *, Merkel's carcinoma *

    Violations of the blood and lymphatic system

    Frequent:

    Anemia

    Infrequent:

    Leukopenia, thrombocytopenia, pancytopenia

    Rarely:

    Aplasticanemic anemia *

    Immune system disorders

    Frequent:

    Allergic reactions (bronchospasm, hypersensitivity, urticaria), a positive reaction to autoantibodies

    Rare:

    Systemic allergic reactions (anaphylactic reactions), systemic vasculitis, sarcoidosis

    Disorders from the endocrine system

    Infrequent:

    Thyroid disorders (hypothyroidism, hyperthyroidism and goiter)

    Disorders from the metabolism and nutrition

    Infrequent:

    Increase in glucose in the blood and increase lipids

    Disorders of the psyche

    Frequent:

    Depression, insomnia

    Disturbances from the nervous system

    Frequent:

    Dizziness, headache, paresthesia

    Infrequent:

    Infringements of balance

    Rare:

    Demyelinating diseases (central and peripheral forms), dysgeusia

    Vision disorders

    Infrequent:

    Visual disturbance (clouding), conjunctivitis, allergic reactions (redness, irritation)

    Heart Disease

    Infrequent:

    Arrhythmia, angina pectoris

    Rare:

    Chronic heart failure (first detected or worsening of the present)

    Vascular disorders

    Frequent:

    Arterial hypertension

    Infrequent:

    Thrombosis (including thrombosis of deep veins and arteries), congestion

    Rare:

    Raynaud's disease

    Disturbances from the respiratory system, chest and mediastinal organs

    Frequent:

    Bronchial asthma and accompanying symptoms (wheezing, bronchial hyperactivity)

    Infrequent:

    Interstitial lung disease

    Disorders from the gastrointestinal tract

    Frequent:

    Dyspepsia, pain in the gastrointestinal tract, nausea, inflammatory diseases of the digestive tract (gastritis, colitis), stomatitis

    Infrequent:

    Constipation, gastroesophageal reflux

    Disturbances from the liver and bile ducts

    Frequent:

    Increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT)

    Infrequent

    Chololithiasis, liver dysfunction

    Disturbances from the skin and subcutaneous tissues

    Frequent:

    Itching, rash, alopecia, dermatitis

    Infrequent:

    Bullous rash, psoriasis (first detected or worsening of existing disease, palmar-plantar .pustulus), urticaria

    Rare:

    Exfoliation, vasculitis (cutaneous)

    Disturbances from musculoskeletal and connective tissue

    Rare:

    Lupus-like syndrome

    Disorders from the kidneys and urinary tract

    Rare:

    Diseases of the urinary bladder, kidney disease

    Violations of the genitals and mammary glands

    Infrequent:

    Breast diseases, menstruation disorders

    General disorders and disorders at the site of administration

    Frequent:

    Hyperthermia, asthenia, reactions at the injection site (erythema, urticaria, compaction, pain, bruising, itching, irritation, paresthesia at the injection site), chest discomfort

    Rare:

    Slow healing at the injection site

    Damage, poisoning, complications associated with the introduction

    Frequent:

    Fractures of bones

    * Observed against other inhibitors of TNF, but not observed in clinical studies of golimumab

    Infections (see the "Caution" section)

    In the controlled period of baseline clinical trials, upper respiratory tract infection was the most frequent adverse reaction (in the nolimum group, the incidence was 12.6% (calculated per 100 patient-years: 60.8, 95% CI: 55.0, 67.1) compared with 11.0% in the control groups (in terms of 100 patient-years: 54.5, 95% CI: 46.1, 64.0)). When patients were monitored during controlled and uncontrolled stages of the study for 2 years (median), the incidence of upper respiratory tract infection per 100 patient-years was 36.0 (95% CI: 34.9, 37.2) in the golimumab groups.

    In the controlled period of basic clinical studies of infection, 25.0% of patients in the golimumab group (in terms of 100 patient-years: 132.0, 95% CI: 123.3, 141.1) were observed compared with 20.2% in (in terms of 100 patient-years: 122.3, 95% CI: 109.5, 136.2). When patients were monitored during controlled and uncontrolled research stages for 2 years (median), the incidence of infections in terms of 100 patient-years was 83.5 (95% CI: 81.8, 85.3) in the golimumab groups.

