Instruction for use: Certolizumab paegol

Trade name of the drug – Simziya

The Latin name of the substance Certolizumab paegol

Certolizumabi paegolum (genus. Certolizumabi paegoli)

Gross formula

C₂₁₁₅H₃₂₅₂N₅₅₆O673S₁₆

Pharmacological group:

Immunosuppressive drugs

The nosological classification (ICD-10)

K50 Crohn's disease [regional enteritis]: Crohn's disease; Crohn's disease with fistula; Granuloma of the intestine; Granulomatous enteritis; Crohn's disease; Regional ileitis; Terminal Ileitis; Enteritis regional

L40.5 Arthropathy psoriasis (M07.0-M07.3 *, M09.0 *): Psoriatic arthritis; Arthropathic form of psoriasis

M06.9 Rheumatoid arthritis, unspecified: Rheumatoid arthritis; Pain syndrome in rheumatic diseases; Pain in rheumatoid arthritis; Inflammation in rheumatoid arthritis; Degenerative forms of rheumatoid arthritis; Children's rheumatoid arthritis; Exacerbation of rheumatoid arthritis; Acute articular rheumatism; Rheumatic arthritis; Rheumatic polyarthritis; Rheumatoid arthritis; Rheumatic polyarthritis; Rheumatoid arthritis; Rheumatoid arthritis; Rheumatoid arthritis of active course; Rheumatoid periarthritis; Rheumatoid polyarthritis; Acute rheumatoid arthritis; Acute rheumatism

M07.3 Other psoriatic arthropathies (L40.5 +): Psoriatic arthritis; Generalized form of psoriatic arthritis; Psoriatic arthritis

M45 Ankylosing spondylitis: Ankylosing spondylarthrosis; Marie-Strumpel disease; Ankylosing spondylitis; Ankylosing spondylitis; Pain syndrome in acute inflammatory diseases of the musculoskeletal system; Pain syndrome in chronic inflammatory diseases of the musculoskeletal system; Bechterew's disease; Ankylosing spondylitis; Diseases of the spinal column; Rheumatic spondylitis; Bechterew-Marie-Strumpel disease

CAS code

428863-50-7

Pharmacology

Mode action - immunosuppressive.

Zertolizumab pegol is an inhibitor of TNFα. TNFα is the main cytokine supporting the inflammatory process in rheumatoid arthritis, Crohn's disease, psoriatic arthritis and axial spondylitis. CERTOLISUMAB PEGOL has a high specific activity against human TNF-α (IC90 is 4 ng / ml for inhibition of TNF-α in vitro during the cytotoxic assay of murine fibrosarcoma cells L929); it has no activity against lymphotoxin-alpha (TNFβ).

It has been shown that cortolizumab pelol neutralizes the membrane bound and soluble human TNFα in a dose-dependent manner. Incubation of human monocytes with cerolizumab by patogol resulted in a dose-dependent inhibition of lipopolysaccharide-induced TNF-α and IL-1β synthesis.

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

Certolizumab pegol does not induce apoptosis in vitro of monocytes and lymphocytes of human peripheral blood, nor does it lead to degranulation of neutrophils.

Susceptibility of the tissue to cerolizumab pegol was studied in ex vivo and in vitro experiments performed on live tissue to assess the possible interaction with cryosections of frozen normal human tissue. With the use of a standard set of human tissues, no evidence of cross reactivity with cervolizumab was obtained by patogol.

Pharmacodynamics

The increased concentration of TNF-α is determined in the synovial fluid of patients with rheumatoid arthritis and plays an important role in the progression of inflammatory, proliferative and destructive changes in the joints, which is the main manifestation of the disease.

The biological properties of TNFα include the activation of molecules of cell adhesion and chemokines, the activation of class I and II molecules of the main histocompatibility complex and direct activation of leukocytes. TNF-α stimulates the formation of cellular mediators of inflammation, including IL-1, PG, FAT, nitric oxide.

Increasing the concentration of TNFα plays a key role in the pathophysiological mechanisms of the development of Crohn's disease, rheumatoid arthritis, psoriatic arthritis and axial spondylitis. Cortolizumab pegol selectively binds to TNFα, suppressing its role as the main mediator of inflammation. In Crohn's disease, TNFα is defined in a significant concentration in the affected areas of the intestinal wall, and its concentration in the feces of patients with Crohn's disease reflects the clinical severity of the disease.

After treatment of cortolizumab with peogol, a decrease in the concentration of C-reactive protein (CRP) in the blood was noted in patients with Crohn's disease.

