ACTEMRA

Tocilizumab-bavi is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H 2 L 2 polypeptide structure.

Each light chain and heavy chain consists of and 448 amino acids, respectively.

The four polypeptide chains are linked intra.

• and inter-molecularly by disulfide bonds.

Tocilizumab-bavi has a molecular weight of approximately 148 kDa.

The antibody is produced in mammalian (Chinese hamster ovary) cells.

TOFIDENCE (tocilizumab-bavi) injection is a sterile, clear to opalescent, colorless to light yellow, preservative-free solution for further dilution prior to intravenous infusion with a pH of approximately 6.2.

Each single-dose vial, formulated in an aqueous solution, is available at a concentration of 20 mg/mL containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of TOFIDENCE.

Each mL of solution contains arginine hydrochloride (10.53 mg), histidine (0.81 mg), L-histidine hydrochloride monohydrate (1.01 mg), polysorbate 80 (0.5 mg), sucrose (20 mg), and water for injection.

Tessilizomap is used to: reduce infection in cases of moderate to severe rheumatide arthritis.

Medically supervised use with caution during pregnancy or breastfeeding.

Current or past infections (such as those caused by fungi, herpes and tuberculosis).

Multiple salinitis.

Receive any vaccines or restaurants before treatment or during treatment.

Chronic infection, or in case of symptoms of infection, or if the patient or one of his relatives is infected with tuberculosis.

Tessilizomab and digestive tractor diseases.

Tocilizumab products bind to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and have been shown to inhibit IL-6-mediated signaling through these receptors.

IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T.

• and B-cells, lymphocytes, monocytes and fibroblasts.

IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation.

IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis. 12.2 Pharmacodynamics In clinical studies in RA patients with the 4 mg per kg and 8 mg per kg intravenous doses decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2.

Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg tocilizumab.

Pharmacodynamic changes were also observed to occur after tocilizumab administration in GCA, PJIA, and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin).

The relationship between these pharmacodynamic findings and clinical efficacy is not known.

In healthy subjects administered tocilizumab in doses from to 28 mg per kg intravenously, absolute neutrophil counts decreased to the nadir to 5 days following tocilizumab administration.

Thereafter, neutrophils recovered towards baseline in a dose dependent manner.

Rheumatoid arthritis and

GCA patients demonstrated a similar pattern of absolute neutrophil counts following tocilizumab administration. 12.3 Pharmacokinetics PK of tocilizumab is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination.

The nonlinear part of tocilizumab elimination leads to an increase in exposure that is more than dose-proportional.

The pharmacokinetic parameters of tocilizumab do not change with time.

Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level.

Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

• Intravenous Administration The pharmacokinetics in healthy subjects and RA patients suggest that PK is similar between the two populations.

The population

PK model was developed from an analysis dataset composed of an IV dataset of 1793 patients from Study I, Study III, Study IV, and Study V. C mean is included in place of AUC tau, since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUC tau.

At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, a terminal half-life of approximately 21.5 days was derived from the population parameter estimates.

For doses of 4 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) C max, C trough, and C mean of tocilizumab at steady state were 86.1 (44.8–202) mcg/mL, 0.1 (0.0–14.6) mcg/mL, and 18.0 (8.9–50.7) mcg/mL, respectively.

For doses of 8 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) C max, C trough, and C mean of tocilizumab were 176 (75.4–557) mcg/mL, 13.4 (0.1–154) mcg/mL, and 54.0 (17–260) mcg/mL, respectively.

C max increased dose-proportionally between doses of and 8 mg/kg IV every 4 weeks, while a greater than dose-proportional increase was observed in C mean and C trough.

At steady-state, C mean and C trough were 3.0 and 134 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.

The accumulation ratios for AUC and

C max after multiple doses of and 8 mg/kg IV Q4W are low, while the accumulation ratios for C trough are higher (2.62 and 2.47, respectively).

C max, greater than 90% of the steady-state value was reached after the 1st IV infusion.

For AUC tau and

C mean, 90% of the steady-state value was reached after the 1st and 3rd infusion for 4 mg/kg and 8 mg/kg IV, while for C trough, approximately 90% of the steady-state value was reached after the 4th IV infusion after both doses.

PK analysis identified body weight as a significant covariate impacting the pharmacokinetics of tocilizumab.

