AVTOZMA- tocilizumab_injection, solution

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. In clinical studies in RA patients with the 4 mg per kg and 8 mg per kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of tocilizumab, 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. , 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 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to the nadir 3 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 [see Warnings and Precautions (5. 4) 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. Rheumatoid Arthritis - Intravenous and Subcutaneous 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, and from an IV and SC dataset of 1759 patients from Studies SC- I and SC-II. C mean 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 trough mean max trough mean max mean trough mean trough The accumulation ratios for AUC and C max trough max mean trough For doses of 162 mg given every other week subcutaneously, the estimated median (range) steady-state C max trough mean For doses of 162 mg given every week subcutaneously, the estimated median (range) steady-state C max trough mean mean trough Accumulation ratios after multiple doses of either SC regimen were higher than after IV regimen with the highest ratios for C trough trough max mean trough Population 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 [see Dosage and Administration (2. 2) Giant Cell Arteritis en dash Subcutaneous and Intravenous Administration The pharmacokinetics of tocilizumab SC in GCA patients was determined using a population pharmacokinetic analysis on a dataset composed of 149 GCA patients treated with 162 mg subcutaneously every week or with 162 mg subcutaneously every other week. For the 162 mg every week dose, the estimated median (range) steady-state C max trough mean mean trough max max trough mean mean trough max 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 trough mean 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 [see Dosage and Administration (2. 3) Polyarticular Juvenile Idiopathic Arthritis en dash Intravenous and Subcutaneous 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 or 52 patients treated with TCZ SC. 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 trough mean max trough mean The accumulation ratios were 1. 16 for AUC 4weeks trough max For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks subcutaneously, the estimated median (range) C max trough mean max trough mean The accumulation ratios were 1. 04 for AUC 4weeks trough max trough max mean trough Systemic Juvenile Idiopathic Arthritis en dash Intravenous and Subcutaneous 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 or 51 patients treated with TCZ SC. 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 trough mean max trough mean The accumulation ratios were 1. 01 for AUC 4weeks trough max For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every week subcutaneously, the estimated median (range) C max trough mean max trough mean The accumulation ratios were 2. 28 for AUC 4weeks trough max max 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 [see Clinical Studies (14. 9) For one dose of 8 mg/kg tocilizumab IV, the estimated median (range) C max day28 max day28 Absorption Following subcutaneous dosing, the absorption half-life was around 4 days in RA and GCA patients. The bioavailability for the subcutaneous formulation was 80%. Following subcutaneous dosing in PJIA patients, the absorption half-life was around 2 days, and the bioavailability for the subcutaneous formulation in PJIA patients was 96%. Following subcutaneous dosing in SJIA patients, the absorption half-life was around 2 days, and the bioavailability for the SC formulation in SJIA patients was 95%. In RA patients the median values of T max In GCA patients, the median values of T max Distribution 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. 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. 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. 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. 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. 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 tocilizumab 8 mg/kg intravenously. The average linear clearance in the population pharmacokinetic analysis was estimated to be 17. 6 mL per hour in patients with baseline ordinal scale category 3 (OS 3, patients requiring supplemental oxygen), 22. 5 mL per hour in patients with baseline OS 4 (patients requiring high-flow oxygen or non-invasive ventilation), 29 mL per hour in patients with baseline OS 5 (patients requiring mechanical ventilation), and 35. 4 mL per hour in patients with baseline OS 6 (patients requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support). For intravenous administration in RA patients, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For subcutaneous administration in RA patients, the concentration-dependent apparent t 1/2 In GCA patients at steady state, the effective t 1/2 1/2 The t 1/2 1/2 The t 1/2 1/2 Specific Populations Population pharmacokinetic analyses in adult rheumatoid arthritis patients and GCA patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. In RA patients, the body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. There was an inverse relationship between tocilizumab exposure and body weight for flat dose subcutaneous regimens. In GCA patients treated with tocilizumab-SC, higher exposure was observed in patients with lower body weight. For the 162 mg every week subcutaneous dosing regimen, the steady-state C mean mean In COVID-19 patients, exposure following body-weight-based intravenous dosing (8 mg per kg tocilizumab up to 100 kg body weight with a maximum dose of 800 mg) was dependent on body weight and disease severity assessed by an ordinal scale (OS). Within an OS category, compared to patients with a mean body weight of 80 kg, exposure was 20% lower in patients weighing less than 60 kg. Exposure in patients weighing more than 100 kg was in the same range as exposure in patients with a mean body weight of 80 kg. For an 80 kg patient, exposure decreases as OS category increases; for each category increase, exposure decreases by 13%. Patients with Hepatic Impairment No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted. Patients with Renal Impairment No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted. Most of the RA and GCA patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab. Approximately one-third of the patients in the tocilizumab-SC GCA clinical trial had moderate renal impairment at baseline (estimated creatinine clearance of 30-59 mL/min). No impact on tocilizumab exposure was noted in these patients. No dose adjustment is required in patients with mild or moderate renal impairment. Drug Interaction Studies In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e. , P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of AVTOZMA, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e. , warfarin) or drug concentration (e. , cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when AVTOZMA is coadministered with drugs where decrease in effectiveness is undesirable, e. , oral contraceptives (CYP3A4 substrates) [see Drug Interactions (7. 2) Simvastatin Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with tocilizumab, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of tocilizumab (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of tocilizumab in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of AVTOZMA (due to normalization of CYP3A4) or higher exposures after discontinuation of AVTOZMA. Omeprazole Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after tocilizumab infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects. Dextromethorphan Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of tocilizumab (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after tocilizumab infusion.

AVTOZMA registered 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. Coronavirus Disease 2019 (COVID-19) ( 1. 5 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). AVTOZMA registered AVTOZMA registered AVTOZMA registered AVTOZMA registered AVTOZMA registered.

