Tocilizumab (Tocilizumabum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Immunosuppressive drugs

Included in the formulation
  • Actemra®
    concentrate d / infusion 
    Hoffmann-La Roche Ltd.     Switzerland
  • Actemra®
    solution PC 
    Hoffmann-La Roche Ltd.     Switzerland
    • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    VED

    ONLS

    АТХ:

    L.04.A.C.07   Tocilizumab

    Pharmacodynamics:

    A recombinant humanized monoclonal antibody to the human interleukin-6 receptor (IL-6) from a subclass of IgG1 immunoglobulins. Tocilizumab selectively binds and inhibits both soluble and membrane IL-6 receptors (sIL-6R and mIL-6R). IL-6 is a multifunctional cytokine produced by various types of cells and participates in paracrine regulation, systemic physiological and pathological processes such as stimulation of Ig secretion, activation of T cells, stimulation of the production of acute phase proteins in the liver, and stimulation of hemopoiesis. IL-6 is involved in the pathogenesis of various diseases, including inflammatory diseases, osteoporosis and neoplasms.

    Pharmacokinetics:

    The pharmacokinetic parameters of tocilizumab do not change with time. More than a dose-dependent increase in systemic exposure and minimal concentration is indicated for doses of 4 and 8 mg / kg every four weeks. Maximum concentration increases in direct proportion to the increase in dose.Half-life depends on the concentration of rheumatoid arthritis. Population pharmacokinetic analysis in adult patients with rheumatoid arthritis showed that age, gender and race do not affect the pharmacokinetics of tocilizumab. Tocilizumab is not required for proper dose adjustment.

    Indications:

    Rheumatoid arthritis with moderate or high activity in adults both in monotherapy and in combination with methotrexate and / or other basic anti-inflammatory drugs, including for inhibition of radiological evidence of joint destruction.

    Active polyarticular juvenile idiopathic arthritis in patients aged 2 years and older both in monotherapy and in combination with methotrexate.

    Active systemic juvenile idiopathic arthritis in patients aged 2 years and older both in monotherapy and in combination with methotrexate.

    ICD-10

    XIII.M05-M14.M05   Seropositive rheumatoid arthritis

    XIII.M05-M14.M08   Juvenile [juvenile] arthritis

    Contraindications:
    • Hypersensitivity to tocilizumab, to any component of the drug in the anamnesis.
    • Active infectious diseases (including tuberculosis).
    • Children under 2 years old for patients with polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis.
    • Age to 18 years for patients with rheumatoid arthritis.
    • Combination with inhibitors of tumor necrosis factor α or the use of anti-TNF antibodies within 1 month after treatment.
    Carefully:Propensity to allergic reactions.
    Pregnancy and lactation:

    Do not use tocilizumab in pregnancy, unless there is an obvious clinical need. When deciding whether to continue or interrupt breastfeeding, continue or cancel therapy with Tocilizumab, the benefits of breastfeeding for the baby should be taken into account and the benefits of continuing therapy for the mother should be taken into account.

    Category of recommendations for FDA is not defined.

    Dosing and Administration:

    The drug is administered intravenously drip in a dose of 8 mg / kg once every 4 weeks.

    A drug tocilizumab can be used both in monotherapy and in combination with methotrexate and / or basic anti-inflammatory drugs.

    It is not recommended to increase the dose of more than 800 mg per infusion to patients with a body weight> 100 kg.

    Side effects:

    Infections: the following serious infectious diseases were registered: pneumonia, phlegmon, infections caused by Herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis, some of which were fatal. Opportunistic infections have been reported.

    Perforation of the gastrointestinal tract: Most cases of perforation of the gastrointestinal tract were recorded as complications of diverticulitis and included diffuse purulent peritonitis, perforation of the lower gastrointestinal tract, fistula and abscess.

    Infusion reactions: The undesirable reactions that were most frequently observed during the administration of the drug were episodes of increased blood pressure. Unwanted reactions that occurred within 24 hours after the end of the drug administration were headache and reactions from the skin (rash, urticaria). These reactions did not lead to restriction of therapy.

    The incidence of anaphylaxis was several times higher in patients receiving the drug at a dose of 4 mg / kg than in patients receiving the drug at a dose of 8 mg / kg. Clinically significant hypersensitivity reactions due to the administration of tocilizumab and requiring discontinuation of treatment were noted in 0.3% of patients.These reactions were observed, as a rule, between the second and the fifth infusion of tocilizumab.

    Immunogenicity: antibodies to tocilizumab were detected in 1.6% of the patients examined. In 5 of them, clinically significant hypersensitivity reactions were noted, which led to a complete withdrawal of treatment. Neutralizing antibodies were detected in 1.1% of patients.