When given

IV on a mg/kg basis, individuals with body weight ≥ 100 kg are predicted to have mean steady-state exposures higher than mean values for the patient population.

Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended in patients with RA.

Arteritis – Intravenous Administration The pharmacokinetics of tocilizumab IV in GCA patients was characterized by a non-compartmental pharmacokinetic analysis which included 22 patients treated with 6 mg/kg intravenously every 4 weeks for 20 weeks.

The median (range) C max, C trough and C mean of tocilizumab at steady state were 178 mcg/mL, 22.7 mcg/mL and 57.5 mcg/mL, respectively.

Steady state trough concentrations were within the range observed in GCA patients treated with tocilizumab by another route of administration.

Based on pharmacokinetic exposure and extrapolation between RA and GCA patients, when given IV on a mg/kg basis, tocilizumab doses exceeding 600 mg per infusion are not recommended in patients with GCA.

Arthritis – Intravenous Administration The pharmacokinetics of tocilizumab (TCZ) in PJIA patients was characterized by a population pharmacokinetic analysis which included 188 patients who were treated with TCZ IV.

For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks intravenously, the estimated median (range) C max, C trough, and C mean of tocilizumab at steady state were 181 (114–331) mcg/mL, 3.28 (0.02–35.4) mcg/mL, and 38.6 (22.2–83.8) mcg/mL, respectively.

For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks intravenously, the estimated median (range) C max, C trough, and C mean of tocilizumab were 167 (125–220) mcg/mL, 0.35 (0–11.8) mcg/mL, and 30.8 (16.0–48.0) mcg/mL, respectively.

The accumulation ratios were 1.05 and 1.16 for AUC 4weeks, and 1.43 and 2.22 for C trough for 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively.

No accumulation for

C max was observed.

Following 10 mg/kg and 8 mg/kg TCZ IV every 4 weeks doses in PJIA patients (aged to 17 years), steady state concentrations (trough and average) were within the range of exposures in adult RA patients following 4 mg/kg and 8 mg/kg every 4 weeks, and steady state peak concentrations in PJIA patients were comparable to those following 8 mg/kg every 4 weeks in adult RA patients.

Arthritis—Intravenous Administration The pharmacokinetics of tocilizumab (TCZ) in SJIA patients was characterized by a population pharmacokinetic analysis which included 89 patients who were treated with TCZ IV.

For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks intravenously, the estimated median (range) C max, C trough, and C mean of tocilizumab were 253 (120–404) mcg/mL, 70.7 (5.26–127) mcg/mL, and 117 (37.6–199) mcg/mL, respectively.

For doses of 12 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks intravenously, the estimated median (range) C max, C trough, and C mean of tocilizumab were 274 (149–444) mcg/mL, 65.9 (19.0–135) mcg/mL, and 124 (60–194) mcg/mL, respectively.

The accumulation ratios were 1.95 and 2.01 for AUC4 weeks, and 3.41 and 3.20 for C trough for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively.

Accumulation data for

C max were 1.37 and 1.42 for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively.

Following every other week dosing with tocilizumab IV, steady state was reached by 8 weeks for both body weight groups.

Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight.

COVID-19 -Intravenous Administration The pharmacokinetics of tocilizumab in COVID-19 patients was characterized by a population pharmacokinetic analysis of a dataset composed of 380 adult patients treated with tocilizumab 8mg/kg intravenously (IV) in the COVACTA study and another clinical study.

For one dose of 8 mg/kg tocilizumab IV, the estimated median (range) C max and C day28 of tocilizumab were 151 mcg/mL and 0.229 mcg/mL, respectively.

For two doses of 8 mg/kg tocilizumab IV separated by at least 8 hours, the estimated median (range) Cmax and Cday28 of tocilizumab was 290 mcg/mL and 7.04 mcg/mL, respectively.

The weight-tiered dosing used in

RECOVERY study, 800 mg for patients >90 kg, 600 mg for patients >65 and ≤90 kg, 400 mg for patients >40 and ≤65 kg, and 8mg/kg for patients ≤40 kg, is comparable to 8 mg/kg dosing and is expected to have similar exposure.

Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation.