    In the controlled period of studies in patients with RA, PsA, AS and non-radiographic axial spondylitis, serious infections were observed in 1.2% of patients in the golimumab group and 1.2% in the control groupx. The incidence of serious infections in terms of 100 patient-years of observation in controlled trials in patients with RA, PsA, AC and non-radiographic axial spondylitis was 7.3 (95% CI: 4.6, 11.1) in the golimumab 100 mg, 2 , 9 (95% CI: 1.2, 6.0) in the golimumab 50 mg group and 3.6 (95% CI 1.5: 7.0) in the placebo group.

    In the controlled period of induction study in patients with YaK, serious infections were observed in 0.8% of patients in the golimumab group, compared with 1.5% of patients in the control groups. Serious infections observed with golimumab therapy included tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal and other opportunistic infections. Some infections ended in a lethal outcome.

    When patients were monitored during controlled and uncontrolled stages of basic clinical trials for 2 years (median), the incidence of serious infections (including opportunistic and tuberculosis) was higher in the 100 mg golimumab group than in the 50 mg golimumab group. The incidence of all serious infections in terms of 100 patient-years was 4.3 (95% CI: 3.8, 4.8) in the 100 mg golimumab group, 2,6 (95% CI: 2,1; 3,2) in the golimumab 50 mg group.

    Malignant tumors (see the "Caution" section)

    Lymphoma

    The frequency of lymphoma in patients who received golimumab in basic clinical trials, was higher than the expected frequency in the general population. When patients were monitored during controlled and uncontrolled stages of these studies for 2 years (median), the incidence of lymphoma was higher in the 100 mg golimumab group than in the 50 mg golimumab group. A diagnosis of lymphoma was made in 9 patients (1 in the 50 mg golimumab group, 8 in the 100 mg golimumab group) with a frequency of 0.03 (95% CI, 0.00, 0.16) and 0, based on 100 patient-years of follow-up, 12 (95% CI: 0.05, 0.24) in the golimumab 50 mg and 100 mg, respectively, 0.00 (0.00, 0,59) in the placebo group. Most cases are documented in a study involving patients transferred from other TNF inhibitors who had a longer duration of the disease and refractory previous therapy.

    Non-lymphocytic malignant tumors

    In the controlled period of basic clinical trials and for approximately 2 years of follow-up, the incidence of non-lymphocytic malignancies (excluding non-melanoma skin cancer) was comparable in the golimumab and control groups.When observed for approximately 2 years, the incidence of non-lymphocytic malignancies (excluding non-melanoma skin cancer) was comparable to that in the general population.

    When patients were observed during controlled and uncontrolled stages of basic clinical trials for 2 years (median), non-melanoma skin cancer was diagnosed in 5 patients in the placebo group. 10 patients in the 50 mg golimumab group and 29 patients in the 100 mg group at a frequency of 100 patient-years of follow-up 0,38 (95% CI: 0,27; 0,52) for the combined groups of golimumab and 0,90 (95% CI: 0,29; 2,10) for the placebo group.

    When observing patients at during controlled and uncontrolled stages of basic clinical trials within 2 years (median) diagnosis of malignant tumor (except melanoma, non-melanoma skin cancer and lymphoma) was given to 5 patients in the placebo group, 19 patients in the 50 mg golimumab group and 30 patients in the 100 mg group from frequency in terms of 100 patient-years of follow-up 0,47 (95% CI: 0,35; 0,63) for the combined groups of golimumab and 0,90 (95% CI: 0,29; 2,10) for the placebo group.

    Cases reported at clinical trials in patients with asthma

    The administration of golimumab was performed subcutaneously at a higher dose than recommended for rheumatic indications (150%) at week 0,with subsequent injections of 200 mg golimumab, 100 mg or 50 mg every 4 weeks up to week 52. 8 cases of development malignant tumors reported in the united groups of golimumab (n= 230) and no case in the placebo group (n= 79): 1 patient with lymphoma, 2 patients with non-melanoma skin cancer, 5 patients with other malignant tumors.

