Simponi - instructions for use, doses, side effects, contraindications

Active substanceGolimumabGolimumab

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Simponi®

solution PC

MSD FARMASYUTIKALS, LLC Russia

Simponi®

solution PC

MSD FARMASYUTIKALS, LLC Russia

Dosage form: & nbspRAzvor for subcutaneous administration.

Composition:

In 1.0 ml of the solution contains:

active substance: golimumab 100 mg;

Excipients: sorbitol 41.0 mg, histidine 0.87 mg, polysorbate-80 0.15 mg, water for injection 1.0 ml.

Description:Popaque or opalescent, colorless or light yellow solution.

Pharmacotherapeutic group:tumor necrosis factor-alpha (TNF-alpha) inhibitors

ATX: & nbsp

L.04.A.B.06 Golimumab

Pharmacodynamics:

Golimumab is a human monoclonal antibody of the class IgGlK, which are produced by a 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 ankylosing spondylitis (AS).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 golimumab 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 (SRV) compared with the placebo group. The Simponi ® preparation caused a significant decrease in serum levels of IL-6, ICAM-1, matrix metalloproteinase-3 (MMP-3) and vascular endothelial growth factor (VEGF) compared with 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 the serum levels of certain markers of bone metabolism (an increase in the levels of osteocalcin and Nterminal propeptide of procollagen type I and decrease in the level of deoxypyridinoline) at the 4th week. 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 (T_max) was from 2 to 6 days. After subcutaneous administration of 50 mg of golimumab to healthy volunteers, the maximum serum concentration (C_max) was 3.1 ± 1.4 μg / ml (mean ± standard deviation). After subcutaneous administration of C_max 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, the absolute bioavailability of a dose of 50 mg or 200 mg of golimumab should correspond to that for a dose of 100 mg.

Distribution

After a single intravenous injection of the drug, the average volume of distribution was 115 ± 19 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 PsA and about 0.8 ± 0.4 μg / ml in patients with AS.

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%. However, the combined use of non-steroidal anti-inflammatory drugs, oral corticosteroids or sulfasalazine did not affect the apparent clearance of golimumab.

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

The Simponi ® preparation 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 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.

Ankylosing spondylitis

Simponi ® is used for the treatment of severe, active ankylosing spondylitis in adult patients whose response to standard therapy has been inadequate.

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 Sympony®, during therapy and for 5 months after the end of the trial, patients should be carefully monitored for infection. In the case of severe infections or sepsis, therapy should be discontinued (see "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 who received TNF inhibitors, including the Simponi ® preparation.

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 TB 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 the 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 were reported cases of development of active tuberculosis in patients who received therapy with Simponi^® during and after 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 should be carefully monitored before 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 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 <18 years of age) 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® preparation, lymphoma cases were more often reported in patients treated with TNF inhibitors than in the control group. In clinical trials of Phase 2 and Phase 3, the incidence 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 reported in therapy with TNF inhibitors have been reported in patients with Crohn's disease, some in patients with ulcerative colitis.Most of them were 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 ® 2 and 3 phase preparation in patients with RA, PsA, 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 ® 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 study using another inhibitor of TNF-α, infliximab,In patients with moderate to severe chronic obstructive pulmonary disease (COPD), a large incidence of lung, head and neck tumors in the TNF inhibitor group was recorded 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 blockers (not golimumab). It is recommended to periodically inspect the skin in patients, especially in patients with risk factors for malignant skin tumors.

Congestive heart failure (CHF)

In the treatment of TNF inhibitors, there have been cases of growth or development of congestive heart failure, including treatment 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 congestive heart failure.

The Simponi ® drug should be used with caution in patients with mild heart failure (NYHA I / II class). 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 Simponi ®, 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 tumor necrosis factor alpha on the background of therapy with TNF inhibitors can lead to the development of autoimmune processes. When clinical symptoms of lupus-like syndrome appear 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 infection and neutropenia and did not lead to an additional clinical effect. Due to the nature of the side effects observed with this combination therapy, 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 use of the Simponi® preparation 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 Simponi^® must be discontinued and appropriate therapy is 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 detected 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 in humans and whether it is absorbed after ingestion. Golimumab was found in milk in monkeys, and since human immunoglobulins are excreted in breast milk, the use of the Simponi® preparation for breastfeeding for at least 6 months after the last injection 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 control ofthe role of qualified doctors with experience in the diagnosis and treatment of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis or ankylosing spondylitis. After training in the hypodermic injection technique, patients can themselves administer the Simponi® preparation if the physician considers this possible, and the physician should continue to monitor the patient.