DOSAGE AND ADMINISTRATION
For RA, pJIA and sJIA, AVTOZMA may be used alone or in combination with methotrexate: and in RA, other non-biologic DMARDs may be used. ( 2 General Administration and Dosing Information ( 2. 1 RA, GCA, PJIA and SJIA 3 3 ( 5. 4 COVID-19 3 3 ( 5. 4 In RA or COVID-19 2. 3 Rheumatoid Arthritis 2. 2 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. Recommended Adult Subcutaneous Dosage: Patients less than 100 kg weight 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response Patients at or above 100 kg weight 162 mg administered subcutaneously every week Giant Cell Arteritis ( 2. 3 Recommended Adult Intravenous Dosage: The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. AVTOZMA can be used alone following discontinuation of glucocorticoids. Recommended Adult Subcutaneous Dosage: The recommended dose is 162 mg given once every week as a subcutaneous injection, in combination with a tapering course of glucocorticoids. A dose of 162 mg given once every other week as a subcutaneous injection, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations. Polyarticular Juvenile Idiopathic Arthritis ( 2. 4 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 Recommended Subcutaneous PJIA Dosage Patients less than 30 kg weight 162 mg once every three weeks Patients at or above 30 kg weight 162 mg once every two weeks Systemic Juvenile Idiopathic Arthritis ( 2. 5 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 Recommended Subcutaneous SJIA Dosage Patients less than 30 kg weight 162 mg every two weeks Patients at or above 30 kg weight 162 mg every week Coronavirus Disease 2019 ( 2. 6 The recommended dosage of AVTOZMA for adult patients with COVID-19 is 8 mg per kg administered by a 60-minute intravenous infusion. Administration of Intravenous Formulation ( 2. 7 For patients with RA, GCA, COVID-19, PJIA, and SJIA patients at or above 30 kg, dilute to 100 mL in 0. 45% 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. Administer as a single intravenous drip infusion over 1 hour; do not administer as bolus or push. Administration of Subcutaneous Formulation ( 2. 8 Follow the Instructions for Use for prefilled syringe and prefilled autoinjector Dose Modifications ( 2. 9 Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia. 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 AVTOZMA with biological DMARDs. 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 3 3 [see Warnings and Precautions (5. 4) COVID-19 3 3 [see Warnings and Precautions (5. 4) AVTOZMA may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection. Recommended Intravenous Dosage Regimen: The recommended dosage of AVTOZMA 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 [see Dosage and Administration (2. 9) Warnings and Precautions (5. 4) Adverse Reactions (6. 1) Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12. 3) Recommended Subcutaneous Dosage Regimen: Patients less than 100 kg weight 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response Patients at or above 100 kg weight 162 mg administered subcutaneously every week When transitioning from AVTOZMA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2. 2) Recommended Intravenous Dosage Regimen: The recommended dosage of AVTOZMA for adult patients given as a 60-minute single intravenous drip infusion is 6 mg per kg every 4 weeks in combination with tapering course of glucocorticoids. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2. 9) Doses exceeding 600 mg per infusion are not recommended in GCA patients [see Clinical Pharmacology (12. 3) Recommended Subcutaneous Dosage Regimen: The recommended dose of AVTOZMA for adult patients with GCA is 162 mg given once every week as a subcutaneous injection in combination with a tapering course of glucocorticoids. A dose of 162 mg given once every other week as a subcutaneous injection in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations. When transitioning from AVTOZMA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2. 9) AVTOZMA may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: The recommended dosage of AVTOZMA 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 Recommended Subcutaneous Dosage Regimen: Recommended Subcutaneous PJIA Dosage Patients less than 30 kg weight 162 mg once every 3 weeks Patients at or above 30 kg weight 162 mg once every 2 weeks When transitioning from AVTOZMA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. 9 AVTOZMA may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: The recommended dose of AVTOZMA 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 Recommended Subcutaneous Dosage Regimen: Recommended Subcutaneous SJIA Dosage Patients less than 30 kg weight 162 mg once every two weeks Patients at or above 30 kg weight 162 mg once every week When transitioning from AVTOZMA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose when the next scheduled intravenous dose is due. 9) Administer AVTOZMA by intravenous infusion only. The recommended dosage of AVTOZMA 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 AVTOZMA 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. Subcutaneous administration is not approved for COVID-19. AVTOZMA for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows: Use a sterile needle and syringe to prepare AVTOZMA. Patients less than 30 kg 50 mL Patients at or above 30 kg weight 100 mL Step 1. Withdraw a volume of 0. 45% Sodium Chloride Injection, USP, equal to the volume of the AVTOZMA injection required for the patient''s dose from the infusion bag or bottle [see Dosage and Administration (2. 5) For Intravenous Use: Volume of AVTOZMA Injection per kg of Body Weight Dosage Indication Volume of AVTOZMA 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 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 AVTOZMA for intravenous infusion from the vial(s) and add slowly into the 0. 45% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming. The fully diluted AVTOZMA solutions for infusion using 0. 9% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) for up to 48 hours or room temperature up to 86°F (30°C) for up to 4 hours and should be protected from light. 45% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) for up to 48 hours or room temperature up to 86°F (30°C) for up to 4 hours and should be protected from light. AVTOZMA solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used. Allow the fully diluted AVTOZMA 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. AVTOZMA 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 AVTOZMA 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 AVTOZMA solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles. AVTOZMA for subcutaneous injection is not intended for intravenous drip infusion. [see Use in Specific Populations (8. 4) Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use AVTOZMA prefilled syringes (PFS) or prefilled autoinjector (AI) exhibiting particulate matter, cloudiness, or discoloration. AVTOZMA for subcutaneous administration should be clear to slightly opalescent and colorless to yellow. Do not use if any part of the PFS or AI appears to be damaged. Patients using AVTOZMA for subcutaneous administration should be instructed to inject the full amount in the syringe (0. 9 mL) or full amount in the autoinjector (0. 9 mL), which provides 162 mg of AVTOZMA, according to the directions provided in the IFU. Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. Serious Infections Hold AVTOZMA treatment if a patient develops a serious infection until the infection is controlled. Laboratory Abnormalities Rheumatoid Arthritis and Giant Cell Arteritis Liver Enzyme Abnormalities [see Warnings and Precautions (5. 4) Lab Value Recommendation for RA Recommendation for GCA Greater than 1 to 3× ULN Dose modify concomitant DMARDs if appropriate For patients receiving intravenous AVTOZMA, reduce dose to 4 mg per kg or hold AVTOZMA until ALT or AST have normalized For patients receiving subcutaneous AVTOZMA, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume AVTOZMA at every other week and increase frequency to every week as clinically appropriate. Dose modify immunomodulatory agents if appropriate For patients receiving intravenous AVTOZMA, hold AVTOZMA until ALT or AST have normalized For patients receiving subcutaneous AVTOZMA, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Greater than 3 to 5× ULN Hold AVTOZMA dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN Hold AVTOZMA dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN Greater than 5× ULN Discontinue AVTOZMA Discontinue AVTOZMA Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5. 4) Lab Value (cells per mm 3 Recommendation for RA Recommendation for GCA ANC greater than 1000 Maintain dose Maintain dose ANC 500 to 1000 Hold AVTOZMA dosing 3 For patients receiving intravenous AVTOZMA, resume AVTOZMA at 4 mg per kg and increase to 8 mg per kg as clinically appropriate For patients receiving subcutaneous AVTOZMA, resume AVTOZMA at every other week and increase frequency to every week as clinically appropriate Hold AVTOZMA dosing 3 For patients receiving intravenous AVTOZMA, resume AVTOZMA at 6 mg per kg For patients receiving subcutaneous AVTOZMA, resume AVTOZMA at every other week and increase frequency to every week as clinically appropriate ANC less than 500 Discontinue AVTOZMA Discontinue AVTOZMA Low Platelet Count [see Warnings and Precautions (5. 4) Lab Value (cells per mm 3 Recommendation for RA Recommendation for GCA 50,000 to 100,000 Hold AVTOZMA dosing 3 For patients receiving intravenous AVTOZMA, resume AVTOZMA at 4 mg per kg and increase to 8 mg per kg as clinically appropriate For patients receiving subcutaneous AVTOZMA, resume AVTOZMA at every other week and increase frequency to every week as clinically appropriate Hold AVTOZMA dosing 3 For patients receiving intravenous AVTOZMA, resume AVTOZMA at 6 mg per kg For patients receiving subcutaneous AVTOZMA, resume AVTOZMA at every other week and increase frequency to every week as clinically appropriate Less than 50,000 Discontinue AVTOZMA Discontinue AVTOZMA Polyarticular and Systemic Juvenile Idiopathic Arthritis Dose reduction of tocilizumab products has not been studied in the PJIA and SJIA populations. Dose interruptions of AVTOZMA are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA and GCA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold AVTOZMA dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue AVTOZMA for a laboratory abnormality should be based upon the medical assessment of the individual patient.
