Index of drugs

Conc. to be prepared sol. to inf. (I.v.). Rheumatoid arthritis - RA. In combination with Methotrexate (MTX): treatment of adult patients with active, progressive rheumatoid arthritis (RA) with severe severity, previously untreated with MTX, and treatment of adult patients with active to moderate to severe AR in whom insufficient response to treatment has been found or intolerance to current treatment with one or more DMARDs or TNF inhibitors. It can be given as monotherapy for MTX intolerance or for patients whose continuation of MTX therapy is not indicated. It has been shown that the drug reduces the rate of progression of joint damage measured radiologically and improves physical fitness when administered jointly with MTX.Juvenile idiopathic arthritis with generalized beginning - uJIAS. Treatment of active juvenile idiopathic arthritis of generalized origin (pJIA) in patients aged at least 2 years who have had an inadequate response to treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids. It can be given as monotherapy (in the case of MTX intolerance and in patients for whom MTX therapy is not indicated) or in combination with MTX.Polyarticular juvenile idiopathic arthritis - pJIAS. In combination with methotrexate (MTX): treatment of active polyarticular juvenile idiopathic arthritis (vJIA, positive or negative rheumatoid factor, and non-statistic, extending form) in patients at least 2 years of age who have had an inadequate response to previous MTX treatment. It can be given as monotherapy for MTX intolerance or for patients in whom continuation of MTX therapy is not indicated.Sol. for injection (subcutaneous). Rheumatoid arthritis - RA. In combination with methotrexate (MTX): treatment of adult patients with active rheumatoid arthritis (RA) of moderate to severe severity who have had an inadequate response to treatment or intolerance of previous treatment with one or more disease-modifying anti-rheumatic drugs (DMARDs) or factor inhibitors necrosis of tumor (TNF). It can be given as monotherapy for MTX intolerance or for patients whose continuation of MTX therapy is not indicated. It has been shown that the drug reduces the rate of progression of joint damage measured radiologically and improves physical fitness when administered jointly with MTX.

1 ml to prepare sol. to inf. contains 20 mg tocilizumab (the medicine contains sodium). 0.9 ml of solution to shock (1 amp-thistle) contains 162 mg tocilizumab.

A humanized IgG1 monoclonal antibody directed against the human interleukin-6 receptor (IL-6), produced by the use of genetic engineering methods. Tocilizumab binds specifically to IL-6 receptors (sIL-6R and mIL-6R), both soluble and bound to cell membranes. It inhibits signal transduction with the participation of sIL-6R and mIL-6R. IL-6 is a pleiotropic pro-inflammatory cytokine produced by many different cells, including T and B lymphocytes, monocytes and fibroblasts. IL-6 is involved in physiological processes such as T-cell activation, induction of immunoglobulin secretion, induction of acute phase protein production in the liver and hematopoiesis stimulation. IL-6 also plays a role in the pathogenesis of diseases, including inflammatory diseases, osteoporosis and cancer. After intravenous administration, tocilizumab is subject to two-phase elimination from circulation. The total clearance of tocilizumab depends on the concentration and is the sum of the linear and non-linear clearance. The linear clearance is 9.5 ml / h. For low concentrations of tocilizumab, concentration-dependent non-linear clearance plays a major role. When clearance of the non-linear clearance pathway occurs (which occurs at higher concentrations of tocilizumab), the clearance becomes linear. T_0,5 tocilizumab depends on concentration. At steady state for a dose of 8 mg / kg administered every 4 weeks effective T_0,5 it decreases with decreasing concentrations during the interval between consecutive administrations and is from 18 to 6 days. For doses of 4 and 8 mg / kg given once every 4 weeks, a greater than dose-proportional increase in AUC and C was observed_min. C_max increased proportionally to the dose. At steady state, predicted AUC and C values_min are respectively 3.2 x and 30 x higher for the 8 mg / kg dose. compared to the 4 mg / kg dose After subcutaneous administration of the drug time to reach the maximum concentration of the drug in the blood (T._max) is 2.8 days. The bioavailability for subcutaneous administration is 79%. For equilibrium, for subcutaneous administration, the concentration-dependent apparent half-life is up to 12 days (162 mg every week) and 5 days (162 mg every 2nd week).

Hypersensitivity to the active substance or to any of the excipients. Active, severe infections.