Patients should be instructed that they should inject 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

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

Ankylosing spondylitis

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

In patients with RA, PsA or AC with a body weight of more than 100 kg in the absence of an adequate response after 3-4 injections, it may be possible to consider increasing the dose of nolimum 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, a graduallower dose 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 old)

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 Simponi® using a prefilled 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 are not trained, please consult a specialist.

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

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

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 to inject 100 mg, take 1 pre-filled syringe with 100 mg golimumab.

- If you need to enter 200 mg, take 2 pre-filled syringes with 10 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.

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 end date of the expiration date through the viewing window, take the pre-filled syringe for its housing and rotate the protective cap of the needle so as to align the end date positionshelf lifein the viewing window.

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

- Do not 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 for advice.

Wait 30 minutes, so that the syringe heats up to 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: Selecting and preparing a place for injection

- 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 want to do several injections at the same time, you should inject the drug into different 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 Fig.Fig. 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 place for injection 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 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).

- Do not touch the needle or 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.

- Do not pull back the piston during the whole procedure.

- Place the needle at an angle of about 45 degrees to the compressed skin. In one quick motion, insert the needle through the skin as deep as it can enter (see Figure 6).

- Insert the product completely by 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, there may be a small amount of blood or fluid. 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 safety surrounding needles and empty The syringes should not be reused.

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

Instructions for the administration of Simponi® using an auto injector / pre-filled syringe pen

If you want to administer Sympony® alone, you must be trained to prepare for injection and self-administered by a qualified technician. If you are not trained, please consult a specialist.

STEP 1: Preparation for use of a pre-filled syringe pen

The figure below (see Figure 9) shows the appearance of the pre-filled syringe pen.

- 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

- Ensure that the correct number of syringes are takenthe.

- If you need to inject 100 mg, take 1 pre-filled syringe pen with 100 mg golimumab.

- If you need to enter 200 mg, take 2 pre-filled syringe pens with 100 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.

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, so that the syringe pen is heated to room temperature

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

- 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: Selecting and preparing a place for injection

Choose a place for injection

- 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, the drug can be injected into the 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 place for injection 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 10).

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

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

Firmly press the syringe handle against the skin

- Take the syringe-pen so that it is convenient for you to hold it in your hand. 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 Figure 11).

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 only press the button in theThat case,if the syringe pen is firmly pressed against the skin, and the safety sleeve is inside the transparent section.

- After pressing the button it will remain in the pressed position, so you do not need to continue pressing on it (see Figure 12).

- 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.

- Take the syringe from the injection site (see Figure 13).

STAGE 4: After injection

Use a ball of cotton or gauze

- At the injection site, there may be a small amount of blood or fluid. 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.

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

- The yellow indicator may not fully occupy 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 14).

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 studies of patients with RA, PsA, AC and YaK, the most frequent adverse reaction was upper respiratory tract infection (in the golimumab group, the frequency was 12.6% compared with 10.7% in the control groups).Among serious adverse events, severe infections (including sepsis, pneumonia, TB, invasive fungal and opportunistic infections), demyelinating diseases, lymphoma, reactivation of viral hepatitis B, chronic heart failure, autoimmune diseases (lupus-like syndrome) and hematologic disorders (cm (See the "Caution" section).