In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L. In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L resulting in a volume of distribution at steady state of 7.46 L. In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L. In pediatric patients with SJIA, the central volume of distribution was 1.87 L, the peripheral volume of distribution was 2.14 L resulting in a volume of distribution at steady state of 4.01 L. In COVID-19 patients treated with one or two infusions of tocilizumab 8 mg/kg intravenously separated by 8 hours, the estimated central volume of distribution was 4.52 L, and the estimated peripheral volume of distribution was 4.23 L, resulting in a volume of distribution of 8.75 L. Elimination Tocilizumab is eliminated by a combination of linear clearance and nonlinear elimination.

The concentration-dependent nonlinear elimination plays a major role at low tocilizumab concentrations.

Once the nonlinear pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.

The saturation of the nonlinear elimination leads to an increase in exposure that is more than dose-proportional.

The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA patients, 6.7 mL per h in GCA patients, 5.8 mL per h in pediatric patients with PJIA, and 5.7 mL per h in pediatric patients with SJIA.

In COVID-19 patients, serum concentrations were below the limit of quantification after 35 days on average following one infusion of.

Actima is a mitamopolytic anti-inflammatory treatment, used for the treatment of rheumaid arthritis.

Actimra for the treatment of corona is widely reported to be used in the new Corona or Coffid-19 treatment protocol, but after a number of clinical tests, the U.S. Food and Drug Department has not established a mitatric efficacy in treating the patients of korona who are suffering from the short-term and need of oxygen.

The following serious adverse reactions are described elsewhere in labeling: Serious.

Infections Gastrointestinal Perforations Laboratory Parameters Immunosuppression Hypersensitivity Reactions, Including Anaphylaxis Demyelinating.

Disorders Active Hepatic Disease and Hepatic Impairment 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.

To report SUSPECTED ADVERSE

REACTIONS, contact Biogen MA Inc.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 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.

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.

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 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.

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.

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.

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.

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

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.

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.

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 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.

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.

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.

These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency.

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.

WA25204, of the 1538 patients with moderate to severe RA 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.

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 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.

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.

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.

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-toci.

There are limited data available on overdoses with tocilizumab products.

One case of accidental overdose was reported with intravenous tocilizumab in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed.

No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia.

In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

Patients who develop adverse reactions should receive appropriate symptomatic treatment.

is contraindicated in patients with known hypersensitivity to tocilizumab products.

Known hypersensitivity to tocilizumab products.

RA, pJIA and sJIA, TOFIDENCE may be used alone or in combination with methotrexate; and in RA, other non-biologic DMARDs may be used.

• It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm 3, platelet count below 100,000 per mm 3, or ALT or AST above 1.5 times the upper limit of normal (ULN).

• It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3, platelet count below 50,000 mm3, or ALT or AST above 10 times ULN.

In RA or

COVID-19 patients, TOFIDENCE doses exceeding 800 mg per infusion are not recommended.

In GCA patients, TOFIDENCE doses exceeding 600 mg per infusion are not recommended.

Rheumatoid Arthritis Recommended Adult Intravenous Dosage

When used in combination with non-biologic DMARDs or as monotherapy the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.

Giant Cell Arteritis Recommended Adult Intravenous Dosage: The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids.

TOFIDENCE can be used alone following discontinuation of glucocorticoids.

Polyarticular Juvenile Idiopathic Arthritis Recommended Intravenous

PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Systemic Juvenile Idiopathic Arthritis Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Coronavirus Disease The recommended dosage of TOFIDENCE for adult patients with COVID-19 is 8 mg per kg administered by a 60-minute intravenous infusion.

Administration of Intravenous Formulation For patients with RA, GCA, COVID-19, PJIA, and SJIA patients at or above 30 kg, dilute to 100 mL in 0.9% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique.

For PJIA and

SJIA patients less than 30 kg, dilute to 50 mL in 0.9% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique.

Administer as a single intravenous drip infusion over 1 hour; do not administer as bolus or push.

Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia. 2.1 General Considerations for Administration Not Recommended for Concomitant Use with Biological DMARDs Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection.

Avoid using TOFIDENCE with biological

Baseline Laboratory Evaluation Prior to Treatment

Obtain and assess baseline complete blood count (CBC) and liver function tests prior to treatment.

RA, GCA, PJIA and SJIA – It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm 3, platelet count below 100,000 per mm 3, or ALT or AST above 1.5 times the upper limit of normal (ULN) .