Against the backdrop of treatment of catarolizumab with patogol, patients with axial spondyloarthritis developed at adulthood, a marked decrease in inflammation symptoms was noted in the sacroiliac joints and in the intervertebral joints - both in the entire population of patients with axial spondylitis and in the subgroups of patients with ankylosing spondylitis And axial spondyloarthritis without radiographic signs.

The use of cortolizumab pegola was accompanied by a marked improvement in the basic performance indicators, which included mobility of the spine and physical functions, intensity of pain, weakness and quality of life. Patients with active psoriatic arthritis who debuted in adulthood, showed a significant improvement in all major efficacy rates against the backdrop of the use of cortolizumab pegola. At the 12th and 24th weeks of treatment of cortolizumab with patogol in patients with psoric arthritis, there was an improvement in parameters characterizing the peripheral activity of the disease (for example, the number of swollen joints, the number of painful / chained joints, the severity of dactylitis and the prevalence of enthesitis). Significant improvements in physical function, reduced arthritic pain, reduced fatigue compared with placebo were noted. Patients treated with pegol treated with cerolizumab reported a significant improvement in their quality of life.

Pharmacokinetics

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

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

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

Excretion. Pegylation (covalent attachment of polyethylene glycol (PEG) to proteins) contributes to a delay in the removal of these compounds from the bloodstream due to various mechanisms, including decreased renal clearance, proteolysis, and immunogenicity. Thus, conjugation with PEG of cerolizumab pegola, which is a Fab'-fragment of the antibody, increases the T1 / 2 Fab'-fragment to a value comparable to T1 / 2 of the whole antibody.

T1 / 2 cervolizumab pegola is about 14 days for all doses studied. In healthy individuals, the rate of excretion of cortolizumab pegola with intravenous administration is from 9.21 to 14.38 ml / h. In Crohn's disease, the clearance of cerolizumab peagol with p / to administration is 17 ml / h, according to population pharmacokinetic analysis.

Similarly, in rheumatoid arthritis, the clearance of cetolizumab pegola for p / to administration is 21 ml / h, according to population pharmacokinetic analysis.

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

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

Parameters of pharmacokinetics in patients with rheumatoid arthritis and Crohn's disease do not differ from the corresponding parameters in healthy volunteers.

Special patient groups

Impaired renal function. It is assumed that in patients with renal insufficiency, the clearance of cerolizumab peagol is reduced, but no special clinical studies have been performed to assess the effect of renal failure on the pharmacokinetics of cerolizumab pegola, and therefore there is insufficient data to recommend a special dosing regimen for moderate to severe renal failure.

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

Elderly patients (≥65 years of age)

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

Floor. The sex of the patients did not influence the parameters of the pharmacokinetics of cepolisumab pegola. As the clearance decreases with decreasing body weight, women can have a somewhat more systematic exposure to cepolizumab pegola.

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

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

Application of the substance Certolizumab paegol

Rheumatoid arthritis is a treatment for rheumatoid arthritis of moderate to high degree of activity in adults (from the age of 18 years) in combination with methotrexate with insufficient response to treatment with basic anti-inflammatory drugs, including methotrexate, or as monotherapy for intolerance or inexpediency of further treatment with methotrexate. It has been shown that cortolizumab pegol when combined with methotrexate reduces the progression of joint damage, assessed by radiography, and improves physical functions.

Crohn's Disease - Treatment of Crohn's disease with moderate to high degree of disease activity in adults with treatment failure basic antiinflammatory drugs.

Axial spondyloarthritis - treatment of severe active axial spondylitis in adults, including ankylosing spondylitis (severe active ankylosing spondylitis with insufficient response to NSAID treatment or with their intolerance in adults) and axial spondylitis without x-ray signs of ankylosing spondylitis (severe active axial spondylitis without x-ray signs of ankylosing spondylitis but with objective evidence of inflammation is to increase the concentration of C-ReA tive protein and / or with appropriate changes in MRI, when an inadequate response to therapy with NSAIDs or their intolerance).

Psoriatic arthritis is the treatment of active psoriatic arthritis in adults in combination with methotrexate with insufficient response to therapy with basic anti-inflammatory drugs or as a monotherapy in case of intolerance or inexpediency in further treatment with methotrexate.

Contraindications

Hypersensitivity to catarolizumab pegola; Sepsis or the risk of sepsis, as well as severe chronic or localized infections in the active stage (including tuberculosis, abscess, other opportunistic infections, including fungal infections (histoplasmosis, candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, nocardiosis, listeriosis, etc.). , Pneumocystis and viral infections, including viral hepatitis B in the reactivation stage, cardiac insufficiency III-IV functional class according to NYHA, simultaneous use of anakinra, abatacept and etanercept, age 18 years.

Pregnancy and breast-feeding

The action category for fetus by FDA is B.