Instructions for Use
AVTOZMA registered Read and follow the Instructions for Use that come with your AVTOZMA Prefilled Syringe before you start using it and each time you get a refill. There may be new information. Before you use AVTOZMA, make sure your healthcare provider shows you the right way to use it. Important Information Do not Do not Do not Do not Do not Storing AVTOZMA Store the unused prefilled syringe in the original carton in a refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze. When removed from the refrigerator, AVTOZMA can be stored up to 3 weeks at or below 77°F (25°C). If not used within the 3 weeks, AVTOZMA should be thrown away (discarded). Keep the prefilled syringe out of direct sunlight. Do not Do not Keep the prefilled syringe out of the reach of children. Parts of your Prefilled Syringe (See Figure A Figure A Preparing for the Injection 1. Gather the supplies for the injection. Figure B Not included in the carton: Figure B 2. Inspect the carton (see Figure C Do not Do not Figure C 3. Inspect the Prefilled Syringe. see Figure D Do not Do not Figure D 4. Wait 30 minutes. Figure E Do not Do not Do not If the prefilled syringe does not reach room temperature, this could cause discomfort and make it hard to push the plunger. Inspect the medicine. Figure F Do not Air bubbles are normal. Wash your hands. Figure G Figure G 7. Choose an injection site (see Figure H Do not Choose a different injection site for each new injection at least 1 inch (2. 5 cm) from the last area you injected. Do not Figure H 8. Clean the injection site. Figure I Do not Do not Figure I Giving the Injection 9. Remove the cap. Figure J Do not You may see a drop of liquid at the tip of the needle. This is normal. If the prefilled syringe is not used within 5 minutes of needle cap removal, the prefilled syringe should be thrown away (disposed of) in the puncture resistant container or sharps container and a new prefilled syringe should be used. step 14 Throw away (dispose of) prefilled syringe Figure N Do not Do not Figure J 10. Insert the prefilled syringe into the injection site. Figure K Do not Do not Figure K 11. Give the injection. Figure L Do not If the plunger is not fully pressed, the needle guard will not extend to cover the needle when it is removed. If the needle is not covered, proceed carefully to dispose of the syringe (see step 14. Throw away (dispose of) prefilled syringe Figure L 12. Remove the prefilled syringe from the injection site. Figure M Some bleeding may occur (see step 13. Care for the injection site In case of skin contact with medicine, wash the area that touched the medicine with water. Do not Figure M After the Injection 13. Care for the injection site. Throw away (dispose of) the prefilled syringe. Figure N Do not Do not Do not Do not Keep the AVTOZMA prefilled syringe and disposal container out of the reach of children. Figure N If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:-made of a heavy-duty plastic-can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out-upright stable during use-leak-resistant-properly labeled to warn of hazardous waste inside the container When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should dispose of used prefilled syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA''s website at: http://www. gov/safesharpsdisposal. Record your injection. This Instructions for Use has been approved by the U. Food and Drug Administration. Manufactured by: CELLTRION, Inc. , 23, Academy-ro, Yeonsu-gu, Incheon, 22014, Republic of Korea Distributed by: CELLTRION USA, Inc. , One Evertrust Plaza Suite 1207, Jersey City, NJ 07302 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M Figure N.
Instructions for Use
AVTOZMA registered Read and follow the Instructions for Use that come with your AVTOZMA prefilled autoinjector before you start using it and each time you get a refill. There may be new information. Before you use AVTOZMA, make sure your healthcare provider shows you the right way to use it. Important Information Do not Do not Do not Do not Do not Storing AVTOZMA Store the unused prefilled autoinjector in the original carton in a refrigerator between 36°F to 46ºF (2°C to 8ºC). Do not When removed from the refrigerator, AVTOZMA can be stored up to 3 weeks at or below 77°F (25°C). If not used within the 3 weeks, AVTOZMA should be thrown away (discarded). Keep the prefilled autoinejctor out of direct sunlight. Do not Do not Keep the prefilled autoinjector out of the reach of children. Parts of your AVTOZMA prefilled autoinjector (See Figure A Preparing for the Injection 1. Gather the supplies for the injection. Figure B Not included in the carton: Figure B 2. Inspect the carton (see Figure C Do not If you are opening the carton for the first time, check to make sure that it is properly sealed. Do not Figure C 3. Inspect the Prefilled. see Figure D Do not Do not Figure D 4. Wait 45 minutes. Figure E Do not Do not Do not If the prefilled autoinjector does not reach room temperature, this could cause discomfort. Inspect the medicine. Figure F Do not Air bubbles are normal. Wash your hands. Figure G Figure G 7. Choose an injection site (see Figure H Do not Choose a different injection site for each new injection at least 1 inch (2. 5 cm) from the last area you injected. Do not Figure H 8. Clean the injection site. Figure I Do not Do not Figure I Giving the Injection 9. Remove the cap. Figure J step 14 Figure O Do not Do not After you remove the cap, the prefilled autoinjector is ready for use. If the prefilled autoinjector is not used within 3 minutes of cap removal, throw away the prefilled autoinjector in a FDA-cleared sharps disposal container and use a new prefilled autoinjector. Figure J 10. Place the prefilled on the injection site. Figure K Figure L Do not Figure K Figure L 11. Give the injection. Figure M nd nd count slowly to 5 Figure M Figure M 12. Remove the prefilled from the injection site. The needle cover will automatically move out and lock into place covering the needle (see Figure N Do not Do not Do not Figure N After the Injection 13. Care for the injection site. Dispose of AVTOZMA. Figure O Do not Do not Do not Do not Keep the AVTOZMA prefilled autoinjector and disposal container out of the reach of children. Figure O If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:-made of a heavy-duty plastic-can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out-upright stable during use-leak-resistant-properly labeled to warn of hazardous waste inside the container When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should dispose of used autoinjectors. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA''s website at: http://www. gov/safesharpsdisposal. Record your injection. This Instructions for Use has been approved by the U. Food and Drug Administration. Manufactured by: CELLTRION, Inc. , 23, Academy-ro, Yeonsu-gu, Incheon, 22014, Republic of Korea Distributed by: CELLTRION USA, Inc. , One Evertrust Plaza Suite 1207, Jersey City, NJ 07302 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M Figure N Figure O.