The safety and efficacy of using the intravenous medicine (end use solution for infusion) in children <2 years has not been established; subcutaneous use (solution for shock) in children <18 years. If a serious infection develops during treatment, tocilizumab should be discontinued until the infection is controlled. Caution should be taken when tocilizumab is used in patients with a history of recurring infections, chronic infections or with co-morbid conditions (eg diverticulitis, diabetes, interstitial lung disease) that may predispose to infections. Careful attention should be paid to early detection of serious infections in RA, uJIA or pJUS patients, as the symptoms and clinical symptoms of acute inflammation may be less pronounced, which is associated with the suppression of the acute phase response. When assessing the patient in terms of the potential for infection, tocilizumab should be considered for C-reactive protein (CRP), neutrophil granulocytes and symptoms and symptoms of infection. Patients should be instructed to report to a doctor immediately if any signs of infection occur. Patients should be screened for latent tuberculosis prior to treatment. Patients with latent tuberculosis should be treated with standard antituberculous medication before treatment with tocilizumab. Patients should be instructed to report to a physician if any symptoms suggestive of tuberculosis infection (eg persistent cough, wasting / weight loss, slight fever). During the biological treatment of RA patients, cases of reactivation of a viral infection (eg with the hepatitis B virus) have been reported. Tocilizumab treatment has not been evaluated in patients who have had a positive test for viral hepatitis in screening. Special care should be taken in patients with a history of ulceration or diverticulitis. In the event of abdominal pain, hemorrhage and / or unexplained changes in the rhythm of defecation accompanied by fever, the patient should undergo immediate clinical evaluation for the early detection of diverticulitis which may lead to gastrointestinal perforation. In the event of an anaphylactic or other severe hypersensitivity / severe infusion reaction, administration should be discontinued immediately and discontinued permanently. Special care should be taken when considering treatment in patients with active liver disease or impaired hepatic function. There were more frequent cases of increased enzyme activity when potentially potent hepatotoxic drugs (eg methotrexate) were administered with the preparation. Liver function tests should be considered, including the assessment of bilirubin if there are clinical indications. Special care should be taken when initiating tocilizumab treatment in patients with increased ALT or AST> 1.5 x ULN (upper limit of normal). Tocilizumab is not recommended for patients with ALT or AST greater than> 5 x ULN. In patients with RA, ALT and AST should be monitored every 4-8 weeks for the first 6 months of treatment and then every 12 weeks. In cases of ALT or AST> 3-5 x ULN confirmed in subsequent determinations, treatment should be temporarily discontinued. . In patients with pJIA and pJIA, ALT and AST should be monitored at the second infusion stage and then according to the principles of good clinical practice. When tocilizumab combination therapy is given at a dose of 8 mg / kg with Methotrexate, a decrease in the number of neutrophils and platelets has been reported. There is an increased risk of neutropenia in patients previously treated with a TNF inhibitor.It is not recommended to start treatment in patients previously untreated with an absolute neutrophil count (ANC) <2 x 10⁹/ L. Special care should be taken when initiating treatment in patients with low platelet counts (ie platelet count <100 x 10)³/ Ml). It is not recommended to continue treatment in patients with ANC <0.5 x 10⁹/ l or platelet count <50 x 10³/ Ml. In RA patients, the number of neutrophils and platelets should be monitored 4 to 8 weeks after the start of treatment and then according to clinical practice. In patients with pJIA and pJIAS the number of neutrophils and platelets should be monitored at the second infusion stage and then according to the principles of good clinical practice. In patients with pJIA, pJIA and RA, lipid metabolism parameters should be monitored from 4 to 8 weeks after the start of treatment. Further treatment of patients should be based on locally accepted clinical guidelines for the treatment of hyperlipidemia. Patients treated with tocilizumab should be particularly observed for signs suggestive of newly-emergent central demyelinating disorders. In patients with RA there is an increased risk of malignant tumors; immunomodulatory preparations may increase the risk of developing a malignant tumor process. Due to the lack of clinical safety data, live and live attenuated vaccines should not be administered during treatment with the preparation. In a randomized open-label study, adults with RA treated with tocilizumab and methotrexate (MTX) received an effective response to vaccination with a 23-valent pneumococcal polysaccharide vaccine and tetanus vaccine, which was comparable to that observed in patients treated with only MTX. It is recommended that all patients, in particular patients with pMIZS and pJIA, should complete all possible deficiencies in the implementation of the immunization program in accordance with current guidelines before starting treatment with tocilizumab. The interval between the administration of live vaccines and the initiation of treatment with the preparation should be in line with the current vaccination guidelines for the use of immunosuppressive agents. In patients with RA, there is an increased risk of cardiovascular disease and standard medical care should be used to control risk factors (eg hypertension, hyperlipidemia). Tocilizumab is not recommended in combination with TNF inhibitors or other biological medicines. Macrophage activation syndrome (ZAM) is a serious life-threatening condition that can occur in patients with pJIA. In clinical trials, the use of tocilizumab in patients during the episode of the active macrophage activation syndrome has not been evaluated. Concentrate for making sol. to inf. contains 26.55 mg (1.17 mmol) of sodium at a maximum dose of 1200 mg, which should be taken into account in patients on a diet limiting sodium consumption. Doses below 1025 mg of the drug contain less than 23 mg (1 mmol) - they are considered "sodium-free".