Women of reproductive age should use reliable contraceptive methods during treatment and for at least 10 weeks after the end.

Active transplacental transfer of IgG occurs due to binding of the Fc fragment of the antibody to the neonatal Fc receptor (FcRn). Zertolizumab pegol consists only of the Fab fragment of the antibody and does not contain the Fc fragment. In a study of reproductive performance in rats, it was shown that during pregnancy, TN3 γ1 (the total surrogate antibody to the cortolizumab pegol, including the Fc fragment) was transferred to the fetus. However, TN3 PF (the surrogate Fab fragment of the antibody to the celolizumab pegol without an Fc fragment) was transferred to the fetus in small or unmeasurable amounts compared to the concentration of the Fc fragment in the mother's blood plasma, which indicates the important role of the Fc fragment in transplacental transfer.

In addition, the data confirming these observations were obtained in vitro using the closed loop model of human placental transport. It was shown that the concentration of cerolizumab pegola in the fetal contour was lower or near the lower limit of its quantitative determination.

In an independent clinical study, in 10 patients with Crohn's disease who received cervolizumab pegol during pregnancy, the concentration of cortolizumab pegola in the blood of mothers, umbilical cord blood, and also the blood of newborns (N = 12) was measured on the day of delivery. The concentration of cerolizumab pegola was very low in cord blood (<0.41-1.66 μg / ml) and in neonatal blood (<0.41-1.58 μg / ml) compared with the concentration in maternal blood (1.87- 59.57 μg / ml). The concentration of PEG was below the detection limit in all samples of cord blood and newborn blood.

Preclinical and clinical data allow one to judge the absence of active FcRn-dependent transplacental transfer of cerolizumab pegola.

Since the data of well-controlled studies of ptogol in pregnant women are not available, it should not be used during pregnancy, except in cases of obvious need.

In connection with the inhibition of TNFα of cerolizumab, the pegol used during pregnancy can affect the parameters of the normal immune response of the newborn.

Although the concentration of cortolizumab pegola in the blood of infants is low, the clinical significance of this data is unclear.

The risk / benefit ratio when using live vaccines during the first 12 weeks of a baby's life should be evaluated by pediatricians. However, cerolizumab pegol does not suppress the humoral immune response when using inanimate vaccines in adults.

In male rodents, a decrease in the motility of spermatozoa and a tendency to decrease in their number without a visible effect on the fertility of the animals were found.

In a clinical study evaluating the effects of cercolizumab pegola on qualitative sperm counts (sperm volume, sperm count and concentration, progressive mobility, percentage of total mobility, viability and morphology of spermatozoa), 20 healthy men were randomized to receive a single sc injection 400 mg Cercolizumab pegola or placebo. During 14 weeks of follow-up, the effect of cerolizumab pegola on qualitative sperm counts was not compared with placebo.

It is not known whether cortolizumab is allocated with peacock breast milk. However, it is known that Ig can penetrate into breast milk, so the risk for a baby breastfed can not be eliminated. If treatment of cortolizumab with patogol is necessary during lactation, breastfeeding should be discontinued.

Side effects of Certolizumab paegol

Rheumatoid arthritis

The most frequently observed adverse reactions related to the infection and invasion groups were in 14.4% of patients receiving pargol and 8% of patients in the placebo group; General disorders and reactions at the site of administration - in 8.8% of patients receiving cerolizumab pegol and 7.4% - placebo, as well as disorders of the skin and subcutaneous tissue - in 7 and 2.4%, respectively.

Therapy was discontinued due to the development of adverse events in 4.4% of patients receiving pertript and 2,7% of patients in the placebo group.

Crohn's disease

In patients with Crohn's disease in controlled studies, serious adverse events were noted in 10.8% of cases in the group receiving pertript and in 8.6% in the placebo group.

The most frequent adverse reactions were rhinopharyngitis (11.1 and 6.7%, respectively), nausea (8 and 6.7%, respectively), infections of the urinary system (5.1% and 4.4%, respectively), abdominal pain (9, 3 and 8.8%, respectively), arthralgia (6.7% and 3.9%, respectively), headache (14.8% and 13.8%, respectively).

Because of undesirable reactions, 11.3% of patients who received cervolizumab pegol stopped therapy and 12.6% received placebo. The most frequent adverse reactions leading to withdrawal of therapy were: diarrhea (0.5% and 0.2%, respectively), abdominal pain (0.9% and 0.4%, respectively) and nausea (0.4% and 0.2% respectively).

Axial Spondyloarthritis

In a placebo-controlled study, a safety profile was evaluated in 325 patients with active axial spondylitis who received cerolizumab pegol for up to 30 months. The profile of the safety of cepolinizate pagola when used in patients with axial spondylitis was similar to that in patients with rheumatoid arthritis and the previous experience with the use of cortolizumab pegola.