    Polyarticular Juvenile Idiopathic Arthritis

    Infections: The most common infections were nasopharyngitis and upper respiratory tract infections. The incidence of severe infections, as well as infections leading to the temporary cessation of the use of tocilizumab, is significantly higher in patients with a body weight <30 kg who received tocilizumab in a dose of 10 mg / kg, compared with patients whose body weight was ≥ 30 kg, receiving tocilizumab in a dose of 8 mg / kg.

    Infusion reactions: reactions associated with infusion in patients with polyarticular juvenile idiopathic arthritis were defined as any phenomenon occurring during or within 24 hours after infusion. In 5.9% of patients who received tocilizumab, infusion reactions were noted directly during infusion, in 20.2% of patients infusion reactions were noted within 24 hours after infusion. Undesirable reactions in patients with polyarticular juvenile idiopathic arthritis, noted during infusion or within 24 hours after infusion, did not differ in nature from those observed in patients with rheumatoid arthritis and systemic juvenile idiopathic arthritis.

    Immunogenicity: antibodies to tocilizumab without developing a hypersensitivity reaction were detected in one patient with a body weight <30 kg receiving 10 mg / kg of tocilizumab, and subsequently discontinued treatment.

    Systemic juvenile idiopathic arthritis.

    In general, adverse reactions in patients with systemic juvenile idiopathic arthritis by their nature did not differ from those observed in patients with rheumatoid arthritis.

    Infections: registered serious infections did not differ from those in patients with rheumatoid arthritis, except for chicken pox and otitis media.

    Infusion reactions: reactions associated with infusion in patients with systemic juvenile idiopathic arthritis were defined as any phenomenon occurring during or within 24 hours after infusion. In patients who received tocilizumab, adverse events were: rashes, urticaria (a serious phenomenon), diarrhea, epigastric discomfort, arthralgia, headache and others. <1% of patients who received tocilizumab, a clinically significant hypersensitivity reaction associated with therapy was registered and required its cancellation.

    Immunogenicity: antibodies to tocilizumab were detected in 2 of 112 patients examined. One of them developed a hypersensitivity reaction, which led to the cancellation of treatment.

    Changes in laboratory indicators (hematologic disorders).

    Neutrophils.

    Rheumatoid arthritis.

    Decrease in the number of neutrophils below 1 × 109/ l was observed in 3.4% of patients who tocilizumab was administered at a dose of 8 mg / kg in combination with baseline anti-inflammatory drugs, compared with less than 0.1% of patients receiving placebo in combination with basic anti-inflammatory drugs. In about half of cases, a decrease absolute number of neutrophils below 1 × 109/ l occurred within 8 weeks after the start of treatment. Decrease in the number of neutrophils below 0.5 ×109/ l reported in 0.3% of patients who received tocilizumab in a dose of 8 mg / kg in combination with basic anti-inflammatory drugs.

    A clear connection between a decrease in the number of neutrophils below 1 × 109/ l and the development of serious infectious diseases was not noted.

    Polyarticular juvenile idiopathic arthritis.

    With routine monitoring of laboratory parameters, a decrease in the number of neutrophils below 1 × 109/ l was noted in 3.7% of patients who received tocilizumab. There was no association between a decrease in the number of neutrophils below 1 × 109/ l and the development of serious infectious diseases.

    Systemic juvenile idiopathic arthritis.

    With routine monitoring of laboratory parameters for 12 weeks of therapy, a decrease in the number of neutrophils below 1 × 109/ l occurred in 7% of patients who received tocilizumab, and was absent in patients treated with placebo.

    In the subsequent follow-up period, a decrease in the number of neutrophils below 1 × 109/ l is registered in 15% of patients receiving tocilizumab.

    A clear connection between a decrease in the number of neutrophils below 1 × 109/ l and the development of serious infectious diseases was not noted.

    Platelets.

    Rheumatoid arthritis.

    Decrease in the number of platelets below 100 × 103/ μL was observed in 1.7% of patients who received tocilizumab in a dose of 8 mg / kg in combination with basic anti-inflammatory drugs, and was not accompanied by the development of episodes of bleeding.

    Polyarticular juvenile idiopathic arthritis.

    With routine monitoring of laboratory indicators, a decrease in the number of platelets ≤ 50 × 103/ ml occurred in 1% of patients who received tocilizumab. These changes were not accompanied by the development of episodes of bleeding.

    Systemic juvenile idiopathic arthritis.

