Simsia, 200 mg/ml 1 ml 2 pcs

In rheumatoid arthritis patients, tumor necrosis factor inhibitor (TNFα) is identified in synovial fluid and plays an important role in the progression of inflammatory, proliferative and destructive changes in the joints, which is a major manifestation of the disease.

The biological activities that have been described for TNFα include regulation of cell adhesion molecules and chemokines, major histocompatibility complex class I and II molecules, and direct activation of leukocytes. TNFα stimulates the formation of inflammatory mediators, including IL-1, prostaglandins, platelet-activating factor, and nitric oxide.

The increase in TNFα concentration plays a key role in the pathophysiological mechanisms of rheumatoid arthritis and Crohn’s disease. Certolizumab pegol selectively binds to TNFα, eliminating its role as a mediator of inflammation. In Crohn’s disease, TNFα is detected in significant concentrations in the intestinal wall, and its concentration in the intestinal contents reflects the clinical severity of the disease.

After treatment with certolizumab pegol, a decrease in blood levels of C-reactive protein (CRP) has been confirmed in Crohn’s disease patients.

Pharmacokinetics

Extraction:Certolizumab pegol is slowly absorbed from the site of administration, reaching Cmax in plasma 54-171 h after administration of a single dose of certolizumab pegol. Absolute bnoavailability is about 80% (76 to 88%).

Distribution:In patients with rheumatoid arthritis and Crohn’s disease, a population-based analysis of certolizumab pegol pharmacokinetic parameters has shown that the volume of distribution of the drug at equilibrium concentrations is estimated at 6 to 8 L.

Metabolism:The metabolism of certolizumab pegol has not been studied in clinical studies. In experimental animal studies it has been shown that excretion is mainly by the kidneys.

Elimation:PEGylation (covalent attachment of polyethylene glycol (PEG) polymers to proteins) slows the metabolism and excretion of these compounds from the body due to various mechanisms, including reduced renal clearance, proteolysis and immunogenicity. Certolizumab pegol is a Fab` fragment of an antibody conjugated to PEG. The conjugation increases the T1/2 of the Fab` fragment to a value comparable to the T1/2 of the whole antibody.

The T1/2 of certolizumab pegol when administered by IV is approximately 14 days. In healthy subjects the excretion rate of certolizumab pegol by IV administration is 9.21 ml/h to 14.38 ml/h. In patients with Crohn’s disease when administered subcutaneously, the clearance rate of certolizumab pegol was about 17 ml/h.

In subcutaneous administration of certolizumab pegol in rheumatoid arthritis, clearance was approximately 21.0 mL/h.

When comparing patients with different body weights, it was shown that patients with a body weight of 70 kg had 29% lower and 38% higher clearance of certolizumab pegol than patients with a body weight of 40 kg and 120 kg, respectively.

The Fab` fragment is a complex protein structure and its metabolism produces simple proteins and amino acids. Released PEG is rapidly excreted by the kidneys, the rate of its excretion has not been established. The plasma concentration of certolizumab pegol is proportional to the dose.

The pharmacokinetic parameters in patients with rheumatoid arthritis and Crohn’s disease do not differ from those in healthy volunteers.

There were no statistical differences in pharmacokinetic parameters in elderly patients compared to younger patients.

The concomitant use of methotrexate, other drugs, gender, and race had no significant effect on the pharmacokinetic parameters of certolizumab pegol in Crohn’s disease and rheumatoid arthritis patients. Body weight and the presence of antibodies to certolizumab pegol influenced the pharmacokinetics of the drug. Nevertheless, there was no evidence of a benefit of using higher doses in the analysis. The presence of antibodies to certolizumab pegol increased drug clearance 3.6-fold.

The clearance of certolizumab pegol is thought to be decreased in patients with renal impairment, but there are no clinical observations to recommend a specific dosing regimen for moderate to severe renal impairment.

There have been no studies of the pharmacokinetics of certolizumab pegol in patients with hepatic impairment.

Indications

Rheumatoid arthritis. The treatment of moderately to highly active rheumatoid arthritis in adults (monotherapy or in combination with basal anti-inflammatory drugs).

Cron’s disease. The treatment of Crohn’s disease in adults with moderate to severe disease severity in case of ineffectiveness of therapy with basal anti-inflammatory drugs.

Active ingredient

Composition

active ingredient: certolizumab pegol 200 mg

How to take, the dosage

Subcutaneously.