Psoriatic arthritis

In a placebo-controlled study, a safety profile was evaluated in 409 patients with psoriatic arthritis who received cerolizumab pegol for up to 30 months.

The safety profile of cortolizumab pegola when used in patients with psoriatic arthritis was similar to that in patients with rheumatoid arthritis and the previous experience with the use of cortolizumab pegola.

Below are listed the undesirable reactions observed in the studies of cepolizumab pegola, which are grouped according to the incidence: very often (≥1 / 10); Often (≥1 / 100, <1/10); Infrequently (≥1 / 1000, <1/100); Rarely (≥1 / 10000, <1/1000); Very rarely (<1/10000); Frequency is not established (it is impossible to estimate from available data).

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

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

On the part of the blood and lymphatic system: often - eosinophilia, eosinopenia, leukopenia (lymphopenia and neutropenia); Infrequently - anemia, thrombocytopenia, lymphadenopathy, thrombocytosis; Rarely - pancytopenia, splenomegaly, erythrocytosis, morphological changes in leukocytes.

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

From the endocrine system: rarely - a violation of the thyroid gland.

From the side of metabolism and nutrition: infrequently - electrolyte disorders, dyslipidemia, a violation of appetite, weight change; Rarely - a change in the concentration of glucose in the blood plasma, hypoalbuminemia, hypoproteinemia, hemosiderosis.

Mental disorders: infrequent - anxiety (including mental stress), mood changes (and related symptoms); Rarely - suicidal attempts, delirium, reduction of mental activity, aggression.

From the side of the nervous system: often - headache (including migraine), sensitivity disorders; Infrequently - peripheral neuropathy, dizziness, tremor, optic neuritis; Rare - demyelinating diseases, including neuritis of the cranial nerve, convulsive attack, extrapyramidal disorders, neuralgia of the trigeminal nerve, impaired coordination of movements and sense of balance, dysphonia, masky facial expression, sleep disturbance.

From the side of the organ of vision: infrequently - a violation of visual perception (including reduced visual acuity), uveitis and blepharitis, dacryoadenitis and dacryocystitis.

From the side of the hearing organ and labyrinthine disturbances: infrequently - vertigo, noise in the ears; Rarely - hearing loss.

On the part of the CAS: often - an increase in blood pressure; Infrequently - cardiomyopathy, heart failure, IHD, arrhythmias (including atrial fibrillation (ciliary arrhythmia), palpitations, hemorrhages, bleeding, VTE (pulmonary embolism, thrombophlebitis), fainting, lowering blood pressure, swelling of the face, extremities, ecchymosis (hematoma, petechia); Rarely - pericarditis, AV-blockade, shock, stroke, atherosclerosis, Raynaud's syndrome, reticular ledo, telangiectasia.

On the part of the respiratory system, chest and mediastinal organs: infrequently - pleural effusion (and associated symptoms), bronchial asthma and its manifestations, dyspnea, congestive and inflammatory changes in the lungs, cough; Rarely - interstitial lung diseases, pneumonitis, ulceration of the nasal mucosa.

From the digestive tract: often - nausea, vomiting; Infrequently - ascites, symptoms of Crohn's disease (stenosis), ulcerous lesions and perforation of various parts of the digestive tract, inflammation of the mucous membrane of the digestive tract, dyspepsia, stomatitis, bloating, dryness of the mucous membrane of the mouth and pharynx; Rarely - intestinal obstruction, painful swallowing, anal fissures, increased intestinal motility.

From the liver and biliary tract: often - hepatitis, increased activity of liver enzymes; Infrequently - liver disease, including cirrhosis, cholestasis, increased bilirubin concentration in the blood plasma; Rarely - cholelithiasis.

From the skin and subcutaneous tissues: often - a rash; Infrequently - alopecia, the onset of psoriasis or weighting of its symptoms, dermatitis, eczema, impaired sweat gland function, skin ulceration, increased photosensitivity, acne, skin pigmentation disorders, dry skin, nail plate lesions and nail bed; Rarely acute febrile neutrophilic dermatosis, exfoliation and skin desquamation, bullous dermatitis, skin ulceration, pink lichen, striae, rosacea, hair structure disorder.

On the part of the musculoskeletal system: infrequently - arthritis, a violation of muscle function; Rarely - a violation of the function of tendons.

From the urinary system: infrequently - a violation of kidney function, hematuria, nephrolithiasis, urethritis, cystitis; Rarely - nephropathy, nephritis.