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. gov/medwatch 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 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. 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) 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 3 3 3 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 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 [see Dosage and Administration (2. 9) [see Warnings and Precautions (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 > 5× ULN 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. 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) 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: en dash en dash en dash en dash 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: Gastrointestinal disorders: Investigations: Blood and lymphatic system disorders: General disorders and administration site conditions: Respiratory, thoracic, and mediastinal disorders Eye disorders: Renal disorders: Endocrine disorders: 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 There was no clear relationship between decreases in neutrophils below 1 × 10 9 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. 4% of patients, respectively, receiving tocilizumab-SC weekly and 3. 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. 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. 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. 7 events per 100 patient years in the tocilizumab-SC weekly group and 160. 4 events per 100 patient years in the tocilizumab-SC every other week group as compared to 156. 2 events per 100 patient years in the placebo + 26 week prednisone taper and 210. 5 events per 100 patient years in the placebo + 52 week taper groups. 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. The overall safety profile observed for tocilizumab administered intravenously in GCA patients was consistent with the known safety profile of tocilizumab. 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. 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. 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 There was no clear relationship between decreases in neutrophils below 1 × 10 9 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 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. 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. 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. 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 9 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 9 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 en dash 2× ULN occurred in 1. 5% of the tocilizumab-IV group and in 0% of placebo patients. Elevation in LDL greater than 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. 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. 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. 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 Table 3 Adverse Reactions Patients are counted once for each category regardless of the number of reactions 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. 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. 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.

AVTOZMA is contraindicated in patients with known hypersensitivity to tocilizumab products [see Warnings and Precautions (5. 6) Known hypersensitivity to tocilizumab products.

Pregnancy: 8. 1 Lactation: 8. 2 Risk Summary The available data with tocilizumab products from a pregnancy exposure registry, retrospective cohort study, pharmacovigilance, and published literature are insufficient to draw conclusions 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 [see Clinical Considerations [see Data 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. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations 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 AVTOZMA in utero [see Warnings and Precautions 5. 9) Disease-associated Maternal Risk 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. Data Animal Data 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 10 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 -/- +/+ -/- Risk Summary No information is available on the presence of tocilizumab products in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab products are transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab products are unknown. The lack of clinical data during lactation precludes clear determination of the risk of tocilizumab products to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AVTOZMA and the potential adverse effects on the breastfed child from AVTOZMA or from the underlying maternal condition. AVTOZMA 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 AVTOZMA by subcutaneous use is indicated for the treatment of pediatric patients with: Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older Active systemic juvenile idiopathic arthritis in patients 2 years of age and older The safety and effectiveness of AVTOZMA 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. Systemic Juvenile Idiopathic Arthritis en dash 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 trough 2weeks 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. 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. Of the 2644 patients who received tocilizumab in Studies I to V [see Clinical Studies (14) 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 [see Adverse Reactions (6. 1) Clinical Studies (14. 9) In the 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 [see Clinical Studies (14. 9) The safety and efficacy of tocilizumab products have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions 5. 8) No dose adjustment is required in patients with mild or moderate renal impairment. Tocilizumab products have not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.

In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non- steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single intravenous dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration (2. 2) In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed. Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab products may restore CYP450 activities to higher levels than those in the absence of tocilizumab products leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of tocilizumab, respectively. The effect of tocilizumab products on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of AVTOZMA, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e. , warfarin) or drug concentration (e. , cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering AVTOZMA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e. , oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab products on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12. 3) Avoid use of live vaccines concurrently with AVTOZMA [see Warnings and Precautions (5.

6 L/min to maintain SpO2 >93%. At baseline, 7% of patients were on low flow oxygen, 80% were on non-invasive ventilation or high flow oxygen, 14% were on invasive mechanical ventilation, and 84% were on corticosteroids. The primary efficacy endpoint was time from randomization to hospital discharge or ''ready for discharge'' up to Day 28. There was no statistically significant difference between the treatment arms with respect to time to hospital discharge or "ready for discharge" through Day 28. Mortality at Day 28 was 18. 1% in the tocilizumab + RDV arm versus 19. 5% in the placebo +RDV arm (weighted difference (tocilizumab arm - placebo arm): -1. Mortality Across Studies in Patients Receiving Baseline Corticosteroids A study-level meta-analysis was conducted on EMPACTA, COVACTA, REMDACTA and RECOVERY studies. For each of the four studies, the risk difference through Day 28 was estimated by the Kaplan-Meier method in the subgroup of patients receiving baseline corticosteroids, summarized in Figure 2. Patients from the RECOVERY trial represent 78. 8% of the total sample size in this meta-analysis. The combined risk difference showed that tocilizumab treatment (n=2261) resulted in a 4. 61% absolute reduction in the risk of death at Day 28 (risk difference=-4. 6%; 95% CI: -7. 9%) compared to SoC (n=2034). Figure 2 Risk Differences Through Day 28 for Baseline Corticosteroid Use Subpopulation in RECOVERY, EMPACTA, COVACTA and REMDACTA studies Figure 2.">OVERDOSAGE
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.
NONCLINICAL TOXICOLOGY
No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab products. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as tocilizumab, is presently unknown. Fertility and reproductive performance were unaffected in male and female mice that received a murine analogue of tocilizumab administered by the intravenous route at a dose of 50 mg/kg every three days.