Do not use during pregnancy unless absolutely necessary. It is not known whether tocilizumab is excreted in human milk - the decision to continue or stop breastfeeding, or to continue or stop the use of the drug should be made taking into account the benefits of breastfeeding and the benefits of treatment for the patient.

Rheumatoid arthritis. Very common: upper respiratory tract infection, hypercholesterolemia. Common: inflammation of the subcutaneous connective tissue, pneumonia, cold sores, shingles, abdominal pain, mouth ulcers, gastritis, rash, pruritus, urticaria, headache and dizziness, increased liver transaminases, weight gain, increased bilirubin total, hypertension, leucopenia, neutropenia, peripheral edema, hypersensitivity reactions, injection site reactions (subcutaneous administration), conjunctivitis, cough, dyspnea. Uncommon: diverticulitis, oral mucositis, gastric ulcer, hypertriglyceridaemia, nephrolithiasis, hypothyroidism. Reported severe infections, some fatal, included active pulmonary or extrapulmonary tuberculosis, invasive lung infections, including candidiasis, aspergillosis, coccidioidomycosis and infectionPneumocystis jiroveci, pneumonia, subcutaneous connective tissue inflammation, herpes zoster, gastritis, diverticulitis, sepsis and bacterial arthritis. There have also been reports of opportunistic infections. Cases of interstitial lung disease (including pneumonia and pulmonary fibrosis) have been reported, some of which have been fatal. In addition, cases of gastrointestinal perforation have been reported, primarily as a complication of diverticulitis, including generalized purulent peritonitis, perforation within the lower gastrointestinal tract, fistula and abscess. During the infusion, hypertension was observed, and headache and skin reactions were observed within 24 hours of infusion administration. The frequency of anaphylactic reactions was several times higher with the 4 mg / kg dose. compared to the 8 mg / kg dose These reactions were mainly reported during the second to fifth infusion. A case of fatal anaphylactic reaction has been reported. Approximately 1.6% of patients developed tocilizumab antibodies; 1.1% of patients developed neutralizing antibodies. Decrease in the number of granulocytes, decrease in the number of platelets (no bleeding), and very rarely pancytopenia have been observed. Clinical data are insufficient to assess the potential incidence of malignancies following exposure to tocilizumab - long-term studies to assess the safety of tocilizumab are ongoing. Very rare cases of post-marketing Stevens-Johnson syndrome have been reported. The safety and immunogenicity identified for subcutaneous administration of tocilizumab was consistent with the known safety profile of tocilizumab administered intravenously. No new or unexpected adverse drug reactions were observed. Injection site reactions were more frequent in the subcutaneous group. Injection site reactions (ie erythema, pruritus, pain and hematoma) were mild to moderate. Most of them resolved without treatment and without having to discontinue the drug.Active juvenile idiopathic arthritis of the onset of generalized and active polyarticular juvenile idiopathic arthritis. Very common: upper respiratory tract infection, nasopharyngitis, headache (pJIAS), neutropenia (uMIZS). Common: nausea (pJIAS), diarrhea, infusion-related reactions (pJIA - headache, nausea and hypotension, including rash, urticaria, diarrhea, abdominal discomfort, joint pain and headache), headache (uMZIS), increase in liver enzymes (vJIAS), neutropenia (pJIAS), decrease in platelet count (uMIZS), increase in cholesterol (uMIZS). Uncommon: decrease in platelets (pJIA), increase in cholesterol (pJIA).Patients with pJIAS. The rate of serious infections and the incidence of infections leading to discontinuation of treatment were numerically higher in patients with a body weight <30 kg taking 10 mg / kg tocilizumab compared to patients with a body weight ≥ 30 kg taking 8 mg / kg tocilizumab. One patient in the <30 kg body group receiving the 10 mg / kg dose had anti-tocilizumab antibodies without any hypersensitivity reactions.Patients at uMZIS. Serious infections reported were similar to those seen in RA patients, with the addition of chickenpox and otitis media. A case of angioneurotic edema has been reported as a response to the infusion. Antibodies against tocilizumab were found in 2 patients, with one of them having a hypersensitivity reaction. IgG concentrations decreased during treatment.