    During the placebo-controlled part of the study, the incidence of all tumors in terms of 100 patient-years was 3.19 (95% CI: 1.38, 6.28) in the golimumab groups, including: lymphoma 0.40 (95% CI: 0.01, 2.20), non-melanoma skin cancer 0.79 (95% CI: 0.10, 2.86) and 1.99 (95% CI: 0.64, 4.63) for other malignant tumors. In the placebo group, the incidence of events in terms of 100 patient-years was 0.00 (95% CI: 0.00, 2.94). The significance of this fact ise is established.

    Neurological disorders

    When patients were observed during controlled and uncontrolled stages of basic clinical trials for 2 years (median), a greater frequency of demyelinating diseases was observed in the 100 mg golimumab group compared to the 50 mg golimumab group.

    Increased activity of hepatic enzymes

    At a controlled stage of basic clinical trials, patients with RA and PsA had a slight increase in ALT activity (> 1 and <3 timesof the upper limit of the norm) in a comparable percentage of patients in the golimumab groups and control groups (22.1-27.4% of patients); in a study in patients with AS and non-radiographic axial spondylitis the frequency of moderate increase in ALT activity in the golimumab group was higher (26.9%) than in the control groups (13.6%). When patients were monitored during controlled and uncontrolled stages of basic clinical trials in patients with RA and PsA for 5 years (median), the frequency of easy increase in ALT activity was comparable in the golimumab and control groups. In the controlled phase of the baseline clinical studies, the induction stage in patients with YaK was slightly increased ALT activity (> 1 and <3 times the upper limit of the norm) in a comparable percentage of patients in the golimumab and control groups (8.0 and 6.9%, respectively ). When patients were monitored during controlled and uncontrolled stages of the baseline clinical trial in patients with YaK for 1 year (on average), a mild increase in ALT activity was noted in 19.4% of patients in the golimumab group during the study of the maintenance phase of therapy.

    In the controlled ethane of basic clinical trials in patients with RA and AS, an increase in ALT activity ≥5 times from the upper limit of the norm was not infrequent. Frequency of activity increase ALT in the golimumab group was higher (0.4-0.9%) than in the control groups (0.0%). This trend was not observed in patients with PsA. When observing patients during controlled and uncontrolled stages of basic clinical trials in patients with RA. PsA and AC for 5 years (median), the frequency of increase in ALT activity ≥5 times from the upper limit of the norm was comparable in the groups of golumumab and control ggroups. In most cases this increase was asymptomatic and decreased / resolved after discontinuation of golimumab therapy or correction of concomitant treatment.

    In a controlled phase of the baseline clinical study, the induction stage in patients with YaK increased ALT activity ≥5 times from the upper limit of the norm was observed in a comparable percentage of patients in the golimumab and placebo groups (0.3% and 1.0%, respectively). When observing patients during controlled and uncontrolled stages of basic clinical trials in patients with YaK within 1 year (on average), the increase in ALT activity ≥5 times from the upper limit of the norm was observed in 0.7% of patients taking golimumab during the study of the supporting stage of therapy.

    In the course of basic clinical trials in patients with RA, PsA, AC and non-radiographic axial spondylitis in 1 patient with previous impairment of liver function, in a clinical study in patients from RA, developed non-infectious hepatitis with jaundice, which ended in a fatal outcome. It is impossible to completely exclude the role of golimumab as a factor that potentially provoked or intensified manifestations of the disease.

    Reactions in place injections

    In the controlled phase of the baseline clinical study, reactions at the injection site were observed in 5,4% patients in the golimumab group compared with 2.0% of the patients in the control groups. The presence of antibodies to golimumab may increase the risk of developing reactions at the injection site. Most of the reactions at the injection site were mild or moderate. Most often, there was erythema at the injection site. Reactions at the injection site did not usually lead to discontinuation of the drug.

    In controlled studies 2b and / or 3 phases in patients with RA, PsA, AC, non-radiographic axial spondylitis, severe persistent asthma and studies of YaK 2/3 phase anaphylactic reactions in patients in the golimumab groups were not recorded.

