Actemra

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Actemra® (Actemra®)

Composition:

Active substance: tocilizumab;

1 ml of concentrate contains 20 mg of tocilizumab;

1 vial contains 80 mg/4 ml or 200 mg/10 ml or 400 mg/20 ml of tocilizumab;

Excipients: polysorbate 80; sucrose; sodium hydrogen phosphate, dodecahydrate; sodium dihydrogen phosphate, dihydrate; water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: liquid, colorless to pale yellow, from clear to opalescent.

Pharmacotherapeutic group.

Immunosuppressants. Interleukin inhibitors. ATC code L04AC07.

Pharmacological properties.

Pharmacodynamics.

Tocilizumab is a recombinant humanized monoclonal antibody to the human interleukin-6 (IL-6) receptor of the immunoglobulin IgG1 subclass, produced by recombinant DNA technology using Chinese hamster ovary cells.

Tocilizumab selectively binds to and inhibits both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). Tocilizumab has been shown to inhibit sIL-6R- and mIL-6R-mediated signaling. IL-6 is a multifunctional proinflammatory cytokine produced by various cell types, including T- and B-cells, monocytes, and fibroblasts. IL-6 is involved in several physiological processes, such as stimulation of Ig secretion, T-cell activation, stimulation of acute-phase protein production in the liver, and stimulation of hematopoiesis. IL-6 plays a role in the pathogenesis of various diseases, including inflammatory disorders, osteoporosis, and malignancies.

In clinical studies of tocilizumab in patients with rheumatoid arthritis, a rapid reduction in levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum amyloid A and fibrinogen was observed. Along with effects on acute-phase markers, tocilizumab therapy was associated with a reduction in platelet count within the normal range. Since tocilizumab reduces IL-6-induced effects on hepcidin production, thereby increasing iron availability, an increase in hemoglobin levels was observed. In patients receiving tocilizumab, CRP levels decreased to within the normal range as early as week 2 of therapy, and this reduction was maintained throughout the treatment period.

In healthy volunteers receiving tocilizumab at doses of 2 to 28 mg/kg, a decrease in absolute neutrophil count to the lowest level was observed on days 3–5 after administration. Subsequently, depending on the dose, neutrophil counts returned to baseline levels. Patients with rheumatoid arthritis demonstrated the same pattern of change in absolute neutrophil count after tocilizumab administration (see section "Adverse reactions").

In patients with COVID-19 who received a single intravenous dose of tocilizumab 8 mg/kg, CRP levels decreased to within normal limits by day 7.

Clinical efficacy.

Rheumatoid arthritis (RA)

The efficacy of tocilizumab (either as monotherapy or in combination with methotrexate (MTX) or disease-modifying antirheumatic drugs (DMARDs)) in reducing signs and symptoms of rheumatoid arthritis was evaluated in five randomized, double-blind, multicenter clinical trials.

Clinical response

In all studies, clinical response according to the American College of Rheumatology (ACR) 20, 50, and 70 criteria at 6 months was statistically significantly higher with tocilizumab 8 mg/kg compared to comparator treatments, regardless of rheumatoid factor status, age, sex, race, number of prior treatment courses, or disease stage. The response to therapy developed rapidly (as early as week 2), increased throughout the treatment course, and was maintained for over 3 years in ongoing open-label extension studies.

Major clinical response

After 2 years of treatment with tocilizumab/MTX, a major clinical response (ACR70 sustained for at least 24 weeks) was achieved in 14% of patients.

Radiographic assessment

Radiographic evaluation of joint destruction inhibition was performed in patients with inadequate response to methotrexate. In 85% of patients (n=348) receiving tocilizumab/MTX for one year, no progression of joint destruction was observed (change in total Sharp score of zero or less), compared to 67% of patients receiving placebo/MTX (n=290) (p≤0.001). This result was maintained over 2 years of therapy (83%; n=353). In 93% of patients (n=271), no progression of joint destruction was observed between weeks 52 and 104 of therapy.

Quality of life measures

All reported outcomes indicated improvement in patients receiving tocilizumab (Health Assessment Questionnaire: Disability Index – HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue scale – FACIT-F, and SF-36 questionnaire. Patients receiving tocilizumab showed clinically significant improvements in physical function (by HAQ-DI index) compared to those receiving DMARDs. Improvement in physical function was maintained for up to 2 years. At week 52, mean changes in HAQ-DI were -0.58 in the tocilizumab 8 mg/kg + MTX group versus -0.39 in the placebo + MTX group. Mean changes in HAQ-DI were maintained at week 104 in the tocilizumab 8 mg/kg + MTX group (-0.61).

Laboratory parameters

A statistically significant improvement in hemoglobin levels was observed at week 24 of tocilizumab treatment compared to DMARD treatment (p<0.0001). Mean hemoglobin levels increased by week 2 of treatment and remained within the normal range up to week 24.

Tocilizumab compared to monotherapy with adalimumab.

In a 24-week double-blind study comparing monotherapy with tocilizumab versus monotherapy with adalimumab, 326 patients with rheumatoid arthritis who had either intolerance to methotrexate or for whom continued methotrexate therapy was considered inappropriate (including patients with inadequate response to methotrexate) were enrolled. Patients in the tocilizumab treatment group received tocilizumab as an intravenous infusion at 8 mg/kg every 4 weeks plus placebo as a subcutaneous injection every 2 weeks. Patients in the adalimumab group received adalimumab as a subcutaneous injection at 40 mg every 2 weeks plus placebo as an intravenous infusion every 4 weeks.

The tocilizumab treatment group achieved significantly higher efficacy in reducing disease activity over 24 weeks (changes in DAS28 and ACR20, 50, 70 criteria) compared to the adalimumab treatment group.

Patients with early RA who had not previously received methotrexate treatment

In a 2-year study involving 1,162 patients with early moderate to severe RA (mean disease duration ≤6 months) who had not previously received MTX treatment, the efficacy of tocilizumab administered intravenously at 4 or 8 mg/kg every 4 weeks in combination with MTX, or tocilizumab as monotherapy (8 mg/kg), was compared to MTX monotherapy in reducing signs, symptoms, and rate of joint damage progression over 104 weeks. The primary endpoint (proportion of patients achieving remission by DAS28 (DAS28 < 2.6 at week 24)) was achieved in a significantly higher proportion of patients in the tocilizumab 8 mg/kg + MTX group (44.8%, p≤0.0001) and in the tocilizumab monotherapy group (38.7%, p≤0.0001) compared to the MTX monotherapy group (15%). The tocilizumab 8 mg/kg + MTX group also demonstrated statistically significant results for key secondary endpoints. A significantly greater number of treatment responses were demonstrated in the tocilizumab monotherapy group at 8 mg/kg across all secondary endpoints, including radiographic endpoints, compared to the MTX monotherapy group.

Systemic juvenile idiopathic arthritis

The efficacy of tocilizumab in the treatment of active systemic juvenile idiopathic arthritis was evaluated in a 12-week randomized, double-blind, placebo-controlled parallel-group study.

Clinical response (improvement of at least 30% by ACR criteria for systemic juvenile idiopathic arthritis) at week 12 and absence of fever (body temperature not exceeding ≥37.5°C over the preceding 7 days) were observed significantly more frequently (p<0.0001) with tocilizumab therapy (in 85% of patients) compared to placebo (in 24.3% of patients).

Clinical response (improvement of at least 30%, 50%, 70%, 90% by ACR criteria for systemic juvenile idiopathic arthritis) was observed significantly more frequently (p<0.0001) with tocilizumab therapy (in 90.7%, 85.3%, 70.7%, 37.3% of patients, respectively) compared to placebo (in 24.3%, 10.8%, 8.1%, 5.4% of patients, respectively).

Systemic manifestations

After 12 weeks of treatment, fever (body temperature not exceeding ≥37.5°C over the preceding 14 days) was absent in 85% of patients in the tocilizumab group compared to 21% in the placebo group.

The mean adjusted pain intensity on the visual analog scale (VAS) decreased by 41 points after 12 weeks of treatment in patients receiving tocilizumab, compared to a 1-point decrease in patients receiving placebo (p<0.0001).

Reduction/discontinuation of corticosteroids

Corticosteroid dose was reduced by at least 20% in 17 patients (24%) receiving tocilizumab compared to 1 patient (3%) in the placebo group, without subsequent increase in disease activity by ACR30 criteria for systemic juvenile idiopathic arthritis or recurrence of systemic symptoms over 12 weeks (p=0.028). Reduction in corticosteroid dose continued, and 44 patients discontinued oral corticosteroids by week 44 while maintaining ACR response criteria.