CLINICAL STUDIES
The efficacy and safety of intravenously administered tocilizumab was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. Tocilizumab was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V). Study I Study II Study III Study IV Study V Clinical Response The percentages of intravenous tocilizumab-treated patients achieving ACR 20, 50 and 70 responses are shown in Table 4. During the 24 week controlled portions of Studies I to V, patients treated with tocilizumab at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with tocilizumab 8 mg per kg. Table 4 Clinical Response at Weeks 24 and 52 in Active and Placebo Controlled Trials of Intravenous Tocilizumab (Percent of Patients) Percent of Patients Response Rate Study I Study II Study III Study IV Study V MTX Tocilizumab 8 mg per kg Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX Placebo + DMARDs Tocilizumab 8 mg per kg + DMARDs Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX N=284 N=286 N=393 N=399 CI: 95% confidence interval of the weighted difference to placebo adjusted for site (and disease duration for Study I only) N=398 N=204 N=213 N=205 N=413 N=803 N=158 N=161 N=170 ACR 20 Week 24 53% 70% 27% 51% 56% 27% 48% 59% 24% 61% 10% 30% 50% Week 52 N/A N/A 25% 47% 56% N/A N/A N/A N/A N/A N/A N/A N/A ACR 50 Week 24 34% 44% 10% 25% 32% 11% 32% 44% 9% 38% 4% 17% 29% Week 52 N/A N/A 10% 29% 36% N/A N/A N/A N/A N/A N/A N/A N/A ACR 70 Week 24 15% 28% 2% 11% 13% 2% 12% 22% 3% 21% 1% 5% 12% Week 52 N/A N/A 4% 16% 20% N/A N/A N/A N/A N/A N/A N/A N/A Major Clinical Responses Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week period Week 52 N/A N/A 1% 4% 7% N/A N/A N/A N/A N/A N/A N/A N/A In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg tocilizumab + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2. 6 compared with placebo +MTX treated patients at week 52. The proportion of tocilizumab-treated patients achieving DAS 28-ESR less than 2. 6, and the number of residual active joints in these responders in Study II are shown in Table 5 Table 5 Proportion of Patients with DAS28-ESR Less Than 2. 6 with Number of Residual Active Joints in Trials of Intravenous Tocilizumab Study II Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX *n denotes numerator of all the percentage. Denominator is the intent-to-treat population. Not all patients received DAS28 assessments at Week 52. DAS28-ESR less than 2. 6 Proportion of responders at week 52 (n) 3% (12) 18% (70) 32% (127) Of responders, proportion with 0 active joints (n) 33% (4) 27% (19) 21% (27) Of responders, proportion with 1 active joint (n) 8% (1) 19% (13) 13% (16) Of responders, proportion with 2 active joints (n) 25% (3) 13% (9) 20% (25) Of responders, proportion with 3 or more active joints (n) 33% (4) 41% (29) 47% (59) The results of the components of the ACR response criteria for Studies III and V are shown in Table 6 Table 6 Components of ACR Response at Week 24 in Trials of Intravenous Tocilizumab Study III Study V Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX Placebo + MTX N=213 N=205 N=204 N=161 N=170 N=158 Component (mean) Baseline Week 24 Data shown is mean at week 24, difference in adjusted mean change from baseline compared with placebo + MTX at week 24 and 95% confidence interval for that difference Baseline Week 24 Baseline Week 24 Baseline Week 24 Baseline Week 24 Baseline Week 24 Number of tender joints (0-68) 33 19 32 14. 5 33 25 31 21 32 17 30 30 Number of swollen joints (0-66) 20 10 19. 5 8 21 15 19. 5 13 19 11 19 18 Pain Visual analog scale: 0 = best, 100 = worst 61 33 60 30 57 43 63. 5 43 65 33 64 48 Patient global assessment 66 34 65 31 64 45 70 46 70 36 71 51 Physician global assessment 64 26 64 23 64 32 66. 5 39 66 28 67. 5 43 Disability index (HAQ) Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities 1. 58 CRP (mg per dL) 2. 06 The percent of ACR 20 responders by visit for Study III is shown in Figure 1 The same patients may not have responded at each timepoint. Figure 1 Radiographic Response In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number. The results from baseline to week 52 are shown in Table 7 Table 7 Mean Radiographic Change from Baseline to Week 52 in Study II Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX N=294 N=343 N=353 SD = standard deviation Week 52 Week 52 analysis employs linearly extrapolated data for patients after escape, withdrawal, or loss to follow up. Total Sharp-Genant Score, Mean (SD) 1. 25 Adjusted Mean difference Difference between the adjusted means (tocilizumab + MTX - Placebo + MTX) -0. 90 Erosion Score, Mean (SD) 0. 15 Adjusted Mean difference -0. 60 Joint Space Narrowing Score, Mean (SD) 0. 10 Adjusted Mean difference -0. 30 The mean change from baseline to week 104 in Total Sharp-Genant Score for the tocilizumab 4 mg per kg groups was 0. 47) and for the 8 mg per kg groups was 0. By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group. In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp-Genant Score change <= 0) at week 52 compared to 78% and 83% in the tocilizumab 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to tocilizumab 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients. Health Related Outcomes In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of tocilizumab demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0. 4 for tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, and placebo treatment groups, respectively. Sixty-three percent (63%) and sixty percent (60%) of patients in the tocilizumab 8 mg per kg and tocilizumab 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of >= 0. 3 units) at week 52 compared to 53% in the placebo treatment group. Other Health-Related Outcomes General health status was assessed by the Short Form Health Survey (SF-36) in Studies I en dash V. Patients receiving tocilizumab demonstrated greater improvement from baseline compared to placebo in the Physical Component Summary (PCS), Mental Component Summary (MCS), and in all 8 domains of the SF-36. Cardiovascular Outcomes Study WA25204 (NCT01331837) was a randomized, open-label (sponsor-blinded), 2-arm parallel-group, multicenter, non-inferiority, cardiovascular (CV) outcomes trial in patients with a diagnosis of moderate to severe RA. This CV safety study was designed to exclude a moderate increase in CV risk in patients treated with tocilizumab compared with a TNF inhibitor standard of care (etanercept). The study included 3,080 seropositive RA patients with active disease and an inadequate response to non- biologic disease-modifying anti-rheumatic drugs, who were aged >=50 years with at least one additional CV risk factor beyond RA. Patients were randomized 1:1 to IV tocilizumab 8 mg/kg Q4W or SC etanercept 50 mg QW and followed for an average of 3. The primary endpoint was the comparison of the time-to-first occurrence of any component of a composite of major adverse CV events (MACE; non-fatal myocardial infarction, non-fatal stroke, or CV death), with the final intent-to-treat analysis based on a total of 161 confirmed CV events (83/1538 [5. 