From the reproductive system and breast: infrequently - menstrual irregularities, uterine bleeding, amenorrhea, dysfunction of the mammary glands, azoospermia; Rarely - premature birth, vaginal discharge, sexual dysfunction, balanitis.

General disorders and reactions at the injection site: often - hyperthermia, pain (unspecified localization), asthenia, pruritus (unspecified localization), reactions at the injection site; Infrequently - formation of fistulas (without specification of localization), chills, flu-like syndrome, violation of temperature sensitivity, night sweats, hot flashes; Damage to the skin, slow healing of wounds.

Laboratory and instrumental data: infrequently - increased activity of CK, AP, total bilirubin, increased blood coagulation time, changes in general urine analysis; Rarely - an increase in the concentration of uric acid in the blood.

With the use of drugs from the class of antagonists of TNF-α, such adverse reactions as carcinoma from Merkel cells, multiple sclerosis, Guillain-Barre syndrome are also associated, but the frequency of their occurrence with the use of cortolizumab pegola is unknown.

Infections

In controlled trials in patients with rheumatoid arthritis, new cases of infectious diseases were observed at a frequency of 1.03 patients per year in patients treated with cortolizumab with pegol and 0.92 patients per year in those receiving placebo. The infections were mainly due to diseases of the upper and lower respiratory tract, urinary system and viral herpetic diseases.

In controlled studies of cases of serious infectious diseases, more patients (0.07 patients per year) were treated with pegol in the group treated with cerolizumab than in those receiving placebo (0.02 patients per year). The most frequent serious infectious diseases were pneumonia and tuberculosis. An increase in the risk of infection with an increase in the duration of the use of cepolizumab pegola has not been established.

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

Tuberculosis

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

Malignant and lymphoproliferative diseases

In controlled trials of TNFα inhibitors, more cases of malignant neoplasm and lymphoma have been reported in patients receiving pertril cortolizumab compared with the control group.

Of the 4049 patients with rheumatoid arthritis who received cerolizumab pegol, lymphoma was diagnosed in 5 patients. In patients with rheumatoid arthritis, especially with severe disease activity, the risk of developing lymphoma is increased.

Of the 2,657 patients who received cervolizumab pegol for Crohn's disease, 1 patient was diagnosed with lymphoma; Also 1 case of lymphoma was observed in the control group, including 1319 people. The incidence of malignant neoplasms and lymphoma in clinical studies of cerolizumab pegola cannot be compared with the results of studies of other TNFα inhibitors and serve as a basis for predicting the incidence of these diseases with the use of cortolizumab pegola in a broader patient population. In patients with Crohn's disease who require prolonged therapy with immunosuppressants, the risk of developing lymphoma is increased compared to the whole population, even if they are not treated with TNFα inhibitors.

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

CHF

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

Immunogenicity

Rheumatoid arthritis. The total number of patients with rheumatoid arthritis and antibodies to cerolizumab pegola, which were determined at least once, was 9.6% in placebo-controlled studies. In about 1/3 of these patients, antibodies displayed neutralizing activity in vitro. In patients who simultaneously received immunosuppressants (methotrexate), the rate of antibody formation was lower than in patients who did not receive them initially. The formation of antibodies was associated with a lower concentration of cerolizumab pegola in blood plasma, and in some patients - with its lower efficacy.

Crohn's disease. In Crohn's disease, 8% of patients who received long-term treatment with cerolizumab peagol, determined antibodies to it, about 6% of them the antibodies were neutralized in vitro. There is no apparent relationship between the formation of antibodies and the efficacy of cerolizumab pegola. In patients who simultaneously received immunosuppressants, the level of antibody production was lower than in patients who did not take them (3 and 11%, respectively).

Psoriatic arthritis. The total number of patients with psoriatic arthritis in a placebo-controlled study who had antibodies to cerolizumab pegol at least once for 24 weeks was 11.7%. The formation of antibodies was associated with a lower concentration of cortolizumab pegola in blood plasma. The number of patients with antibodies to cerolizumab pegol was not enough to give a definite assessment of the relationship between the antibody titre and the efficacy of cepolizumab pegola.

Axial spondylitis. In a placebo-controlled study with axial spondyloarthritis, the total number of patients who had antibodies to cerolizumab pegol at least once for 24 weeks was 4.4%. The formation of antibodies was associated with a lower concentration of cortolizumab pegola in blood plasma. The number of patients with antibodies to cerolizumab pegol was not enough to give a definite assessment of the relationship between the antibody titre and the efficacy of cepolizumab pegola.