    Antinuclear antibodies (ANA) / antibodies to double-stranded DNA (dsDNA)

    When monitoring patients during the controlled and uncontrolled basic stages of clinical trials for 1 year 3.5% Group golimumab and 2.3% in the control groups were first ANA-positive (titers of 1: 160 and higher). The formation of antibodies to dsDNA in patients who had initial negative tests for antibodies to dsDNA, when observed for 1 year, was infrequent.

    Overdose:

    Single intravenous doses up to 10 mg / kg in the clinical trial were not accompanied by dose-limiting toxicity. In case of an overdose, the patient is advised to monitor the signs or symptoms of unwanted effects and immediately prescribe symptomatic treatment.

    Interaction:

    Interaction studies have not been conducted.

    Simultaneous application with other biological medicinal products

    Simultaneous application of the Simponi® preparation with drugs used for similar indications, including anakinra or abatacept,Not recommended.

    Live vaccines and medications containing infectious agents

    Living vaccines and medications containing infectious agents are not should be apply simultaneously with therapy with Simponi ® (see section "Special instructions").

    Methotrexate

    Although the joint use of MT leads to an increase in the equilibrium minimum concentrations of the Simponi ® preparation in patients with RA, PsA and AC, the data obtained indicate that there is no need to correct the dose of Simponi ® or MT (see the section "Pharmacokinetics").

    Special instructions:

    Live vaccines and medications containing infectious agents

    Patients taking the Simponi ® preparation may receive concomitant vaccination, but not with live vaccines (see "Interactions with Other Drugs"). Data on the response to vaccination or the possibility of secondary transmission of infection with live vaccines in patients receiving therapy with TNF inhibitors are insufficient. The use of live vaccines can lead to a clinical manifestation of infections, including disseminated infection.The use of drugs containing infectious agents, such as live attenuated bacteria (eg, BCG instillation for the treatment of cancer), can lead to a clinical manifestation of infections, including disseminated infection. It is not recommended simultaneous use of drugs containing infectious agents, and Simponi ®.

    Allergic reactions

    Sensitivity to latex

    The protective cap of the needle on the pre-filled syringe is made of dry natural rubber containing latex, which can cause allergic reactions in patients sensitive to latex.

    Special patient groups

    Children

    Special studies of the Simponi ® preparation in children have not been carried out.

    Elderly patients

    In Phase 3 studies in patients with RA, PsA, AC, and YaK, the incidence of adverse events, serious adverse events and serious infections with Sympony® was similar between patients 65 years of age and older and younger patients. However, when treating elderly patients, care should be taken and special attention should be given to the occurrence of infections. Patients at the age of 45 years and older did not participate in the study of non-radiographic axial spondylitis.

    Renal and hepatic impairment

    Special studies of the Simponi ® drug in patients with impaired renal and hepatic function were not performed. Care must be taken when treating patients with impaired hepatic function.

    Clinical efficacy in the treatment of rheumatoid arthritis

    The efficacy and safety of the Simponi ® preparation was studied in three multicenter, randomized, double-blind, placebo-controlled trials in more than 1500 patients aged ≥18 years with a moderate or severe active RA diagnosed according to the criteria of the American College of RheumatologyACR) at least 3 months prior to screening: in adult patients in whom the response to BPVP therapy, including MT, was inadequate; in adult patients who had not previously received MT and TNF inhibitors; in patients who previously received one or more TNF inhibitors. Simponi ® was administered subcutaneously in doses of 50 mg or 100 mg (with or without MT) every 4 weeks. The duration of the placebo-controlled phase was 24 weeks.

    In general, the clinical efficacy of Simponi ® in doses of 50 mg and 100 mg did not differ significantly.

    In all 3 phase trials, the proportion of patients responding adequately to treatment at 14 and 24 weeks in the Simponi® group was higher than in the control groups. Response to the criteria ACR was observed 4 weeks after the start of treatment with Simponi ® (when the results were first evaluated) and persisted for the next 24 and 104 weeks.

    When treated with Simponi®, a clinically and statistically significant improvement in physical function and quality of life was found in comparison with placebo. A statistically significant improvement in the ability to work and a decrease in fatigue were noted.