4%] for tocilizumab; 78/1542 [5. 1%] for etanercept) reviewed by an independent and blinded adjudication committee. Non-inferiority of tocilizumab to etanercept for cardiovascular risk was determined by excluding >80% relative increase in the risk of MACE. The estimated hazard ratio (HR) for the risk of MACE comparing tocilizumab to etanercept was 1. 05; 95% CI (0. The efficacy and safety of subcutaneously administered tocilizumab was assessed in two double-blind, controlled, multicenter studies in patients with active RA. One study, SC-I ( NCT01194414 NCT01232569 In SC-I, 1262 patients were randomized 1:1 to receive tocilizumab-SC 162 mg every week or intravenous tocilizumab 8 mg/kg every four weeks in combination with DMARD(s). In SC-II, 656 patients were randomized 2:1 to tocilizumab-SC 162 mg every other week or placebo, in combination with DMARD(s). The primary endpoint in both studies was the proportion of patients who achieved an ACR20 response at Week 24. The clinical response to 24 weeks of tocilizumab-SC therapy is shown in Table 8 Table 8 Table 8 Clinical Response at Week 24 in Trials of Subcutaneous Tocilizumab (Percent of Patients) SC-I Per Protocol Population SC-II Intent To Treat Population TCZ SC 162 mg every week + DMARD TCZ IV 8mg/kg + DMARD TCZ SC 162 mg every other week + DMARD Placebo + DMARD N=558 N=537 N=437 N=219 TCZ = tocilizumab ACR20 Week 24 69% 73. 4% 61% 32% Weighted difference (95% CI) -4% (-9. 0) ACR50 Week 24 47% 49% 40% 12% Weighted difference (95% CI) -2% (-7. 4) ACR70 Week 24 24% 28% 20% 5% Weighted difference (95% CI) -4% (-9. 9) Change in DAS28 [Adjusted mean] Week 24 -3. 7 Adjusted mean difference (95% CI) 0 (-0. 1) DAS28 < 2. 6 Week 24 38. 0% Weighted difference (95% CI) 0. 2) The results of the components of the ACR response criteria and the percent of ACR20 responders by visit for tocilizumab-SC in Studies SC-I and SC-II were consistent with those observed for tocilizumab-IV. Radiographic Response In study SC-II, the progression of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified total Sharp score (mTSS). At week 24, significantly less radiographic progression was observed in patients receiving tocilizumab-SC every other week plus DMARD(s) compared to placebo plus DMARD(s); mean change from baseline in mTSS of 0. 23, respectively, with an adjusted mean difference of -0. These results are consistent with those observed in patients treated with intravenous tocilizumab. Health Related Outcomes In studies SC-I and SC-II, the mean decrease from baseline to week 24 in HAQ-DI was 0. 3, and the proportion of patients who achieved a clinically relevant improvement in HAQ-DI (change from baseline of >= 0. 3 units) was 65%, 67%, 58% and 47%, for the subcutaneous every week, intravenous 8 mg/kg, subcutaneous every other week, and placebo treatment groups, respectively. Other Health-Related Outcomes General health status was assessed by the SF-36 in Studies SC-I and SC-II. In Study SC-II, patients receiving tocilizumab every other week demonstrated greater improvement from baseline compared to placebo in the PCS, MCS, and in all 8 domains of the SF-36. In Study SC-I, improvements in these scores were similar between tocilizumab-SC every week and tocilizumab-IV 8 mg/kg. The efficacy and safety of subcutaneously administered tocilizumab was assessed in a single, randomized, double-blind, multicenter study in patients with active GCA. In Study WA28119 (NCT01791153), 251 screened patients with new-onset or relapsing GCA were randomized to one of four treatment arms. Two subcutaneous doses of tocilizumab (162 mg every week and 162 mg every other week) were compared to two different placebo control groups (pre-specified prednisone-taper regimen over 26 weeks and 52 weeks) randomized 2:1:1:1. The study consisted of a 52-week blinded period, followed by a 104-week open-label extension. All patients received background glucocorticoid (prednisone) therapy. Each of the tocilizumab-treated groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 52 weeks designed to be more in keeping with standard practice. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined by a patient attaining a sustained (1) absence of GCA signs and symptoms from Week 12 through Week 52, (2) normalization of erythrocyte sedimentation rate (ESR) (to < 30 mm/hr without an elevation to >= 30 mm/hr attributable to GCA) from Week 12 through Week 52, (3) normalization of C-reactive protein (CRP) (to < 1 mg/dL, with an absence of successive elevations to >= 1mg/dL) from Week 12 through Week 52, and (4) successful adherence to the prednisone taper defined by not more than 100 mg of excess prednisone from Week 12 through Week 52. Tocilizumab 162 mg weekly and 162 mg every other week + 26 weeks prednisone taper both showed superiority in achieving sustained remission from Week 12 through Week 52 compared with placebo + 26 weeks prednisone taper (Table 9). Both tocilizumab treatment arms also showed superiority compared to the placebo + 52 weeks prednisone taper (Table 9). Table 9 Efficacy Results from Study WA28119 PBO + 26 weeks prednisone taper PBO + 52 weeks prednisone taper TCZ 162mg SC QW + 26 weeks prednisone taper TCZ 162 mg SC Q2W + 26 weeks prednisone taper Patients not completing the study to week 52 were classified as non-responders in the primary and key secondary analysis: PBO+26: 6 (12. 0%), PBO+52: 5 (9. 8%), TCZ QW: 15 (15. 0%), TCZ Q2W: 9 (18. Sustained remission Sustained remission was achieved by a patient meeting all of the following components: absence of GCA signs and symptoms b c d e Responders, n (%) 7 (14. 1%) Unadjusted difference in proportions vs PBO + 26 weeks taper N/A N/A 42. 1% Unadjusted difference in proportions vs PBO + 52 weeks taper N/A N/A 38. 4% Components of Sustained Remission Sustained absence of GCA signs and symptoms Patients who did not have any signs or symptoms of GCA recorded from Week 12 up to Week 52. 1%) Sustained ESR<30 mm/hr Patients who did not have an elevated ESR >=30 mm/hr which was classified as attributed to GCA from Week 12 up to Week 52. 5%) Sustained CRP normalization Patients who did not have two or more consecutive CRP records of >= 1mg/dL from Week 12 up to Week 52. 4%) Successful prednisone tapering Patients who did not enter escape therapy and received <= 100mg of additional concomitant prednisone from Week 12 up to Week 52. 1%) The estimated annual cumulative prednisone dose was lower in the two tocilizumab dose groups (medians of 1887 mg and 2207 mg on tocilizumab QW and Q2W, respectively) relative to the placebo arms (medians of 3804 mg and 3902 mg on placebo + 26 weeks prednisone and placebo + 52 weeks prednisone taper, respectively). Intravenously administered tocilizumab in patients with GCA was assessed in WP41152 (NCT03923738), an open-label PK-PD and safety study to determine the appropriate intravenous dose of tocilizumab that achieved comparable PK-PD profiles to the tocilizumab-SC regimen. At enrollment, all patients (n=24) were in remission on tocilizumab-IV. In Period 1, all patients received open- label tocilizumab-IV 7 mg/kg every 4 weeks for 20 weeks. Patients who completed Period 1 and remained in remission (n=22) were eligible to enter Period 2, and received open-label tocilizumab-IV 6 mg/kg every 4 weeks for 20 weeks. The efficacy of intravenous tocilizumab 6 mg/kg in adult patients with GCA is based on pharmacokinetic exposure and extrapolation to the efficacy established for subcutaneous tocilizumab in patients with GCA [see Clinical Pharmacology (12. 