The formation of antibodies

In clinical studies, 4% of patients with Crohn's disease who received cerolizumab pegol, and 2% of patients receiving placebo, marked the formation of antinuclear antibodies (ANA). In studies of TNFα inhibitors, incl. Cortolizumab pegola, in some patients with rheumatoid arthritis, formation of ANA has also been noted. In clinical studies of cerolizumab pegola in rheumatoid arthritis and Crohn's disease, some patients developed symptoms similar to lupus-like syndrome. The effect of prolonged treatment of cortolizumab with pegol on the development of an autoimmune process has not been established.

Hypersensitivity reactions

The following symptoms, which are similar to hypersensitivity reactions, were observed in rare cases after the administration of pegola to patients: angioedema, allergic dermatitis, itching rash, dyspnea, hot flashes, lowering of blood pressure, reactions at the site of injection, feeling of malaise, hyperthermia, rash, whey Disease and fainting.

Reactions at the site of administration

In some patients, the following reactions at the site of administration were observed with the patogol at the site of administration: erythema, pruritus, subcutaneous hematoma, pain, edema or bruising.

There were no cases of cancellation of therapy due to the development of local reactions.

Increased activity of CKF

The incidence of increased CK activity in patients with axial spondyloarthritis was generally higher than in the population of patients with rheumatoid arthritis, both in the pegol group receiving 4.7 and 0.8%, respectively, and placebo at 2.8 and 0.4% respectively.

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

Interaction

Simultaneous use of cercrolizumab peagol with GCS, NSAID, analgesics, salicylates, antibacterial, antiviral drugs, as well as immunosuppressants (azathioprine, mercaptopurine, methotrexate) did not influence the parameters of the pharmacokinetics of cercrolizumab pegola.

Overdose

In the clinical studies, the relationship between toxicity and doses of cerolizumab pegola has not been documented. With SC the introduction of cortolizumab pegola in a dose of up to 800 mg and IV injection at a dose of 20 mg / kg overdose symptoms were not noted. In case of symptoms of overdose, careful monitoring of the patient's condition and symptomatic therapy are necessary.

Routes of administration

SC.

Precautions for the substance Certolizumab paegol

Infections

Patients should be carefully screened for infections, incl. Chronic and local foci of infection, prior to the appointment of cortolizumab pegola, during and after treatment. Considering the long T1 / 2 cervolizumab pegola, patient monitoring should be carried out throughout this period.

Patients with a newly diagnosed infection on the background of cervolizumab treatment with pegol should be closely monitored.

When TNF antagonists, including cortolizumab pegol, were reported, sepsis, tuberculosis and other severe infections with bacterial, mycobacterial, invasive fungal, viral and / or parasitic pathogens were reported.

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

In the case of a severe infection, treatment of cervolizumab with peogol should be discontinued.

Prior to the appointment of cortolizumab peagol, the benefit-risk ratio of this therapy should be carefully assessed in patients with chronic or recurrent or opportunistic infections in the history, in patients undergoing concomitant immunosuppressive therapy, in patients who predispose to infection, as well as when changing their place of residence or Trips to areas with high incidence of tuberculosis, mycoses, histoplasmosis and other infections.

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

Tuberculosis

As with the use of other TNFα inhibitors, cases of reactivation of tuberculosis or new cases of tuberculosis (including pulmonary militarization, extrapulmonary localization and disseminated form) were noted with the patogol in the treatment of cerolizumab.

Prior to the appointment of cortolizumab pegola, it is necessary to evaluate the relationship between the benefits and risks of this therapy, taking into account the risk factors for developing tuberculosis.

Prior to the treatment of catarolizumab with pegol, all patients should be screened to exclude active or latent (latent) tuberculosis. This examination should include a detailed study of the patient's history in order to exclude the previous tuberculosis, to identify possible contacts with patients with tuberculosis, and to obtain data on ongoing or ongoing immunosuppressive therapy. All patients undergo appropriate screening tests, for example, the tuberculin skin test (or another study to identify latent tuberculosis), and chest radiography. It should be taken into account that in some cases it is possible to obtain a false-negative result of the tuberculin test, especially in patients with a severe clinical condition and a decreased immune status. When carrying out the tuberculin test, the papule size of 5 mm or more is considered positive even if BCG vaccination was previously performed. Consideration should be given to the need for a prophylactic course of treatment for tuberculosis before the appointment of cortolizumab pegola to patients who, with evidence of previously transmitted tuberculosis or signs of latent flow, cannot confirm previous adequate antituberculous therapy, as well as patients with risk factors for tuberculosis, despite a negative test result For the detection of latent tuberculosis. To resolve the issue of the need for a course of anti-tuberculosis therapy for each individual patient, consultation with a phthisiatrician is necessary.