    In a study involving adult patients who had not previously received MT, an assessment of the effect of Simponi® on radiologic progression was made using a scale vdH-S, which takes into account the number and severity of joint erosions and narrowing of joint cracks in the hands and feet. Number of patients without new erosions or changes in the initial scale vdH-S ≤ 0 was significantly higher in patients in the Simponi® group than in the control groups (p = 0.003).The effect on radiologic progression achieved at 52 weeks was maintained up to 104 weeks.

    In patients who remained in the study and continued therapy with Simponi ®, the effect on radiographic indices was maintained from 104 to 256 weeks.

    Clinical efficacy in the treatment of psoriatic arthritis

    The safety and efficacy of Simponi® was studied in a multicenter, randomized, double-blind, placebo-controlled trial in 405 adult patients with active PsA who did not respond to non-steroidal anti-inflammatory drugs or DMAP. In this study, the time since the diagnosis was made PcA was at least 6 months before enrollment, the diameter of plaque damage to the skin was not less than 2 cm. Patients with various subtypes of PsA, including polyarthritis without rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), arthritis of distal interphalangeal joints (15%), spondylitis with peripheral arthritis (11%) and mutilating arthritis (1%). Previous therapy with TNF antagonist was the exclusion criterion.Simponi ® was administered subcutaneously in doses of 50 mg or 100 mg every 4 weeks with or without MT. Randomized patients were assigned a placebo (n= 113), Simponi® 50 mg (n= 146) and Simponi® preparation 100 mg (n= 146). The primary endpoint was the proportion of patients who achieved a 20% improvement in the criteria ACR (ACR 20) after 14 weeks. Results of treatment were compared with placebo for 24 weeks.

    In general, the clinical efficacy of Simponi ® in doses of 50 mg and 100 mg did not differ significantly.

    Improvement in the main parameters characterizing the activity of the disease was noted already at the first examination (4 weeks) after the start of treatment and persisted for 24 weeks. The response rate at 14 weeks was similar in patients with various PsA subtypes, including polyarthritis without rheumatoid nodules, asymmetric peripheral arthritis, distal interphalangeal joint arthritis, and spondylitis with peripheral arthritis. The number of patients with mutilating arthritis was not sufficient to evaluate the efficacy. The frequency of response to treatment with Simponi ® was comparable in patients who received and did not receive MT.

    When treated with Simponi ®, there was an improvement in the indices of psoriatic arthritis, including the number of swollen joints, the number of painful joints, dactylitis and enthesitis. In addition, patients who received the Simponi ® preparation showed a significant improvement in skin and nail psoriasis.

    Treatment with Simponi ® resulted in a significant improvement in physical function, as well as in the quality of life. The work ability has increased significantly, and the time spent with the patient of caregivers or patients has decreased.

    In patients who remained in the study and continued therapy with Simponi®, the effect on clinical performance persisted from 104 to 256 weeks.

    Clinical efficacy in the treatment of axial spondylitis

    Clinical efficacy in the treatment of ankylosing spondylitis

    Security and the effectiveness of Simponi ® was studied in a multicenter, randomized, placebo-controlled study in 356 adult patients with active AS. The study included patients who had signs of AC activity despite treatment with nonsteroidal anti-inflammatory drugs or with DMARD and who had not previously received TNF antagonists.From the study excluded patients with complete ankylosis of the spine. The Simponi ® preparation was administered subcutaneously every 4 weeks. Randomized patients were assigned a placebo (n= 78), Simponi® preparation 50 mg (n= 138) and the Simponi® preparation 100 mg (n= 140). The primary endpoint was the proportion of patients who achieved improvement in the form of ASAS 20 in 14 weeks. Efficacy was compared with placebo for 24 weeks.

    In general, the clinical efficacy of Simponi ® in doses of 50 mg and 100 mg did not differ significantly.

    Compared to placebo, treatment with Simponi ® resulted in a significant reduction in symptoms at 14 and 24 weeks. Improvement in the basic indices of AS activity was noted at the first evaluation of treatment results (4 weeks) and persisted for 24 weeks.