Quality of life measures

In patients receiving tocilizumab, a clinically significant improvement in physical function (by CHAQ-DI index) was observed (p<0.0001) compared to patients receiving placebo (77% vs. 19%, respectively).

Laboratory parameters

Initial hemoglobin levels were below the lower limit of normal in 50 of 75 (67%) patients in the tocilizumab group. Hemoglobin levels increased to within normal range after 12 weeks in 40 (80%) patients receiving tocilizumab, compared to 2 of 29 (7%) patients in the placebo group (p<0.0001).

Active polyarticular juvenile idiopathic arthritis

The efficacy of tocilizumab was evaluated in study WA19977 (consisting of three parts), including an open-label extension phase in children with active polyarticular juvenile idiopathic arthritis. The primary endpoint was the number of patients with flare by ACR30 criteria from week 16 to week 40. Flare occurred in 48% of patients (48.1%, 39/81) receiving placebo compared to 25.6% (21/82) of patients receiving tocilizumab. This difference was statistically significant (p=0.0024).

COVID-19

RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial in a collaborative group of hospitalized adult patients diagnosed with COVID-19

RECOVERY was a large-scale, randomized, controlled, open, multicenter platform trial conducted in the United Kingdom to evaluate the efficacy and safety of potential treatments for hospitalized adult patients with severe COVID-19. All eligible patients received standard care and participated in initial (primary) randomization. Eligible patients had clinical suspicion or laboratory confirmation of SARS-CoV-2 infection and had no medical contraindications to any treatment. Patients with clinical signs of progressive COVID-19 (defined as oxygen saturation <92% on room air or receiving oxygen therapy and CRP level ≥75 mg/L) were eligible for a second randomization to intravenous administration of Actemra® or standard care alone.

Efficacy analysis was performed in the overall population of randomized patients (4,116 patients) according to the intention-to-treat (ITT) principle. Patients were randomized as follows: 2,022 patients to the Actemra® + standard care group and 2,094 patients to the standard care alone group. Baseline demographic and disease characteristics were well balanced between treatment groups. The mean age of participants was 63.6 years (standard deviation [SD] 13.6 years). Most patients were male (67%) and of Caucasian race (76%). The mean (range) CRP level was 143 mg/L (75–982).

At the time of enrollment, 0.2% (n=9) of patients did not require oxygen therapy, 45% required low-flow oxygen therapy, 41% required non-invasive ventilation, and 14% required mechanical ventilation; 82% of patients received systemic corticosteroids. The most common comorbidities were diabetes (28.4%), heart disease (22.6%), and chronic lung disease (23.3%).

The primary outcome was time to death by day 28. The hazard ratio comparing the Actemra® + standard care group to the standard care alone group was 0.85 (95% CI: 0.76–0.94), which was statistically significant (p=0.0028). The probability of death by day 28 was estimated at 30.7% in the Actemra® group and 34.9% in the standard care group, respectively. The risk difference was -4.1% (95% CI: -7.0% to -1.3%), consistent with the primary analysis results. The hazard ratio for the predefined subgroup of patients receiving systemic corticosteroids at baseline was 0.79 (95% CI: 0.70–0.89), and for the predefined subgroup not receiving systemic corticosteroids at baseline was 1.16 (95% CI: 0.91–1.48).

The median time to hospital discharge was 19 days in the tocilizumab + standard care group and >28 days in the standard care group (hazard ratio [95% CI] = 1.22 [1.12–1.33]).

Among patients who did not require mechanical ventilation at enrollment, the proportion of patients who required mechanical ventilation or died by day 28 was 35% (619/1754) in the tocilizumab + standard care group and 42% (754/1800) in the standard care group (hazard ratio [95% CI] = 0.84 [0.77–0.92], p<0.0001).

Pharmacokinetics.

Rheumatoid arthritis

Absorption

Pharmacokinetic parameters of tocilizumab were evaluated in a population pharmacokinetic analysis of data from 1,793 patients with rheumatoid arthritis who received tocilizumab infusion (at 4 mg/kg or 8 mg/kg) over 1 hour every 4 weeks for 24 weeks.

For tocilizumab at 8 mg/kg every 4 weeks, the following parameters were observed: estimated mean (± standard deviation) steady-state AUC – 38,000 ± 13,000 h•µg/mL, Cmin and Cmax – 15.9 ± 13.1 µg/mL and 182 ± 50.4 µg/mL, respectively. Accumulation ratios for AUC and Cmax were low: 1.22 and 1.06, respectively. The accumulation ratio was higher for Cmin (2.49), as expected due to nonlinear clearance at low concentrations. Steady state was reached after the first dose for Cmax, and by weeks 8 and 20 for AUC and Cmin, respectively.

AUC, Cmin, and Cmax of tocilizumab increased with increasing body weight. For patients with body weight ≥100 kg, predicted mean (± standard deviation) steady-state AUC, Cmin, and Cmax of tocilizumab were 50,000 ± 16,800 µg•h/mL, 24.4 ± 17.5 µg/mL, and 226 ± 50.3 µg/mL, respectively, exceeding the average exposure values in the patient population (i.e., patients with all body weight ranges).

The dose-response curve for tocilizumab plateaus at higher exposures, demonstrating reduced efficacy with each further increase in tocilizumab concentration; that is, clinically meaningful increases in efficacy were not observed in patients treated with tocilizumab doses >800 mg. Therefore, a single infusion of tocilizumab exceeding 800 mg per infusion is not recommended (see section "Dosage and administration").

COVID-19

Pharmacokinetics of tocilizumab were characterized using a population pharmacokinetic analysis of data from 380 adult patients with COVID-19 in studies WA42380 (COVACTA) and CA42481 (MARIPOSA), who received a single infusion of tocilizumab at 8 mg/kg or two infusions separated by at least 8 hours. The following parameters (predicted mean ± standard deviation) were calculated for tocilizumab at 8 mg/kg: area under the curve over 28 days (AUC0-28) was 18,312 (5,184) h•µg/mL, concentration on day 28 (Cday28) was 0.934 (1.93) µg/mL, and maximum concentration (Cmax) was 154 (34.9) µg/mL. AUC0-28, Cday28, and Cmax were also calculated after administration of two doses of tocilizumab at 8 mg/kg separated by 8 hours (predicted mean ± standard deviation): 42,240 (11,520) h•µg/mL, 8.94 (8.5) µg/mL, and 296 (64.7) µg/mL, respectively.

Distribution

In patients with rheumatoid arthritis, the central volume of distribution is 3.72 L, the peripheral volume is 3.35 L, and the steady-state volume of distribution is 7.07 L.

In adult patients with COVID-19, the central volume of distribution is 4.52 L, the peripheral volume is 4.23 L, resulting in a volume of distribution of 8.75 L.

Elimination

After intravenous administration, tocilizumab is eliminated from systemic circulation via dual elimination: linear clearance and concentration-dependent nonlinear clearance. In patients with rheumatoid arthritis, linear clearance is 9.5 mL/h. In adult patients with COVID-19, linear clearance was 17.6 mL/h in patients with baseline ordinal scale category 3 (OS 3, patients requiring oxygen therapy), 22.5 mL/h in patients with baseline OS 4 (patients requiring high-flow oxygen therapy or non-invasive ventilation), 29 mL/h in patients with baseline OS 5 (patients requiring mechanical ventilation), and 35.4 mL/h in patients with baseline OS 6 (patients requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support). Nonlinear, concentration-dependent clearance is most significant at low tocilizumab concentrations. Once nonlinear clearance becomes saturated at high tocilizumab concentrations, clearance is primarily determined by linear clearance.

In patients with rheumatoid arthritis, the half-life (t1/2) is concentration-dependent. At steady state, achieved after administration of 8 mg/kg every 4 weeks, the effective half-life t1/2 decreased in parallel with decreasing concentration across the dosing interval from 18 to 6 days.

In patients with COVID-19, serum concentrations were below the lower limit of quantification on average 35 days after a single intravenous infusion of tocilizumab at 8 mg/kg.