The treatment must be prescribed and monitored by a physician experienced in the diagnosis and treatment of rheumatoid arthritis or Crohn’s disease. Patients can self-administer the drug after training in hypodermic techniques and under the supervision of medical personnel.

Simsia is used as a ready-to-use 200 mg solution (1.0 ml single dose syringe).

Rheumatoid arthritis

The initial recommended dose is 400 mg as two subcutaneous injections of 200 mg per day in weeks 1, 2 and 4 of treatment, 200 mg once every 2 weeks thereafter. For maintenance treatment after achieving low disease activity it is recommended to inject 400 mg once every 4 weeks.

Cron’s disease

The initial recommended dose is 400 mg as two subcutaneous injections of 200 mg on the same day in weeks 1, 2, and 4 of treatment; then 400 mg once every 4 weeks.

Instruction for Subcutaneous Injection Techniques

Preparing for Injection

Be sure of the following before injecting the drug:

– the name of the drug is on the package and syringe;

– the expiration date of the drug has not expired;

– the integrity of the drug package is intact and the protective seals are maintained on the bottom and top of the carton pack;

– the drug has not been frozen or exposed to direct sunlight;

– the contents of the syringe are clear, the color is not altered, there are no visible particles in the solution.

If all of the above requirements are met, the product can be used as directed.

Each pack of the drug contains a disposable syringe with a needle and two individually packed alcohol swabs.

Inject one syringe and one alcohol swab. You must also have 1 additional cotton swab (not included) and a used needle and syringe disposal container designed to prevent the risk of infection and stabbing injury when handling needles.

Each syringe contains a single injection dose (200 mg). You may need to inject more than once on the first day as prescribed by your doctor. If the drug is prescribed in a dose of 400 mg, 200 mg is injected 2 times in one day (2 subcutaneous injections). The drug is injected under the skin in the area of the abdomen and the front surface of the thigh. If it is necessary to inject twice, the drug should be injected in anatomically different areas (e.g., right and left side, or abdomen and thigh).

Pick the package out of the refrigerator and place it on a clean, well-lit, flat work surface. Remove the syringe containing the product and allow it to warm to room temperature for 30 minutes.

Select and prepare the injection site

Wash your hands thoroughly with soap and water. Determine the injection site(s), taking into account the need to inject in anatomically different areas. Keep a distance of at least 3 cm between previously used injection sites (injection sites should be marked). Do not inject the drug in areas where the skin is damaged or red. When injecting under the skin of the anterior abdominal wall, do not inject within 5 cm of the navel. Alternate injection sites to avoid the risk of local skin reactions.

Please use a tissue containing alcohol to treat the injection site. Do not touch the treated skin area prior to injection.

Use prefilled syringes

Pick the cap off the needle by pulling up on the plastic ring. Be careful not to touch the needle. Move the needle cap to the side.

Turn the syringe with the needle up and remove any air bubbles from the solution by gently tapping the syringe and applying gentle pressure to the plunger. A drop of product may appear from the needle.

Turn the syringe with the needle down, avoiding touching the skin on your hands or other parts of your body with the needle. Hold the syringe in one hand, and with the other hand gather the skin fold of the pre-treated area of skin. Insert the needle at a 45° angle to the surface of the body in a rapid movement, but without using excessive force.

Holding the base of the syringe, begin to slowly pull the plunger upward to make sure that the needle does not hit a blood vessel. If blood appears in the syringe, it means you have hit a blood vessel, so if you don’t, carefully remove the needle and discard the product. Do not use this syringe again!

If blood does not appear in the syringe, slowly inject the entire solution subcutaneously, with a constant small effort.

When the injection is complete, remove the needle from the skin without changing the angle, then place a cotton swab over the injection site for 10 seconds. Do not wipe the injection site. Slight bleeding may occur, a bandage may be applied to the injection site to stop bleeding if necessary.

If a repeat injection is necessary, repeat the above procedure to inject a further 200 mg of product.

Disposal of waste

Never reuse the syringe and needle, do not put the cap back on the needle. Used syringes and needles must be disposed of by placing them in a special safety container for disposal. When the container is 2/3 full, it is sealed and sent for disposal.

Interaction

The concomitant use of glucocorticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics, antibacterial and antiviral drugs, as well as immunosuppressants (azathioprine, mercaptopurine, methotrexate) had no effect on the pharmacokinetic parameters of the drug.