    Treatment with the Simponi ® drug contributed to a significant improvement in physical function, which was evaluated at 14 and 24 weeks. In patients treated with the Simponi ® preparation, the improvement in physical function persisted for 24 weeks. The quality of life also improved significantly after 14 weeks. In addition, a significant improvement in sleep and ability to work has been revealed.

    In patients who remained in the study and continued therapy with Simponi ®.The effect on clinical indicators persisted from 24 to 256 weeks.

    Clinical efficacy in the treatment of non-radiographic axial spondylitis

    Safety and efficacy of the drug Simponi® were studied in a multicenter, randomized, double-blind, placebo-controlled study (GO-ANOTAD) in 107 adult patients with severe active form of non-radiographic axial spondylitis (patients meeting the criteria ASAS classification of axial spondylitis, but not meeting the criteria of the modified New York AC classification). The study included patients who showed signs of disease activity (AC activity index (BASDAI)≥4 and criteria according to the visual analog scale (VAS) for total pain in back ≥4, each on a scale of 0 to 10 cm), despite the treatment of NSAIDs, and who had not previously received therapy with other biological agents, including therapy with TNF antagonists. Patients were randomized to placebo or drug Simponi® 50 mg, subcutaneously every 4 weeks. From the 16th week an open stage of the study began, in which all patients received drug therapy Simponi® 50 mg subcutaneously every 4 weeks until the 48th week. The analysis was made on two indicators for all patients (AT, N=197) and patients with objective signs of inflammation (OSI, N = 158, such as an increase in the concentration of CRP and / or confirmation of sakroileitis according to MRI data at the beginning of the study). In this study, the effectiveness of the drug Simponi® for 16 weeks compared with placebo. The primary endpoint was the proportion of patients who improved at view ASAS 20 per The 16th week. The main results are presented in Table 2 and are described below.

    Table 2. Main results of the study GO-ANOTAD on the 16th week

    Improvements in signs and symptoms


    All patients (AT)

    Patients with objective signs of inflammation (OSI)


    Placebo

    Simponi® 50 mg

    Placebo

    Simponi® 50 mg

    na

    100

    97

    80

    78

    Patients responding to treatment,%

    ASAS 20

    40%

    71%**

    38%

    77%**

    ASAS 40

    23%

    57%**

    23%

    60%**

    ASAS 5/6

    23%

    54%**

    23%

    63%**

    ASAS partial remission

    18%

    33%*

    19%

    35%*

    ASDAS-Cb <1,3

    13%

    33%*

    16%

    35%*

    VASDAI 50

    30%

    58%**

    29%

    59%**

    Inhibition of inflammation in the sacroiliac joints, is determined c using MRI


    Placebo

    Simponi® 50 mg

    Platsebo

    Simponi® 50 mg

    nc

    87

    74

    69

    61

    mean change at sacroiliac joints, defined by means of mrt on a scale sparccd

    -0,9

    -5,3**

    -1,2

    -6,4**

    a n- the number of randomized and assigned patients:

    b concentration of disease activity scale ac (asdas-c), (at-placebo, n=90; at- simponi® 50 mg, n=88: aboutsiplacebo, n-71; aboutsi - simponi® 50 mg, n=71);

    c n - Quantitativecyour patients for whom there are the initial data and the data obtained on the 16th week;

    d sparcc (Canadian research consortium for spondyloarthritis):

    ** p<0.0001 for simponi® in comparison with placebo:

    * p<0.05 for simponi® in comparison with placebo.

    a statistically significant improvement in symptoms and signs of severe active non-radiographic axial spondylitis was demonstrated in patients treated with simponi® 50 mg compared to patients receiving placebo at week 16 (see Table 2). an improvement in the main parameters characterizing the activity of the disease was noted already at the first examination (4 weeks) after the start of treatment with the simponi® preparation.

    a statistically significant decrease in inflammation in the sacroiliac joints, determined by means of mrt on a scale sparcc, was observed in patients treated with simponi® 50 mg compared to patients receiving placebo at week 16 (see Table 2). pain estimated as total back pain and nocturnal pain on a scale vas, and the activity of the disease, determined on a scale asdas-c, also showed a statistically significant improvement at week 16 at compared with baseline values ​​in patients treated with simponei® 50 mg, compared with patients receiving placebo at week 16 (p<0,0001).