Linearity

Pharmacokinetic parameters of tocilizumab do not change over time. The greatest dose-dependent increase in AUC and Cmin is observed at doses of 4 and 8 mg/kg every four weeks. Cmax increases proportionally with dose. At steady state, calculated AUC and Cmin were 3.2 and 30 times higher, respectively, at 8 mg/kg compared to 4 mg/kg.

Systemic juvenile idiopathic arthritis

Tocilizumab pharmacokinetics were evaluated in a population pharmacokinetic analysis of data from 140 patients with systemic juvenile idiopathic arthritis who received tocilizumab at 8 mg/kg intravenously every 2 weeks (patients with body weight ≥30 kg), 12 mg/kg intravenously every 2 weeks (patients with body weight <30 kg), 162 mg subcutaneously weekly (patients with body weight ≥30 kg), or 162 mg subcutaneously every 10 days or every 2 weeks (patients with body weight <30 kg).

Table 1

Predicted median ± standard deviation of steady-state pharmacokinetic parameters after intravenous administration in patients with systemic juvenile idiopathic arthritis

*τ = 2 weeks for intravenous dosing regimens

Cmean – mean concentration

After intravenous administration, approximately 90% of steady-state was achieved by week 8 with dosing regimens of 12 mg/kg (body weight < 30 kg) and 8 mg/kg (body weight ≥ 30 kg) every 2 weeks.

In patients with systemic juvenile idiopathic arthritis, the central volume of distribution was 1.87 L, and the peripheral volume of distribution was 2.14 L, resulting in a volume of distribution at steady state of 4.01 L. Linear clearance was estimated as a parameter of population pharmacokinetic analysis and was 5.7 mL/hour.

In patients with systemic juvenile idiopathic arthritis, the half-life of tocilizumab at 12 weeks is approximately 16 days for both patient weight groups (8 mg/kg for patients with body weight ≥ 30 kg and 12 mg/kg for patients with body weight < 30 kg).

Active polyarticular juvenile idiopathic arthritis (pJIA)

The pharmacokinetics of tocilizumab in patients with polyarticular juvenile idiopathic arthritis were determined in a population pharmacokinetic analysis that included 237 patients receiving tocilizumab treatment at a dose of 8 mg/kg intravenously every 4 weeks (patients with body weight ≥ 30 kg), 10 mg/kg intravenously every 4 weeks (patients with body weight < 30 kg), 162 mg subcutaneously every 2 weeks (patients with body weight ≥ 30 kg), or 162 mg subcutaneously every 3 weeks (patients with body weight < 30 kg).

Table 2

Estimated median ± standard deviation of pharmacokinetic parameters at steady state after intravenous administration in patients with pJIA

*τ = 4 weeks for intravenous administration regimens

Cmean – mean concentration

After intravenous administration, approximately 90% of steady-state was achieved by week 12 with a dosage of 10 mg/kg (body weight < 30 kg) and by week 16 with a dosage of 8 mg/kg (body weight ≥ 30 kg).

The elimination half-life of tocilizumab in patients with active polyarticular juvenile idiopathic arthritis during the dosing interval at steady state is approximately 16 days for both weight categories of patients (8 mg/kg for patients with body weight ≥30 kg and 10 mg/kg for patients with body weight <30 kg).

Pharmacokinetics in special clinical populations

Patients with hepatic impairment: The pharmacokinetics of tocilizumab in patients with hepatic impairment has not been studied.

Patients with renal impairment: The pharmacokinetics of tocilizumab in patients with renal impairment has not been studied. In the majority of patients included in the population pharmacokinetic analysis, renal function was normal or there was mild renal impairment (creatinine clearance by Cockcroft-Gault formula <80 mL/min and ≥50 mL/min), which did not affect the pharmacokinetics of tocilizumab.

Sex, race, age: Population pharmacokinetic analysis in patients with rheumatoid arthritis and patients with COVID-19 showed that age, sex, and race do not influence the pharmacokinetics of tocilizumab.

Results of the population PK analysis in patients with COVID-19 confirm that body weight and disease severity are covariates with a significant impact on the linear clearance of tocilizumab.

Clinical characteristics.

Indications.

Rheumatoid arthritis

Actemra**®** in combination with methotrexate is indicated for:

• treatment of severe, active and progressive rheumatoid arthritis in adults who have not previously received methotrexate therapy;
• treatment of rheumatoid arthritis with moderate to high disease activity in adults who have shown an inadequate response or intolerance to prior therapy with one or more disease-modifying antirheumatic drugs or tumor necrosis factor antagonists.

Actemra**®** may be prescribed as monotherapy in such patients if methotrexate is not tolerated or if continuing methotrexate therapy is inappropriate. When administered in combination with methotrexate, Actemra**®** inhibits the progression of joint damage as assessed radiographically and improves physical function.

Coronavirus disease 2019 (COVID-19)

Treatment of coronavirus disease 2019 (COVID-19) in adult patients receiving systemic corticosteroids and requiring oxygen supplementation or mechanical ventilation.

Systemic juvenile idiopathic arthritis

Treatment of active systemic juvenile idiopathic arthritis in patients aged 2 years and older who have shown an inadequate response to prior therapy with nonsteroidal anti-inflammatory drugs and systemic corticosteroids. Actemra**®** may be prescribed both as monotherapy (in case of methotrexate intolerance or if methotrexate therapy is inappropriate) and in combination with methotrexate.

Polyarticular juvenile idiopathic arthritis

Treatment of active polyarticular juvenile idiopathic arthritis in combination with methotrexate (positive or negative rheumatoid factor or extended oligoarticular form) in patients aged 2 years and older who have shown an inadequate response to prior methotrexate therapy. Actemra**®** may be prescribed both as monotherapy (in case of methotrexate intolerance or if continuation of methotrexate therapy is inappropriate) and in combination with methotrexate.

Contraindications.

Hypersensitivity to tocilizumab or to any other component of the medicinal product. Active, serious infections, except for COVID-19 (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adult patients.

Population pharmacokinetic analysis did not reveal any influence of methotrexate, nonsteroidal anti-inflammatory drugs, or corticosteroids on the clearance of tocilizumab.

Concomitant single-dose administration of tocilizumab at 10 mg/kg and methotrexate at 10–25 mg once weekly did not significantly affect methotrexate exposure.

Since the formation of hepatic CYP450 isoenzymes is suppressed by cytokines (e.g., IL-6, which promotes chronic inflammation), treatment with agents that inhibit cytokine activity (including tocilizumab) may alter the expression of CYP450 isoenzymes.

In vitro studies conducted on cultured human hepatocytes have shown that IL-6 causes a reduction in the expression of CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzymes. Administration of tocilizumab normalizes the expression of these isoenzymes.

Serum concentrations of simvastatin (a CYP3A4 substrate) decreased by 57% one week after a single dose of tocilizumab in patients with RA, compared to similar or slightly elevated concentrations in healthy volunteers.

Careful monitoring is required at the initiation or upon completion of treatment with Actemra**®** in patients receiving individually adjusted doses of medicinal products metabolized by CYP450 isoenzymes 3A4, 1A2, or 2C9 (e.g., methylprednisolone, dexamethasone (with potential risk of glucocorticoid withdrawal syndrome), atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, cyclosporine, or benzodiazepines), as dose adjustments may be required to maintain therapeutic efficacy. Due to the long t1/2 of Actemra**®**, its effect on CYP450 enzyme activity may persist for several weeks after discontinuation of therapy.

Special precautions for use.

In order to improve traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly documented in the patient's medical records.

Patients with rheumatoid arthritis, systemic juvenile idiopathic arthritis, and polyarticular juvenile idiopathic arthritis

Infections. Serious infections (sometimes fatal) have been observed in patients receiving immunosuppressive agents, including tocilizumab (see section "Side effects"). It is contraindicated to initiate treatment with Actemra® in patients with active infections (see section "Contraindications"). In the event of serious infections, treatment with Actemra® should be discontinued until the infection resolves (see section "Side effects"). Healthcare providers should exercise caution when prescribing Actemra® to patients with a history of recurrent or chronic infections, as well as in patients with concomitant conditions predisposing to infections (e.g., diverticulitis, diabetes mellitus, and interstitial lung disease).

To enable early detection of serious infectious diseases, close monitoring of patients receiving biological agents is essential, as symptoms of acute inflammation may be masked due to suppression of the acute-phase response. The impact of tocilizumab on C-reactive protein, neutrophils, and symptoms and signs of infection should be considered when assessing the possibility of infection in a patient. Patients, as well as parents/guardians of children with systemic juvenile idiopathic arthritis or polyarticular juvenile idiopathic arthritis, should be informed about the need to seek immediate medical attention if any symptoms suggestive of infection occur, to ensure timely diagnosis and appropriate treatment.