The incidence of serious infections and neutropenia may be significantly increased with combined therapy of Simsia with anakinra, abatacept, as well as etanercept. Co-administration of Simsia with these drugs has not shown clinical benefit and is not recommended.

Contraindications

Hypersensitivity to certolizumab pegol and other ingredients of the drug; sepsis or risk of sepsis, including chronic or localized infections in the active stage (including tuberculosis, fungal diseases – histoplasmosis, candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, nocardiasis, listeriosis and others, pneumocystic and viral infections); moderate and severe heart failure (functional class III-IV according to NYHA classification), pregnancy and lactation; children (under 18 years); concomitant use of anakinra, abatacept and etanercept.

With caution. Chronic heart failure I-II FC, immunodeficiency states, marked changes in the cellular composition of the blood (leukopenia, thrombocytopenia, pancytopenia, etc.), diseases predisposing to the development or activation of infections (diabetes, hepatitis, etc.), renal failure of moderate and severe severity, multiple sclerosis and other demyelinating diseases, advanced age.

Side effects

The most serious adverse reactions were infections, cancer, and heart failure. In the controlled trials, the most common were upper respiratory tract infections (18%), skin rashes (9%) and urinary tract infections (8%).

In patients with rheumatoid arthritis in controlled trials with Simzia treatment adverse reactions were noted in 10.7% of cases, and in the placebo group – in 6.6%.

The most common adverse reactions were in the area of “infections and invasions” – in 15.5% of patients treated with Simsia and in 7.6% of patients in the placebo group; and “general disorders and complications related to the route of administration” in 10.0% of patients treated with Simsia and 9.7% of patients treated with placebo.

The treatment was discontinued due to the development of adverse reactions in 5% of patients treated with Simsia* and in 2.5% of patients who did not receive the drug (placebo group). The most frequent reasons for discontinuing Simsia treatment were tuberculosis (0.5%), hyperthermia, urticaria, pneumonia, and skin rash (0.3%).

In Crohn’s disease in controlled trials, the most common adverse reactions were the following: Upper respiratory tract infections (rhinopharyngitis, laryngitis, acute respiratory viral infection (ARI)) in 20% of patients treated with Simsia and 13% of patients not treated; urinary tract infections (cystitis, bacteriuria) in 7% of patients treated with Simsia and 6% of placebo; arthralgia in 6% of patients treated with Simsia and 4% of placebo; headache in 14.8% of patients treated with Simsia and 13.5% with placebo; and abdominal pain in 9.3% of patients treated with Simsia and 8.8% with placebo.

The study excluded due to significant adverse reactions 11.3% of patients treated with Simsia and 12.6% of patients not treated with the drug. The most common reactions were: diarrhea (0.4% and 0%, respectively), abdominal pain (0.4% and 0.2%), and nausea (0.4% and 0.2%).

The adverse reactions were grouped by frequency of occurrence: very frequently (≥1/10); frequently (≥1/100, < 1/10); infrequently (≥1/1000,

Infections and invasions: often – bacterial infections (abscess), viral infections (caused by herpes virus, papillomavirus, influenza); infrequent – sepsis (including multiple organ failure and septic shock), tuberculosis, fungal infections (including opportunistic).

Benign tumors, malignant neoplasms and other formations (including cysts and polyps): infrequent – solid tumors, non-melanoma skin cancer, precancerous conditions (oral mucosal leukoplakia, melanocytic nevus), benign tumors and cysts (including papillomas); rarely – lymphoma, gastrointestinal tumors, melanoma.

Hematopoietic and lymphatic system disorders: often – eosinophilia, eosinopenia, leukopenia (lymphopenia and neutropenia); infrequently – anemia, thrombocytopenia, lymphadenopathy, thrombocytosis; rarely – pancytopenia, splenomegaly, erythrocytosis, morphologically altered leukocytes.

Injury to the immune system: infrequent – vasculitis, SLE (systemic lupus erythematosus), hypersensitivity to the drug, psoriasis and related diseases, allergic disorders, positive reaction to autoantibodies; rarely – angioedema, sarcoidosis, serum disease, panniculitis (including erythema nodosa).

From the endocrine system: rarely – disruption of thyroid function.

Metabolic disorders: infrequent – electrolyte disorders, dyslipidemia, appetite disorder, changes in body weight; rarely – changes in plasma glucose concentration, hypoalbuminemia, hypoproteinemia, hemosiderosis.