Patients should be closely monitored, paying attention to symptoms such as persistent cough, sputum, weight loss, subfebrile fever, which may indicate tuberculosis. If active tuberculosis is diagnosed before or during therapy, do not start or continue treatment with catarolizumab with peogol, and appropriate antituberculous therapy should be initiated.

Reactivation of viral hepatitis B (HBV)

HBV reactivation was reported in patients who are chronic carriers of this virus (including those with positive surface antigen) who received TNFα inhibitors, including cerolizumab pegol. In some cases, the disease was fatal. Prior to the appointment of cortolizumab pegola, patients should undergo a screening to identify the hepatitis B virus. Patients who have had a positive test for hepatitis B virus should be advised of a specialist in the treatment of hepatitis B.

Patients who carry hepatitis B virus, who are treated with cegololizumab by peolol, should be under constant surveillance to detect signs and symptoms of active HBV infection in time for the entire course of therapy and in the next few months after the end of treatment. Corresponding data on the treatment of patients with HBV infection with antiviral drugs concomitant with TNF antagonists for preventing the reactivation of HBV has not been obtained.

If patients develop symptoms of reactivation of hepatitis B virus, then celezolizumab pegola should be discontinued and an effective antiviral and appropriate maintenance therapy should be prescribed.

Vaccination

Vaccination of patients treated with pegol treatment with cerolizumab is allowed, except for the use of live or live attenuated vaccines.

There is no evidence of a response to vaccination or secondary transmission of infection through live vaccine to patients receiving cerolizumab pegol. Live vaccines and live attenuated vaccines are not recommended for treatment with catarolizumab by peogol. All necessary measures for vaccination should be carried out in accordance with the current national vaccination calendar, if possible before the start of treatment of cervolizumab with pegol. Certolizumab pegol does not inhibit the humoral immune response to pneumococcal polysaccharide vaccine or influenza vaccine.

Malignant and lymphoproliferative diseases

In clinical studies, lymphoma and malignant neoplasms were more common in patients treated with cortolizumab pegol, compared with patients in the placebo group. However, a limited number of patients in the control group and a short time of their treatment do not allow making unequivocal conclusions. There have been no studies in which patients with a history of malignant tumors have participated, or studies in which the treatment of catarolizumab with pegol would have continued after the detection of malignant neoplasms. Therefore, in this group of patients the treatment of cervolizumab with patogol is recommended to be administered with caution. In patients with rheumatoid arthritis, especially in a subgroup with very high disease activity, the risk of developing lymphoma is elevated.

In patients with Crohn's disease and other diseases in which prolonged immunosuppressive therapy is prescribed, the risk of developing lymphoma, in comparison with the whole patient population, can also be increased even if therapy with TNFα inhibitors is not performed.

Cases of acute and chronic leukemia have been reported with the use of TNF-α inhibitors in rheumatoid arthritis and other indications. Even in the absence of therapy with TNFα inhibitors, the risk of developing leukemia in patients with rheumatoid arthritis is higher (about 2 times) than in the population as a whole. There are reports of malignant neoplasms, incl. With a fatal outcome, in adults and children treated with TNF-α inhibitors (at the start of treatment before the age of 18 years, inclusive). Approximately half of these cases are diagnosed with lymphomas (including Hodgkin's lymphoma and non-Hodgkin's lymphomas). The remaining cases included various malignant neoplasms, incl. And rare, which, as a rule, were associated with therapy with immunosuppressants. Malignant neoplasms developed on average after 30 months of treatment (from 1 to 84 months). Most patients received concomitant therapy with immunosuppressants. These cases were published in the postmarketing period and were obtained from various sources of security information, including registers and spontaneous post-marketing messages.

During post-marketing follow-up, cases of hepatic-splenic T-cell lymphoma, a rare type of T-cell lymphoma with extremely aggressive course of the disease and, as a rule, fatal outcome, were recorded in patients receiving therapy with TNFα inhibitors. Most cases associated with the use of TNF-α antagonists have been observed in adolescents and young men with Crohn's disease and ulcerative colitis. Almost all of these patients were treated with immunosuppressants, azathioprine and / or 6-mercaptopurine in combination with TNFα inhibitors at or before the diagnosis.

Skin cancer

With the use of TNF-α inhibitors, including cerolizumab pegol, melanoma and carcinoma from Merkel cells were reported. It is recommended to periodically inspect the skin of all patients, and especially those who have risk factors for skin cancer.

COPD

A study of another drug from the group of TNFα inhibitors in patients with moderate and severe COPD showed an increased risk of malignant neoplasms (mainly with lung and head and neck localization) in the group of patients treated with the TNFα inhibitor compared to the control group . All patients were active smokers. Therefore, care should be taken when treating patients with COPD with TNF-α inhibitors, as well as patients with an increased risk of developing malignant tumors due to active smoking.