Tuberculosis. Prior to initiating Actemra® therapy, as with other biological agents used in the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, and polyarticular juvenile idiopathic arthritis, patients should be screened for latent tuberculosis. If latent tuberculosis is detected, standard anti-mycobacterial therapy should be initiated before starting Actemra®. Physicians should be aware of the risk of false-negative results from tuberculin skin tests and interferon-gamma release assays, particularly in critically ill patients and those with immunodeficiency.

Patients should be instructed to seek medical advice promptly if signs/symptoms suggestive of tuberculosis infection (e.g., persistent cough, fatigue/weight loss, low-grade fever) develop during or after Actemra® therapy.

Reactivation of viral infections. Reactivation of viral infections (e.g., hepatitis B) has been observed with the use of biological agents in the treatment of RA. Patients with positive screening results for hepatitis were excluded from clinical trials of Actemra®.

Diverticulitis complications. Cases of diverticular perforation as a complication of diverticulitis have been reported in patients with rheumatoid arthritis receiving Actemra® (see section "Side effects"). Tocilizumab should be used with caution in patients with a history of gastrointestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis (abdominal pain, bleeding and/or unexplained changes in bowel habits accompanied by fever) should be evaluated promptly to detect diverticulitis, which may be associated with gastrointestinal perforation.

Hypersensitivity reactions. Serious hypersensitivity reactions have been observed during infusion of Actemra® (see section "Side effects"). Such reactions may be more severe and potentially fatal in patients who have previously experienced hypersensitivity reactions during prior infusions, even if they received premedication with corticosteroids and antihistamines. Appropriate emergency measures for the treatment of anaphylactic reactions must be readily available in case such a reaction occurs during tocilizumab administration. If an anaphylactic reaction or other serious hypersensitivity/infusion reaction occurs, tocilizumab infusion must be stopped immediately and tocilizumab therapy discontinued.

Active liver disease and hepatic insufficiency. Treatment with Actemra®, particularly in combination with methotrexate, may be associated with increased liver transaminase activity; therefore, caution is advised in patients with active liver disease or hepatic insufficiency (see sections "Dosage and administration", "Side effects").

Hepatotoxicity. Transient or intermittent, mild to moderate elevations in liver transaminase levels have frequently been reported during treatment with Actemra® (see section "Side effects"). The frequency of such enzyme elevations increases when potentially hepatotoxic agents (e.g., methotrexate) are used concomitantly with Actemra®. Other liver function tests, including bilirubin levels, should be considered when clinically indicated.

Serious drug-induced liver injury, including acute liver failure, hepatitis, and jaundice, has been observed with Actemra® (see section "Side effects"). Serious liver injury has occurred from 2 weeks to more than 5 years after initiation of Actemra® therapy. Cases of liver failure requiring liver transplantation have been reported. Patients should be advised to seek immediate medical attention if symptoms of liver injury occur.

Caution should be exercised when initiating Actemra® therapy in patients with ALT/AST levels exceeding the upper limit of normal (ULN) by more than 1.5 times. In patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis, Actemra® therapy is not recommended if baseline ALT/AST levels exceed ULN by more than 5 times.

In patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis, ALT/AST levels should be monitored every 4–8 weeks during the first 6 months of treatment, followed by monitoring every 12 weeks. Dose recommendations, including discontinuation of Actemra® based on liver transaminase activity, are provided in the section "Dosage and administration". Treatment should be interrupted if ALT or AST levels increase to 3–5 times ULN, confirmed by repeat testing.

Blood disorders. Following treatment with tocilizumab 8 mg/kg in combination with methotrexate, decreases in neutrophil and platelet counts have been observed (see section "Side effects"). Patients previously treated with tumor necrosis factor (TNF) antagonists may have an increased risk of developing neutropenia.

Initiation of Actemra® therapy is not recommended in patients with an absolute neutrophil count (ANC) below 2 × 10⁹/L who have not previously received Actemra®. Caution should be exercised when considering initiation of Actemra® in patients with low platelet counts (i.e., platelet count below 100 × 10³/μL). Continuing treatment in patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, or systemic juvenile idiopathic arthritis who have ANC < 0.5 × 10⁹/L or platelet count < 50 × 10³/μL is not recommended.

Severe neutropenia may be associated with an increased risk of serious infections, although clinical trials of Actemra® have not established a clear correlation between reduced neutrophil counts and the occurrence of serious infections.

In patients with rheumatoid arthritis, neutrophil and platelet counts should be monitored every 4–8 weeks from the start of Actemra® therapy, and thereafter according to standard clinical practice. Dose adjustment recommendations based on ANC and platelet count are provided in the section "Dosage and administration".

In patients with systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis, neutrophil and platelet counts should be assessed during the second infusion and thereafter according to standard clinical practice.

Lipid metabolism changes. Increases in lipid parameters (total cholesterol, LDL, HDL, triglycerides) have been observed in patients receiving tocilizumab (see section "Side effects"). In most patients, the atherogenic index did not increase, and elevated total cholesterol levels responded to lipid-lowering therapy.

In patients with rheumatoid arthritis and in patients with systemic juvenile idiopathic arthritis or polyarticular juvenile idiopathic arthritis, lipid parameters should be evaluated 4–8 weeks after initiation of Actemra® therapy. Management of patients should follow national guidelines for the treatment of hyperlipidemia.

Neurological disorders. Patients should be closely monitored for early signs suggestive of demyelinating disorders of the central nervous system. The potential of tocilizumab to induce demyelinating disorders of the central nervous system is currently unknown.

Malignancies. The risk of malignancies is increased in patients with rheumatoid arthritis. The use of immunomodulatory medicinal products may further increase this risk.

Vaccination. Live or live-attenuated vaccines should not be administered concurrently with Actemra® therapy, as the clinical safety of such combination has not been established. In a randomized open-label study, adult patients with rheumatoid arthritis receiving Actemra® and methotrexate were able to mount an effective immune response to the 23-valent pneumococcal polysaccharide vaccine and tetanus toxoid. It is recommended that all patients, especially those with systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis, receive vaccinations according to the current national immunization schedule prior to starting Actemra® therapy, if possible. An appropriate interval (in accordance with current immunization guidelines for patients receiving immunosuppressive therapy) should be observed between live vaccination and initiation of Actemra® therapy.

Cardiovascular risk. Patients with rheumatoid arthritis have an increased risk of cardiovascular disorders. Those with risk factors (e.g., arterial hypertension, hyperlipidemia) should be managed according to standard treatment guidelines.

Concomitant use with tumor necrosis factor antagonists. There is no experience with concomitant use of Actemra® and TNF antagonists or any other biological agents in the treatment of patients with rheumatoid arthritis, systemic juvenile idiopathic arthritis, or polyarticular juvenile idiopathic arthritis. Concomitant use of Actemra® with other biological agents is not recommended.

Sodium. Actemra® contains 1.17 mmol (or 26.55 mg) of sodium per maximum dose of 1200 mg; therefore, patients on a sodium-restricted diet should take this into account. Doses below 1025 mg of Actemra® contain less than 1 mmol of sodium (23 mg) and are considered sodium-free.

Patients with COVID-19

• The efficacy of Actemra® has not been established in the treatment of COVID-19 in patients without elevated C-reactive protein levels (see subsection "Clinical efficacy").
• Actemra® should not be used in patients with COVID-19 who are not receiving systemic corticosteroids, due to the inability to exclude increased mortality in this patient subgroup (see subsection "Clinical efficacy").

Infections. Actemra® should not be administered to patients with COVID-19 who have any other concurrent serious active infections. Healthcare providers should exercise caution when considering Actemra® for patients with a history of recurrent or chronic infections or with comorbidities (e.g., diverticulitis, diabetes mellitus, interstitial lung disease) that may increase the risk of infections.

Hepatotoxicity. ALT or AST levels may increase in hospitalized patients with COVID-19. Multi-organ failure involving the liver is recognized as a complication of severe COVID-19. The decision to use tocilizumab should be made considering the benefit-risk balance for treating COVID-19 versus the potential risks associated with tocilizumab. Tocilizumab is not recommended in patients with COVID-19 and ALT or AST levels more than 10 times the ULN. In patients with COVID-19, ALT/AST levels should be monitored according to current standard clinical practice.

