1 INDICATIONS AND USAGE Tocilizumab-anoh is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of: Rheumatoid Arthritis (RA) ( 1.1 ) Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

Giant Cell Arteritis (GCA) ( 1.2 ) Adult patients with giant cell arteritis.

Polyarticular Juvenile Idiopathic Arthritis (PJIA) ( 1.3 ) Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis.

Systemic Juvenile Idiopathic Arthritis (SJIA) ( 1.4 ) Patients 2 years of age and older with active systemic juvenile idiopathic arthritis.

Cytokine Release Syndrome (CRS) ( 1.5 ) Adults and pediatric patients with 2 years of age and older with chimeric antigen receptor (CAR) T-cell-induced severe or life-threatening cytokine release syndrome.

Coronavirus Disease 2019 (COVID-19) ( 1.6 ) Hospitalized adult patients with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

1.1 Rheumatoid Arthritis (RA) Tocilizumab-anoh is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

1.2 Giant Cell Arteritis (GCA) Tocilizumab-anoh is indicated for the treatment of giant cell arteritis (GCA) in adult patients.

1.3 Polyarticular Juvenile Idiopathic Arthritis (PJIA) Tocilizumab-anoh is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

1.4 Systemic Juvenile Idiopathic Arthritis (SJIA) Tocilizumab-anoh is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older.

1.5 Cytokine Release Syndrome (CRS) Tocilizumab-anoh is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older.

1.6 Coronavirus Disease 2019 (COVID-19) Tocilizumab-anoh is indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen, non- invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Serious Infections [see Warnings and Precautions (5.1) ] Gastrointestinal Perforations [see Warnings and Precautions (5.2) ] Laboratory Parameters [see Warnings and Precautions (5.4) ] Immunosuppression [see Warnings and Precautions (5.5) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.6) ] Demyelinating Disorders [see Warnings and Precautions (5.7) ] Active Hepatic Disease and Hepatic Impairment [see Warnings and Precautions (5.8) ] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions.

( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION USA Inc., at 1-800-560-9414 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies.

In these studies, patients received doses of tocilizumab-IV 8 mg per kg monotherapy (288 patients), tocilizumab- IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or tocilizumab-IV 4 mg per kg in combination with methotrexate (774 patients).

The all exposure population includes all patients in registration studies who received at least one dose of tocilizumab-IV.

Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years.

All patients in these studies had moderately to severely active rheumatoid arthritis.

The study population had a mean age of 52 years, 82% were female and 74% were Caucasian.

The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1) ] .

The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with tocilizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking tocilizumab-IV and 3% for placebo-treated patients.

The most common adverse reactions that required discontinuation of tocilizumab-IV were increased hepatic transaminase values (per protocol requirement) and serious infections.

Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the tocilizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group.

The rate of infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 133 and 127 events per 100 patient- years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group.

The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis.

The overall rate of infections with tocilizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.

Serious Infections In the 24 week, controlled clinical studies, the rate of serious infections in the tocilizumab-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group.

The rate of serious infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.

In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies.

The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis.

Cases of opportunistic infections have been reported [see Warnings and Precautions (5.1) ] .

In the cardiovascular outcomes Study WA25204, the rate of serious infections in the tocilizumab 8 mg/kg IV every 4 weeks group, with or without DMARD, was 4.5 per 100 patient-years, and the rate in the etanercept 50 mg weekly SC group, with or without DMARD, was 3.2 per 100 patient-years [see Clinical Studies (14.1) ].

Gastrointestinal Perforations During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with tocilizumab-IV therapy.

In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies.

Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess.

Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti- inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see Warnings and Precautions (5.2) ] .

The relative contribution of these concomitant medications versus tocilizumab-IV to the development of GI perforations is not known.

Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group.

The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria.

These events were not treatment limiting.

Anaphylaxis Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with tocilizumab-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population.

These reactions were generally observed during the second to fourth infusion of tocilizumab-IV.

Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions (5.6) ] .

Laboratory Abnormalities Neutropenia In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm 3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group.

Approximately half of the instances of ANC below 1000 per mm 3 occurred within 8 weeks of starting therapy.

Decreases in neutrophil counts below 500 per mm 3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group.