Unwanted reactions observed in clinical trials and

post-registration period of using the Simponi® preparation are listed in Table 1. They are distributed according to system-organ classes and frequenciese 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%), is unknown (can not be estimated from the 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, opportunistic infections (invasive fungal infections [histoplasmosis, coccidioidomycosis, pneumocystis], bacterial, atypical mycobacterial and protozoal), bacterial arthritis, pyelonephritis
Rare:	Reactivation of hepatitis B, tuberculosis, 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:	Aplastic 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:	Congestive 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:	Increase in alanine aminotransferase (ALT), aspartate aminotransferase (ACT)
Infrequent	Chololithiasis, liver dysfunction
Disturbances from the skin and subcutaneous tissues
Frequent:	Itching, rash, alopecia, dermatitis
Infrequent:	Psoriasis (detected for the first time or worsening of the existing disease, palmar-plantar, pustular), 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
* Have been observed against a background of other studies of golimumab of TNF inhibitors, but have not been observed in clinical studies of golimumab

Infections (see the "Caution" section)

In the controlled period of basic clinical trials, upper respiratory tract infection was the most frequent adverse reaction (in the golimumab group, the incidence was 12.6% (calculated per 100 patient-years: 60.9, 95% CI: 54.9, 67.3) compared with 10.7% in the control groups (in terms of 100 patient-years: 53.2, 95% CI: 44.4, 63.2)). When patients were observed during controlled and uncontrolled research stages for 2 years (median), the incidence of upper respiratory tract infection per 100 patient-years was 35.9 (95% CI: 34.8, 37.1) in the golimumab groups.

In the controlled period of basic clinical studies of infection, 22.8% of patients in the golimumab group (in terms of 100 patient-years: 130.4, 95% CI: 121.6, 139.7) were observed compared with 19.9% in control groups (in terms of 100 patient-years: 123.0, 95% CI: 109.4, 137.8). 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 and AS, serious infections were observed in 1.4% of patients in the golimumab group and 1.3% of patients in the control groups. The incidence of serious infections in terms of 100 patient-years of observation in controlled trials in patients with RA, PsA and AC was 7.4 (95% CI: 4.6, 11.1) in the golimumab 100 mg, 3.3 (95 % CI: 1.3, 6.9) in the golimumab 50 mg group and 4.2 (95% CI 1.8, 8.2) 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 golimumab 100 mg, 2.7 (95% CI: 2.2, 3.3) 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) at a rate of 0.03 (95% CI: 0.00, 0.16) and 0, 12 (95% CI: 0.05, 0.24) in the golimumab 50 mg and 100 mg, respectively, 0.00 (0.00, 0.63) in the placebo group. Most cases are documented in a study involving patients who have been transferred from other inhibitors of FIO who have had a long duration of the disease and refractory of 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 malignant tumors (excluding non-melanoma cancerskin) was comparable in the golimumab groups 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 in the 100 mg group at a frequency of 100 patient-years of follow-up, 0.39 (95% CI: 0.28, 0.53) for combined golimumab groups and 0.95 (95% CI: 0.31, 2.22) for the placebo group.

When patients were observed during controlled and uncontrolled stages of basic clinical trials for 2 years (median), a diagnosis was made of a malignant tumor (other than non-melanoma skin cancer) in 5 patients in the placebo group, 20 in the 50 mg golimumab group and 32 in the 100 mg group with a frequency of 0.51 (95% CI: 0.38, 0.67) for the combined golimumab groups and 0.95 (95% CI: 0.31, 2.22) for the placebo group .

Cases reported in clinical studies in patients with asthma

The administration of golimumab was subcutaneously administered at a higher dose (150%) at week 0, with subsequent injections of 200 mg, 100 mg or 50 mg of golimumab every 4 weeks up to week 52. 8 cases of tumor development were diagnosed in 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 non-lymphocytic 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 value of this fact is not 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

In a controlled phase of the baseline clinical studies, a slight increase in ALT activity (> 1 and <3 times the upper limit of the norm) was observed in patients with RA and PsA in a comparable percentage of patients in the golimumab and control groups (22.1-27.4% of patients) ; in the study in patients with AS, the frequency of moderate increase in ALT in the golimumab group was higher (25.6%) than in the control groups (3.9%). 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 patients with AS, the incidence of a slight increase in ALT activity in the golimumab groups was higher than in the 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 observing patients during controlled and uncontrolled stages of basicclinical studies in patients with YaK within 1 year (on average), a slight increase in ALT activity markedcin 17.4% of patients in the golimumab group during the study of the maintenance phase of therapy.