Treatment should be initiated by a physician experienced in the diagnosis and treatment of RA, uJIA or pJIA. Patients treated with tocilizumab should receive a patient warning card. During the administration of the drug, access to appropriate equipment and medicines should be provided in the event of an anaphylactic reaction.Conc. to be prepared sol. to inf. (intravenously). Rheumatoid arthritis. Adults: 8 mg / kg once every 4 weeks, patients with a body weight> 100 kg, a dose of more than 800 mg per infusion is not recommended. In clinical trials, doses above 1.2 g have not been evaluated.Abnormal liver enzymes:> 1 to 3 x upper limit of normal (GGN) - modify the dose of co-administered MTX in cases where it is appropriate, if the increased values ​​in this range persist, the dose of tocilizumab should be reduced to 4 mg / kg. or temporarily stop its administration until it returns to normal ALT or AST values, if the clinical condition of the patient allows it, tocilizumab 4 mg / kg may be re-administered. or 8 mg / kg; > 3 to 5 x ULN (confirmed in subsequent determinations): temporarily discontinue tocilizumab until values ​​reach <3 x ULN and act as above.(> 1 to 3 x ULN), if the elevated values ​​are> 3 x ULN, treatment should be discontinued; > 5 x ULN - discontinue treatment.Small absolute number of neutrophilsANC> 1 x 10⁹/ l - maintain the current dose; ANC 0.5-1 x 10⁹/ l - temporarily discontinue tocilizumab when the ANC value increases> 1 x 10⁹/ l, tocilizumab 4 mg / kg should be resumed, which can then be increased to 8 mg / kg. if the clinical condition of the patient allows it; ANC <0.5 x 10⁹/ l - stop treatment. It is not recommended to start treatment in patients not previously treated with tocilizumab with an absolute neutrophil count (ANC) <2 x 10⁹/ L.Low number of platelets50-100 x 10³/ μl - temporarily discontinue tocilizumab when the platelet count increases> 100 x 10³/ μl, the administration of tocilizumab 4 mg / kg should be resumed, which can then be increased to 8 mg / kg. if the clinical condition of the patient allows it; <50 x 10³/ μl - discontinue treatment.Active juvenile idiopathic arthritis with generalized onset. Children ≥ 2 years of age: 8 mg / kg once every 2 weeks in patients with b. ≥30 kg or 12 mg / kg once every 2 weeks in patients with b. <30 kg. The dose should be calculated based on the patient's weight before each administration. The dose can only be changed based on constant changes in the patient's weight over time.Abnormal liver enzymes:> 1 to 3 x ULN - modify the dose of MTX administered in parallel, if appropriate, if the increased values ​​in this range persist, the administration of tocilizumab should be discontinued until return to normal ALT or AST; > 3 to 5 x ULN: modify the dose of MTX administered concurrently in cases where appropriate, temporarily discontinue tocilizumab until values ​​reach <3 x ULN and act as before. (> 1 to 3 x ULN); > 5 x ULN - discontinue treatment.Small absolute number of neutrophilsANC> 1 x 10⁹ l - maintain the current dose; ANC 0.5-1 x 10⁹/ l - temporarily discontinue tocilizumab when the ANC value increases> 1 x 10⁹/ l, tocilizumab should be resumed; ANC <0.5 x 10⁹/ l - stop treatment.Low number of platelets50-100 x 10³/ μl - modify the dose of co-administered MTX in cases where appropriate, temporarily discontinue tocilizumab administration when the platelet count increases> 100 x 10³/ μl, tocilizumab should be resumed; <50 x 10³/ μl - discontinue treatment. The data suggest that clinical improvement is observed within 6 weeks of the start of tocilizumab treatment. In the case of patients who do not show any improvement during this period, the continuation of the therapy should be carefully considered once again.Active polyarticular juvenile idiopathic arthritis. Children ≥ 2 years of age: 8 mg / kg once every 4 weeks in patients with ≥30 kg or 10 mg / kg once every 4 weeks in patients with <30 kg. The dose should be calculated based on the patient's weight before each administration. The dose can only be changed based on constant changes in the patient's weight over time.Abnormal liver enzymes:> 1 to 3 x ULN - modify the dose of MTX administered in parallel, if appropriate, if the increased values ​​in this range persist, the administration of tocilizumab should be discontinued until return to normal ALT or AST; > 3 to 5 x ULN: modify the dose of MTX administered concurrently in cases where appropriate, temporarily discontinue tocilizumab until values ​​reach <3 x ULN and act as before. (> 1 to 3 x ULN); > 5 x ULN - discontinue treatment.Small absolute number of neutrophilsANC> 1 x 10⁹/ l - maintain the current dose; ANC 0.5-1 x 10⁹/ l - temporarily discontinue tocilizumab when the ANC value increases> 1 x 10⁹/ l, tocilizumab should be