3) Clinical Studies (14. 3) The efficacy of tocilizumab was assessed in a three-part study, WA19977 (NCT00988221), including an open- label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis (PJIA), who had an inadequate response to methotrexate or inability to tolerate methotrexate. Patients had at least 6 months of active disease (mean disease duration of 4. 7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 +/- 14 active joints). The patients treated had subtypes of JIA that at disease onset included Rheumatoid Factor Positive or Negative Polyarticular JIA, or Extended Oligoarticular JIA. Treatment with a stable dose of methotrexate was permitted but was not required during the study. Concurrent use of disease modifying antirheumatic drugs (DMARDs), other than methotrexate, or other biologics (e. , TNF antagonists or T cell costimulation modulator) were not permitted in the study. Part I consisted of a 16-week active tocilizumab treatment lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Eligible patients weighing at or above 30 kg received tocilizumab at 8 mg/kg intravenously once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either tocilizumab 8 mg/kg or 10 mg/kg intravenously every four weeks. At the conclusion of the open-label Part I, 91% of patients taking background MTX in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study. The proportions of patients with JIA ACR 50/70 responses in Part I were 84. 0%, and 64%, respectively for patients taking background MTX in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy. In Part II, patients (ITT, n=163) were randomized to tocilizumab (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape. The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16. JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16. Tocilizumab treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% [21/82] versus 48% [39/81]; adjusted difference in proportions -21%, 95% CI: -35%, -8%). During the withdrawal phase (Part II), more patients treated with tocilizumab showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo. Subcutaneously administered tocilizumab in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) was assessed in WA28117 (NCT01904279), a 52-week, open-label, multicenter, PK-PD and safety study to determine the appropriate subcutaneous dose of tocilizumab that achieved comparable PK/PD profiles to the tocilizumab-IV regimen. PJIA patients aged 1 to 17 years with an inadequate response or inability to tolerate MTX, including patients with well-controlled disease on treatment with tocilizumab-IV and tocilizumab-naïve patients with active disease, were treated with subcutaneous tocilizumab based on body weight. Patients weighing at or above 30 kg (n = 25) were treated with 162 mg of tocilizumab-SC every 2 weeks and patients weighing less than 30 kg (n = 27) received 162 mg of tocilizumab-SC every 3 weeks for 52 weeks. Of these 52 patients, 37 (71%) were naive to tocilizumab and 15 (29%) had been receiving tocilizumab-IV and switched to tocilizumab-SC at baseline. The efficacy of subcutaneous tocilizumab in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous tocilizumab in polyarticular JIA patients and subcutaneous tocilizumab in patients with RA [see Clinical Pharmacology (12. 5) The efficacy of tocilizumab for the treatment of active SJIA was assessed in WA18221 (NCT00642460), a 12- week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (tocilizumab:placebo = 2:1) to one of two treatment groups: 75 patients received tocilizumab infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab in the open-label extension phase at weight appropriate dosing. The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR 30 response) at Week 12 and absence of fever (no temperature at or above 37. 5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e. , 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ). Primary endpoint result and JIA ACR response rates at Week 12 are shown in Table 10 Table 10 Efficacy Findings at Week 12 Tocilizumab Placebo Primary Endpoint: JIA ACR 30 response + absence of fever Responders 85% 24% Weighted difference 62 - JIA ACR Response Rates at Week 12 JIA ACR 30 Responders 91% 24% Weighted difference The weighted difference is the difference between the tocilizumab and Placebo response rates, adjusted for the stratification factors (weight, disease duration, background oral corticosteroid dose and background methotrexate use). 67 - (95% CI) CI: confidence interval of the weighted difference. (51, 83) JIA ACR 50 Responders 85% 11% Weighted difference 74 - (95% CI) (58, 90) JIA ACR 70 Responders 71% 8% Weighted difference 63 - (95% CI) (46, 80) The treatment effect of tocilizumab was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks). Systemic Features Of patients with fever or rash at baseline, those treated with tocilizumab had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37. 5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks). Corticosteroid Tapering Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), tocilizumab patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) tocilizumab patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) tocilizumab patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more. Health Related Outcomes Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the tocilizumab treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of >= 0. 13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group. Subcutaneously administered tocilizumab in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) was assessed in WA28118 (NCT01904292), a 52-week, open-label, multicenter, PK-PD and safety study to determine the appropriate subcutaneous dose of tocilizumab that achieved comparable PK/PD profiles to the tocilizumab-IV regimen. Eligible patients received tocilizumab subcutaneously dosed according to body weight, with patients weighing at or above 30 kg (n = 26) dosed with 162 mg of tocilizumab every week and patients weighing below 30 kg (n = 25) dosed with 162 mg of tocilizumab every 10 days (n=8) or every 2 weeks (n=17) for 52 weeks. Of these 51 patients, 26 (51%) were naive to subcutaneous tocilizumab and 25 (49%) had been receiving tocilizumab intravenously and switched to subcutaneous tocilizumab at baseline. The efficacy of subcutaneous tocilizumab in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous tocilizumab in systemic JIA patients [see Clinical Pharmacology (12. 