Blood disorders. Tocilizumab therapy is not recommended in patients with COVID-19 who have ANC < 1 × 10⁹/L or platelet count < 50 × 10³/μL. In patients with COVID-19, neutrophil and platelet counts should be monitored according to current standard clinical practice (see section "Dosage and administration").

Systemic juvenile idiopathic arthritis

Macrophage activation syndrome. Macrophage activation syndrome is a serious, life-threatening condition that may develop in patients with systemic juvenile idiopathic arthritis. Tocilizumab has not been studied in patients during episodes of macrophage activation syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate data on the use of Actemra® during pregnancy. Animal studies have shown an increased risk of spontaneous abortion/embryo-fetal death at high doses. The potential risk in humans is unknown. Women of childbearing potential should use effective contraception during treatment and for 3 months after discontinuation of the drug.

Actemra® should not be used during pregnancy; it should be administered only if absolutely necessary.

Breastfeeding

It is unknown whether Actemra® is excreted in human breast milk. Penetration of tocilizumab into animal breast milk has not been studied. The decision to continue/stop breastfeeding or to continue/discontinue Actemra® therapy should be based on the benefits of breastfeeding for the child and the benefits of Actemra® therapy for the mother.

Fertility

Available preclinical data indicate no effect on fertility during tocilizumab treatment.

Ability to drive and use machines.

Actemra® has a minor influence on the ability to drive and use machinery (see section "Side effects", dizziness).

Method of Administration and Dosage

Treatment should be initiated by a specialist experienced in the diagnosis and treatment of rheumatoid arthritis, COVID-19, systemic juvenile idiopathic arthritis, or polyarticular juvenile idiopathic arthritis.

All patients receiving Actemra® must be provided with a patient reminder card.

After reconstitution, Actemra® must be administered as an intravenous infusion over 1 hour to patients with rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, and COVID-19.

Rheumatoid Arthritis

The recommended dose is 8 mg/kg administered once every 4 weeks as an intravenous infusion over at least 1 hour. Actemra® should be diluted to 100 mL with sterile 0.9% sodium chloride solution under aseptic conditions.

Dose increases above 800 mg per infusion are not recommended for patients with body weight exceeding 100 kg (see section "Pharmacokinetics").

Doses higher than 1.2 g have not been studied in clinical trials.

Dose modification recommendations based on laboratory parameter changes (see section "Special Warnings and Precautions for Use").

Elevated liver enzyme levels

*ULN – upper limit of normal

Low absolute neutrophil count (ANC)

Initiation of therapy with Actemra**®** is not recommended in patients who have not previously received Actemra**®** treatment if the ANC is less than 2 × 10⁹/L.

Low platelet count

Coronavirus disease 2019 (COVID-19)

The recommended dose for treatment of COVID-19 is 8 mg/kg as a single 60-minute intravenous infusion for patients receiving systemic corticosteroids who require supplemental oxygen or mechanical ventilation (see section "Clinical efficacy"). If clinical symptoms worsen or do not improve after the first dose, one additional infusion of Actemra® at a dose of 8 mg/kg may be administered. The interval between the two infusions should be at least 8 hours.

Patients with body weight greater than 100 kg should not receive doses exceeding 800 mg/infusion (see section "Pharmacokinetics").

Use of Actemra® is not recommended in patients with COVID-19 and the following laboratory abnormalities:

Systemic Juvenile Idiopathic Arthritis

The safety and efficacy of intravenous administration of Actemra**®** in children under 2 years of age have not been established.

The recommended dose for patients aged 2 years and older with body weight <30 kg is 12 mg/kg every 2 weeks; for patients with body weight ≥30 kg – 8 mg/kg every 2 weeks, administered intravenously as an infusion over at least 1 hour.

For patients with body weight ≥30 kg, Actemra**®** should be diluted to a final volume of 100 mL with sterile, pyrogen-free 0.9% sodium chloride solution under aseptic conditions.

For patients with body weight <30 kg, Actemra**®** should be diluted to a final volume of 50 mL with sterile, pyrogen-free 0.9% sodium chloride solution under aseptic conditions.

The dose should be recalculated at each administration based on the patient’s body weight. Dose adjustments should only occur in response to significant changes in body weight over time.

Dose modification recommendations based on laboratory parameter changes (see section "Adverse Reactions")

If necessary, it is recommended to adjust the dose or discontinue concomitantly administered methotrexate and/or other medications and to interrupt tocilizumab treatment until clinical reassessment. Since many comorbid conditions can influence laboratory parameters in systemic juvenile idiopathic arthritis, the decision to discontinue tocilizumab due to abnormal laboratory findings should be based on individual clinical assessment of each patient.

Elevated liver enzyme levels

*ULN – upper limit of normal

Low absolute neutrophil count (ANC)

Low platelet count

There are insufficient clinical data to assess the impact of reducing the dose of tocilizumab in patients with systemic juvenile idiopathic arthritis who have laboratory test abnormalities.

Available data confirm that clinical improvement is observed within 6 weeks after initiation of treatment with Actemra**®**. A careful reassessment of the need for continuing treatment is required in patients who show no signs of clinical improvement within this treatment period.

Polyarticular juvenile idiopathic arthritis

The safety and efficacy of intravenous Actemra**®** in children under 2 years of age have not been established.

The recommended dose for patients aged 2 years and older is 8 mg/kg administered once every 4 weeks for patients with body weight ≥30 kg, or 10 mg/kg administered once every 4 weeks for patients with body weight less than 30 kg. The dose should be recalculated at each administration based on the patient's body weight. Dose adjustments should only occur in response to significant changes in the patient's body weight over time.

The table below outlines laboratory abnormalities for which interruption of tocilizumab is recommended in patients with polyarticular juvenile idiopathic arthritis. If necessary, the dose of concomitant methotrexate and/or other medicinal products should be adjusted or discontinued, and tocilizumab treatment should be interrupted pending clinical evaluation. Since many comorbid conditions can influence laboratory parameters in polyarticular juvenile idiopathic arthritis, the decision to discontinue tocilizumab due to laboratory abnormalities should be based on individual clinical assessment of each patient.

Elevated liver enzymes

Low absolute neutrophil count (ANC)

Low platelet count

Reduction of tocilizumab dose due to laboratory abnormalities has not been studied in patients with polyarticular juvenile idiopathic arthritis.

Available data confirm that clinical improvement occurs within 12 weeks after initiation of treatment with Actemra**®**. A careful reassessment of continuing treatment is required in patients who show no signs of clinical improvement within this treatment period.

Dosing in special situations.

Children. The efficacy and safety of tocilizumab in children under 2 years of age have not been studied.

Elderly patients. Dose adjustment is not required in elderly patients (>65 years of age).

Patients with renal impairment. Dose adjustment is not required in patients with mild renal impairment. The use of tocilizumab in patients with moderate to severe renal impairment has not been studied. Renal function should be closely monitored in such patients.

Patients with hepatic impairment. The use of Actemra**®** has not been studied in patients with impaired liver function. Therefore, no dosage recommendations can be provided.

Preparation of the solution

Parenteral medicinal products should be visually inspected for particulate matter and discoloration prior to administration. Only solutions that are clear or opalescent, colorless or pale yellow, and free from visible particulate matter may be used for dilution. Sterile needles and syringes should be used to prepare Actemra® for administration.

For patients with rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, and COVID-19 with body weight ≥ 30 kg, Actemra**®** should be diluted to a final volume of 100 mL using sterile, pyrogen-free 0.9% (9 mg/mL) sodium chloride solution for injection under aseptic conditions.

For patients with systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis with body weight < 30 kg, Actemra**®** should be diluted to a final volume of 50 mL using sterile, pyrogen-free 0.9% (9 mg/mL) sodium chloride solution for injection under aseptic conditions.

If infusion reactions occur, the infusion should be slowed or stopped, and appropriate medicinal products/supportive therapy should be administered immediately; see section "Special precautions for use".

Patients with rheumatoid arthritis and COVID-19

Under aseptic conditions, withdraw from a 100 mL infusion bag an amount of sterile, pyrogen-free 9 mg/mL (0.9%) sodium chloride solution for injection equivalent to the volume of Actemra® concentrate required for the patient's dose. Withdraw the required volume of Actemra® concentrate (0.4 mL/kg) from the vial and add it to a 100 mL infusion bag. The final solution volume should be 100 mL. Gently invert the infusion bag to mix the solution and avoid foaming.