There was no clear relationship between decreases in neutrophils below 1000 per mm 3 and the occurrence of serious infections.

In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.4) ] .

Thrombocytopenia In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm 3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.

In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.4) ] .

Elevated Liver Enzymes Liver enzyme abnormalities are summarized in Table 1 .

In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tocilizumab-IV, or reduction in tocilizumab-IV dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.10) ] .

These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see Warnings and Precautions (5.3 , 5.4) ] .

Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V For a description of these studies, see Section 14, Clinical Studies .

Tocilizumab 8 mg per kg MONOTHERAPY Methotrexate Tocilizumab 4 mg per kg + DMARDs Tocilizumab 8 mg per kg + DMARDs Placebo + DMARDs N = 288 (%) N = 284 (%) N = 774 (%) N = 1582 (%) N = 1170 (%) ULN = Upper Limit of Normal AST (U/L) > ULN to 3× ULN 22 26 34 41 17 > 3× ULN to 5× ULN 0.3 2 1 2 0.3 > 5× ULN 0.7 0.4 0.1 0.2 < 0.1 ALT (U/L) > ULN to 3× ULN 36 33 45 48 23 > 3× ULN to 5× ULN 1 4 5 5 1 > 5× ULN 0.7 1 1.3 1.5 0.3 In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials.

In Study WA25204, of the 1538 patients with moderate to severe RA [see Clinical Studies (14.1) ] and treated with tocilizumab, elevations in ALT or AST >3 × ULN occurred in 5.3% and 2.2% patients, respectively.

One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab.

Lipids Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of tocilizumab-IV in the controlled 24 week clinical trials.

Increases were observed at this time point and remained stable thereafter.

Increases in triglycerides to levels above 500 mg per dL were rarely observed.

Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below: –Mean LDL increased by 13 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in tocilizumab 8 mg per kg monotherapy.–Mean HDL increased by 3 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in tocilizumab 8 mg per kg monotherapy.–Mean LDL/HDL ratio increased by an average of 0.14 in the tocilizumab 4 mg per kg+DMARD arm, 0.15 in the tocilizumab 8 mg per kg+DMARD, and 0.26 in tocilizumab 8 mg per kg monotherapy.–ApoB/ApoA1 ratios were essentially unchanged in tocilizumab-treated patients.

Elevated lipids responded to lipid lowering agents.

In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials.

Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tocilizumab or of other tocilizumab products.

In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies.

Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal.

Thirty patients (1%) developed neutralizing antibodies.

Malignancies During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving tocilizumab-IV, compared to 8 malignancies in patients in the control groups.

Exposure-adjusted incidence was similar in the tocilizumab-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).

In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period [see Warnings and Precautions (5.5) ] .

Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg tocilizumab-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2.

Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg Tocilizumab plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD 24 Week Phase 3 Controlled Study Population Tocilizumab 8 mg per kg MONOTHERAPY Methotrexate Tocilizumab 4 mg per kg + DMARDs Tocilizumab 8 mg per kg + DMARDs Placebo + DMARDs Preferred Term N = 288 (%) N = 284 (%) N = 774 (%) N = 1582 (%) N = 1170 (%) Upper Respiratory Tract Infection 7 5 6 8 6 Nasopharyngitis 7 6 4 6 4 Headache 7 2 6 5 3 Hypertension 6 2 4 4 3 ALT increased 6 4 3 3 1 Dizziness 3 1 2 3 2 Bronchitis 3 2 4 3 3 Rash 2 1 4 3 1 Mouth Ulceration 2 2 1 2 1 Abdominal Pain Upper 2 2 3 3 2 Gastritis 1 2 1 2 1 Transaminase increased 1 5 2 2 1 Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with tocilizumab-IV in controlled trials were: Infections and Infestations: oral herpes simplex Gastrointestinal disorders: stomatitis, gastric ulcer Investigations: weight increased, total bilirubin increased Blood and lymphatic system disorders: leukopenia General disorders and administration site conditions: edema peripheral Respiratory, thoracic, and mediastinal disorders : dyspnea, cough Eye disorders: conjunctivitis Renal disorders: nephrolithiasis Endocrine disorders: hypothyroidism 6.2 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) The tocilizumab-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies.

Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously and 8 mg/kg intravenously every four weeks in 1262 adult subjects with rheumatoid arthritis.

Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week subcutaneously or placebo in 656 patients.

All patients in both studies received background non-biologic DMARDs.

The safety observed for tocilizumab-SC administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of injection site reactions (ISRs), which were more common with tocilizumab-SC compared with placebo SC injections (IV arm).

Injection Site Reactions In the 6-month control period, in SC-I, the frequency of ISRs was 10.1% (64/631) and 2.4% (15/631) for the weekly tocilizumab-SC and placebo SC (IV-arm) groups, respectively.

In SC-II, the frequency of ISRs was 7.1% (31/437) and 4.1% (9/218) for the every other week tocilizumab-SC and placebo groups, respectively.

These ISRs (including erythema, pruritus, pain and hematoma) were mild to moderate in severity.

The majority resolved without any treatment and none necessitated drug discontinuation.

Immunogenicity In the 6-month control period in SC-I, 0.8% (5/625) in the tocilizumab-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies.

In SC-II, 1.6% (7/434) in the tocilizumab-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti- tocilizumab antibodies; of these, 1.4% (6/434) in the tocilizumab-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies.

A total of 1454 (>99%) patients who received tocilizumab-SC in the all exposure group have been tested for anti- tocilizumab antibodies.

Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies.

The rate is consistent with previous intravenous experience.

No correlation of antibody development to adverse events or loss of clinical response was observed.

Laboratory Abnormalities Neutropenia During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 × 10 9 /L occurred in 2.9% and 3.7% of patients receiving tocilizumab-SC weekly and every other week, respectively.

There was no clear relationship between decreases in neutrophils below 1 × 10 9 /L and the occurrence of serious infections.

Thrombocytopenia During routine laboratory monitoring in the tocilizumab-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤50,000/mm 3 .

Elevated Liver Enzymes During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥3 × ULN occurred in 6.5% and 1.4% of patients, respectively, receiving tocilizumab-SC weekly and 3.4% and 0.7% receiving tocilizumab-SC every other week.

Lipid Parameters Elevations During routine laboratory monitoring in the tocilizumab-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving tocilizumab-SC weekly, every other week and placebo, respectively.

6.3 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) The safety of subcutaneous tocilizumab has been studied in one Phase III study (WA28119) with 251 GCA patients.

The total patient years duration in the tocilizumab-SC GCA all exposure population was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study.

The overall safety profile observed in the tocilizumab-SC treatment groups was generally consistent with the known safety profile of tocilizumab.

There was an overall higher incidence of infections in GCA patients relative to RA patients.

The rate of infection/serious infection events was 200.2/9.7 events per 100 patient years in the tocilizumab-SC weekly group and 160.2/4.4 events per 100 patient years in the tocilizumab-SC every other week group as compared to 156.0/4.2 events per 100 patient years in the placebo + 26 week prednisone taper and 210.2/12.5 events per 100 patient years in the placebo + 52 week taper groups.

6.4 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab-IV was studied in an open label PK-PD and safety study in 24 patients with GCA who were in remission on tocilizumab-IV at time of enrollment.

Patients received tocilizumab 7 mg/kg every 4 weeks for 20 weeks, followed by 6 mg/kg every 4 weeks for 20 weeks.

The total patient years exposure to treatment was 17.5 years.

The overall safety profile observed for tocilizumab administered intravenously in GCA patients was consistent with the known safety profile of tocilizumab.

6.5 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate.

The total patient exposure in the tocilizumab-IV all exposure population (defined as patients who received at least one dose of tocilizumab-IV) was 184.4 patient years.

At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate.

In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.7) ] .

Infections The rate of infections in the tocilizumab-IV all exposure population was 163.7 per 100 patient years.

The most common events observed were nasopharyngitis and upper respiratory tract infections.

The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years).

The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%).

Infusion Reactions In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion.

In the tocilizumab-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion.

The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension.

In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.7) ] .

No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.

Immunogenicity One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.

Laboratory Abnormalities Neutropenia During routine laboratory monitoring in the tocilizumab-IV all exposure population, a decrease in neutrophil counts below 1 × 10 9 per L occurred in 3.7% of patients.

There was no clear relationship between decreases in neutrophils below 1 × 10 9 per L and the occurrence of serious infections.