Psychiatric disorders: infrequent – anxiety (including anxiety), mood changes (and related symptoms); rarely – suicide attempts, delirium, decreased thought activity, aggression.

Nervous system disorders: often – headache (including migraine), sensory disturbances; infrequent – peripheral neuropathy, dizziness, tremor, optic neuritis; rare – auditory neuritis, seizure, extrapyramidal disorders, trigeminal neuralgia, impaired coordination of movements and sense of balance, dysphonia, mask-like expression, sleep disorders; frequency not known – multiple sclerosis.

Overlooking organ: infrequent – visual disturbances (including decreased visual acuity), uveitis and phlebaritis, dacryoadenitis and dacryocystitis, tear production disorders.

Hearing organ: infrequently, vertigo; rarely, decreased hearing, tinnitus.

From the cardiovascular system: often – increased blood pressure; infrequent – cardiomyopathy, heart failure, coronary heart disease, arrhythmias (including atrial fibrillation), palpitations, hemorrhages, bleeding, hypercoagulation (TELA, thrombophlebitis), syncope, reduced blood pressure, edema (face, extremities), ecchymoses (hematomas, petechiae); Rarely – pericarditis, atrioventricular block, stroke, atherosclerosis, Raynaud’s syndrome, reticular lvedo, telangiectasia.

In the respiratory system: infrequent – pleural effusion (and related symptoms), bronchial asthma and its manifestations, dyspnea, congestive and inflammatory changes in the lungs, cough; rarely – interstitial changes in the lungs, pneumonitis, ulceration of the nasal mucosa.

Digestive system disorders: frequently – nausea, vomiting; infrequently – ascites, Crohn’s disease symptoms (stenosis), ulcerative lesions and perforations (various parts of the GI tract), inflammation of GI mucosa, dyspepsia, stomatitis, peritoneal irritation symptoms, dry mouth and throat mucosa; rarely – intestinal obstruction, dysphagia, anal fissures, increased bowel motility.

Hepatobiliary system disorders:often – hepatitis, increased activity of “liver” enzymes; infrequent – liver cirrhosis, cholestasis, increased concentration of bilirubin in plasma; rarely – cholithiasis.

Skin and subcutaneous fat: often – rash; infrequently – alopecia, dermatitis, eczema, sweat gland dysfunction, ulcerative dermatitis, photosensitivity, acne, areas of depigmentation, dry skin, lesions of nail plate and nail bed, ; rarely – acute Febrile neutrophilic dermatosis, skin exfoliation and desquamation, bullous dermatitis, pink lichen, stretch marks, hair structure disorders.

Motor system disorders: infrequent – arthritis, muscle dysfunction; rarely – tendon dysfunction.

Since the urinary system: infrequent – renal dysfunction, hematuria, nephrolithiasis, urethritis, cystitis; rarely – nephropathy, nephritis.

Reproductive system disorders: infrequent – menstrual disorders, uterine bleeding, amenorrhea, breast dysfunction, azoospermia; rarely – premature labor, vaginal discharge, sexual dysfunction, balanitis. Other: frequently – hyperthermia, pain (unspecified localization), asthenia, pruritus (unspecified localization), skin reactions at the injection site; infrequently – fistula formation (no localization specified), chills, flu-like syndrome, temperature sensitivity disorders, increased night sweats, “tides”; skin damage, slow wound healing.

In laboratory parameters: infrequent – increased activity of creatinine phosphokinase (CPK), alkaline phosphatase, total bilirubin, increased clotting time, changes in total urine analysis; rarely – increase of uric acid in blood.

Infections

In controlled trials in patients with rheumatoid arthritis, new cases of infectious disease were observed at a rate of 0.91 patients per year in patients treated with Simsia and 0.72 patients per year in patients not treated with the drug. Infections included upper respiratory tract diseases, viral herpetic diseases, urinary tract infections, and lower respiratory tract infections.

In controlled trials, there were more cases of serious infectious diseases in the group treated with Simzia (0.06 patients per year) than in the group not treated with the drug (0.02 patients per year). Serious infectious diseases included: tuberculosis, pneumonia, subcutaneous inflammation, and pyelonephritis. No increase in the risk of infections was found with increasing duration of use of Simsia.