• It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3, platelet count below 50,000 mm3, or ALT or AST above 10 times ULN 2.2 Recommended Dosage for Rheumatoid Arthritis TOFIDENCE may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion.

The recommended dosage of TOFIDENCE for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.

Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.

Doses exceeding 800 mg per infusion are not recommended in RA patients.

When transitioning from intravenous therapy with

TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dose is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.

Doses exceeding 600 mg per infusion are not recommended in GCA patients.

TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose. 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis TOFIDENCE may be used as an intravenous infusion alone or in combination with methotrexate.

Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.

The recommended dosage of TOFIDENCE for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia. 2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis TOFIDENCE may be used as an intravenous infusion or in combination with methotrexate.

Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.

The recommended dose of TOFIDENCE for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia. 2.6 Coronavirus Disease 2019 (COVID-19) Administer TOFIDENCE by intravenous infusion only.

The recommended dosage of

TOFIDENCE for treatment of adult patients with COVID-19 is 8 mg per kg administered as a single 60-minute intravenous infusion.

If clinical signs or symptoms worsen or do not improve after the first dose, one additional infusion of TOFIDENCE may be administered at least 8 hours after the initial infusion.

Doses exceeding 800 mg per infusion are not recommended in patients with COVID-19. 2.7 Preparation and Administration Instructions for Intravenous Infusion TOFIDENCE for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows: Use a sterile needle and syringe to prepare TOFIDENCE.

Patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% Sodium Chloride Injection, USP, and then follow steps and 2 below.

Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps and 2 below.

Step 1.

Withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the TOFIDENCE injection required for the patient's dose from the infusion bag or bottle.

Volume of TOFIDENCE Injection per kg of Body Weight Dosage Indication Volume of TOFIDENCE injection per kg of body weight 4 mg/kg Adult RA 0.2 mL/kg 6 mg/kg Adult GCA 0.3 mL/kg 8 mg/kg Adult RA Adult COVID-19 SJIA and PJIA (greater than or equal to 30 kg of body weight) 0.4 mL/kg 10 mg/kg PJIA (less than 30 kg of body weight) 0.5 mL/kg 12 mg/kg SJIA (less than 30 kg of body weight) 0.6 mL/kg Step 2.

Withdraw the amount of

TOFIDENCE for intravenous infusion from the vial(s) and add slowly into the 0.9% Sodium Chloride Injection, USP infusion bag or bottle.

To mix the solution, gently invert the bag to avoid foaming.

The fully diluted

TOFIDENCE solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored refrigerated at 36°F to 46°F (2°C to 8°C) for up to 24 hours or room temperature at 68°F to 77°F (20°C to 25°C) for up to 12 hours and should be protected from light.

TOFIDENCE solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.

Allow the fully diluted

TOFIDENCE solution to reach room temperature prior to infusion.

The infusion should be administered over 60 minutes, and must be administered with an infusion set.

Do not administer as an intravenous push or bolus.

TOFIDENCE should not be infused concomitantly in the same intravenous line with other drugs.

No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of TOFIDENCE with other drugs.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

If particulates and discolorations are noted, the product should not be used.

Fully diluted

TOFIDENCE solutions are compatible with infusion bags and/or infusion sets with the following materials: polypropylene, polyethylene, polyolefin, polyvinyl chloride, polyethersulfone, polyurethane, nylon and stainless steel. 2.8 Dosage Modifications due to Serious.

Infections or Laboratory Abnormalities Serious.

Infections Hold TOFIDENCE treatment if a patient develops a serious infection until the infection is controlled.

Laboratory Abnormalities Rheumatoid Arthritis and Giant Cell Arteritis Liver Enzyme Abnormalities Lab Value Recommendation for RA Recommendation for GCA Greater than to 3× ULN Dose modify concomitant DMARDs if appropriate.

For persistent increases in this range

For patients receiving intravenous TOFIDENCE, reduce dose to 4 mg per kg or hold TOFIDENCE until ALT or AST have normalized.

Dose modify immunomodulatory agents if appropriate

For persistent increases in this range: For patients receiving intravenous TOFIDENCE, hold TOFIDENCE until ALT or AST have normalized.

Greater than to 5× ULN (confirmed by repeat testing) Hold TOFIDENCE dosing until less than 3.