    a statistically significant improvement in the mobility of the spine was detected, determined by the metrological index of the disease as (basmi) and statistically significant improvement in physical function, determined by the functional index of ac (inasfi) in patients treated with the simponi ® 50 mg preparation, compared with patients receiving placebo (p <0.0001). in patients treated with the simponi ® preparation, a significantly greater improvement in the quality of life was observed in the evaluation according to the questionnaires asqol and eq-5d, physical and mental components of the questionnaire sf-36, as well as a significant improvement in productivity in assessing the questionnaire wpai, compared with patients receiving placebo.

    in patients with objective signs of inflammation (osi) Also statistically significant results were shown for all endpoints described earlier. a similar improvement in symptoms and signs,mobility of the spine and physical function was revealed at week 16 up to 24 weeks in patients who remained in the study and received therapy with the sympony drug® 50 mg.

    clinical efficacy in the treatment of ulcerative colitis

    the efficacy of the Simponi ® preparation was studied in two randomized, placebo-controlled, double-blind studies in adult patients.

    in the study of remission induction (pursuit-induction) patients with moderate or heavy active yak (from 6 to 12 points on the scale of Mayo, at least 2 by subscale endoscopy), in whom the response to standard therapy was insufficient or absent or who had a dependence on corticosteroids. in part of the study to confirm the dose of 761 patients was randomized into 3 groups: 400 mg of the drug simponi® subcutaneously at week 0 and 200 mg at week 2, 200 mg of the drug simponi® subcutaneously at week 0 and 100 mg at week 2, placebo subcutaneously at week 0 and at week 2. Simultaneous administration of the continuous dosage of aminosalicylates, corticosteroids and / or immunosuppressants orally was allowed. in this study, the effectiveness of the drug simponi® within 6 weeks.

    results of the study supporting therapy (pursuit-maintenance) are based on an evaluation of the data of 456 patients who had a clinical response to previous therapy with the drug simponi® into the induction stage. patients were randomized into 3 groups: 50 mg of the drug simponi®, 100 mg of the preparation simponi® or placebo; the drug was administered subcutaneously every 4 weeks. simultaneous administration of constant doses of aminosalicylates, corticosteroids and / or immunosuppressants orally was allowed. in this study, the efficacy of the Simponi® drug was assessed for 54 weeks.

    Table 3. The main results of the pursuit-induction and pursuit-maintenance studies

    pursuit-induction


    placebo

    n = 251

    simponi®

    200/100 mg, n = 253

    percentage of patients

    Patients with a clinical response at week 6a

    30%

    51%**

    Patients with clinical remission at 6 weeksb

    6%

    18%**

    Patients with mucosal repair at week 6c

    29%

    42%*

    Rursuit -maintenance


    placebod

    n = 154

    simponi®

    50 mg n = 151

    simponi®

    100 mg n = 151

    percentage of patients

    maintaining the response (patients with a clinical response at week 54)e

    31%

    47%*

    50%**

    persistent remission (patients with clinical remission on the 30th and 54th weeks)f

    16%

    23%g

    28%*

    Where:

    n number of patients:

    ** p ≤ 0.001;

    * p ≤0.01;

    a is defined as a decrease in the initial result on the mei scale by ≥30% and by ≥3 points,accompanied by a reduction in the number of points on the scale of rectal bleeding by ≥1 or if the score on this scale is from 0 to 1;

    b was defined as a result of a mei scale of ≤ 2 points in the absence of results for individual subscales> 1;

    from is defined as the result of the subscale endoscopy ot 0 to 1 point;

    d only the induction stage;

    e the activity of ulcerative colitis in patients was assessed by a partial result of the mei scale every 4 weeks (loss of response was confirmed by endoscopy). therefore, patients who retained the response were at the stage of a prolonged clinical response at each evaluation for 54 weeks;

    f the patient should be in remission at both week 30 and week 54 (without signs of loss of response at any point in time for 54 weeks) to achieve persistent remission;

    g among patients weighing less than 80 kg a greater number of patients receiving maintenance therapy with golimumab at 50 mg demonstrated persistent clinical remission compared to patients receiving placebo.

    the number of patients who had persistent mucosal healing (patients with mucosal healing at the 30th and 54th weeks) was more in the drug group simponi® (42% in the 50 mg group (nominal p <0.05) and 42% in the 100 mg group (nominal value p <0, 005)) compared with the placebo group (27%).