Patients with systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis with body weight ≥ 30 kg

Under aseptic conditions, withdraw from a 100 mL infusion bag an amount of sterile, pyrogen-free 9 mg/mL (0.9%) sodium chloride solution for injection equivalent to the volume of Actemra® concentrate required for the patient's dose. Withdraw the required volume of Actemra® concentrate (0.4 mL/kg) from the vial and add it to a 100 mL infusion bag. The final solution volume should be 100 mL. Gently invert the infusion bag to mix the solution and avoid foaming.

Patients with systemic juvenile idiopathic arthritis with body weight < 30 kg

Under aseptic conditions, withdraw from a 50 mL infusion bag an amount of sterile, pyrogen-free 9 mg/mL (0.9%) sodium chloride solution for injection equivalent to the volume of Actemra® concentrate required for the patient's dose. Withdraw the required volume of Actemra® concentrate (0.6 mL/kg) from the vial and add it to a 50 mL infusion bag. The final solution volume should be 50 mL. Gently invert the infusion bag to mix the solution and avoid foaming.

Patients with polyarticular juvenile idiopathic arthritis with body weight < 30 kg

Under aseptic conditions, withdraw from a 50 mL infusion bag an amount of sterile, pyrogen-free 9 mg/mL (0.9%) sodium chloride solution for injection equivalent to the volume of Actemra® concentrate required for the patient's dose. Withdraw the required volume of Actemra® concentrate (0.5 mL/kg) from the vial and add it to a 50 mL infusion bag. The final solution volume should be 50 mL. Gently invert the infusion bag to mix the solution and avoid foaming.

Storage of the prepared solution

The prepared (diluted) infusion solution of Actemra**®** is physically and chemically stable in 0.9% sodium chloride solution.

From the standpoint of physical and chemical stability, the solution may be stored for up to 24 hours at 30°C and up to 2 weeks in a refrigerator at 2°C to 8°C.

From a microbiological perspective, the prepared solution should be used immediately.

If not used immediately, the time and conditions of storage of the prepared solution are the responsibility of the person performing the administration and should not exceed 24 hours at 2°C to 8°C, and only if the solution was prepared under controlled and validated aseptic conditions.

Any unused medicinal product or waste should be disposed of in accordance with local requirements.

Children.

The safety and efficacy of Actemra**®** in children under 2 years of age have not been established.

Overdose.

Data on overdose with Actemra**®** are limited. In one accidental overdose of 40 mg/kg administered as a single dose to a patient with multiple myeloma, no adverse reactions were observed. No serious adverse reactions were observed in healthy volunteers who received a single dose of Actemra**®** up to 28 mg/kg, although dose-limiting neutropenia was observed.

Children

No cases of overdose in children have been reported.

Adverse Reactions

Clinical Trials

The most frequently reported adverse reactions (occurring in ≥5% of patients receiving monotherapy with tocilizumab or combination therapy with tocilizumab and disease-modifying antirheumatic drugs for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis) were upper respiratory tract infections, nasopharyngitis, headache, hypertension, and increased ALT levels.

In most cases, serious adverse reactions were serious infections, diverticulitis complications, and hypersensitivity reactions.

The most commonly reported adverse reactions (occurring in ≥5% of patients receiving tocilizumab for the treatment of COVID-19) were increased liver transaminase levels, constipation, and urinary tract infection.

Data on adverse reactions known from clinical trials and/or post-marketing experience, spontaneous reports, literature sources, and non-interventional studies are presented below using Medical Dictionary for Regulatory Activities (MedDRA) system organ class and frequency categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and very rare (<1/10,000). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Rheumatoid Arthritis (RA)

The safety profile of tocilizumab was evaluated in four placebo-controlled trials (Phase II, III, IV, and V), one controlled trial using methotrexate (Phase I), and in the extension periods of these trials.

The double-blind controlled period in four trials lasted 6 months (Phase I, III, IV, and V) and up to 2 years in one trial (Phase II). In the double-blind controlled trials, 774 patients received tocilizumab at a dose of 4 mg/kg in combination with methotrexate, 1870 patients received tocilizumab at a dose of 8 mg/kg in combination with methotrexate or other disease-modifying antirheumatic drugs, and 288 patients received monotherapy with tocilizumab at a dose of 8 mg/kg.

The long-term safety population included all patients who received at least one dose of tocilizumab, both during the double-blind controlled period and the open-label extension period of the trials. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3296 for at least 1 year, 2806 for at least 2 years, and 1222 for 3 years.

Infections and infestations: very common – upper respiratory tract infections; common – cellulitis, pneumonia, infections caused by Herpes simplex type 1 and Herpes zoster; uncommon – diverticulitis.

Blood and lymphatic system disorders: common – leukopenia, neutropenia, hypofibrinogenemia.

Immune system disorders: rare – anaphylaxis (fatal)^1,2,3.

Endocrine disorders: uncommon – hypothyroidism.

Metabolism and nutrition disorders: very common – hypercholesterolemia*; uncommon – hypertriglyceridemia.

Nervous system disorders: common – headache, dizziness.

Eye disorders: common – conjunctivitis.

Vascular disorders: common – hypertension.

Respiratory, thoracic and mediastinal disorders: common – cough, dyspnea.

Gastrointestinal disorders: common – oral mucosal ulcers, gastritis, abdominal pain; uncommon – stomatitis, gastric ulcer.

Hepatobiliary disorders: rare – drug-induced liver injury, hepatitis, jaundice; very rare – liver failure.

Skin and subcutaneous tissue disorders: common – rash, pruritus, urticaria; rare – Stevens-Johnson syndrome³.

Renal and urinary disorders: uncommon – nephrolithiasis.

General disorders and administration site conditions: common – peripheral edema, hypersensitivity reactions.

Investigations: common – increased liver transaminase levels, increased body weight, increased total bilirubin*.

*Including increases detected during routine laboratory monitoring (see text below).

1See section "Contraindications".

2See section "Special warnings and precautions for use".

3This adverse reaction was identified during post-marketing surveillance but was not observed in controlled clinical trials.

The frequency category was estimated as the upper limit of the 95% confidence interval calculated based on the total number of patients who received tocilizumab in clinical trials.

Additional information on specific adverse reactions.

Infections: In 6-month controlled trials, the infection rate with tocilizumab 8 mg/kg in combination with a disease-modifying antirheumatic drug was 127 events per 100 patient-years compared to 112 events per 100 patient-years in the placebo plus disease-modifying antirheumatic drug group. The overall infection rate in the entire study population was 108 per 100 patient-years.

In 6-month controlled clinical trials, the rate of serious infections in patients receiving Actemra**®** 8 mg/kg in combination with a disease-modifying antirheumatic drug was 5.3 events per 100 patient-years compared to 3.9 events per 100 patient-years in the placebo plus disease-modifying antirheumatic drug group. With Actemra**®** monotherapy, the rate of serious infections was 3.6 events per 100 patient-years compared to 1.5 events per 100 patient-years with methotrexate monotherapy.

In the entire study population, the overall rate of serious infections (bacterial, viral, fungal) was 4.7 per 100 patient-years. Serious infections, some with fatal outcomes, included active tuberculosis (pulmonary or extrapulmonary forms), invasive pulmonary infections (including candidiasis, aspergillosis, coccidioidomycosis, and Pneumocystis pneumonia), pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. Opportunistic infections have been reported.

Interstitial lung disease. Lung function disorders may increase the risk of infections. Post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis) have been received, some of which were fatal.

Gastrointestinal perforation (GI). During 6-month controlled trials, the overall rate of GI perforation in the Actemra**®** group was 0.26 events per 100 patient-years. In the entire study population, the overall rate of GI perforation was 0.28 events per 100 patient-years. Most GI perforations were reported as complications of diverticulitis and included generalized purulent peritonitis, lower GI tract perforation, fistula, and abscess.

Infusion reactions. During 6-month controlled trials, adverse reactions related to administration (individual events occurring during or within 24 hours after infusion) occurred in 6.9% of patients receiving Actemra**®** 8 mg/kg in combination with a disease-modifying antirheumatic drug and in 5.1% of patients receiving placebo plus disease-modifying antirheumatic drug. Reactions during infusion were mainly episodes of increased blood pressure. Reactions within 24 hours after infusion included headache and skin reactions (rash, urticaria). These reactions did not lead to treatment discontinuation.