In a controlled phase of basic clinical trials in patients with PA and AS increased ALT activity ≥5 times from the upper limit of the norm was noted infrequently. The frequency of increased ALT activity in the golimumab groups 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 ALT activity increase by 5 times from the upper limit of the norm was comparable in the groups of golimumab and control groups. In most cases this increase was asymptomatic and decreased / resolved after discontinuation of golimumab therapy or correction of concomitant treatment.

At a controlled stage of the baseline clinical studies, the induction stage in YaK patients increased ALT activity ≥5 times from the upper limit of the norm in a comparable percentage of patients in the golimumab and placebo groups (0.3% and 1.0%, respectively).When patients were monitored during controlled and uncontrolled stages of basic clinical trials in patients with YaK for 1 year (on average), an 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 basic clinical trials in patients with RA, PsA and AC in 1 patient with previous impairment of liver function, non-infectious hepatitis with jaundice, which ended in a lethal outcome, developed. It is impossible to completely exclude the role of golimumab as a factor that potentially provoked or intensified manifestations of the disease.

Reactions at the injection site

In a controlled phase of basic clinical trials, reactions at the injection site were observed in 5.1% of patients in the golimumab group, compared with 2.0% of 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 3 phases in patients with RA, PsA, AS, severe persistent asthma and studies of YA2 / 3-phase anaphylactic reactions in patients in the golimumab groups were not recorded.

Antinuclear antibodies (AHA) / antibodies to double-stranded DNA (DsDNA)

When patients were observed during controlled and uncontrolled stages of basic clinical trials for 1 year, 3.5% in the golimumub group and 2.3% in the control groups were first AHA positive (titers 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 study was 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 Simponi ® with medicines used for similar indications, including anakinra or abatacept, is not recommended.

Live vaccines and medications containing infectious agents

Live vaccines and medications containing infectious agents should not be used concomitantly with Simponi ® therapy (see section "Special instructions").

Methotrexate

Although the combined 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 for correction of the dose of Simponi ® or MT (see 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"). The data on the response to vaccination or the possibility of secondary transmission of infection when using live vaccines in TNF-inhibiting therapies are inadequate.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 not different in patients 65 years of age or older and younger patients.However, when treating elderly patients, care should be taken and special attention should be given to the occurrence of infections.

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 ACR criteria was observed 4 weeks after the start of treatment with the Simponi ® preparation (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 multicentre, randomized, double-blind, placebo-controlled study in 405 adult patients with active PsA who did not respond to non-steroidal anti-inflammatory drugs or DMAP. In this study, the time from the time of the diagnosis of PsA was at least 6 months before enrollment, the diameter of plaque damage of the skin was not less than 2 cm. The study included 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® 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 inthe activity 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 ankylosing spondylitis The safety and efficacy of the Simponi ® preparation was studied in a multicenter, randomized, placebo-controlled study in 356 adult patients with active AS. The study included patients who showed signs of AS activity despite treatment with nonsteroidal anti-inflammatory drugs or with DMARD. They 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 AS AS 20 in 14 weeks. Efficacy was compared with placebo for 24 weeks.

In general, the clinical efficacy of Simponi in doses of 50 mg and100 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 ulcerative colitis

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

In a study of remission induction (PURSUIT-Induction) patients with moderate or severe active YaK (6 to 12 on the Mayo scale, at least 2 on the subscale endoscopy) were evaluated for those who had insufficient or no response to standard therapy or who were dependent on corticosteroids. In the part of the study on dose confirmation, 761 patients were randomized into 3 groups: 400 mg of Simponi ® subcutaneously at week 0 and 200 mg at week 2, 200 mg of Simponi ® subcutaneously at week 0 and 100 mg at week 2, placebo subcutaneously weekly 0 and at week 2. Simultaneous administration of constant doses of aminosalicylates, corticosteroids, and / or immunosuppressants was administered orally. In this study, the efficacy of Simponi® was evaluated within 6 weeks.

Supportive therapy (PURSUIT-Maintenance) are based on an evaluation of the data of 456 patients who have received a clinical response to previous therapy with the Simponi ® preparation in the induction stage.Patients were randomized into 3 groups: 50 mg of Simponi®, 100 mg of 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® preparation was assessed for 54 weeks.