resumed; ANC <0.5 x 10⁹/ l - stop treatment.Low number of platelets50-100 x 10³/ μl - modify the dose of co-administered MTX in cases where appropriate, temporarily discontinue tocilizumab administration when the platelet count increases> 100 x 10³/ μl, tocilizumab should be resumed; <50 x 10³/ μl - discontinue treatment. The data suggest that clinical improvement is observed within 12 weeks of the initiation of tocilizumab.In the case of patients who do not show any improvement during this period, the continuation of the therapy should be carefully considered once again. Tocilizumab dose reduction has not been performed due to abnormal laboratory results in patients with pJIA or pJIA. The decision to discontinue tocilizumab in a patient with pJIA or pJIA due to abnormal laboratory results should be based on a patient's medical examination.Specific groups of patients. No dose adjustment is required in patients ≥65 years and in patients with mild renal impairment. The preparation has not been studied in patients with moderate to severe renal impairment, and renal function should be closely monitored in these patients. The preparation has not been tested in patients with impaired hepatic function (no recommendation on a posology). The safety and efficacy of the intravenous medicine in children <2 years has not been established.Way of giving. After dilution, an intravenous infusion lasting 1 hour. Patients with rheumatoid arthritis, uJIA and pMIZS o. ≥ 30 kg: dilute to a volume of 100 ml with a sterile, pyrogen-free NaCl solution (0.9%); patients with pJIA and pMIZS about <30 kg: dilute to a final volume of 50 ml with a sterile, pyrogen-free NaCl solution (0.9%).Sol. for injection (administrationodskórne). Rheumatoid arthritis: 162 mg once a week. The possibility of self-administered subcutaneous administration of the drug should be assessed. There are only limited data on the change of drug administration from the intravenous pharmaceutical form to the subcutaneous fixed dose. Administration of the drug should be continued at weekly intervals. Patients who have changed the mode of administration from intravenous to subcutaneous, must take the first subcutaneous dose instead of the planned intravenous dose under the supervision of a physician.Abnormal liver enzymes:> 1 to 3 x upper limit of normal (GGN) - modify the dose of simultaneously administered DMARDs in cases where it is appropriate, if the increased values ​​in this range persist, reduce the frequency of administration to one dose every 2 weeks or interrupt discontinuation until return to normal ALT or AST values, return to weekly or weekly 2, if clinically warranted; > 3 to 5 x ULN (confirmed in subsequent determinations): temporarily discontinue tocilizumab until values ​​reach <3 x ULN and act as above. (> 1 to 3 x ULN), if the elevated values ​​are> 3 x ULN, treatment should be discontinued; > 5 x ULN - discontinue treatment.Small absolute number of neutrophilsANC> 1 x 10⁹/ l - maintain the current dose; ANC 0.5-1 x 10⁹/ l - temporarily discontinue tocilizumab when the ANC value increases> 1 x 10⁹/ l, tocilizumab should be resumed every 2nd week and go to weekly administration when the patient's clinical condition allows; ANC <0.5 x 10⁹/ l - stop treatment. It is not recommended to start treatment in patients not previously treated with tocilizumab with an absolute neutrophil count (ANC) <2 x 10⁹/ L.Low number of platelets50-100 x 10³/ μl - temporarily discontinue tocilizumab when the platelet count increases> 100 x 10³/ μl, tocilizumab should be resumed every 2nd week and go to weekly administration when the patient's clinical condition allows; <50 x 10³/ μl - discontinue treatment.Skiped dose. If you miss a weekly subcutaneous dose within 7 days of the scheduled day of dosing, take the Next scheduled day. If you miss a subcutaneous dose every 2 weeks within 7 days of the planned dose, immediately take the missed dose and take the next dose on the next scheduled day.Special groups of patients. No dose adjustment is required in patients ≥65 years and in patients with mild renal impairment. The preparation has not been studied in patients with moderate to severe renal impairment, and renal function should be closely monitored in these patients. The preparation has not been tested in patients with impaired hepatic function (no recommendation on a posology). The safety and efficacy of a subcutaneous medicine in children under 18 years have not been established.Way of giving. Subcutaneously, in the abdomen, thigh and upper arm. Areas of injections should be changed. Never inject in signs, scars or areas where the skin is sensitive, bruised, inflamed, hard or damaged. The entire contents (0.9 ml) of the pre-filled syringe must be given by subcutaneous injection.