Thrombocytopenia During routine laboratory monitoring in the tocilizumab-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm 3 without associated bleeding events.

Elevated Liver Enzymes During routine laboratory monitoring in the tocilizumab-IV all exposure population, elevation in ALT or AST at or greater than 3 × ULN occurred in 4% and less than 1% of patients, respectively.

Lipids During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 × ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 × ULN occurred in one patient (0.5%).

6.6 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) The safety of tocilizumab-SC was studied in 52 pediatric patients 1 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate.

The total patient exposure in the PJIA tocilizumab-SC population (defined as patients who received at least one dose of tocilizumab-SC and accounting for treatment discontinuation) was 49.5 patient years.

In general, the safety observed for tocilizumab administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of injection site reactions (ISRs), and neutropenia.

Injection Site Reactions During the 1-year study, a frequency of 28.8% (15/52) ISRs was observed in tocilizumab-SC treated PJIA patients.

These ISRs occurred in a greater proportion of patients at or above 30 kg (44.0%) compared with patients below 30 kg (14.8%).

All ISRs were mild in severity and none of the ISRs required patient withdrawal from treatment or dose interruption.

A higher frequency of ISRs was observed in tocilizumab-SC treated PJIA patients compared to what was seen in adult RA or GCA patients [see Adverse Reactions (6.2 and 6.3) ] .

Immunogenicity Three patients, 1 patient below 30 kg and 2 patients at or above 30 kg, developed positive anti-tocilizumab antibodies with neutralizing potential without developing a serious or clinically significant hypersensitivity reaction.

One patient subsequently withdrew from the study.

Neutropenia During routine laboratory monitoring in the tocilizumab-SC all exposure population, a decrease in neutrophil counts below 1 × 10 9 per L occurred in 15.4% of patients, and was more frequently observed in the patients less than 30 kg (25.9%) compared to patients at or above 30 kg (4.0%).

There was no clear relationship between decreases in neutrophils below 1 × 10 9 per L and the occurrence of serious infections.

6.7 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The data described below reflect exposure to tocilizumab-IV in one randomized, double-blind, placebo- controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy.

At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate.

The trial included a 12 week controlled phase followed by an open-label extension.

In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with tocilizumab- IV (8 or 12 mg per kg based upon body weight).

After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab-IV in the open-label extension phase.

The most common adverse events (at least 5%) seen in tocilizumab-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea.

Infections In the 12 week controlled phase, the rate of all infections in the tocilizumab-IV group was 345 per 100 patient- years and 287 per 100 patient-years in the placebo group.

In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.

In the 12 week controlled phase, the rate of serious infections in the tocilizumab-IV group was 11.5 per 100 patient years.

In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years.

The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media.

Macrophage Activation Syndrome In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with tocilizumab-IV.

One patient in the placebo group escaped to tocilizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70.

Two additional patients developed MAS during the long-term extension.

All 3 patients had tocilizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae.

Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the tocilizumab-IV SJIA clinical development experience; however no definitive conclusions can be made.

Infusion Reactions Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA.

Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion.

In the 12 week controlled phase, 4% of tocilizumab-IV and 0% of placebo treated patients experienced events occurring during infusion.

One event (angioedema) was considered serious and life- threatening, and the patient was discontinued from study treatment.

Within 24 hours after infusion, 16% of patients in the tocilizumab-IV treatment group and 5% of patients in the placebo group experienced an event.

In the tocilizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache.

One of these events, urticaria, was considered serious.

Anaphylaxis Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with tocilizumab-IV during the controlled and open label extension study [see Warnings and Precautions (5.6) ] .

Immunogenicity All 112 patients were tested for anti-tocilizumab antibodies at baseline.

Two patients developed positive anti- tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.

Laboratory Abnormalities Neutropenia During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 10 9 per L occurred in 7% of patients in the tocilizumab-IV group, and in no patients in the placebo group.

In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the tocilizumab-IV group.

There was no clear relationship between decrease in neutrophils below 1 × 10 9 per L and the occurrence of serious infections.

Thrombocytopenia During routine monitoring in the 12 week controlled phase, 1% of patients in the tocilizumab-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm 3 .

In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the tocilizumab-IV group, with no associated bleeding.