Table 2. Main research results PRURSUIT-Induction and PURSUIT-Maintenance

PURSUIT-Induction
	Placebo N = 251	Simponi® 200 / 100mg, N = 253
Percentage of patients
Patients with a clinical response at week 6^a	30%	51%**
Patients with clinical remission at week 6^b	6%	18%**
Patients with mucosal repair at week 6^c	29%	42%**
PURSUIT-Maintenance
	Placebo^d N = 154	Simponi® 50 mg N = 151	Simponi® 100 mg N = 151
Percentage of patients
Maintaining Response (Patients with a Clinical Response at Week 54)^e	31%	47%*	50%**
Persistent remission (patients with clinical remission at 30 and 54 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 Mayo score by> 30% and> 3 points, accompanied by a decrease in the number of points on the rectal bleeding scale by> 1 or if the score on this scale is from 0 to 1;

^b was defined as a result on the Mayo scale <2 points in the absence of results for individual subscales> 1;

^from is defined as the result of a subscale of endoscopy from 0 to 1 point; ^d ^donly the induction stage;

^e the activity of ulcerative colitis in patients was assessed by a partial Mayo scale result every 4 weeks (loss of response was confirmed by endoscopy). Consequently, 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 showed persistent clinical remission compared to patients receiving placebo.

The number of patients who had persistent mucosal healing (patients with mucosal healing at 30 and 54 weeks) was greater in the Simponi group (42% in the 50 mg group (nominal p <0.05) and 42% in the 100 mg group ( the nominal value of 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 Simponi® preparation at a dose of 50 mg (38%, 30/78) and a dose of 100 mg (30%, 25/82) placebo (21%, 18/87). The number of patients who stopped taking corticosteroids by week 54 was greater in the Simponi® group at a dose of 50 mg (41%, 32/78) and a dose of 100 mg (33%, 27782) compared with the placebo group (22% 19/87).

By week 6, the use of the Simponi® preparation significantly improved the quality of life of patients, which is confirmed by an improvement in the indicators specific for the disease (IBDQ) compared with the original level. Among patients receiving maintenance therapy with the Simponi ® preparation, an improvement in the quality of life measured according to IBDQ, was maintained for 54 weeks.

Immunogenicity

Antibodies to golimumab were detected in 5% (105/2115) patients with RA, PsA and AC who received the Simponi ® preparation for 52 weeks in the 3-phase studies. The frequency of antibody formation was comparable in patients with various rheumatic diseases. Patients receiving concomitant MT therapy had a lower antibody production rate than patients who received Simponi® without MT (3% [41/1262] and 8% [64/853], respectively).

Antibodies to golimumab were detected in 3% (26/946) of patients with YaK who received the Simponi® preparation for 54 weeks in studies 2 and 3 of the phase. In 68% (21/31) of antibody-positive patients, neutralizing antibodies were detected in vitro. In the treatment 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 judge definitely 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:

The Simponi ® preparation may have a minor effect on the ability to drive and work with machinery due to the possible development of adverse reactions from the nervous system and the visual organs (see.section "Side effect").

Form release / dosage:

Solution for subcutaneous administration, 100 mg / 1.0 ml.

Packaging:

By 1.0 ml sterile solution into disposable syringes of 1 ml volume of glass type I with a fixed needle in stainless steel, protected by a cap of latex-containing dry natural rubber, as part of the delivery device UltraSafe Passive .

1 a disposable syringe, along with the instruction for use, is placed in a cardboard box or 3 disposable syringes (each packed in a cardboard pack together with an instruction for use) is placed in a cardboard box.

By 1.0 ml of a sterile solution into disposable syringes of 1 ml volume from a Type I glass with a fixed stainless steel needle protected by a cap of latex-containing dry natural rubber, as part of a syringe pen 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 of the year.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003825

Date of registration:07.09.2016

Expiration Date:07.09.2021

The owner of the registration certificate:MSD FARMASYUTIKALS, LLC MSD FARMASYUTIKALS, LLC Russia

Manufacturer: & nbsp