CHF

In the treatment of TNFα inhibitors, including cerolizumab pegol, there have been reports of cases of CHF and its progression. Ca terolizumab pegol should be used with caution in patients with NYHA class I-II functional class CHF.

CERTOLISUMABEG PEGOL should be discontinued with the first diagnosed CHF or the detection of symptoms of its progression. It is recommended to prescribe symptomatic therapy.

Hypersensitivity reactions

The following symptoms that may resemble hypersensitivity reactions have been observed in patients in rare cases after the administration of cortolizumab pegola: angioedema, dyspnea, decreased blood pressure, skin rash, serum sickness and urticaria.

Some of these reactions are noted after the first application of cerolizumab pegola.

If the above reactions occur, the administration of cortolizumab peagol should be stopped immediately and appropriate treatment started.

Neurological disorders

The use of TNF-α antagonists in rare cases was associated with the development of new or increasing severity of already existing clinical symptoms and / or radiologic signs of demyelinating disease, including multiple sclerosis.

In patients with an existing or newly emerging demyelinating disease, the risk / benefit ratio should be carefully weighed before starting treatment with catarolizumab with pegol. Rare cases of neurological diseases, including convulsive disorders, neuritis and peripheral neuropathies, have been noted in the treatment of cervolizumab with pegol.

Immunosuppression

Due to the fact that TNFα is a mediator of the inflammation process and modulates the cellular immune response, in the treatment of cervolizumab with peogol, it is impossible to exclude the possibility of inhibiting the immune system of the organism and reducing the body's resistance to infections and increasing the risk of developing malignant neoplasms.

The formation of antibodies

Treatment of cortolizumab with peogol can be accompanied by the formation of antinuclear antibodies and infrequently - the development of lupus-like syndrome.

If the patient develops symptoms similar to a lupus-like syndrome in the face of treatment with catarolizumab, the treatment should be discontinued. The effect of prolonged therapy of cortolizumab with pegol on the development of autoimmune diseases is unknown. Special studies of cervolizumab pegola in systemic lupus erythematosus have not been conducted.

Hematologic reactions

There have been reports of rare cases of pancytopenia and very rare cases of aplastic anemia with the use of TNFα inhibitors. Caution should be exercised when prescribing cervolizumab pegola to patients who have a history of marked changes in blood test results. All patients and their relatives should be aware of the need for immediate medical care if the patient develops signs and symptoms characteristic of hematologic disorders or infection (eg, prolonged fever, sore throat, hematoma formation, bleeding, pale skin ). Such patients are recommended to conduct a medical examination, including a detailed clinical blood test. When confirming the diagnosis of pancytopenia or other significant hematologic disorders, treatment should be discontinued.

Combination Therapy

Reports of severe infections and neutropenia have been obtained in clinical trials with the combined use of cortolizumab pegola with other inhibitors of TNFα-anakinro (IL-1 antagonist) or abatacept (modulator of C28 activity on the T cell surface), as well as with etanercept. The joint use of cortolizumab pegola with these agents or other biological basic anti-inflammatory drugs has not shown an additional clinical advantage and is therefore not recommended.

Elderly patients

In clinical studies, a higher incidence of infectious diseases has been observed in patients aged 65 years and older than younger patients, although these data are limited. Caution is advised when using cortolizumab pegola in elderly patients, special attention is required by patients of this group regarding the possible development of infection.

Effect on blood coagulability

Against the backdrop of the use of cortolizumab peagol, a false positive increase in APTT is possible in patients who do not have coagulation disorders. The increase in APTT was observed with the use of various methods, including a test with lupus anticoagulant. No evidence has been obtained of the effect of the treatment of cortolizumab with pegol on blood coagulation in vivo.

In patients receiving treatment with catarolizumab peagol, special attention should be paid to the interpretation of blood coagulation indicators that go beyond the normal values, regardless of the analytical method.

Influence on other parameters of blood coagulability (eg thrombin time, PT) is not established.

Surgical interventions

There are limited data on the safety of surgical procedures in patients receiving ptogol cervolizumab. When planning a surgical operation, it is necessary to take into account that T1 / 2 of cervolizumab pegola is 14 days. If during the treatment of catarolizumab with patogol, a patient needs surgical intervention, it is necessary to ensure constant monitoring of the patient for the timely detection of signs of infections and taking appropriate measures.

Influence on the ability to drive vehicles and work with machinery. After the introduction of cortolizumab pegola, dizziness, visual impairment and fatigue may occur, which may have an adverse effect on the ability to carry out activities requiring concentration and high speed of psychomotor reactions. Therefore, when these symptoms appear, one should refrain from managing vehicles and working with complex mechanisms.