    With routine monitoring of laboratory parameters for 12 weeks of therapy, a decrease in the platelet count ≤ 100 × 103/ ml occurred in 1% of patients, in the subsequent observation period, a decrease in the number of platelets below 100 × 103/ ul was recorded in 3% of patients receiving tocilizumab. These changes were not accompanied by the development of episodes of bleeding.

    Increased activity of hepatic transaminases.

    Rheumatoid arthritis.

    Adherence to monotherapy with tocilizumab drugs that have a potential hepatotoxic effect (for example, methotrexate), led to an increase in the incidence of increased transaminase activity.An increase in hepatic transaminase activity was not accompanied by a clinically significant increase in the level of direct bilirubin, as well as clinical manifestations of hepatitis or liver failure. In patients who received tocilizumab in a dose of 8 mg / kg in combination with basic anti-inflammatory drugs, the frequency of exceeding the upper limit of the norm of indirect bilirubin was 6.2%. Transient increase in ALT activity (more than 3 times the upper limit of normal), observed in adult patients with early rheumatoid arthritis moderate or high degree of activity (mean duration of the disease ≥ 6 months) who had not previously received methotrexate therapy had a more pronounced tendency to return to normal values ​​compared with the population of patients with rheumatoid arthritis.

    Polyarticular juvenile idiopathic arthritis.

    With routine monitoring of laboratory parameters, an increase in ALT or ACT activity in ≥ 3 times the upper limit of the norm was registered in 3.7% and <1% of patients, respectively.

    Systemic juvenile idiopathic arthritis.

    With routine monitoring of laboratory parameters in the 12-week treatment period, an increase in ALT or AST activity is ≥ 3 times higher upper limit of the norm registered in 5% and 3% of patients who received tocilizumab, respectively. In the subsequent follow-up period, an increase in ALT or ACT activity of ≥ 3-fold upper limit of the norm, was registered in 12% and 4% of patients who received tocilizumab, respectively.

    Change in lipid metabolism.

    Rheumatoid arthritis.

    In therapy with TOCILIZUMAB, there was an increase in lipid metabolism (total cholesterol, triglycerides, HDL, LDL). A sustained increase in total cholesterol> 6.2 mmol / l (240 mg / dl) was observed in 24% of patients, and a steady increase in LDL-≥ 4.1 mmol / L (160 mg / dL) in 15% of patients. In most patients, the atherogenicity index did not increase, and the increase in total cholesterol was effectively corrected by hypolipidemic drugs.

    Polyarticular juvenile idiopathic arthritis.

    With routine monitoring of laboratory parameters, an increase in the total cholesterol> 1.5 × VGN-2 × VLN was observed in one patient (0.5%) who received tocilizumab. An increase in the LDL> 1.5 × VGN-2 × VLN was noted in only one patient (0.5%) who received tocilizumab.

    Systemic juvenile idiopathic arthritis.

    An increase in the total cholesterol> 1.5 × VGN-2 × VLN occurred in 1.5% of patients who received tocilizumab. An increase in LDL> 1.5 × VGN-2 × IBN occurred in 1.9% of patients who received tocilizumab.

    Overdose:Available data on drug overdose tocilizumab are limited. In one case, an unintentional overdose of the drug at a dose of 40 mg / kg in a patient with multiple myeloma of adverse reactions was not noted. There were also no serious adverse reactions in healthy volunteers who received a single dose of the drug tocilizumab in a dose of up to 28 mg / kg, although there was neutropenia, requiring a dose reduction.
    Interaction:

    Population pharmacokinetic analysis of clinical studies did not reveal any effect of methotrexate, NSAIDs or glucocorticosteroids on the clearance of tocilizumab.

    The pharmacokinetic parameters of tocilizumab remain unchanged with the simultaneous use of other drugs for the treatment of rheumatoid arthritis (such as antimalarial drugs (chlorohrinin and its derivatives), immunosuppressants (azathioprine, leflunomide), folic acid and its derivatives, inhibitors of COX-2 (celecoxib) and analgesics (paracetamol, tramadol, codeine and their derivatives)).

    Simultaneous single administration of tocilizumab at a dose of 10 mg / kg and methotrexate in a dose of 10-25 mg once a week had no clinically significant effect on the exposure of methotrexate.

    Studies to study the combined use of tocilizumab with other biological basic anti-inflammatory drugs have not been conducted.

    Since the expression of the hepatic isoenzymes of CYP450 is inhibited by cytokines (eg, IL-6, which stimulates chronic inflammation), with cytokine-inhibiting agents (eg, tocilizumab), the expression of CYP450 isoenzymes may be impaired.

    In studies in vitro, conducted on human hepatocyte culture, it was shown that IL-6 causes a decrease in the expression of isoenzymes CYP1A2, CYP2C9, CYP2C19 and CYP3A4. The use of tocilizumab normalizes the expression of these isoenzymes.