    Among 54% of patients (247/456) who received concomitant corticosteroid therapy at the time of onset of maintenance therapy, the number of patients with a clinical response without corticosteroids at week 54 was greater in the groups receiving the drug simponi® in a dose of 50 mg (38%, 30/78) and a dose of 100 mg (30%, 25/82) compared with the placebo group (21%, 18/87). the number of patients who stopped taking corticosteroids by week 54 was more in the drug groups simponi® in a dose of 50 mg (41%, 32/78) and a dose of 100 mg (33%, 27/82) compared with the placebo group (22%, 19/87).

    by the 6th week, the use of the drug simponi® significantly improved the quality of life of patients, which is confirmed by the improvement of indicators specific for the disease (ibdq), in comparison with the initial level. among patients who received maintenance therapy with the drug simponi®, improved quality of life, measured according to ibdq, was maintained for 54 weeks.

    immunogenicity

    antibodies to golimumab were detected in 5% (105/2115) patients with pa, psa, and ac, who received the drug simponi® for 52 weeks in 3 phase studies.the frequency of antibody formation was comparable in patients with various rheumatic diseases. in patients receiving concomitant mT therapy, the frequency of antibody production was lower than in patients who took the drug simponi® without mt (3% [41/1262] and 8% [64/853], respectively).

    antibodies to golimumab were identified the 4% (4/93) of patients with non-radiographic axial spondylitis who received the simponi® preparation for 16 weeks. antibodies to golimumab were detected by 3% (26/946) of patients with yak receiving the drug simponi® for 54 weeks in studies 2 and 3 phases. in 68% (21/31) of antibody-positive patients, neutralizing antibodies were detected in vitro. when treated with concomitant therapy with immunosuppressants (azathioprine, 6-mercaptopurine and methotrexate), the number of patients with antibodies to golimumab (2%, 6/389) was less than in the treatment without concomitant therapy (4%, 28/809).

    the presence of antibodies to golimumab may increase the risk of developing reactions at the injection site. the low incidence of antibodies to golimumab does not allow one to definitely judge the relationship between immunogenicity and clinical efficacy or safety.

    since the immunogenicity assay is product-specific and specific for each individual kit of reagents, comparing the concentration of antibodies to different products is not correct.

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

    A drug Simponi® can have little effect on the ability to drive and work with machinery in connection with the possible development of adverse reactions from the nervous system and the eyes (see section "Side effect").

    Form release / dosage:

    Solution for subcutaneous administration, 50 mg / 0.5 ml.

    Packaging:

    0.5 ml of sterile solution into disposable syringes of 1 ml type I glass with a fixed stainless steel needle protected by a rigid or flexible protective cap of latex-containing dry natural rubber, as part of the delivery device UltraSafe Passive®. 1 disposable syringe, together with the instruction for use, is placed in a cardboard box or 3 disposable syringes (each packed in a cardboard pack together with the instruction for use) is placed in a cardboard box.

    By 0.5 ml sterile solution into disposable syringes of 1 ml volume from glass type I with a fixed needle made of stainless steel,protected by a flexible protective cap made of latex-containing dry natural rubber, as a part of the syringe handle SmartJect®. 1 disposable syringe pen (in or without a blister tray), together with the instruction for use, is placed in a cardboard box or 3 disposable syringes (each packed in a cardboard box (in or without a blister tray) together with an instruction for use) is placed in cardboard tutu.

    Storage conditions:

    In the dark place at a temperature of 2 to 8 ° C. Do not freeze. Do not shake.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after expiry date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001686
    Date of registration:02.05.2012
    Expiration Date:02.05.2012
    The owner of the registration certificate:MSD FARMASYUTIKALS, LLC MSD FARMASYUTIKALS, LLC Russia
    Manufacturer: & nbsp
    CILAG, AG Switzerland
    Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.
    Information update date: & nbsp23.12.2015
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