The incidence of infections in controlled studies in Crohn’s disease patients was 38.0% in patients treated with Simsia and 30.0% in patients not treated with the drug. Respiratory tract infections were mostly observed (20.0% in patients treated with Simsia and 13.0% in placebo patients). The incidence of clinically significant serious infections in controlled trials was 3.0% in patients treated with Simsia and 1.0% in those treated with placebo. Serious infections included both bacterial and viral diseases, pneumonia, and pyelonephritis.

Tuberculosis

The use of drugs of the TNFα inhibitor group, may be accompanied by the development of tuberculosis process activity, with treatment with Simsia there are also reports of severe and fatal cases of tuberculosis. In completed and ongoing clinical trials in all known indications among 5118 patients treated with Simsia, the incidence of tuberculosis was approximately 0.61 per 100 patients per year. The highest number of cases was observed in countries endemic for tuberculosis. Reports include cases of pulmonary and disseminated tuberculosis. Opportunistic infections have been reported in isolated cases. There have been cases of death in patients with tuberculosis and opportunistic infections.

Malignant and lymphoproliferative diseases

In controlled studies of TNFα inhibitors, there has been a trend toward an increased incidence of malignancies and lymphoma compared to patients not receiving TNFα inhibitors.

In rheumatoid arthritis patients, lymphoma was diagnosed in 3 of the 2367 patients who received Simsia, about twice as often as expected in the population average. Rheumatoid arthritis patients, especially when the disease is active, have an increased risk of developing lymphoma.

Of 2,657 patients with Cron’s disease who received Simsia, 1 case of lymphoma was reported, and 1 case of lymphoma was observed in patients who did not receive Simsia (from a control group of 1,319 patients).

The incidence of malignancies and lymphoma in clinical trials of Simsia should not be compared with the results of studies of TNFα inhibitors, and the expected incidence of these diseases also cannot be predicted when used in clinical practice. Crohn’s disease patients on long-term immunosuppressant therapy have an increased risk of developing lymphoma compared with the general population, even if they are not treated with TNFα inhibitors.

Heart failure

In the background of treatment with Simsia, there have been cases of occurrence and progression of chronic heart failure. They were moderate, and were diagnosed within the first year of treatment with Simsia.

The immune system

The total number of rheumatoid arthritis patients with antibodies to Simsia that were determined at least once was 7.7% in the phase III drug trials. About 1/3 of patients (2.6% of the total population) had antibodies with neutralizing activityin vitro. Patients treated with immunosuppressants (methotrexate) had a lower rate of antibody formation than patients who did not receive them. Antibody formation was associated with lower plasma concentrations of Simsia and, in some patients, with lower efficacy.

In Cron’s disease patients treated with Simsia, the total number of patients who tested positive for antibodies to the drug during long-term therapy was 8%, and about 6% neutralized in vitro. There was no apparent relationship between antibody formation and efficacy of Simsia when administered according to its dosing regimen. Patients with concomitant use of immunosuppressants had lower levels of antibody formation (3% and 11%, respectively).

Autoantibody formation

In Crohn’s disease in clinical trials, autoantibody formation was noted in 4% of patients treated with Simzia and 2% of patients who did not receive it. In studies of TNFα inhibitor drugs, including the use of Simsia, autoantibodies have been observed in some patients with rheumatoid arthritis. In studies of both rheumatoid arthritis and Crohn’s disease, cases of “lupus-like” syndrome are infrequent. The effect of long-term treatment with Simsia on the development of autoimmunity has not been established.

High sensitivity reactions

The following hypersensitivity reactions may occur: angioedema, allergic dermatitis, itching rash, dyspnea, hot flashes, decreased blood pressure, skin reactions at the injection site, feeling of malaise, hyperthermia, rash, wheezing and fainting.

Injection site reactions

The following symptoms have been observed: erythema, itching, subcutaneous hematoma, pain. There have been no cases of withdrawal of the drug due to the development of local reactions.

Overdose

The maximum tolerated dose of certolizumab pegol has not been established. No symptoms of overdose have been observed with subcutaneous administration of Simsia up to 800 mg and intravenous injection of 20 mg/kg. In case of overdose symptoms, the patient’s condition should be closely monitored and symptomatic therapy should be carried out.

Pregnancy use

Pregnant women should not be treated with Simsia due to lack of experience with its use during pregnancy. Women of reproductive age should use reliable methods of contraception during treatment and for at least 10 weeks after its completion. It has not been established whether certolizumab pegol is excreted with breast milk. However, it is known that immunoglobulins can penetrate into breast milk, so breastfeeding should be discontinued during treatment with Simsia.