    The effect of tocilizumab on CYP isoenzymes (other than CYP2C19 and CYP2D6) is of clinical importance for preparations that are substrates of CYP450, with a narrow therapeutic index and / or for which doses are selected individually.

    In patients with rheumatoid arthritis, the concentration of simvastatin (substrate CYP3A4) 1 week after a single injection of tocilizumab was reduced by 57%, that is, slightly elevated or similar to that of healthy volunteers.

    At the beginning or at the conclusion of a course of therapy with Tocilizumab, patients receiving medications at individually matched doses should be carefully monitored and metabolized by CYP450 3A4, 1A2 or 2C9 isoenzymes (for example, atorvastatin, blockers of slow calcium channels, theophylline, warfarin, phenytoin, ciclosporin or benzodiazepines). To ensure the therapeutic effect of these drugs may need to increase their dose. Given the long half-life of tocilizumab, its effect on the activity of CYP450 isoenzymes may persist for several weeks after cessation of therapy.

    Special instructions:

    Infections: in patients receiving immunosuppressants (including the drug tocilizumab) there were serious cases of infectious diseases (sometimes with a lethal outcome).Do not start treatment with TOCILIZUMAB in patients with active infectious diseases. With the development of serious infections, therapy with TOCILIZUMAB should be interrupted until the infection is eliminated. Caution should be exercised when using tocilizumab in patients with recurrent infectious diseases in the anamnesis, as well as with concomitant diseases predisposing to the development of infections (for example, with diverticulitis, diabetes mellitus).

    Special care should be taken to early detection of serious infectious diseases in patients with moderate to high activity rheumatoid arthritis or in patients with polyarticular juvenile idiopathic arthritis or systemic juvenile idiopathic arthritis, receiving biological preparations, since the signs or symptoms of acute inflammation can be erased in connection with the suppression of the reaction of the acute phase. Patients and parents / guardians of children with from polyarticular juvenile idiopathic arthritis or systemic juvenile idiopathic arthritis it is necessary to instruct about an immediate access to a doctor for any symptoms,indicating the occurrence of infection, with the purpose of timely diagnosis and the necessary treatment.

    Complications of diverticulitis: patients with rheumatoid arthritis reported cases of perforation of the diverticulum as a complication of diverticulitis. Caution should be exercised when using tocilizumab in patients with gastroesophageal ulcers or diverticulitis in the anamnesis. Patients with signs possibly indicating a complicated diverticulitis (abdominal pain) should be immediately examined for the purpose of early detection of gastrointestinal perforation.

    Tuberculosis: before the appointment of tocilizumab, as with the appointment of other biological agents for the treatment of rheumatoid arthritis, of polyarticular juvenile idiopathic arthritis or system juvenile idiopathic arthritis, a preliminary examination of patients for latent tuberculosis should be carried out. When detecting latent tuberculosis, a standard course of antimycobacterial therapy should be performed before starting treatment with TOCILIZUMAB.

    Immunization: it should not be immunized with live and live attenuated vaccines concomitantly with tocilizumab therapy, since the safety of such a combination is not established.There is no data on secondary transmission of infection from patients receiving live vaccines to patients receiving tocilizumab. In patients with rheumatoid arthritis receiving treatment with tocilizumab or methotrexate, the response to the 23-valent pneumococcal polysaccharide vaccine and tetanus toxoid was comparable to that of patients receiving methotrexate monotherapy.

    It is recommended that before the start of treatment with TOCILIZUMAB, all patients, especially those with polyarticular juvenile idiopathic arthritis or systemic juvenile idiopathic arthritiswere vaccinated in accordance with the national vaccination calendar. The interval (in accordance with current immunization recommendations) in patients receiving immunosuppressive therapy should be observed between immunization with live vaccines and initiation of therapy with tocilizumab.

    Hypersensitivity reactions: with infusion of tocilizumab, severe hypersensitivity reactions were observed. In the post-marketing application, severe hypersensitivity and anaphylaxis occurred in patients,received different doses of tocilizumab irrespective of the presence of concomitant therapy for the treatment of rheumatoid arthritis, premedication and / or hypersensitivity reactions in the anamnesis. With post-marketing use of tocilizumab for intravenous administration, fatal cases have been reported. These phenomena occurred already during the first infusion of the drug.

    With intravenous administration of tocilizumab, a set of necessary measures should be envisaged to treat a possible anaphylactic reaction.

    If an anaphylactic reaction or other serious hypersensitivity reaction occurs, the administration of tocilizumab should be stopped immediately and the therapy should not be resumed in the future.