The rate of anaphylaxis (8 of 4009 patients, 0.2%) was several times higher in patients receiving the 4 mg/kg dose compared to those receiving the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with Actemra**®** administration requiring treatment discontinuation occurred in 56 of 4009 patients (1.4%) in controlled and open-label clinical trials. These reactions mostly occurred between the second and fifth infusions of Actemra**®** (see section "Special warnings and precautions for use"). A case of fatal anaphylactic reaction during tocilizumab treatment was reported post-marketing (see section "Special warnings and precautions for use").

Immunogenicity. Antibodies to tocilizumab were detected in 46 of 2876 patients (1.6%) in 6-month controlled trials. Clinically significant hypersensitivity reactions occurred in 6 of these patients, leading to complete treatment discontinuation in 5. Neutralizing antibodies were detected in 30 patients (1.1%).

Laboratory parameter changes

Neutrophils. In 6-month controlled trials, a decrease in neutrophil count below 1 × 10⁹/L was observed in 3.4% of patients receiving Actemra**®** 8 mg/kg in combination with a disease-modifying antirheumatic drug, compared to less than 0.1% in the placebo plus disease-modifying antirheumatic drug group. Approximately half of the cases of neutrophil count reduction below 1 × 10⁹/L occurred within 8 weeks of treatment initiation. A reduction in neutrophil count below 0.5 × 10⁹/L was reported in 0.3% of patients receiving Actemra**®** 8 mg/kg in combination with a disease-modifying antirheumatic drug. Infections associated with neutropenia were reported.

The pattern and frequency of neutrophil count reduction in the overall controlled and study population corresponded to the results observed in 6-month controlled clinical trials.

Platelets. In 6-month controlled trials, a decrease in platelet count below 100 × 10³/μL was observed in 1.7% of patients receiving Actemra**®** 8 mg/kg in combination with a disease-modifying antirheumatic drug, compared to less than 1% in the placebo plus disease-modifying antirheumatic drug group. These changes were not associated with bleeding episodes.

The pattern and frequency of platelet count reduction in the overall controlled and study population corresponded to the results observed in 6-month controlled clinical trials.

Pancytopenia was very rarely reported during the post-marketing period.

Elevated liver transaminase activity. In 6-month controlled clinical trials, transient elevation of ALT/AST activity (exceeding ULN by more than 3 times) was observed in 2.1% of patients receiving Actemra**®** 8 mg/kg and in 4.9% of patients receiving methotrexate. These changes occurred in 6.5% of patients receiving Actemra**®** 8 mg/kg in combination with a disease-modifying antirheumatic drug and in 1.5% of patients receiving placebo plus disease-modifying antirheumatic drug.

Adding potentially hepatotoxic drugs (e.g., methotrexate) to tocilizumab monotherapy increased the frequency of transaminase elevation. ALT/AST elevation exceeding ULN by more than 5 times was observed in 0.7% of patients receiving Actemra**®** monotherapy and in 1.4% of patients receiving Actemra**®** in combination with a disease-modifying antirheumatic drug. In most cases, Actemra**®** therapy was discontinued. During the double-blind controlled period, routine laboratory monitoring showed that the frequency of indirect bilirubin levels above the upper limit of normal in patients receiving tocilizumab 8 mg/kg in combination with a disease-modifying antirheumatic drug was 6.2%. Overall, elevated indirect bilirubin levels from 1 to 2 times above ULN were observed in 5.8% of patients and more than 2 times above ULN in 0.4%.

The pattern and frequency of ALT/AST elevation in the overall controlled and study population corresponded to the results observed in 6-month controlled clinical trials.

Lipid metabolism parameter changes. During routine laboratory monitoring in 6-month controlled trials, increases in lipid metabolism parameters (total cholesterol, triglycerides, LDL-C, and/or HDL-C) were frequently observed with Actemra**®** therapy. Sustained elevation of total cholesterol >6.2 mmol/L was observed in 24% of patients, and sustained elevation of LDL-C ≥4.1 mmol/L in 15% of patients.

Elevated lipid parameters were effectively managed with lipid-lowering agents.

The pattern and frequency of lipid parameter elevation in the overall controlled and study population corresponded to the results observed in 6-month controlled clinical trials.

Malignancies

There is insufficient clinical data to assess the potential risk of malignancies following tocilizumab use. Long-term safety evaluation is ongoing.

Skin reactions

Cases of Stevens-Johnson syndrome were rarely reported during the post-marketing period.

Patients with COVID-19

The safety assessment of Actemra**®** in patients with COVID-19 was based on data from three randomized, double-blind, placebo-controlled trials (ML42528, WA42380, and WA42511). Overall, 974 patients received Actemra**®** in these trials. Safety data from the RECOVERY trial are not included due to limited safety data collection.

The adverse reactions listed below by MedDRA system organ class were based on events occurring in at least 3% of patients receiving Actemra**®** and more frequently than in patients receiving placebo, in the pooled safety-evaluable population from clinical trials ML42528, WA42380, and WA42511.

List of adverse reactions¹ identified in the pooled safety-evaluable population in clinical trials of Actemra*®** for* COVID-19²

Infections and infestations: common – urinary tract infection.

Metabolism and nutrition disorders: common – hypokalemia.

Psychiatric disorders: common – anxiety, insomnia.

Vascular disorders: common – hypertension.

Hepatobiliary disorders: common – increased liver transaminase levels.

Gastrointestinal disorders: common – constipation, diarrhea, nausea.

¹ Patients are counted only once for each frequency category, regardless of the number of adverse reactions.

² Including identified reactions reported in trials WA42511, WA42380, and ML42528.

Description of specific adverse reactions

Infections

In the pooled safety-evaluable population from trials ML42528, WA42380, and WA42511, the frequency of infections/serious infections was approximately similar in patients with COVID-19 receiving tocilizumab (30.3%/18.6%, n=974) and those receiving placebo (32.1%/22.8%, n=483).

The safety profile observed in the subgroup receiving systemic corticosteroids was consistent with the safety profile of tocilizumab in the overall population described above. In this subgroup, infections and serious infections occurred in 27.8% and 18.1% of patients receiving intravenous tocilizumab, respectively, compared to 30.5% and 22.9% in the placebo group.

Laboratory parameter abnormalities

The frequency of laboratory parameter abnormalities was generally similar in patients with COVID-19 receiving one or two intravenous doses of Actemra**®** and those receiving placebo in randomized, double-blind, placebo-controlled trials, with some exceptions. Decreased platelet and neutrophil counts and increased ALT and AST levels were more frequently observed in patients receiving intravenous Actemra**®** compared to placebo (see sections "Dosage and administration" and "Special warnings and precautions for use").

Patients with systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis

Data on the safety profile of tocilizumab in patients with systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis are described below. Overall, adverse reactions in these patients were similar to those in patients with rheumatoid arthritis.

Data on adverse reactions observed in patients with systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis are presented below by MedDRA system organ class and frequency categories: very common (≥1/10), common (≥1/100 to <1/10), or uncommon (≥1/1000 to <1/100).

Infections and infestations: very common: upper respiratory tract infections, nasopharyngitis.

Nervous system disorders: very common: headache (in patients with polyarticular juvenile idiopathic arthritis); common: headache (in patients with systemic juvenile idiopathic arthritis).

Gastrointestinal disorders: common: nausea (in patients with polyarticular juvenile idiopathic arthritis), diarrhea.

General disorders and administration site conditions: common: infusion reactions¹.

Investigations: common: increased liver enzyme (transaminase) levels in patients with polyarticular juvenile idiopathic arthritis; very common: decreased neutrophil count in patients with systemic juvenile idiopathic arthritis; common: decreased neutrophil count in patients with polyarticular juvenile idiopathic arthritis; common: decreased platelet count in patients with systemic juvenile idiopathic arthritis; uncommon: decreased platelet count in patients with polyarticular juvenile idiopathic arthritis; common: increased cholesterol levels in patients with systemic juvenile idiopathic arthritis; uncommon: increased cholesterol levels in patients with polyarticular juvenile idiopathic arthritis.