7) The efficacy of tocilizumab for the treatment of COVID-19 was based on RECOVERY ( NCT04381936 NCT04372186 NCT04320615 NCT04409262 RECOVERY (Randomised Evaluation of COVID-19 Therapy) Collaborative Group Study in Hospitalized Adults Diagnosed with COVID-19 RECOVERY was a randomized, controlled, open-label, multicenter platform study conducted in the United Kingdom to evaluate the efficacy and safety of potential treatments in hospitalized adult patients with severe COVID-19 pneumonia. Eligible patients for the tocilizumab portion of the study had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical contraindications to any of the treatments and had clinical evidence of progressive COVID-19 (defined as oxygen saturation <92% on room air or receiving oxygen therapy, and CRP >=75 mg/L). Patients were then randomized to receive either standard of care (SoC) or intravenous tocilizumab at a weight-tiered dosing comparable to the recommended dosage [see Clinical Pharmacology (12. 3) Efficacy analyses were performed in the intent-to-treat (ITT) population comprising 4116 adult patients who were randomized to the tocilizumab + SoC arm (n=2022) or to the SoC arm (n=2094). The mean age of participants was 64 years (range: 20 to 101), and patients were 67% male, 76% White, 11% Asian, 3% Black or African American, and 1% mixed race. At baseline, 0. 2% of patients were not on supplemental oxygen, 45% of patients required low flow oxygen, 41% of patients required non-invasive ventilation or high-flow oxygen, and 14% of patients required invasive mechanical ventilation; 82% of patients were reported to be receiving systemic corticosteroids. The primary efficacy endpoint was time to death through Day 28. The results for the overall population and the subgroups of patients who were or were not receiving systemic corticosteroids at time of randomization are summarized in Table 11. Table 11 Mortality through Day 28 in RECOVERY Tocilizumab+ SoC N=2022 P-value reflects that the RECOVERY trial primary analysis results were statistically significant at the two-sided significance level of alpha SoC Hazard Ratio Risk Difference Mortality 621 (30. 7%) 729 (34. 3) By baseline receipt of corticosteroid use Mortality for patients receiving systemic corticosteroids at randomization Probabilities of dying by Day 28 were estimated by the Kaplan-Meier method. 482/1664 (29. 0%) 600/1721 (34. 8) Mortality for patients not receiving systemic corticosteroids at randomization 139/357 (39. 0%) 127/367 (34. 5) EMPACTA EMPACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with SoC in hospitalized, non-ventilated adult patients with COVID-19 pneumonia. Eligible patients were at least 18 years of age, had confirmed SARS-CoV-2 infection by a positive reverse-transcriptase polymerase chain reaction (RT-PCR) result, had pneumonia confirmed by radiography, and had SpO2 < 94% on ambient air. Of the 389 patients randomized, efficacy analyses were performed in the modified intent-to-treat (mITT) population comprising 377 patients who were randomized and received study medication (249 in the tocilizumab arm; 128 in the placebo arm). The mean age of participants was 56 years (range: 20 to 95); 59% of patients were male, 56% were of Hispanic or Latino ethnicity, 53% were White, 20% were American Indian/Alaska Native, 15% were Black/African American and 2% were Asian. At baseline, 9% patients were not on supplemental oxygen, 64% patients required low flow oxygen, 27% patients required high-flow oxygen, and 73% were on corticosteroids. The primary efficacy endpoint evaluated time to progression to mechanical ventilation or death through Day 28. The hazard ratio comparing tocilizumab to placebo was 0. 56 (95% CI, 0. 97), a statistically significant result (log-rank, p-value = 0. The cumulative proportion of patients who required mechanical ventilation or died by Day 28 was 12. 0% (95% CI, 8. 9%) in the tocilizumab arm and 19. 3% (95% CI, 13. 4%) in the placebo arm. Mortality at Day 28 was 10. 4% in the tocilizumab arm versus 8. 6% in the placebo arm (weighted difference (tocilizumab arm - placebo arm): 2. 0% [95% CI, -5. COVACTA COVACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with SoC for the treatment of adult patients hospitalized with severe COVID- 19 pneumonia. The study randomized 452 patients who were at least 18 years of age with confirmed SARS-CoV- 2 infection by a positive RT-PCR result, had pneumonia confirmed by radiography, and had oxygen saturation of 93% or lower on ambient air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mmHg or less. At baseline, 3% of patients were not on supplemental oxygen, 28% were on low flow oxygen, 30% were on non-invasive ventilation or high flow oxygen, 38% were on invasive mechanical ventilation, and 22% were on corticosteroids. The primary efficacy endpoint was clinical status on Day 28 assessed on a 7-category ordinal scale that ranged from "discharged" to "death. " There were no statistically significant differences observed in the distributions of clinical status on the 7-category ordinal scale at Day 28 when comparing the tocilizumab arm to the placebo arm. Mortality at Day 28 was 19. 7% in the tocilizumab arm versus 19. 4% in the placebo arm (weighted difference (tocilizumab arm - placebo arm): 0. 3% [95% CI, -7. REMDACTA REMDACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with intravenous remdesivir (RDV) 200 mg on Day 1 followed by 100 mg once daily for a total of 10 days in hospitalized patients with severe COVID-19 pneumonia. The study randomized 649 adult patients with SARS-CoV-2 infection confirmed by a positive polymerase chain reaction (PCR) result, pneumonia confirmed by radiography, and who required supplemental oxygen > 6 L/min to maintain SpO2 >93%. At baseline, 7% of patients were on low flow oxygen, 80% were on non-invasive ventilation or high flow oxygen, 14% were on invasive mechanical ventilation, and 84% were on corticosteroids. The primary efficacy endpoint was time from randomization to hospital discharge or ''ready for discharge'' up to Day 28. There was no statistically significant difference between the treatment arms with respect to time to hospital discharge or "ready for discharge" through Day 28. Mortality at Day 28 was 18. 1% in the tocilizumab + RDV arm versus 19. 5% in the placebo +RDV arm (weighted difference (tocilizumab arm - placebo arm): -1. Mortality Across Studies in Patients Receiving Baseline Corticosteroids A study-level meta-analysis was conducted on EMPACTA, COVACTA, REMDACTA and RECOVERY studies. For each of the four studies, the risk difference through Day 28 was estimated by the Kaplan-Meier method in the subgroup of patients receiving baseline corticosteroids, summarized in Figure 2. Patients from the RECOVERY trial represent 78. 8% of the total sample size in this meta-analysis. The combined risk difference showed that tocilizumab treatment (n=2261) resulted in a 4. 61% absolute reduction in the risk of death at Day 28 (risk difference=-4. 6%; 95% CI: -7. 9%) compared to SoC (n=2034). Figure 2 Risk Differences Through Day 28 for Baseline Corticosteroid Use Subpopulation in RECOVERY, EMPACTA, COVACTA and REMDACTA studies Figure 2.

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