    Active liver disease and liver failure: therapy with tocilizumab, especially simultaneously with methotrexate, may be associated with an increase in hepatic transaminase activity, so caution should be exercised in patients with active liver disease or liver failure.

    Reactivation of viral infections: In patients with rheumatoid arthritis who received therapy with biological agents, cases of reactivation of a viral infection (eg, hepatitis B virus) were observed. Patients who had a positive result in screening for hepatitis were not included in clinical studies of tocilizumab.

    Demyelinating diseases: care should be taken with a view to early detection of symptoms, possibly indicating the development of demyelinating CNS diseases. At present, the ability of TOCILIZUMAB to cause a demyelinating disease of the CNS is not known.

    Systemic Juvenile Idiopathic Arthritis

    The macrophage activation syndrome is a serious life threatening condition that can develop in patients with systemic juvenile idiopathic arthritis. The efficacy and safety of tocilizumab during the onset of the macrophage activation syndrome has not been studied.

    Changes in laboratory indicators

    For all indications

    Neutropenia: Tocilizumab therapy was associated with a higher incidence of neutropenia. Caution should be exercised in prescribing tocilizumab to patients with neutropenia,that is, with an absolute number of neutrophils <2.0 ×109/ l. When absolute number of neutrophils < 0,5×109/ l treatment with TOCILIZUMAB is not recommended.

    In rheumatoid arthritis, the number of neutrophils should be monitored on the day of the 2nd or 3rd infusion, and subsequently in accordance with clinical practice. Recommendations for dosing the drug depending on the absolute number of neutrophils are presented in the section "Dosage regimen".

    When polyarticular juvenile idiopathic arthritis or system juvenile idiopathic arthritis the number of neutrophils should be monitored on the day of the second infusion, and subsequently in accordance with clinical practice.

    Thrombocytopenia: Tocilizumab therapy was associated with a decrease in the number of platelets and was not associated with serious cases of bleeding. Care should be taken when deciding whether to start therapy with TOCILIZUMAB at a platelet count below 100 ×103/ μl. Treatment is not recommended with platelet count <50 ×103/ μl.

    In rheumatoid arthritis, the number of platelets on the day of the 2nd or 3rd infusion should be monitored, and subsequently in accordance with clinical practice.Recommendations for dosing the drug depending on the number of platelets are presented in the section "Dosage regimen".

    When polyarticular juvenile idiopathic arthritis or system juvenile idiopathic arthritisthe number of platelets should be monitored on the day of the second infusion, and subsequently in accordance with clinical practice.

    Increased activity of hepatic transaminases: There was an easy or moderate increase in hepatic transaminase activity without signs of hepatic insufficiency. The incidence of such changes increased with the use of tocilizumab in conjunction with drugs with a potential hepatotoxic effect (eg, methotrexate). Caution should be exercised when deciding whether to start therapy with TOCILIZUMAB in patients with ALT or AST that exceeds the upper limit of the norm by more than 1.5 times. Tocilizumab therapy is not recommended with an ALT or AST score higher than upper limit of the norm more than 5 times.

    In rheumatoid arthritis, ALT and AST should be monitored on the day of the 2nd or 3rd infusion, and thereafter in accordance with clinical practice.Recommendations for dosing the drug depending on the activity of hepatic transaminases are presented in the section "Dosage regimen".

    When polyarticular juvenile idiopathic arthritis or system juvenile idiopathic arthritis ALT and AST should be monitored on the day of the 2nd infusion, and then in accordance with clinical practice.

    Change in lipid metabolism: there was an increase in lipid metabolism (total cholesterol, LDL, triglycerides).

    In rheumatoid arthritis, lipid metabolism should be assessed on the day of the second or third infusion with tocilizumab, and polyarticular juvenile idiopathic arthritis or system juvenile idiopathic arthritis - on the day of the 3rd, 4th or 5th infusion. The management of patients should be guided by national guidelines for the treatment of hyperlipidemia.

    Features of the drug at the first admission or when it is canceled

    Studies to study the possibility of TOCILIZUMAB to cause dependence were not conducted. Based on the available data, tocilizumab does not have such an effect.

    Use in Pediatrics

    Safety and effectiveness of the use of tocilizumab in children have not been established, except for systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis (children under 2 years have not been studied).

    Impact on the ability to drive vehicles and manage mechanisms.

    Studies to study the effect of the drug on the ability to drive vehicles and mechanisms were not conducted. However, given the fact that dizziness was often observed with tocylizumab, patients who experience this undesirable reaction should be advised not to drive vehicles and mechanisms until dizziness stops.

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