Elevated Liver Enzymes During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3× ULN occurred in 5% and 3% of patients, respectively in the tocilizumab-IV group and in 0% of placebo patients.

In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3× ULN occurred in 13% and 5% of tocilizumab-IV treated patients, respectively.

Lipids During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5× ULN – 2× ULN occurred in 1.5% of the tocilizumab-IV group and in 0% of placebo patients.

Elevation in LDL greater than 1.5× ULN – 2× ULN occurred in 1.9% of patients in the tocilizumab-IV group and 0% of the placebo group.

In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data.

6.8 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) The safety profile of tocilizumab-SC was studied in 51 pediatric patients 1 to 17 years of age with SJIA who had an inadequate clinical response to NSAIDs and corticosteroids.

In general, the safety observed for tocilizumab administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of ISRs where a higher frequency was observed in tocilizumab-SC treated SJIA patients compared to PJIA patients and adult RA or GCA patients [see Adverse Reactions (6.2 , 6.3 and 6.6) ] .

Injection Site Reactions (ISRs) A total of 41.2% (21/51) SJIA patients experienced ISRs to tocilizumab-SC.

The most common ISRs were erythema, pruritus, pain, and swelling at the injection site.

The majority of ISRs reported were Grade 1 events and all ISRs reported were non-serious and none required patient withdrawal from treatment or dose interruption.

Immunogenicity Forty-six of the 51 (90.2%) patients who were tested for anti-tocilizumab antibodies at baseline had at least one post-baseline screening assay result.

No patient developed positive anti-tocilizumab antibodies post-baseline.

6.9 Clinical Trials Experience in Patients with Cytokine Release Syndrome Treated with Intravenous Tociliaumb (Tocilizumab-IV) In a retrospective analysis of pooled outcome data from multiple clinical trials 45 patients were treated with tocilizumab 8 mg/kg (12 mg/kg for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CAR T cell-induced CRS.

A median of 1 dose of tocilizumab (range, 1-4 doses) was administered.

No adverse reactions related to tocilizumab were reported [see Clinical Studies ( 14.9 )].

6.10 Clinical Trials Experience in COVID-19 Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab in hospitalized COVID-19 patients was evaluated in a pooled safety population that includes patients enrolled in EMPACTA, COVACTA, AND REMDACTA.

The analysis of adverse reactions included a total of 974 patients exposed to tocilizumab.

Patients received a single, 60-minute infusion of intravenous tocilizumab 8 mg/kg (maximum dose of 800 mg).

If clinical signs or symptoms worsened or did not improve, one additional dose of tocilizumab 8 mg/kg could be administered between 8- 24 hours after the initial dose.

Adverse reactions summarized in Table 3 occurred in at least 3% of tocilizumab-treated patients and more commonly than in patients on placebo in the pooled safety population.

Table 3 Adverse Reactions Patients are counted once for each category regardless of the number of reactions Identified From the Pooled COVID-19 Safety Population Adverse Reaction Tocilizumab 8 mg per kg Placebo N = 974 (%) N = 483 (%) Hepatic Transaminases increased 10% 8% Constipation 9 % 8% Urinary tract infection 5% 4% Hypertension 4% 1% Hypokalaemia 4% 3% Anxiety 4% 2% Diarrhea 4% 2% Insomnia 4% 3% Nausea 3% 2% In the pooled safety population, the rates of infection/serious infection events were 30%/19% in patients receiving tocilizumab versus 32%/23% receiving placebo.

Laboratory Abnormalities In the pooled safety population of EMPACTA, COVACTA, and REMDACTA, neutrophil counts <1000 cells/mcl occurred in 3.4% of patients who received tocilizumab and 0.5% of patients who received placebo.

Platelet counts <50,000 cells/mcl occurred in 3.2% of patients who received tocilizumab and 1.5% of patients who received placebo.

ALT or AST at or above 5× ULN occurred in 11.7% of patients who received tocilizumab and 9.9% of patients who received placebo.

6.11 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tocilizumab products.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions: Fatal anaphylaxis, Stevens-Johnson Syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6) ] Pancreatitis Drug-induced liver injury, Hepatitis, Hepatic failure, Jaundice [see Warnings and Precautions (5.3) ] Hypofibrinogenemia