(tocilizumab-bavi) injection is a preservative-free, sterile, clear to opalescent, colorless to light yellow solution.

TOFIDENCE is supplied as 80 mg/4 mL (NDC 64406-024-01), 200 mg/10 mL (NDC 64406-022-01), and 400 mg/20 mL (NDC 64406-023-01) individually packaged 20 mg/mL single-dose vials for further dilution prior to intravenous infusion.

Do not use beyond expiration date on the container or package.

TOFIDENCE must be refrigerated at 36°F to 46°F (2°C to 8°C).

Do not freeze.

Protect the vials from light by storage in the original package until time of use.

Do not use beyond expiration date on the container or package.

TOFIDENCE must be refrigerated at 36°F to 46°F (2°C to 8°C).

Do not freeze.

Protect the vials from light by storage in the original package until time of use.

The available data with tocilizumab products from a pregnancy exposure registry, retrospective cohort study, pharmacovigilance, and published literature are insufficient to draw conclusion about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

These studies had methodological limitations, including small sample size of tocilizumab exposed groups, missing exposure and outcomes information, and lack of adjustment for cofounders.

Monoclonal antibodies, such as tocilizumab products, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant.

In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every to 4 weeks.

The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition.

Based on the animal data, there may be a potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Fetal/Neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester.

Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to TOFIDENCE in utero.

Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis is associated with increased disease activity.

Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50.

Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre.

• and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning).

There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.

Parturition is associated with significant increases of IL-6 in the cervix and myometrium.

The literature suggests that inhibition of

IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition.

For mice deficient in

IL-6 (ll6 -/ - null mice), parturition was delayed relative to wild-type (ll6 +/+ ) mice.

Administration of recombinant

IL-6 to ll6 -/.

• null mice restored the normal timing of delivery.

TOFIDENCE by intravenous use is indicated for the treatment of pediatric patients with: Active systemic juvenile idiopathic arthritis in patients 2 years of age and older Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older The safety and effectiveness of TOFIDENCE in pediatric patients with conditions other than PJIA or SJIA have not been established.

The safety and effectiveness in pediatric patients below the age of 2 have not been established in PJIA or SJIA.

Arthritis – Intravenous Use A multicenter, open-label, single arm study to evaluate the PK, safety and exploratory PD and efficacy of tocilizumab over 12-weeks in SJIA patients (N=11) under 2 years of age was conducted.

Patients received intravenous tocilizumab 12 mg/kg every two weeks.

Concurrent use of stable background treatment with corticosteroids, MTX, and/or non-steroidal anti-inflammatory drugs was permitted.

Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer).

The primary

PK endpoints (C max, C trough and AUC 2weeks ) of tocilizumab at steady-state in this study were within the ranges of these parameters observed in patients with SJIA aged to 17 years.

The safety and immunogenicity of tocilizumab for patients with SJIA under 2 years of age was assessed descriptively.

SAEs, AEs leading to discontinuation, and infectious AEs were reported by 27.3%, 36.4%, and 81.8% of patients.

Six patients (54.5%) experienced hypersensitivity reactions, defined as all adverse events occurring during or within 24 hours after an infusion considered related to tocilizumab.

Three of these patients experienced serious hypersensitivity reactions and were withdrawn from the study.

Three patients with hypersensitivity reactions (two with serious hypersensitivity reactions) developed treatment induced anti-tocilizumab antibodies after the event.

There were no cases of

MAS based on the protocol-specified criteria, but 2 cases of suspected MAS based on Ravelli criteria Ravelli A, Minoia F, Davì S on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, et al.

Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis.

Diseases 2016;75:481-489. .

Of the 2644 patients who received tocilizumab in Studies I to V, a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older.

The frequency of serious infection among tocilizumab treated subjects 65 years of age and older was higher than those under the age of 65.

As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

In the

EMPACTA, COVACTA, and REMDACTA studies, of the 974 COVID-19 patients in the tocilizumab arm, 375 (39%) were 65 years of age or older.

No overall differences in safety or effectiveness of tocilizumab were observed between patients 65 years of age and older and those under the age of 65 years of age in these studies.

RECOVERY study, of the 2022 COVID-19 patients in the tocilizumab arm, 930 (46%) were 65 years of age or older.

No overall differences in effectiveness of tocilizumab were observed between patients 65 years of age and older and those under the age 65 years of age in this study.