¹ Infusion reactions in patients with polyarticular juvenile idiopathic arthritis include, but are not limited to, headache, nausea, and hypotension. Infusion reactions in patients with systemic juvenile idiopathic arthritis include, but are not limited to, rash, urticaria, diarrhea, epigastric discomfort, arthralgia, and headache.

Patients with polyarticular juvenile idiopathic arthritis

The safety profile of intravenous Actemra**®** was evaluated in 188 patients with polyarticular juvenile idiopathic arthritis aged 2 to 17 years. Total exposure was 184.4 patient-years. The frequency of adverse reactions in patients with polyarticular juvenile idiopathic arthritis is indicated above. The types of adverse reactions in these patients were similar to those in patients with RA and systemic juvenile idiopathic arthritis. Compared to adult RA patients, nasopharyngitis, headache, nausea, and decreased neutrophil count were more frequently reported in patients with polyarticular juvenile idiopathic arthritis. Increased cholesterol levels were less frequently reported in these patients than in adult RA patients.

Infections

The overall infection rate in the entire patient population was 163.7 per 100 patient-years. The most common infections were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients with body weight <30 kg receiving tocilizumab 10 mg/kg (12.2 per 100 patient-years) compared to patients with body weight ≥30 kg receiving tocilizumab 8 mg/kg (4.0 per 100 patient-years). The rate of infections leading to treatment discontinuation was also numerically higher in patients with body weight <30 kg receiving tocilizumab 10 mg/kg (21.4%) compared to patients with body weight ≥30 kg receiving tocilizumab 8 mg/kg (7.6%).

Infusion reactions

In patients with polyarticular juvenile idiopathic arthritis, infusion reactions were defined as all events occurring during or within 24 hours after infusion. In the overall population receiving tocilizumab, infusion reactions occurred in 11 patients (5.9%) during infusion and in 38 patients (20.2%) within 24 hours after infusion. The most common reactions during infusion were headache, nausea, and hypotension; within 24 hours after infusion, dizziness and hypotension. Overall, adverse reactions observed during or within 24 hours after infusion were similar to those reported in patients with RA and systemic juvenile idiopathic arthritis.

Clinically significant hypersensitivity reactions associated with tocilizumab requiring treatment discontinuation were not reported.

Immunogenicity

One patient with body weight <30 kg receiving tocilizumab 10 mg/kg developed positive antibodies to tocilizumab without hypersensitivity reaction. This patient withdrew from the study.

Neutrophils

During standard laboratory monitoring in all patients receiving tocilizumab, a decrease in neutrophil count below 1 × 10⁹/L was observed in 3.7% of patients.

Platelets

During standard laboratory monitoring in all patients receiving tocilizumab, a decrease in platelet count ≤50 × 10³/μL was observed in 1% of patients without associated bleeding.

Elevated liver transaminase activity

During standard laboratory monitoring in all patients receiving tocilizumab, elevation of ALT or AST activity (exceeding ULN by ≥3 times) was observed in 3.7% and <1% of patients, respectively.

Lipid metabolism parameter changes

During standard laboratory monitoring in the intravenous Actemra**®** study (WA19977), increases in LDL-C and total cholesterol levels from baseline to ≥130 mg/dL and ≥200 mg/dL, respectively, were observed in 3.4% and 10.4% of patients at any time during the study treatment.

Patients with systemic juvenile idiopathic arthritis

The safety profile of intravenous Actemra**®** was evaluated in 112 children with systemic juvenile idiopathic arthritis aged 2 to 17 years. In the 12-week double-blind controlled period of the clinical trial, 75 patients received tocilizumab (8 mg/kg or 12 mg/kg depending on body weight). After 12 weeks or due to worsening disease, patients continued treatment in the open-label extension period.

Overall, adverse events in patients with systemic juvenile idiopathic arthritis were similar to those in patients with rheumatoid arthritis. The frequency of adverse reactions in these patients is indicated above. Compared to adult RA patients, nasopharyngitis, decreased neutrophil count, elevated liver transaminases, and diarrhea were more frequently reported in patients with systemic juvenile idiopathic arthritis. Increased cholesterol levels were less frequently reported in these patients than in adult RA patients.

Infections. In the 12-week controlled trial, the overall infection rate was 344.7 per 100 patient-years in the intravenous Actemra**®** group and 287 per 100 patient-years in the placebo group. In the open-label extension period (Part II), the overall infection rate remained similar at 306.6 per 100 patient-years.

In the 12-week controlled trial, the rate of serious infections was 11.5 per 100 patient-years in the intravenous Actemra**®** group. In the open-label extension period, the overall rate of serious infections remained stable at 11.3 per 100 patient-years after 1 year. Reported serious infections were similar to those observed in patients with rheumatoid arthritis. Additionally, serious infections included varicella and otitis media.

Infusion reactions. In patients with systemic juvenile idiopathic arthritis, infusion reactions were defined as all events occurring during or within 24 hours after infusion. In the 12-week controlled trial, infusion reactions occurred in 4% of patients in the tocilizumab group, with one event (angioedema) being serious and life-threatening, leading to complete treatment discontinuation.

In the 12-week controlled trial, infusion reactions occurring within 24 hours after infusion were reported in 16% of patients in the tocilizumab group and 5.4% in the placebo group. In the tocilizumab group, infusion reactions included, but were not limited to, rash, urticaria, diarrhea, epigastric discomfort, arthralgia, and headache. One of these events (urticaria) was serious.

Clinically significant hypersensitivity reactions associated with tocilizumab requiring discontinuation were reported in 1 of 112 patients (<1%) receiving tocilizumab during the controlled and open-label extension periods.

Immunogenicity. Testing for anti-tocilizumab antibodies was performed in all 112 patients. Anti-tocilizumab antibodies were detected in two patients. One of these patients experienced hypersensitivity reactions leading to complete discontinuation of tocilizumab. The frequency of anti-tocilizumab antibody formation may be underestimated due to the influence of tocilizumab on the antibody assay and higher tocilizumab concentrations in children compared to adults.

Neutrophils. During routine laboratory monitoring in the 12-week controlled trial, a decrease in neutrophil count below 1 × 10⁹/L was observed in 7% of patients in the tocilizumab group and not observed in the placebo group.

In the open-label extension period, a decrease in neutrophil count below 1 × 10⁹/L was observed in 15% of patients in the tocilizumab group.

Platelets: During routine laboratory monitoring in the 12-week controlled trial, a decrease in platelet count ≤100 × 10³/μL was observed in 1% of patients in the tocilizumab group and 3% in the placebo group.

In the open-label extension period, a decrease in platelet count below 100 × 10³/μL was observed in 3% of patients in the tocilizumab group. These changes were not associated with bleeding.

Elevated liver transaminase activity. During routine laboratory monitoring in the 12-week controlled trial, elevation of ALT or AST activity (exceeding ULN by ≥3 times) was observed in 5% and 3% of patients, respectively, in the tocilizumab group and in 0% of patients in the placebo group.

In the open-label extension period, elevation of ALT or AST activity (exceeding ULN by more than 3 times) was observed in 12% and 4% of patients, respectively, in the tocilizumab group.

Immunoglobulin G. During therapy, IgG levels decrease. At various time points in the study, levels below the normal range were observed in 15 patients.

Lipid metabolism parameter changes. During routine laboratory monitoring in the 12-week controlled phase (study WA18221), increases in LDL-C and total cholesterol levels from baseline to ≥130 mg/dL and ≥200 mg/dL, respectively, were observed in 13.4% and 33.3% of patients at any time during the study treatment.

In the open-label extension period (WA18221), increases in LDL-C and total cholesterol levels from baseline to ≥130 mg/dL and ≥200 mg/dL, respectively, were observed in 13.2% and 27.7% of patients at any time during the study treatment.

Shelf life.

3 years.

Storage conditions.

Store at 2 to 8 °C in the original packaging, protected from light. Keep out of reach of children. Do not freeze.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products except 0.9% sodium chloride solution (see section "Dosage and administration").

Packaging.

80 mg/4 mL or 200 mg/10 mL or 400 mg/20 mL concentrate for solution for infusion (20 mg/mL) in a clear neutral glass vial (Type I) stoppered with a butyl rubber stopper, crimped with an aluminum cap, and closed with a plastic cap. Packaged in cartons containing 1 or 4 vials.

Prescription status.

Prescription only.

Manufacturer.

F. Hoffmann-La Roche Ltd

Manufacturer's address and place of business.

Wurmsweg, 4303 Kaiseraugst, Switzerland